Elektrolytstörungen bei Tumorerkrankungen - osp-stuttgart.de · • Hepatorenales Syndrom durch...

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Präsentation Robert-Bosch-Krankenhaus 1 Elektrolytstörungen bei Tumorerkrankungen Mark Dominik Alscher Freitag, 20. September 13

Transcript of Elektrolytstörungen bei Tumorerkrankungen - osp-stuttgart.de · • Hepatorenales Syndrom durch...

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Präsentation Robert-Bosch-Krankenhaus 1

Elektrolytstörungen bei Tumorerkrankungen Mark Dominik Alscher

Freitag, 20. September 13

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prärenal

• Exsikkose bei

- unzureichender Flüssigkeits- zufuhr - Erbrechen/Diarrhoe - Hyperkalzämie → Polyurie• Thrombotische Mikroangio- pathie - nach Stammzelltransplantation - medikamentös Gemcitabin Mitomycin C• Hepatorenales Syndrom durch veno-okklusive Erkrankung nach Hochdosis-Chemotherapie und Stammzelltransplantation

Abb. 3.43: Renale Beteiligung bei Tumorerkrankungen und Chemotherapie

renal postrenal

glomerulär tubulo-interstitiell

• Sekundäre membranöse Glomerulopathie

• Sekundäre Minimal Change- Glomerulopathie bei T-Zell- assoziierten lymphoprolifera- tiven Erkrankungen und Thymomen• Sekundäre fokal segmentale Glomerulosklerose - bei Plasmazellerkrankungen - und monoklonaler Gammo- pathie unklarer Signifikanz (MGUS) - unter Pamidronat-Therapie• AL-Amyloidose bei multiplem Mylelom• Leichtkettennephropathie

• Akute Tubulusnekrose

- toxisch (Sepsis) - medikamentös (Cisplatin)• renale Tumorinfiltration bei Lymphomen und Leukämien• Leichtkettennephropathie• Tubuläre Obstruktion - Myelomniere („Cast-Nephro- pathie“) - Tumorlysesyndrom → Urat-Nephropathie → Calcium-Phosphat- Ablagerungen

• Obstruktion der ableiten-

den Harnwege durch - sekundäre retroperito- neale Fibrose bei Tumorerkrankungen - Verlegung der Ureteren- mündung oder der Urethra bei Prostatakarzinom Uteruskarzinom Blasentumoren

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underdosing can lead to ineffective cancertreatment. Thus, because the CKD-ESRDpopulation has a higher prevalence ofcancer and the CKD-ESRD populationis increasing, more precise dosing rec-ommendations for this population areneeded.31

One suggestion would be for the reg-ulatory agencies, such as the U.S. Foodand Drug Administration and the Euro-peanMedicinesAgency, to encourage thatessential data on renal and dialysis clear-ance on new chemotherapeutic agents bemade available. Monitoring renal func-tion inpatients receiving chemotherapy isessential; however, using serum creati-nine in malnourished patients with can-cer can overestimate kidney function,thereby risking chemotoxicity. Further-more,monitoring nephrotoxicity byusingserum creatinine will delay the identifica-tion of kidney injury, especially in patientswith normal baseline function and a largerenal reserve. More reliable measures areto use GFR to ensure appropriate dosingbased on actual kidney function andkidney injury biomarkers to ensure earlydetection of kidney injury.22

Fluid-Electrolyte Abnormalities inCancerFluid and electrolytes abnormalities areextremely common in patients with can-cer receiving chemotherapy because ofthe associated nausea, vomiting, anddiarrhea and effects of the underlyingdisease on the nephron. In a recentsurvey, hyponatremia was noted in near-ly 50% of hospitalized patients withcancer.32 Although syndrome of inap-propriate antidiuretic hormone due totumor-associated ectopic antidiuretichormone, chemotherapeutic agents,nausea, antidepressants, pain, or painmedications is a widely known cause ofhyponatremia in patients with cancer,intravenous hydration used during che-motherapy is a frequent cause for wors-ening hyponatremia. Hyponatremia isassociated with an increase in mortalityin patients with cancer.32 Therapy for hy-ponatremia in patients with cancer is sim-ilar to that in noncancer settings, althoughin practice sodium chloride tablets aremore frequently used than the imposition

of strict fluid restriction. Hypokalemia isalso common in patients with cancer,mostly because of reduced potassium in-take and excess gastrointestinal loss butoccasionally because of endocrine tu-mors.33 Renal tubular injury can occurfrommyeloma proteins and several drugsthat are tubular toxins causing potassiumwasting and hypokalemia.3,34 Steroidsused as part of a chemotherapeutic regi-men can, through their mineralocorticoideffects, also cause hypokalemia. Unlike inthe noncancer setting, hypomagnesemiais fairly common in patients with cancer,especially those receiving some of theabove-mentioned tubular toxins. A majoradverse effect of cetuximab that targets theepidermal growth factor receptor is theoccurrence of reversible urinary magne-sium loss leading to hypomagnesemia, afinding that has helped to clarify the roleof epidermal growth factor receptor in tu-bular magnesium transport.35,36 Treatinghypomagnesemia in patients with cancercan be challenging and may occasionallyrequire intravenous administration be-cause large doses of oral magnesium canprovoke severe diarrhea.37

Hypophosphatemia is more commonthan hyperphosphatemia in patients withcancer, but both can occur in the settingof several cytotoxic drugs. Uptake ofphosphorus by rapidly growing tumorscan occasionally cause hypophosphate-mia, whereas rapid breakdown of tumorswith chemotherapy, exemplified by tu-mor lysis syndrome associated with Bur-kitt lymphoma treated with rituximab,can lead to severe hyperphosphatemia.Derangement in calcium homeostasis isfairlycommoninpatientswithcancer.Hy-percalcemia can be mediated by tumor-secreted parathyroid hormone–relatedprotein or from tumor-induced osteolysisor excess calcitriol production.38 Tumorsmay also release cytokines that activateosteoclasts directly or through such medi-ators as granulocyte macrophage colony-stimulating factors.39 Availability ofseveral drugs for treating hypercalcemia,including the potent bisphosphonates,has dramatically improved hypercalce-miamanagement in patients with cancer,but some of these drugs are associatedwith their own nephrotoxicity.40

ONCONEPHROLOGY AS APOSSIBLE SUBSPECIALTY INNEPHROLOGY

Medical practice in the inpatient cancersetting presents an enormous opportu-nity for teaching medical students andfellows the fundamentals of nephrology.Given the assorted nephrologic prob-lems in patients with cancer (listed inTable 1) and their increasing frequency,the view among a number of nephrolo-gists working with patients with canceris that onconephrology should be con-sidered a specialized area within ne-phrology. If such a consideration is valid,entering an onconephrology fellowshipthrough an accredited academic nephrol-ogy program at comprehensive cancercare centers might follow the 2-year gen-eral nephrology fellowship training. Aformalized training program would helptransform onconephrology into a dis-tinct discipline within nephrology, sim-ilar to transplant nephrology; enhancethe options in the specialty of nephrology

Table 1. Common clinical issuesrelated to nephrologic management inpatients with cancer

Volume depletionAKISepsis and septic shockSevere fluid and electrolytes derangementsSevere acid-base disordersHyponatremiaHypokalemiaHyperkalemiaHypercalcemiaRenal toxicity of chemotherapeutic agentsRenal toxicity of nonchemotherapeutic drugtreatments

Tumor lysis syndromeMyeloma-related kidney injuryTumor- or tumor treatment–relatedmicroangiopathies and GN

Tumor- or tumor treatment–related nephroticsyndrome

Stem cell transplant–associated acute andchronic kidney injuries

Cancer-associated obstructive uropathiesModifications of dosing of chemotherapy inpatients with CKD and ESRD who havecancer

Management of nutrition and dialysis inpatients with ESRD receiving cancer therapy

28 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 26–30, 2013

SPECIAL ARTICLE www.jasn.org

Onconephrology: The Latest Frontier in the War against Kidney Disease

JASN 2013;24:26

depletion, increased propensity to de-velop contrast nephropathy, tumor lysissyndrome, abnormal uric acid homeo-stasis, hypercalcemia, myeloma andmyeloma kidney, direct parenchymalinvolvement of the tumor, intense chemo-therapy protocols often involving nephro-toxic drugs, stem cell transplants withimmunosuppression leading to sepsis,veno-occlusive disease, graft versus hostdisease, thrombotic microangiopathy,and a variety of additional causes andmechanisms.16–23 Furthermore, cancertherapy is increasingly available toelderly patients, a subpopulation that isparticularly vulnerable to nephrotoxicdrugs and intravenous radiocontrastmedia.24

The list of potentially nephrotoxicdrugs used in patients with cancer, espe-cially after stem cell transplantation, islong, and often includes several wellknown unavoidable nephrotoxins, suchas platinum compounds, methotrexate,anti-VEGF agents, calcineurin inhibitors,aminoglycosides, colistin, acyclovir,amphotericin, cidofovir, and bisphosho-nates.3 It is well known that several che-motherapeutic agents can lead to AKI,but what is less well known is that re-duced renal function (whether from thechemotherapeutic agents themselves orfrom other mechanisms, such as volumedepletion) can initiate a vicious cycle(Figure 1). Kidney failure leads to highersystemic chemotherapeutic levels thatproduce severe systemic toxicity, often re-sulting in neutropenic sepsis, multiorganfailure, and death. Therefore, optimizingthe renal status of the patient before che-motherapy, such as by correcting volumestatus, removing potential nephrotoxicagents, and taking precautionary mea-sures against tumor lysis, can reduce thechance for AKI and chemotoxicity risks.

Patients receiving outpatient chemo-therapy are at higher risk for prerenalAKI, but the risk is reduced in patientsreceiving in-home intravenous fluid. Arecent analysis of 3560 patients admittedto theUniversity of TexasM.D.AndersonCancer Center (MDACC) in Houstonover 3 months revealed an incidence rateof AKI of 14.5% according to the AcuteKidney Injury Network criteria, a ratethreefold higher than that in the non-cancer setting.4,25 This and other studiesalso report poor clinical outcomes in pa-tients with cancer who develop AKI inthe hospital.13,20 Dialysis was required in10% of these patients, and nearly 30%–

40% of oligoanuric patients requiringdialysis had to be treated with continu-ous renal replacement treatment becauseof severe septic shock, fluid overload, ortumor lysis syndrome.15 The experiencefrom MDACC also shows that sustainedlow-efficiency dialysis in the continuousmode simplifies continuous renal re-placement therapy while providing ef-fective dialysis and meeting the needfor continuous fluid removal in these pa-tients, who often receive a large amountof blood products.15

It is often discussed whether it isappropriate to administer dialysis to crit-ically ill patients with cancer. The datafrom two studies suggest that the short-term survival rates in critically ill patientswith cancer requiring acute dialysis aresimilar to thoseofpatientswithoutcancer,and renal recovery can be expected insome patients.15,26 Lesswell known is thatthe onset of AKI in patients with cancercan lead to inadequate or incomplete can-cer therapy, thus reducing the potentialfor cancer cure or longer-term survival.Many patients with cancer are hospital-ized electively; this circumstance providesan opportunity to test the efficacy of AKIprevention or preconditioning strategies,especially in those at high risk for AKI,such as patients with diabetes, hemato-logic cancer, or myeloma, or patientsreceiving nephrotoxic chemotherapy orallogeneic stem cell transplantation.4,13,27

CKD Burden in CancerThe striking increase in cancer survivorsdue to early diagnosis and newer, more

effective treatments has also increased thenumber of survivors with CKD. Chemo-therapeutic agents, such as platinum-based compounds, ifosfamide, anti-VEGFagents, tyrosine kinase inhibitors, meth-otrexate, and several other drugs used forcancer therapy cause AKI, which resultsin residual CKD.3 CKD is also prevalentin patients who have received therapy forrenal cell carcinoma (because therapyoften involves nephrectomy and anti-VEGF treatment), in patients with my-eloma, and in patients with cancerreceiving a conditioning regimen andstem cell transplantation.11,27,28 Becausemany cancer survivors have residual re-nal injury and survival is significantlylower in patients with cancer who haveCKD, avoidance of AKI or progression toCKD in cancer survivors has importantimplications.21

Patients with CKD are also oftenexcluded from hematopoietic stem celltransplantation because of unacceptablemorbidity andmortality. In patientswithmyeloma and ESRD, simultaneous allo-geneic stem cell transplantation andkidney transplantation from an HLA-matched donor has been used.19 Patientswith cancer who have CKD may, thus,benefit from early referral to a nephrol-ogist and long-term nephrology follow-up visits.

Unique ChemotherapeuticChallenges in CKD and ESRDPopulationsAnticancer therapy can be challenging,especially when the patient’s renal functionis compromised. Althoughmost of the an-ticancer drugs are eliminated through thekidneys, formal data on renal or dialysisclearance for these drugs are scarce andoften incomplete. The available dosagerecommendations of these agents for theCKD-ESRD population are based on datafrom small series, case reports, and expertopinion.29 Few studies are available tovalidate the dosing recommendations. Apharmacokinetic modeling study of che-motherapeutic agents used in patientswith cancer undergoing dialysis suggestedthat these agents are generally overdosed.30

Overdosing can aggravate systemic toxici-ties, with fatal consequences, whereas

Figure 1. Chemotoxicity and kidney injury.This vicious cycle leads to enhanced sys-temic toxicity.

J Am Soc Nephrol 24: 26–30, 2013 Onconephrology 27

www.jasn.org SPECIAL ARTICLE

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ELECTROLYTE DISORDERS IN PATIENTS WITH CANCER — Malignancy can be associated with a variety of electrolyte disorders. These include hypercalcemia, hyponatremia and hypernatremia, hypokalemia and hyperkalemia, and hypomagnesemia.Hyponatremia and hypernatremia — There are two major mechanisms of hyponatremia in patients with cancer:

• SIADH. Malignancy is one of the most common causes of SIADH. Small cell cancer of the lung and primary or secondary brain tumors are most often responsible, although a similar syndrome can be induced by high-dose intravenous cyclophosphamide and the vinca alkaloids, vincristine or vinblastine.

• Hypovolemia due to gastrointestinal fluid losses and poor oral intake.

Diabetes insipidus, with polyuria and polydipsia, can also occur in patients with cancer. Hypernatremia will occur if the patient does not have access to or cannot drink water:

• Primary or secondary malignancies in the brain (most often lung cancer, leukemia, or lymphoma) can involve the hypothalamic-pituitary region and lead to central diabetes insipidus; neurosurgery for brain tumors is also an important cause.

• Hypercalcemia in patients with cancer can lead to nephrogenic diabetes insipidus.

Abnormalities in potassium balance — Hypokalemia can result from gastrointestinal losses (due to vomiting or diarrhea induced by chemotherapy) or to renal losses (due to ifosfamide, cisplatin or, in some patients with leukemia, lysozymuria). Hyperkalemia may result from renal failure of any cause or the tumor lysis syndrome, which is accompanied by hyperphosphatemia, hypocalcemia, and hyperuricemia.

Abnormalities in magnesium balance — Tubular dysfunction due to chemotherapy drugs, particularly cisplatin, can lead to urinary magnesium wasting and hypomagnesemia.

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Agenda•Hypercalcämie

•Hyper- / Hyponatriämie- SIADH- Diarrhoen- Diabetes insipidus

•Hyper- / Hypokaliämie- Tumor-Lyse-Syndrom

•Hypomagnesiämie

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PlasmazellenFreitag, 20. September 13

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Ursachen der renalen Beteiligung bei MMAkutes reversibles Nierenversagen– Dehydration– Hyperkalzämie– Infektion– Kontrastmittel und Medikamente (Aminoglykoside, nichtsteroidale Antirheumatika)– Cast nephropathy („Myelomniere“)Chronische Niereninsuffizienz– irreversible Myelomniere– Leichtkettennephropathie (light chain deposition disease)– AL-Amyloidose– renale PlasmazellinfiltrationProteinurie und nephrotisches Syndrom– Leichtkettennephropathie (light chain deposition disease)– AL-AmyloidoseProximale tubuläre Dysfunktion (Fanconi-Syndrom)– renale tubuläre Azidose– renaler Phosphatverlust Hypophosphatämie Osteomalazie

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UpToDate 2013

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of vitamin D had been isolated, chemically identified, and syn-thesized (15, 16). This compound, 25-hydroxyvitamin D3

[25(OH)D3], is now currently monitored in serum to indicate thevitamin D status of patients, as discussed below. However,25(OH)D3 itself is metabolically inactive and must be modifiedbefore function. The final active hormone derived from vitaminD was isolated and identified in 1971, and its structure wasdeduced as 1!,25-dihydroxyvitamin D3 [1,25(OH)2D3] (17) andconfirmed by synthesis (18). The pathway that vitamin D mustfollow is illustrated in Figure 2 and forms the basis of the vitaminD endocrine system. For !2 decades, there was consistent re-visitation of the concept that more than one hormone was derivedfrom vitamin D, and !33 metabolites of vitamin D were identi-fied (19).However, it soonbecameclear that allmetaboliteswereeither less active or rapidly cleared and were thus intermediatesin the degradation of this important molecule. The most impor-tant of these metabolites are 24,25-dihydroxyvitamin D3 and1!,24(R),25-trihydroxyvitamin D3 produced by the enzymeCYP24, which is induced by the vitamin D hormone itself (20).

Much is known about the enzymes that produce 1,25(OH)2D3

and their regulation, but a great deal remains to be learned (20).Two enzymes are thought to function in the 25-hydroxylationstep. They are not exclusively hepatic but are largely functionallyactive in the liver. The mitochondrial enzyme, which is not spe-cific for vitamin D, has been cloned and a knockout mouse strainhas been prepared, without any apparent effect on vitamin Dmetabolism, which suggests that there is an alternate 25-hydroxylase (21). A microsomal hydroxylase was recentlycloned and could represent the missing enzyme (22). The25(OH)D3 1!-hydroxylase was cloned by 3 different laborato-ries (reviewed in ref 20), and the sites of vitamin D-dependent

rickets type I were identified in several studies (20). Very im-portant was the generation of 1!-hydroxylase knockout mice,which exhibit a phenotype virtually identical to the human vita-min D-dependent rickets type I phenotype. Therefore, the en-zymes that activate vitamin D have been identified.

Of major metabolic importance is the mode of disposal ofvitamin D and its hormonal forms. The cytochrome P-450 en-zyme now called CYP24 was isolated in pure form by Ohyamaand Okuda (23) and the complementary DNA and gene werecloned, which yielded a 24-hydroxylase-null mutant (reviewedin 20). No significant phenotype resulted except for a large ac-cumulation of 1,25(OH)2D3 in the circulation, which producedsecondary effects on cartilaginous growth (20, 24). CYP24 is anextremely active enzyme, but the gene remains silent in vitaminD deficiency; it is induced by the hormonal form of vitamin Ditself. Therefore, pulses of the vitamin D hormone program itsown death through induction of the 24-hydroxylase. The 24-hydroxylase is able to metabolize vitamin D to its excretionproduct calcitroic acid (20). 25(OH)D3 can also be degradedthrough this pathway. 24-Hydroxylase and its regulation areimportant factors in the determination of the circulating concen-trations of the hormonal form of vitamin D.

PHYSIOLOGIC FUNCTIONS OF VITAMIN D

A diagrammatic explanation of the role of the vitamin D hor-mone in mineralizing the skeleton and preventing hypocalcemictetany is presented in Figure 3 (20). Plasma calcium concentra-tions are maintained at a very constant level, and this level issupersaturating with respect to bone mineral. If the plasma be-comes less than saturated with respect to calcium and phosphate,then mineralization fails, which results in rickets among childrenand osteomalacia among adults (24). The vitamin D hormonefunctions to increase serum calcium concentrations through 3separate activities. First, it is the only hormone known to inducethe proteins involved in active intestinal calcium absorption.Furthermore, it stimulates active intestinal absorption of phos-phate. Second, blood calcium concentrations remain in the nor-mal range even when an animal is placed on a no-calcium diet.Therefore, an animalmust possess the ability tomobilize calciumin the absence of calcium coming from the environment, ie,

FIGURE 1. Structure of vitamin D3, or cholecalciferol, and its numberingsystem.

FIGURE 2. Metabolic activation of vitamin D3 to its hormonal form,1,25(OH)2D3.

FIGURE 3. Diagrammatic representation of the role of the vitamin Dhormone and the parathyroid hormone (PTH) in increasing plasma calciumconcentrations to prevent hypocalcemic tetany (neuromuscular) and to pro-vide for mineralization of the skeleton.

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Am J Clin Nutr 2004;80(suppl):1689S–96SFreitag, 20. September 13

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Holick M. N Engl J Med 2007;357:266-281

VD, Ca, Ph

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Das Mnemotechnische Kunstwort „vitamins trap“ (Vitaminfalle) kann für das

Erinnern der Differentialdiagnose nützlich sein (Pont 1989):

V Vitamine A und D

I Immobilisation

T Thyreotoxikose

A Addison-Erkrankung

M Milch-Alkali-Syndrom

I inflammatorische Darmerkrankung

N Neoplasien

S Sarkoidose

T Thiazide und andere Medikamente

R Rhabdomyolyse

A AIDS

P Paget-Krankheit, parenterale Ernährung, Parathyreoideaerkrankungen.

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Ursachen der HyperkalzämieUrsachen der Hyperkalzämie

Häufig •Primärer Hyperparathyreoidismus (HPT)•Hyperkalzämie bei Tumoren

Gelegentlich •Thyreotoxikose•Sarkoidose•Vitamin-D-Intoxikation•Immobilisierung•Calcium-Alkali-Syndrom•Benigne familiäre hypokalzurische Hyperkalzämie•Tertiärer HPT•Thiazide

Selten •Weitere granulomatöse Erkrankungen•Theophyllinintoxikation•Massive Mammahyperplasie•Idiopathische infantile Hyperkalzämie•Lithiumintoxikationen•NNR-Insuffizienz•Vitamin-A-Intoxikation•Malignes neuroleptisches Syndrom•Aluminiumintoxikation•Sepsis•AIDS•Aspirinintoxikation•Morbus Paget mit Frakturen•Hypothyreose•Nach ANV durch Rhabdomyolyse•Varianten des Milch-Alkali-Syndroms („Kreidefresser“)•Aufnahme von hypertonischem Meerwasser

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Vorgehen Hyper-

kalzämie

Messung des Serum-Kalzium:Falls erhöht è Ionisiertes Ca++ é

Klinische Routine:Anamnese, körperliche Untersuchung, Röntgen-Thorax, Sono, Labor (AP, Eiweiß, El´pho.)

Neoplasie/ Plasmozytom, Sarkoidose Kein fassbarer Befund

PTH-BestimmungHyperparathyreoidismus

Lithiumintoxikation

PTHrP-BestimmungNeoplasie

Vitamin-D2-BestimmungVitamin-D-Intoxikation

Vitamin-D3-Bestimmung

Vitamin-D-IntoxikationGranulomatöse

ErkrankungLymphom

ImmobilisationM. Paget

Thyreotoxikose

PTH: é

PTHrP: é

VD2é

VD3é

PTH: ê

PTHrP: è

VD3ê

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Therapie bei Tumor-assoziierter Hyperkazämie

monitoring, and it can induce secondary electrolytedisturbances; therefore, it is not recommended (16).Unless hypercalcemia is mild, additional therapies aretypically required. The bisphosphonates are very effec-tive, although some members of this class are associatedwith kidney toxicities, and dosing guidelines based onGFR should be followed. Gallium nitrate is approvedfor the treatment of hypercalcemia in malignancy, and itappears to be at least as effective as bisphosphonates atreducing serum calcium levels (18). Calcitonin may beused in severe hypercalcemia, but its effect is transientand must be used in conjunction with other therapies.In patients who have severe AKI or preexisting CKDthat precludes aggressive hydration or treatment withbisphosphonates, dialysis with low or zero calciumdialysate may also be an effective option (15,19). Aflow chart outlining management of hypercalcemia inmalignancy is shown in Figure 22.

Hypokalemia

Hypokalemia is another very common electrolyteabnormality in cancer patients. Although hypokalemiamay result from the usual causes in the generalpopulation, there are a number of cancer-specificcauses of hypokalemia that the clinician should befamiliar with (see Table 7 for a review of cancer-specific causes of hypokalemia). Redistribution ofpotassium from the extracellular to the intracellularspace can be induced by treatment with granulocyte-macrophage colony stimulating factor (GM-CSF). The

robust myelopoiesis induced by GM-CSF causes up-take of extracellular potassium into new hematopoieticcells (20). Nonrenal losses of potassium occur throughthe gastrointestinal tract during chronic diarrhea. Threetumors that cause chronic diarrhea are villous adenoma,vasoactive intestinal peptide-oma (VIPoma), andZollinger-Ellison syndrome. All are tumors that secretepromotility and secretory factors that cause diarrhea(21–23).

Renal potassium losses specific to cancer patientsinclude tumors that promote renal potassium loss, suchas ACTH-producing tumors. Examples include smallcell tumors, neuroendocrine tumors, and occasionallyin renal cell or colon carcinomas. They induce renalpotassium loss through mineralocorticoid excess, whichupregulates the tubular Na/K/ATPase (24). Tubulartoxicity from light chains may cause full or partialFanconi syndrome, including hypokalemia (25).

Several chemotherapies induce hypokalemiathrough renal losses. mAbs that target the EGF receptor(EGFR) are now a recognized cause of both hypomag-nesemia and secondary hypokalemia. Cao et al. per-formed a meta-analysis of 11 clinical trials comprising2254 patients treated with cetuximab between 2000 and2008 (26). Hypokalemia was found in 8% of patientsoverall. In trials that compared cetuximab with a non-cetuximab regimen, cetuximab conferred a statisti-cally significant increased risk of moderate or severehypokalemia (potassium,3.0 mg/dl; odds ratio [OR],1.81; 95% confidence interval [95% CI], 1.12–2.93).The mechanism by which anti-EGFR antibodies inducehypokalemia is through hypomagnesemia (discussedbelow).

Cisplatinum is also associated with hypokalemia,most likely secondary to hypomagnesemia as well.Magnesium deficiency causes hypokalemia by increas-ing distal potassium secretion. Intracellular magne-sium concentrations fall in hypomagnesemic states,and this releases magnesium-mediated tonic inhibitionof ROMK channels in the apical membrane of thedistal tubule, causing increased potassium secretion(27). The primary toxicity of ifosfamide is renal; it cancause direct proximal tubule toxicity and Fanconisyndrome with associated hypokalemia (28). Treatmentof hypokalemia in cancer patients consists of replace-ment and identifying the underlying cause. In cases oftumor-related hypokalemia, reduction of tumor burdenthrough surgery or chemotherapy is often sufficient, andin most cases of chemotherapy-induced hypokalemia

Figure 22. Treatment algorithm for hypercalcemia associ-ated with malignancy. IV, intravenous. Reprinted withpermission from Rosner MH, Dalkin AC: Onco-nephrology:The pathophysiology and treatment of malignancy-associ-ated hypercalcemia. Clin J Am Soc Nephrol 7: 1722–1729,2012.

Nephrology Self-Assessment Program - Vol 12, No 1, January 2013 55

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Agenda•Hypercalcämie

•Hyper- / Hyponatriämie- SIADH- Diarrhoen- Diabetes insipidus

•Hyper- / Hypokaliämie- Tumor-Lyse-Syndrom

•Hypomagnesiämie

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Prävalenz einer Hyponatriämie

38 | JANUARY 2013 | VOLUME 9 www.nature.com/nrneph

while in hospital or remains uncorrected throughout the hospital stay.10 This group found a linear increase in mortality with decreases in serum sodium concentration below the normal range of 138–142 mmol/l, but other

Key points

■ Hyponatraemia is the most common electrolyte disturbance in clinical practice and its most common mediator is the nonosmotic release of arginine vasopressin

■ In the elderly, hyponatraemia predisposes to falls and fractures and may worsen cognitive impairment; in patients with heart failure, hyponatraemia reflects severe haemodynamic alterations and is associated with worse morbidity and mortality

■ In patients with liver cirrhosis, hyponatraemia is associated with increased mortality, hepatorenal syndrome, hepatic encephalopathy, and reduced quality of life

■ Hyponatraemia carries a worse prognosis in patients with chronic kidney disease, including those with end-stage renal disease

■ Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is classified as euvolaemic hyponatraemia, and therefore hypovolaemic or hypervolaemic causes of hyponatremia need to be excluded

■ In addition to fluid restriction, vasopressin-receptor antagonists are now available in some countries to treat hyponatremia in heart failure, cirrhosis and SIADH

authors have reported that mortality increases nonline-arly as serum sodium decreases below 134 mmol/l.11 Low serum sodium has been strongly and consistently associ-ated with increased mortality in patients with pneumo-nia,12 heart failure,13 and liver cirrhosis14 and in those in the ICU.15 The prevalence of hyponatraemia in various patient populations is summarized in Table 1;16–48 these different populations provide the outline for our Review of this important topic.

Hyponatraemia in the elderly Epidemiological studies have confirmed the increased prevalence of hyponatraemia in the elderly popula-tion. It is estimated that 7–11% of healthy elderly people over 65 years of age have serum sodium concentrations of 137 mmol/l or less.19,20 In a study of 419 elderly out-patients, 46 (11%) were found to have at least one episode of hyponatraemia (defined as a serum sodium concentra-tion <135 mmol/l) during a 24-month follow-up period.20 Moreover, 27 of 46 (60%) of these patients fulfilled the criteria for syndrome of inappropriate secretion of anti-diuretic hormone (SIADH). Although most patients had one or more possible aetiologies of hyponatraemia, including diseases or medications, in seven patients no apparent cause of hyponatraemia was determined. More advanced age correlated with an increased occurrence of hyponatraemia. In total, 43% of individuals aged 75 years or older were hyponatraemic, and this elderly group of patients constituted 100% of those with SIADH.

The elderly population living in chronic care facilities, such as nursing homes or rehabilitation centres, have a high prevalence of hyponatraemia.21,49,50 The prevalence of hyponatraemia among elderly nursing home residents has been reported to be between 18% and 22.5% over a 12-month observational period.22–24 However, one study reported that as many as 53% of nursing home patients had at least one episode of hyponatraemia during a 12-month period.25 Comorbidities, such as central nervous system diseases, cardiovascular diseases and diabetes mellitus did not differ significantly between the patients with and without hyponatraemia. Notably, all patients with spinal cord disease had at least one episode of hyponatraemia that theoretically could have been caused by arterial baroreceptor failure with nonosmotic release of arginine vasopressin (AVP).51 Many of the nursing home patients with hyponatraemia had received hypotonic saline or glucose, and the criteria of SIADH were fulfilled in 78% of all hyponatraemic patients in the nursing home.25 Notably, among the 12 patients who received nutritional support via tube feeding, 11 developed hyponatraemia. A low sodium concentra-tion in the tube feeding diet may have contributed to the hypo natraemia, as reported elsewhere.52

A study from Taipei found that 37.5% of hypo-natraemic elderly patients in long-term care facilities fulfilled the criteria of SIADH.50 In another report from Australia, 51.5% of hyponatraemic patients in rehabili-tation hospitals had SIADH.21 Thus, as with outpatient hypo natraemia, advanced age is a major risk factor for inpatient hyponatraemia.21,50

Table 1 | Prevalence of hyponatraemia in different patient populations

Patient group Prevalence (%) References

ICU patients 11.0–29.6 Stelfox et al. (2010)16

DeVita et al. (1990)17

Funk et al. (2010)18

Elderly outpatients 7.2–11.0 Caird et al. (1973)19

Miller et al. (1996)20

Elderly inpatients 18.0–53.0 Anpalahan et al. (2008)21

Miller (1998)22

Kleinfeld et al. (1979)23

Sunderam et al. (1983)24

Miller et al. (1995)25

Patients with heart failure 10.2–27.0 Bettari et al. (2012)26

Konstam et al. (2007)27

Shorr et al. (2011)28

DeWolfe et al. (2010)29

Mohammed et al. (2010)30

Klein et al. (2005)31

Gheorghiade et al. (2007)32

Patients with cirrhosis 20.8–49.4 Solà et al. (2012)33

Shaikh et al. (2010)34

Kim et al. (2009)35

Yun et al. (2009)36

Angeli et al. (2006)37

Patients with cancer 3.7–47.0 Berghmans et al. (2000)38

Doshi et al. (2012)39

Patients with pneumonia 8.1–27.9 Zilberberg et al. (2008)12

Nair et al. (2007)40

Predialysis patients with CKD 13.6 Kovesdy et al. (2012)41

Patients on dialysis 29.3 Waikar et al. (2011)42

Marathon runners 3.0–13.0 Almond et al. (2005)43

Knechtle et al. (2011)44

Kipps et al. (2011)45

Mettler et al. (2008)46

Elderly patients with falls 9.1–13.0 Gankam Kengne et al. (2008)47

Sandhu et al. (2009)48

Abbreviations: CKD, chronic kidney disease; ICU, intensive care unit.

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Tumoren:

3,7-47,0%

Nat Rev Nephrol 2013;9:37Freitag, 20. September 13

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Sturzrisiko bei Hyponatriämie

Nat Rev Nephrol 2013;9:37

NATURE REVIEWS | NEPHROLOGY VOLUME 9 | JANUARY 2013 | 45

deficits.47 Underlying causes of hyponatraemia were not studied. However, up to 24.2% of these hyponatraemic patients in one study were taking SSRIs,48 which can induce hyponatraemia and cause impaired sensorium and mobility deficits.149

Moreover, experimental chronic hyponatraemia has been found to be associated with sarcopenia.150 The presence of sarcopenia could predispose to falls by decreasing muscle mass and strength, particularly in elderly individuals.

The prospective Rotterdam study investigated the association of hyponatraemia with the risk of falls in 5,208 patients aged greater than 55 years. In total, 7.7% of individuals included in the study had hypo natraemia. The presence of hyponatraemia was associated with an increased risk of recent falls. Moreover, baseline hyponatraemia was associated with an increased inci-dence of nonvertebral fractures over 6–7 years of follow-up.148,151 No relationship, however, was found between serum sodium concentration and bone mineral density.

Although emerging evidence has revealed a close cor-relation between hyponatraemia and the risk of falls and fractures, no data are available to show whether correction of hyponatraemia decreases this risk.

Available therapies for hyponatraemia The treatment of hyponatraemia is dependent on several factors. These factors include the symptoms present, the duration of hyponatraemia, and the diagnostic category (namely hypovolaemic, hypervolaemic or euvolaemic hyponatraemia).1,152 In hyponatraemic patients with severe symptoms including obtundation, coma, sei-zures, and respiratory arrest, the treatment of choice is 3% hypertonic saline (513 mmol/l) to decrease brain oedema and avoid brainstem herniation and cardio-respiratory arrest. Although not evidence-based, a prac-tical approach is a 100 ml bolus of 3% sodium chloride to be repeated within 30 min if no clinical improvement occurs.153 This approach will increase serum sodium concentration by 2–4 mmol/l and thereby attenuate the brain oedema. In rare cases, however, this amount of hypertonic saline may be insufficient. Concomitant furosemide use could increase serum sodium concen-tration even more. In patients with transtentorial brain herniation secondary to hyponatraemia, researchers have reported the more rapid (>5 mmol/l per hour) correction of serum sodium using 23.4% saline (30–60 ml bolus).154

In most cases, such severe symptomatology occurs when acute hyponatraemia has developed over less than 24–48 h, when brain adaptation has not yet occurred. Patients with moderate neurological symptoms due to

hyponatraemia may present with confusion, disorienta-tion, nausea and alerted mental status. This scenario can occur with either acute or chronic hyponatraemia. Such moderate symptoms may progress to more severe neuro-logical abnormalities and therefore should prob ably also be treated with hypertonic saline. This approach, however, should be used with caution so as to avoid too rapid a correction of hyponatraemia. In patients with either severe or moderate symptoms, fluid restriction should be instituted and the patient followed carefully in hospital.

Minimal symptoms of hyponatraemia include head-ache, inability to concentrate, irritability, altered mood and depression. Patients with these symptoms generally have more chronic hyponatraemia and can be treated with fluid restriction. The degree of fluid restriction depends on the patient’s urine output. For example, if a patient’s daily urine output is 1,200 ml, their daily oral fluid intake should be restricted to 750 ml. The water in food generally equates to the amount of insensible loss. Such fluid restriction will generally increase the patient’s serum sodium concentration by 1–2 mmol per day. The higher the urinary-to-plasma osmolality ratio, the less effective fluid restriction becomes, and long-term compliance, particularly outside the hospital, is poor. Although some patients with mild hyponatraemia can be managed by fluid restriction alone, this strategy is insuf-ficient in some cases. In elderly females with chronic hyponatraemic encephalopathy, normal saline infusion was reported to be associated with much better outcomes than was fluid restriction alone.155

Administration of demeclocycline can result in a vas-opressin-resistant diabetes insipidus and enable more liberal fluid intake. However, owing to drug accumula-tion and toxic effects, demeclocycline is contraindicated in patients with either heart failure or cirrhosis.156 Oral urea (15–30 g per day in divided doses) has been used to treat hyponatraemia; this agent works by causing a solute diuresis (that is, increased solute-free water excretion). The main criticism associated with urea is its bitter taste.157 Because of its poor palatability, oral urea should be given with orange juice. In the inten-sive care unit setting, urea (0.5–1 g/kg per day) can be given via gastric tube.158 Soupart et al. have reported that urea has a similar efficacy and tolerance compared to vasopressin-receptor antagonists in the long-term treat-ment of patients with SIADH.159 A loop diuretic admin-istered together with increased sodium intake can also enhance solute-free water excretion.160 The US FDA has not approved demeclocycline, urea or furosemide and sodium chloride to treat hyponatraemia.

Table 2 | Risk of falls in patients with ‘asymptomatic’ hyponatraemia

Group n Individuals with falls (%)

Odds ratio Adjusted odds ratio*

‘Asymptomatic’ chronic hyponatraemia 122 21.3 9.45 (95% CI 2.64–34.09); P <0.001

67.43 (95% CI 7.48–607.42); P <0.001

Normonatraemic controls 244 5.35 1.00 1.00

*Adjusted for age, sex, and covariates. Permission obtained from Excerpta Medica Inc. © Renneborg, B. et al. Am. J. Med. 119, 71.e1–71.e8 (2006).54

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+ Magensekretion: 2l/die

+ Galle-Pankreassekret: 1,5l/d

+ Dünndarmsekretion: 3-4l/d

- 3-6l/d: Resorption Jejunum

- 2-4l/d: Resorption Ileum

- 1-2l/d: Resorption Kolon

Nahrung: 2-3l/d

Stuhl: 0,1-0,2l/d

= 4-5l/d

= 5,5-6,5l/d

= 8,5-10,5l/d

= 3-6l/d

= 1,1-2,2l/d

Wasserverschiebungen intestinal

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Wasser 2-3 L/TagElektrolyte

1000 mlH2O alsHeißluft

1-2 L Urin und Elektrolyte

IZR(mmol/l)K = 130Na = 8Cl = 7

PO4 = 35Mg = 22Prot = 90

etc

Osm = 290

EZR(mmol/l)Na = 140

K = 4Ca = 2Mg = 1

Cl = 105HCO3 = 24Prot = 10

etc

Osm = 290

13 L 27 L

40 L

3 L Plasmavolumen

10 L interstitielles Volumen

Na+

K+

Freitag, 20. September 13

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Normales Extrazellulärvolumen

Antinatriurese

Natriurese

Gegenregulation Niere

Aktivierung Volumensensoren

Volumenkontraktion

Volumenexpansion

Aktivierung Volumensensoren

Gegenregulation Niere

Freitag, 20. September 13

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RAAS: Volumen- und RR-Regulation

Volumenmangel Effekt. arterielles Blutvolumen

Renale Hypoperfusion

RR

Na+

Na+

Stretch der aff. Arteriole

NaCl an Macula densa

Kardiale + arterielle Barorezeptoren

KatecholamineRenin

AT-II

GFR

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AT-II

AT1

RR Volumen

Renin

Na+

K+Na+

Na+

AT1

Vaso- konstriktion

AT1

Aldosteron

Renale Na+-Resorption

Freitag, 20. September 13

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Gegenregulation Niere

Die drei „hypovolämischen Hormone“:

•Renin

•Noradrenalin

•ADH

Freitag, 20. September 13

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Wasser und Natriumrückresorption = 99%

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David H. Ellison

Natriumrückresorption in der Niere

Freitag, 20. September 13

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Medikamentös induzierte Hyponatriämie

Nat Rev Nephrol 2013;9:37

NATURE REVIEWS | NEPHROLOGY VOLUME 9 | JANUARY 2013 | 39

These observations support the concept of a SIADH-like condition related to ageing.20,50,53 Hyponatraemia is generally modest in elderly patients with SIADH, but this population may be at increased risk of developing symp-tomatic hyponatraemia with intercurrent illnesses and medication use. Moreover, hyponatraemia in the elderly would predispose to falls and fractures and could worsen cognitive impairment.47,54,55 So-called ‘asymptomatic’ hyponatraemia has been shown to be associated with unstable gait and decreased reaction times.54

Another factor in the capacity to excrete solute-free water is the rate of urinary solute excretion. In a healthy individual with AVP suppressed, a minimal urinary osmolality of 50 mOsm/l and daily solute intake of 600 mOsm, 12 l of solute-free water is excreted to main-tain daily solute balance. With this maximal urinary dilu-tion, a patient with primary polydipsia would therefore have to drink more than 12 l per of water day to become hyponatraemic. By contrast, with the same minimal urinary osmolality of 50 mOsm, and a 300 mOsm daily solute intake, 6 l of water is excreted to maintain daily solute balance. Therefore, a patient with primary polydipsia and a decreased solute intake can become hyponatraemic when only drinking in excess of 6 l daily. It is known that beer drinkers, who ingest very little solute, may become hyponatraemic in spite of maximal suppression of AVP and maximal urinary dilution; this phenomenon has been termed potomania.56 Whether very elderly individuals who have lost their appetite can become hyponatraemic secondary to decreased solute intake and excretion remains unproven. More com-monly, a dry mouth secondary to use of medications with anticholinergic activity could induce thirst in the elderly, resulting in increased water intake that could cause hypo natraemia. On the other hand, hypernatraemia can also occur in the elderly secondary to a decreased thirst drive and this perturbation, like hyponatraemia, has also been shown to be associated with increased mortality.57

Thiazide diuretics are one of the most common causes of hyponatraemia in the elderly. Of note, thi-azides can cause both hypovolaemic and euvolaemic types of hyponatraemia. In a large study of hypertensive patients on a relatively low dose of thiazide in a primary care setting, hyponatraemia was present in 18% of those aged greater than 70 years and only 4% of those aged younger than 51 years.58 Moreover, polypharmacy is very common in the elderly population and an increas-ing number of other medications are also recognized to cause hyponatraemia (Box 1).59

Hyponatraemia in heart failureHyponatraemia is common in patients with advanced heart failure. One study reported that 38% of patients admitted for acute decompensated heart failure had hyponatraemia and that a further 28% developed hyponatraemia during the hospital admission.10 Hyponatraemia was associated with increased mortal-ity and hospital readmission. The authors found that the significant relationship between decreased sodium and increased mortality began with a serum sodium

concentration of less than 138 mmol/l and that the more severe the hyponatraemia, the higher the mortality. Hyponatraemia was also associated with an increased length of hospital stay. As 30% of patients with acute decompensated heart failure are readmitted within 60 days,60 hyponatraemia could be a marker indicating that a patient needs a more careful follow-up and perhaps alterations in their therapy (for example, changes in doses of renin–angiotensin–aldosterone system [RAAS] blockers, β-blockers, and/or diuretics).

The long-term effect of hyponatraemia was analysed in a large group of patients undergoing cardiac cathetheri-zation who had a left ventricular ejection fraction of less than 40% and grade II or III heart failure according to the New York Heart Association Classification.26 Patients were followed for an average of 4.5 years. In this long-term study, the presence of hyponatraemia was inde-pendently associated with increased all-cause mortality, cardiovascular mortality and rehospitalization. Another study reported that on multivariate analysis, heart failure patients with hyponatraemia had a poorer quality of life than heart failure patients with a normal plasma sodium concentration.61 Therefore, hyponatraemia is a serious risk factor in chronic, as well as acute, heart failure.

The relationship between hyponatraemia, activation of the neurohumoral axis and survival in patients with advanced heart failure is also affected by decreased renal function. This association of decreased renal function

Box 1 | Drugs associated with hyponatraemia*

Vasopressin analogues ■ Desmopressin ■ Oxytocin

Drugs that potentiate the renal action of vasopressin ■ Chlorpropamide ■ Cyclophosphamide ■ Nonsteroidal anti-inflammatory drugs ■ Acetaminophen

Drugs that enhance vasopressin release ■ Chlorpropamide ■ Clofibrate ■ Carbamazepine/oxcarbazepine ■ Vincristine ■ Nicotine ■ Narcotics ■ Antipsychotics/antidepressants ■ Ifosfamide

Drugs that cause hyponatraemia by unknown mechanisms ■ Haloperidol ■ Fluphenazine ■ Amitriptyline ■ Thioridazine ■ Fluoxetine ■ Methamphetamine ■ MDMA (ecstasy) ■ Sertraline

*Not including diuretics. Abbreviation: MDMA, 3,4-methylenedioxymethamphetamine. Permission obtained from Wolters Kluwer Health © Berl, T. & Schrier, R. Disorders of water metabolism. In Renal and Electrolyte Disorders 6th edn (ed. Schrier, R.) (Philadelphia, Lippincott Williams & Wilkins, 2003).59

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NATURE REVIEWS | NEPHROLOGY VOLUME 9 | JANUARY 2013 | 39

These observations support the concept of a SIADH-like condition related to ageing.20,50,53 Hyponatraemia is generally modest in elderly patients with SIADH, but this population may be at increased risk of developing symp-tomatic hyponatraemia with intercurrent illnesses and medication use. Moreover, hyponatraemia in the elderly would predispose to falls and fractures and could worsen cognitive impairment.47,54,55 So-called ‘asymptomatic’ hyponatraemia has been shown to be associated with unstable gait and decreased reaction times.54

Another factor in the capacity to excrete solute-free water is the rate of urinary solute excretion. In a healthy individual with AVP suppressed, a minimal urinary osmolality of 50 mOsm/l and daily solute intake of 600 mOsm, 12 l of solute-free water is excreted to main-tain daily solute balance. With this maximal urinary dilu-tion, a patient with primary polydipsia would therefore have to drink more than 12 l per of water day to become hyponatraemic. By contrast, with the same minimal urinary osmolality of 50 mOsm, and a 300 mOsm daily solute intake, 6 l of water is excreted to maintain daily solute balance. Therefore, a patient with primary polydipsia and a decreased solute intake can become hyponatraemic when only drinking in excess of 6 l daily. It is known that beer drinkers, who ingest very little solute, may become hyponatraemic in spite of maximal suppression of AVP and maximal urinary dilution; this phenomenon has been termed potomania.56 Whether very elderly individuals who have lost their appetite can become hyponatraemic secondary to decreased solute intake and excretion remains unproven. More com-monly, a dry mouth secondary to use of medications with anticholinergic activity could induce thirst in the elderly, resulting in increased water intake that could cause hypo natraemia. On the other hand, hypernatraemia can also occur in the elderly secondary to a decreased thirst drive and this perturbation, like hyponatraemia, has also been shown to be associated with increased mortality.57

Thiazide diuretics are one of the most common causes of hyponatraemia in the elderly. Of note, thi-azides can cause both hypovolaemic and euvolaemic types of hyponatraemia. In a large study of hypertensive patients on a relatively low dose of thiazide in a primary care setting, hyponatraemia was present in 18% of those aged greater than 70 years and only 4% of those aged younger than 51 years.58 Moreover, polypharmacy is very common in the elderly population and an increas-ing number of other medications are also recognized to cause hyponatraemia (Box 1).59

Hyponatraemia in heart failureHyponatraemia is common in patients with advanced heart failure. One study reported that 38% of patients admitted for acute decompensated heart failure had hyponatraemia and that a further 28% developed hyponatraemia during the hospital admission.10 Hyponatraemia was associated with increased mortal-ity and hospital readmission. The authors found that the significant relationship between decreased sodium and increased mortality began with a serum sodium

concentration of less than 138 mmol/l and that the more severe the hyponatraemia, the higher the mortality. Hyponatraemia was also associated with an increased length of hospital stay. As 30% of patients with acute decompensated heart failure are readmitted within 60 days,60 hyponatraemia could be a marker indicating that a patient needs a more careful follow-up and perhaps alterations in their therapy (for example, changes in doses of renin–angiotensin–aldosterone system [RAAS] blockers, β-blockers, and/or diuretics).

The long-term effect of hyponatraemia was analysed in a large group of patients undergoing cardiac cathetheri-zation who had a left ventricular ejection fraction of less than 40% and grade II or III heart failure according to the New York Heart Association Classification.26 Patients were followed for an average of 4.5 years. In this long-term study, the presence of hyponatraemia was inde-pendently associated with increased all-cause mortality, cardiovascular mortality and rehospitalization. Another study reported that on multivariate analysis, heart failure patients with hyponatraemia had a poorer quality of life than heart failure patients with a normal plasma sodium concentration.61 Therefore, hyponatraemia is a serious risk factor in chronic, as well as acute, heart failure.

The relationship between hyponatraemia, activation of the neurohumoral axis and survival in patients with advanced heart failure is also affected by decreased renal function. This association of decreased renal function

Box 1 | Drugs associated with hyponatraemia*

Vasopressin analogues ■ Desmopressin ■ Oxytocin

Drugs that potentiate the renal action of vasopressin ■ Chlorpropamide ■ Cyclophosphamide ■ Nonsteroidal anti-inflammatory drugs ■ Acetaminophen

Drugs that enhance vasopressin release ■ Chlorpropamide ■ Clofibrate ■ Carbamazepine/oxcarbazepine ■ Vincristine ■ Nicotine ■ Narcotics ■ Antipsychotics/antidepressants ■ Ifosfamide

Drugs that cause hyponatraemia by unknown mechanisms ■ Haloperidol ■ Fluphenazine ■ Amitriptyline ■ Thioridazine ■ Fluoxetine ■ Methamphetamine ■ MDMA (ecstasy) ■ Sertraline

*Not including diuretics. Abbreviation: MDMA, 3,4-methylenedioxymethamphetamine. Permission obtained from Wolters Kluwer Health © Berl, T. & Schrier, R. Disorders of water metabolism. In Renal and Electrolyte Disorders 6th edn (ed. Schrier, R.) (Philadelphia, Lippincott Williams & Wilkins, 2003).59

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Nierenschädigung durch Chemotherapie

452 | AUGUST 2009 | VOLUME 5 www.nature.com/nrneph

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of adenosine in the kidney rises.41 Theophylline, a non-selective adenosine receptor antagonist, might therefore be a useful prophylactic agent for reducing renal dys function induced by nephro toxic drugs.47

Erythropoietin has shown promise in decreasing renal injury in rats with cis platin nephrotoxicity.48 These methods have yet to be used in humans to demonstrate efficacy in the prevention of cisplatin nephrotoxicity.

Table 1 | Renal dysfunction associated with common anticancer agents

Drug Renal toxicity Mechanism Possible preventive strategies Treatment/s

Cisplatin ARF; tubular damage; renal concentration defect; polyuria; hypomagnesemia;12 rarely HUS

Toxic damage to the S3 segment of proximal tubule,14 loop of Henle, and distal tubules

Volume infusion;13,21 amifostine33

Avoid further use; volume infusion; magnesium repletion; supportive management; dialysis for uremia

Ifosfamide Subclinical tubular damage in most patients;60 type 1 RTA; Fanconi syndrome;60,63 severe electrolyte depletion; nephrogenic diabetes insipidus; reversible ARF; rarely CKD

Proximal tubular damage by metabolites such as chloracetaldehyde; total dose-related toxicity

Limit total dose;66 Mesna (questionable bene!t);57 avoid concomitant cisplatin

Bicarbonate; phosphate; electrolyte repletion

Cyclophosphamide Hemorrhagic cystitis

Hyponatremia

Hemorrhagic cystitis: direct toxic effectHyponatremia: increased ADH effect72

Mesna for hemorrhagic cystitis Disease is usually self-limiting

Nitrosoureas Slowly progressive, dose-related, irreversible renal failure, most commonly with streptozocin78,79

Glomerular sclerosis and chronic tubulointerstitial nephritis81

Volume infusion; avoid high doses

Electrolyte supplementation;, supportive management; dialysis for uremia

Mitomycin C TTP and HUS often presents as ARF; more common if total dose >60 mg86

Thrombotic microangiopathic lesions; glomerular infarction85

No established preventive measures

Plasmapheresis;87 Staphylococcus A column immunoadsorption88

Mithramycin High doses can lead to tubular injury and ATN96

Unclear—probably direct toxicity

Dose modi!cation (clear data not available)

Supportive measures

Azacitidine Mild subclinical tubular dysfunction (70% of patients); symptomatic proximal tubular damage92

Tubular damage No established preventive measures

Bicarbonate and electrolyte supplementation

Gemcitabine Rare incidence of HUS (0.015%)93 Microangiopathy No established preventive measures

Supportive measures

Methotrexate Nonoliguric renal failure with high dose therapy (1.8%)96

Precipitation of methotrexate and 7-hydroxymethotrexate into renal tubules

Volume infusion; alkalinization with sodium bicarbonate; leucovorin rescue97

Supportive measures; high-"ux dialysis to reduce methotrexate levels;98 carboxypeptidase-G2 rapid excretion of methotrexate99

Pentostatin Transient elevation of creatinine99 Unclear mechanism but might be dose-related100

Volume infusion4 Supportive

Interleukin 2 Prerenal ARF—completely reversible in most patients

Plasma depletion by capillary leak102

No established preventive measures

Volume infusion

Interferon ! Proteinuria (15–20% of treated individuals),108 usually reversible; rarely nephrotic syndrome;109 mild, reversible ARF

Minimal-change disease; ATN

No established preventive measures

Supportive measures

Bevacizumab Proteinuria; rarely, nephrotic syndrome123

Immune-complex-mediated focal proliferative glomerulonephritis

No established preventive measures

Supportive measures

Cetuximab Hypomagnesemia32 Magnesium channel TRPM6 deactivation by EGF blocking action127

No established preventive measures

Magnesium supplementation

Geftinib and imatinib

ARF (very rare);130

hypophosphatemia134Proximal tubular injury No established preventive

measuresSupportive measures; electrolyte repletion

Bisphosphonates ARF Acute tubular necrosis142,143

Avoid zoledronate in patients with severe underlying renal disease. Pamidronate and ibandronate can be given in reduced doses to such patients

Supportive measures

Abbreviations: ADH, antidiuretic hormone; ARF, acute renal failure; ATN, acute tubular necrosis; CKD, chronic kidney disease; EGF, epidermal growth factor; HUS, hemolytic uremic syndrome; RTA, renal tubular acidosis; TTP, thrombotic thrombocytopenic purpura; TRPM6, transient receptor potential cation channel, subfamily M, member 6.

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Nierenschädigung durch Chemotherapie

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of adenosine in the kidney rises.41 Theophylline, a non-selective adenosine receptor antagonist, might therefore be a useful prophylactic agent for reducing renal dys function induced by nephro toxic drugs.47

Erythropoietin has shown promise in decreasing renal injury in rats with cis platin nephrotoxicity.48 These methods have yet to be used in humans to demonstrate efficacy in the prevention of cisplatin nephrotoxicity.

Table 1 | Renal dysfunction associated with common anticancer agents

Drug Renal toxicity Mechanism Possible preventive strategies Treatment/s

Cisplatin ARF; tubular damage; renal concentration defect; polyuria; hypomagnesemia;12 rarely HUS

Toxic damage to the S3 segment of proximal tubule,14 loop of Henle, and distal tubules

Volume infusion;13,21 amifostine33

Avoid further use; volume infusion; magnesium repletion; supportive management; dialysis for uremia

Ifosfamide Subclinical tubular damage in most patients;60 type 1 RTA; Fanconi syndrome;60,63 severe electrolyte depletion; nephrogenic diabetes insipidus; reversible ARF; rarely CKD

Proximal tubular damage by metabolites such as chloracetaldehyde; total dose-related toxicity

Limit total dose;66 Mesna (questionable bene!t);57 avoid concomitant cisplatin

Bicarbonate; phosphate; electrolyte repletion

Cyclophosphamide Hemorrhagic cystitis

Hyponatremia

Hemorrhagic cystitis: direct toxic effectHyponatremia: increased ADH effect72

Mesna for hemorrhagic cystitis Disease is usually self-limiting

Nitrosoureas Slowly progressive, dose-related, irreversible renal failure, most commonly with streptozocin78,79

Glomerular sclerosis and chronic tubulointerstitial nephritis81

Volume infusion; avoid high doses

Electrolyte supplementation;, supportive management; dialysis for uremia

Mitomycin C TTP and HUS often presents as ARF; more common if total dose >60 mg86

Thrombotic microangiopathic lesions; glomerular infarction85

No established preventive measures

Plasmapheresis;87 Staphylococcus A column immunoadsorption88

Mithramycin High doses can lead to tubular injury and ATN96

Unclear—probably direct toxicity

Dose modi!cation (clear data not available)

Supportive measures

Azacitidine Mild subclinical tubular dysfunction (70% of patients); symptomatic proximal tubular damage92

Tubular damage No established preventive measures

Bicarbonate and electrolyte supplementation

Gemcitabine Rare incidence of HUS (0.015%)93 Microangiopathy No established preventive measures

Supportive measures

Methotrexate Nonoliguric renal failure with high dose therapy (1.8%)96

Precipitation of methotrexate and 7-hydroxymethotrexate into renal tubules

Volume infusion; alkalinization with sodium bicarbonate; leucovorin rescue97

Supportive measures; high-"ux dialysis to reduce methotrexate levels;98 carboxypeptidase-G2 rapid excretion of methotrexate99

Pentostatin Transient elevation of creatinine99 Unclear mechanism but might be dose-related100

Volume infusion4 Supportive

Interleukin 2 Prerenal ARF—completely reversible in most patients

Plasma depletion by capillary leak102

No established preventive measures

Volume infusion

Interferon ! Proteinuria (15–20% of treated individuals),108 usually reversible; rarely nephrotic syndrome;109 mild, reversible ARF

Minimal-change disease; ATN

No established preventive measures

Supportive measures

Bevacizumab Proteinuria; rarely, nephrotic syndrome123

Immune-complex-mediated focal proliferative glomerulonephritis

No established preventive measures

Supportive measures

Cetuximab Hypomagnesemia32 Magnesium channel TRPM6 deactivation by EGF blocking action127

No established preventive measures

Magnesium supplementation

Geftinib and imatinib

ARF (very rare);130

hypophosphatemia134Proximal tubular injury No established preventive

measuresSupportive measures; electrolyte repletion

Bisphosphonates ARF Acute tubular necrosis142,143

Avoid zoledronate in patients with severe underlying renal disease. Pamidronate and ibandronate can be given in reduced doses to such patients

Supportive measures

Abbreviations: ADH, antidiuretic hormone; ARF, acute renal failure; ATN, acute tubular necrosis; CKD, chronic kidney disease; EGF, epidermal growth factor; HUS, hemolytic uremic syndrome; RTA, renal tubular acidosis; TTP, thrombotic thrombocytopenic purpura; TRPM6, transient receptor potential cation channel, subfamily M, member 6.

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Key points

Renal tubular function can be affected by antibiotic treatment without !a concurrent reduction in glomerular filtration rate

Hypokalemia is a frequent complication of antimicrobial therapy !Treatment with aminoglycosides can affect renal tubular function in several !ways and can lead to hypokalemia, as well as acidosis and alkalosis

If unexpected disturbances in electrolyte and/or acid–base balance occur !in a patient, their prescribed medications should be carefully checked

region of the nephron; we briefly present the physiol-ogy of each segment and describe the pathophysiology of antibiotic-induced changes (Table 1) in terms of renal reabsorption of water and ions of sodium (Na+), potas-sium (K+) and hydrogen (H+). The renal tubular effects of antiretroviral drugs, which can cause Fanconi syn-drome and nephrogenic diabetes insipidus,6 are beyond the scope of this Review.

Proximal tubulePhysiologyIn the proximal tubule 50–80% of the filtrate is re absorbed. The main mechanism of sodium re absorption involves sodium hydrogen exchanger type 3 (NHE-3), via which Na+ enters the cell in exchange for H+ secreted into the tubular fluid, and the baso lateral Na+,K+-ATPase (Figure 1), which pumps Na+ out of the cell and into the interstitium.7 Carbonic anhydrase converts H+ and bicarbonate ions in the tubular fluid to carbonic acid, which dissociates into water and carbon dioxide. Water and carbon dioxide are subsequently re absorbed through aquaporin 1 water channels in the apical plasma membrane.8 Intracellular carbonic an hydrase converts the water and carbon dioxide back to H+ and bicarbonate ions; H+ is secreted into the tubular fluid again and the bicarbonate ions are transported across the basolateral membrane.

Derangement of this process may lead to proximal (type II) renal tubular acidosis.9 Another role of the proximal tubule in acid–base balance is in ammonia-genesis (the formation of NH4

+ from glutamine).8 Several solutes, such as phosphate, glucose and amino acids, are reabsorbed in the proximal tubule by secondary, active, sodium-coupled cotransporters, and consequently anti-biotics that disrupt Na+ influx into renal tubular cells also disturb reabsorption of these solutes. K+, calcium ions (Ca2+) and magnesium ions (Mg+) are reabsorbed in the proximal tubule through solvent drag, (paracellular) diffusion and apparent active transport.10

Antibiotic-induced effectsThe two main groups of antibiotics that can affect proxi-mal tubular function and cause fluid and electro lyte disorders are the aminoglycosides and tetracyclines (Figure 1).

Aminoglycosides act therapeutically by binding to prokaryotic ribosomes and inhibiting bacterial protein synthesis.11 In the kidney, aminoglycosides are freely filtered and subsequently reabsorbed in the proximal tubule by megalin, a low-affinity, high-capacity, endo-cytic receptor,12 with subsequent attachment of the antibiotic to phospholipid membranes.13 Thus, receptor- mediated endocytosis has an important role in the accumula tion of aminoglycosides in the proximal tubule. Mitochondrial ribosomes seem to be more sensi tive to aminoglycosides than do cytosolic ribosomes or those bound to the endoplasmic reticulum, perhaps because mitochondria are thought to be derived from (and in

Table 1 | Fluid, electrolyte and acid–base disturbances caused by antibiotic treatment

Clinical disturbance and relevant drugs

Frequency Mechanism Reference

Hyponatremia

Trimethoprim Rare Blocks ENaCs 57

Cipro!oxacin Rare Vasopressin release by increased intracranial pressure

97

Hypernatremia

Amphotericin B Rare Downregulation of aquaporin 2 74

Demeclocycline Frequent Reduced vasopressin-stimulated water transport

82

Hypokalemia

Amphotericin B Frequent Disruption of cell membrane, leading to potassium leak

66

Penicillin Frequent Nonreabsorbable anion 84

Aminoglycosides Frequent Bartter-like syndrome by CaSR stimulation

18

Capreomycin Frequent Bartter-like syndrome by CaSR stimulation

45

Hyperkalemia

Trimethoprim Frequent Blocks ENaCs 54,55

Penicillin Rare Potassium load 102

Amphotericin B Rare Shift to the extracellular compartment

103

High-anion-gap metabolic acidosis

Penicillins Rare Pyroglutamate acidosis 96

Linezolid Rare Mitochondrial toxicity 90

Virtually all antibiotics Rare D-Lactic acidosis (enteric bacterial overgrowth)

92

Non-anion-gap metabolic acidosis

Tetracyclines Rare Fanconi syndrome 89

Aminoglycosides Rare Fanconi syndrome 26

Trimethoprim Frequent Blocks ENaCs 64

Amphotericin B Frequent Disruption of cell membrane, leading to proton leak

66

Metabolic alkalosis

Aminoglycosides Rare Bartter-like syndrome by CaSR stimulation

18

Capreomycin Rare Bartter-like syndrome by CaSR stimulation

45

Abbreviations: CaSR; calcium-sensing receptor; ENaC, epithelial sodium channel.

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Key points

Renal tubular function can be affected by antibiotic treatment without !a concurrent reduction in glomerular filtration rate

Hypokalemia is a frequent complication of antimicrobial therapy !Treatment with aminoglycosides can affect renal tubular function in several !ways and can lead to hypokalemia, as well as acidosis and alkalosis

If unexpected disturbances in electrolyte and/or acid–base balance occur !in a patient, their prescribed medications should be carefully checked

region of the nephron; we briefly present the physiol-ogy of each segment and describe the pathophysiology of antibiotic-induced changes (Table 1) in terms of renal reabsorption of water and ions of sodium (Na+), potas-sium (K+) and hydrogen (H+). The renal tubular effects of antiretroviral drugs, which can cause Fanconi syn-drome and nephrogenic diabetes insipidus,6 are beyond the scope of this Review.

Proximal tubulePhysiologyIn the proximal tubule 50–80% of the filtrate is re absorbed. The main mechanism of sodium re absorption involves sodium hydrogen exchanger type 3 (NHE-3), via which Na+ enters the cell in exchange for H+ secreted into the tubular fluid, and the baso lateral Na+,K+-ATPase (Figure 1), which pumps Na+ out of the cell and into the interstitium.7 Carbonic anhydrase converts H+ and bicarbonate ions in the tubular fluid to carbonic acid, which dissociates into water and carbon dioxide. Water and carbon dioxide are subsequently re absorbed through aquaporin 1 water channels in the apical plasma membrane.8 Intracellular carbonic an hydrase converts the water and carbon dioxide back to H+ and bicarbonate ions; H+ is secreted into the tubular fluid again and the bicarbonate ions are transported across the basolateral membrane.

Derangement of this process may lead to proximal (type II) renal tubular acidosis.9 Another role of the proximal tubule in acid–base balance is in ammonia-genesis (the formation of NH4

+ from glutamine).8 Several solutes, such as phosphate, glucose and amino acids, are reabsorbed in the proximal tubule by secondary, active, sodium-coupled cotransporters, and consequently anti-biotics that disrupt Na+ influx into renal tubular cells also disturb reabsorption of these solutes. K+, calcium ions (Ca2+) and magnesium ions (Mg+) are reabsorbed in the proximal tubule through solvent drag, (paracellular) diffusion and apparent active transport.10

Antibiotic-induced effectsThe two main groups of antibiotics that can affect proxi-mal tubular function and cause fluid and electro lyte disorders are the aminoglycosides and tetracyclines (Figure 1).

Aminoglycosides act therapeutically by binding to prokaryotic ribosomes and inhibiting bacterial protein synthesis.11 In the kidney, aminoglycosides are freely filtered and subsequently reabsorbed in the proximal tubule by megalin, a low-affinity, high-capacity, endo-cytic receptor,12 with subsequent attachment of the antibiotic to phospholipid membranes.13 Thus, receptor- mediated endocytosis has an important role in the accumula tion of aminoglycosides in the proximal tubule. Mitochondrial ribosomes seem to be more sensi tive to aminoglycosides than do cytosolic ribosomes or those bound to the endoplasmic reticulum, perhaps because mitochondria are thought to be derived from (and in

Table 1 | Fluid, electrolyte and acid–base disturbances caused by antibiotic treatment

Clinical disturbance and relevant drugs

Frequency Mechanism Reference

Hyponatremia

Trimethoprim Rare Blocks ENaCs 57

Cipro!oxacin Rare Vasopressin release by increased intracranial pressure

97

Hypernatremia

Amphotericin B Rare Downregulation of aquaporin 2 74

Demeclocycline Frequent Reduced vasopressin-stimulated water transport

82

Hypokalemia

Amphotericin B Frequent Disruption of cell membrane, leading to potassium leak

66

Penicillin Frequent Nonreabsorbable anion 84

Aminoglycosides Frequent Bartter-like syndrome by CaSR stimulation

18

Capreomycin Frequent Bartter-like syndrome by CaSR stimulation

45

Hyperkalemia

Trimethoprim Frequent Blocks ENaCs 54,55

Penicillin Rare Potassium load 102

Amphotericin B Rare Shift to the extracellular compartment

103

High-anion-gap metabolic acidosis

Penicillins Rare Pyroglutamate acidosis 96

Linezolid Rare Mitochondrial toxicity 90

Virtually all antibiotics Rare D-Lactic acidosis (enteric bacterial overgrowth)

92

Non-anion-gap metabolic acidosis

Tetracyclines Rare Fanconi syndrome 89

Aminoglycosides Rare Fanconi syndrome 26

Trimethoprim Frequent Blocks ENaCs 64

Amphotericin B Frequent Disruption of cell membrane, leading to proton leak

66

Metabolic alkalosis

Aminoglycosides Rare Bartter-like syndrome by CaSR stimulation

18

Capreomycin Rare Bartter-like syndrome by CaSR stimulation

45

Abbreviations: CaSR; calcium-sensing receptor; ENaC, epithelial sodium channel.

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many ways resemble) bacteria.14 The inhibition of microsomal protein synthesis is an early manifestation of gentamicin’s nephrotoxic effects, which occur well before the induction of necrosis in proximal tubular cells.14 Localization of amino glycosides to the mito-chondrion results in mitochondrial dysfunction and impaired generation of ATP,15 which in turn reduces the activity of the basolateral Na+,K+ATPase. Several other mech anisms of aminoglycoside-induced toxic effects in renal tubular cells have been proposed, such as inhibition of the phosphatidylinositol cascade16 and lysosomal instability,17 but these processes might only be involved in late-stage disease when extensive damage has occurred. Aminoglycosides can also affect individual cellular transporters; in rats, gentamicin 80 mg/kg per day for 7 days led to decreased expression of NHE-3 in the proximal tubule.18

Aminoglycosides induce proteinuria and enzymuria in humans19 and animal models.20 Long-term administra-tion of 80 mg/kg per day gentamicin to rats resulted in a more than fivefold increase in urinary total protein excretion and increased excretion of enzymes associ-ated with the brush-border membrane.20 In proximal tubule cells the activity of enzymes involved in the citric acid cycle was markedly reduced. This observa-tion seems to confirm previous findings that genta-micin-induced toxic effects on the proximal tubule primarily result from damaged mitochondrial function and ATP production. Since endocytosis is an energy- dependent process, impaired mitochondrial function-ing could also explain the increase in proteinuria seen in aminoglycoside-treated patients.

Gentamicin can stimulate the extracellular calcium-sensing receptor (CaSR) in the thick ascending limb of the loop of Henle21 and, therefore, identification of this receptor in the apical membrane of the proximal tubule is of potential interest with regard to gentamicin toxicity.22,23 In vitro, administration of aminoglycosides initially causes alterations in cellular signaling and proliferation of cells that express the CaSR, followed by apoptosis.24 Gentamicin-induced cell death could be prevented by administration of a CaSR antagonist.25 However, the physiological function or functions of the CaSR in the proximal tubule and its putative involvement in aminoglycoside toxicity remain unclear.

Disturbances of proximal tubular function associ-ated with aminoglycosides either affect isolated trans-port mechanisms or have a generalized nature that is referred to as Fanconi syndrome. Although this syndrome is usually accompanied by a reduction in glomer ular filtra tion rate, several patients with pre-served renal function have been described.26 Generally, tubular function is restored after discontinuation of the drug.27 An early indication of aminoglycoside-induced disturbances in proximal tubular function is increased urinary excretion of amino acids.28 In patients with cystic fibrosis, N-acetyl-!-"-glucosaminidase (a lysosomal enzyme present in renal proximal tubule cells) has been

advocated as a sensitive urinary marker of aminoglyco-side-induced tubular damage.29 Interestingly, in mouse models of genta micin-induced nephrotoxic effects, cell-ular accumula tion of gentamicin and increased urinary excretion of N-acetyl-!-"-glucosaminidase was pre-vented by treatment with cationic proteins and their peptide fragments, which stopped gentamicin from binding to the endocytic receptor, megalin.30 Moreover (also in mice), megalin deficiency offers protection from aminoglycoside accumulation in the proximal tubule.12 Megalin proteins can become saturated with bound aminoglycosides. This saturation can be exploited by employing once-daily doses of aminoglycosides, which has been shown to limit their toxic effects.31

A second group of antibiotic agents implicated in Fanconi syndrome is the tetracyclines. Proximal tubular damage can sometimes be induced by tetracycline metabolites within 1 week of starting treatment.32,33 Tetracyclines may enter the proximal tubular epithelial cell through organic anion transporters, either across the basolateral or the apical plasma membranes (Figure 1).34 Ribosomes are the main intracellular target of tetra-cycline. Although this drug binds to eukaryotic ribo-somes with an affinity at least 15 times lower than that for bacterial ribosomes,35 its renal toxic effects are likely to result largely from partial inhibition of ribosomal protein synthesis.36 Like aminoglycosides, tetracyclines preferentially affect mitochondrial ribosomes owing to their resemblance to bacterial ribosomes.37 Histological examination of kidney tissue after tetracycline

Solute transporter

Solutes

Lumen Interstitium

Proximal tubule cell

Megalin–cubulin

Na+

hOAT4

NHE-3ADP ATP Na+,K+-

ATPase

H+

Na+

2K+

3Na+

Tetracyclines

TetracyclinesGentamicin – –

Mitochondrion

Ribosomes

Mitochondrion

hOAT1–3

Figure 1 | Antibiotics that affect proximal tubule cells. Gentamicin enters the cell through the megalin–cubulin system, while tetracyclines enter via apical or basolateral organic anion transporters. Gentamicin and tetracyclines can impair the function of mitochondrial ribosomes and interfere with the conversion of ADP to ATP. Consequently, these antibiotics inhibit the Na+,K+-ATPase pump, which is dependent upon ATP, and also indirectly (dashed lines) inhibit NHE-3 and other sodium-dependent solute transporters, including transporters for amino acids, uric acid and glucose. Abbreviations: H+, hydrogen ions; hOAT, organic anion transporter; K+, potassium ions; Na+, sodium ions; NHE-3, sodium hydrogen exchanger 3.

ProximalerTubulus

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treatment showed a striking vacuolization of the proximal tubule epithelium.38

The main clinical presentation of tetracycline toxic effects is hypokalemia secondary to increased distal delivery of sodium bicarbonate.33 Glucosuria, amino-aciduria, and phosphaturia are also seen, consistent with Fanconi syndrome.

Amphotericin B induces enzymuria (that is, signifi-cantly increased urinary excretion of N-acetyl-!-"-glucos-aminidase, !-glucuronidase, alanine amino peptidase and #-glutamyltransferase) in rats. This finding suggests that proximal tubular damage is present.39 No clinical occur-rences of Fanconi syndrome have, however, been reported in patients treated with this drug.

Thick ascending limbPhysiologyThe thick ascending limb of the loop of Henle performs several tasks. It is water-impermeable, but is a major site for reabsorption of Na+, K+ and chloride ions (Cl–) through kidney-specific Na+,K+,Cl– symporter chan-nels (NKCC2, now renamed solute carrier family 12, member 1).7 Removal of these ions from the lumen con-tents results in increased medullary osmolality, which provides the driving force for water reabsorption in the collecting duct. The reabsorption of Na+ and subsequent recycling of K+ to the lumen via the apical ATP-sensitive

inward-rectifier potassium channel (ROMK) leads to the luminal positive charge required for the paracellular reabsorption of divalent cations, such as Ca2+.

In Bartter syndrome, Na+, K+ and Cl– transport are impaired because of an autosomal-recessive mutation in genes that encode the Na+,K+,Cl– symporters NKCC1 and NKCC2, ROMK, or basolateral chloride channels (SLC12A2, SLC12A1, KCNJ1 and others).40 Reabsorption of Na+ and Ca2+ is closely linked in this nephron segment and, consequently, the activities of both NKCC2 and ROMK are influenced by serum Ca2+ concentrations. In the thick ascending limb of the loop of Henle, the CaSR is present on the basolateral epithelial cell membrane. Increased serum Ca2+ levels stimulate this receptor and lead to reductions in secondary, active reabsorption of Na+, which reduces the luminal positive driving force and results in increased urinary calcium excretion.22

Antibiotic-induced effectsA Bartter-like syndrome characterized by hypokalemic metabolic alkalosis, hypomagnesemia, hypocalcemia and serum creatinine levels within the normal range has been described in patients treated with amino glycosides.41,42 Gentamicin, a polyvalent, cationic molecule, is thought to activate the CaSR in the thick ascending limb of the loop of Henle (Figure 2) and the distal convoluted tubule. Thus, aminoglycoside treatment can lead to abnormalities that resemble those seen in patients with autosomal-dominant hypocalcemia,43 which is caused by gain-of-function mutations in the CASR gene.21 This condition is also termed type V Bartter syndrome.40 Studies of gentamicin administration in rats showed increased excretion of Na+, K+, Ca2+ and Mg+. At a dose of 40 mg/kg, gentamicin decreased the expression of NKCC1 in the thick ascending limb of the loop of Henle and induced a Bartter-like syndrome (Figure 2).18 These findings are also compatible with an effect of gentamicin on the basolateral CaSR.

Among patients who develop a Bartter-like syndrome, most are female. In all such patients, the clinical symp-toms always resolve when aminoglycosides are with-drawn.21 The dose above which this effect of gentamicin on the thick ascending limb of the loop of Henle occurs varies widely (for example, some case reports noted total gentamicin doses of 1.2–2.6 g).21 In a prospective study performed in 127 consecutive patients treated with aminoglycosides, we observed hypokalemia in 13% of the patients, whereas the incidence of Bartter-like syn-drome was 2% (R Zietse, R Zoutendijk and EJ Hoorn, unpublished data).

Multidrug regimens used to treat tuberculosis are frequently associated with hypokalemia.44 Although multiple factors in individuals with tuberculosis could lead to hypokalemia, its occurrence is strongly associ-ated with the use of capreomycin. This drug, similarly to genta micin, may induce a Bartter-like syndrome, in which renal wasting of Na+ and Cl– results in volume depletion, hyperaldosteronism and hypokalemia.45

Lumen Interstitium

Thick ascending limb cell

K+

NKCC2

ROMK

K+

Na+

2CI–

2K+

3Na+

Paracellulardiffusion

Na+, Ca2+,K+, Mg2+

– –

CaSR

Na+,K+-ATPase

Ca2+

Gentamicin

Tight junction

Figure 2 | Antibiotics that affect the thick ascending limb of the loop of Henle. Gentamicin, other aminoglycosides and capreomycin can stimulate the CaSR. This stimulation can disrupt electrolyte transport via inhibition of four different pathways that involve NKCC2, ROMK, Na+,K+-ATPase and/or paracellular diffusion. Inhibition of these transport mechanisms leads to increased urinary excretion of Na+, K+, Mg2+ and Ca2+, and associated electrolyte disorders. Abbreviations: Ca2+, calcium ions; CaSR, calcium-sensing receptor; Cl–, chloride ions; K+, potassium ions; Mg2+, magnesium ions; Na+, sodium ions; NKCC2, the kidney-specific Na+,K+,Cl– symporter, now termed solute carrier family 12 member 1; ROMK, renal outer medullary potassium channel.

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Distal convoluted tubulePhysiologyAs part of the ‘aldosterone-sensitive’ distal nephron, the distal convoluted tubule is involved in electro neutral re absorption of Na+ and Cl– through the thiazide- sensitive sodium-chloride cotransporter.7 Throughout the connecting tubule, the epithelial Na+ channel (ENaC) is expressed, which, when activated by aldosterone, leads to a transmembrane voltage potential that is negative on the apical side.46 This electrochemical driving force is important in the secretion of K+ ions. Although H+

ions undergo active transport towards the lumen by H+-ATPase, the luminal negative charge is also impor-tant for effective secretion of H+ in the distal parts of the nephron.

The distal convoluted tubule is the only site of trans-cellular magnesium reabsorption, where Mg+ enter the cell through apical transient receptor potential cation channel subfamily M member 6 (TRPM6).47 This channel seems to interact with the thiazide-sensitive sodium- chloride cotransporter, as absent or inhibited activity of this cotransporter leads to downregulation of TRPM6 and results in hypomagnesemia.48

Antibiotic-induced effectsGentamicin might affect the distal convoluted tubule as well as upstream nephron segments, since magnesium wasting is a common adverse effect of aminoglycoside treatment. A causal relationship between gentamicin administration and magnesium wasting has been sug-gested by studies in nonhuman primates.49 In healthy human individuals, gentamicin caused an immediate, transient, and substantial increase in fractional renal excretion of Mg+ and Ca2+, which could be consistent with altered transport of these ions in the distal convo-luted tubule.50 From studies performed in an immortal-ized mouse distal convoluted tubule cell line, Kang et al.51 concluded that gentamicin acts through an effect on the extracellular polyvalent-cation-sensing receptor, which is present in distal convoluted tubule cells.

Collecting ductPhysiologyFunctionally, the collecting duct can be divided into cortical and medullary parts. The medullary collect-ing duct can be further subdivided into inner and outer regions.

The cortical collecting duct is part of the aldo sterone-sensitive segment of the nephron. The main means of cation transport throughout the whole aldo sterone-sensitive segment is Na+ entry from the luminal fluid through ENaCs, which leads to a trans membrane voltage potential that is negative on the lumen side, and to K+ secretion through the ROMK channel (Figure 3).

Both the inner and outer medullary collecting ducts are essential to determine the concentration of the urine. An increase in serum osmolality leads to the release of vasopressin by the pituitary gland. Vasopressin acts on its

receptor V2 on the basolateral membrane of the principal cells in the collecting duct (Figure 3), which results in the insertion of aquaporin 2 in the apical plasma membrane. In concert with the constitutively expressed aquaporin 3 and aquaporin 4 channels on the basolateral membrane, these water channels enable the reabsorption of water, driven by the osmotic gradient between the lumen and interstitium. Moreover, in mouse studies, stimulation of V2 increased urea reabsorption through increased expression of urea transporters in the inner medullary collecting duct, which increases the ability of the kidney to reabsorb water.52

Finally, the collecting duct is important in main-tenance of the acid–base balance (Figure 4). Both the cortical and inner medullary collecting ducts contain a subset of specialized, intercalated cells that express H+-ATPase and H+,K+-ATPase. H+ in these cells are actively transported to the lumen. Whereas the proxi-mal tubule contributes to acid–base homeostasis by the reabsorption of filtered bicarbonate, this distal nephron segment is able to produce ‘new’ bicarbonate, which is essential to buffer the net 50–70 mmol per day of H+ that is ingested or produced by degradation of protein. Failure of distal H+ secretion leads to distal (type I) renal tubular acidosis.53

Penicillin

Trimethroprim

Lumen Interstitium

Collecting duct principal cell

ROMK

K+

Na+

2K+

3Na+

ATP

cAMPH2O AQP2

+–

AC

Vasopressin

Demeclocycline

?

?–

– ––

– –

K+

Amphotericin B

Na+,K+-ATPase

hOAT1hOAT3

V2

ENaC

Figure 3 | Antibiotics that affect collecting-duct principal cells. Trimethoprim blocks ENaCs similarly to amiloride, which causes Na+ wasting, reduced kaliuresis, and distal renal tubular acidosis (because H+ excretion decreases). Penicillin acts as a nonreabsorbable anion that maintains a luminal negative charge if aldosterone-driven Na+ reabsorption is increased. This negative charge stimulates K+ secretion and may cause hypokalemia. Demeclocycline and amphotericin B both cause nephrogenic diabetes insipidus, by inhibiting vasopressin-stimulated V2–AQP2 signaling. Amphotericin B creates pores in cell membranes; once inside, it inhibits Gs! proteins and/or adenylate cyclase. These pores leak K+, which induces hypokalemia. How demeclocycline disrupts vasopressin–aquaporin signaling is unknown, but it probably enters the cell via hOAT1 or hOAT3. Abbreviations: AC, adenylate cyclase; AQP2, aquaporin 2; cAMP, cyclic AMP; ENaC, epithelial sodium channel (amiloride-sensitive sodium channel); hOAT, organic anion transporter; K+, potassium ions; Na+, sodium ions; V2, vasopressin 2 receptor.

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Nierenschädigung durch Antibiotika

Nat Rev Nephrol 2009;5:209

198 | APRIL 2009 | VOLUME 5 www.nature.com/nrneph

REVIEWS

Antibiotic-induced effectsAll the transport mechanisms in the collecting ducts can be affected by a variety of antibiotics, including trimetho-prim, amphotericin B, penicillins, and demeclo cycline (Figures 3 and 4).

Hyperkalemia is a common adverse effect of treat-ment with trimethoprim, which is frequently prescribed in combination with sulfamethoxazole (one part to five parts) as co-trimoxazole.54,55 Less frequently, administra-tion of trimethoprim leads to renal tubular Na+ wasting that may induce hypovolemia-induced vasopressin release and hyponatremia.54,56 Trimethoprim acts on the apical membrane of the cortical collecting duct, where it inhibits Na+ influx via ENaCs, which decreases the net driving force for K+ exit across the apical cell membrane and results in inhibition of K+ secretion.57 Renal failure increases the risk of trimethoprim-induced hyper-kalemia, but potassium excretion was also decreased in healthy volunteers with normal renal function who received this drug.58

On the basolateral membrane of the cortical collect-ing duct, trimethoprim inhibits Na+,K+-ATPase,59 which further reduces the kidney’s ability to excrete potas-sium. Two strategies have been employed to ameliorate trimethoprim-induced antikaliuresis. One strategy is to increase distal urine flow by the infusion of saline and administration of a loop diuretic (such as furosemide); the other is alkalinization of the urine, for example with acetazolamide.60,61 Only cationic trimethoprim com-petes with Na+ for ENaC transport.62 Thus, increased urinary pH decreases the concentration of positively charged trimethoprim and reduces its antikaliuretic effect.62 The voltage effect of inhibition of ENaCs also affects the ability of the distal nephron to excrete H+.

Indeed, treatment with trimethoprim might also result in voltage- dependent distal renal tubular acidosis.63

Amphotericin B is an effective drug for the treatment of systemic fungal infections. It alters the perme ability of fungal cell membranes by binding to ergosterol in the lipid bilayer. Unfortunately, amphotericin B can also bind to cholesterol in mammalian cell membranes, and the altered ion permeability that results is the cause of a vast spectrum of renal toxic effects.64 Such effects occur in a considerable number of patients treated with ampho-tericin B. For example, Wingard et al.65 observed doubling of serum creatinine levels in 53% of treated patients, and creatinine levels exceeded 221 μmol/l in 29% of patients. Several mechanisms have been proposed to explain the reduction in glomerular filtration rate induced by amphotericin B. Although the mediator of this effect is as yet unclear, amphotericin B administra tion is associ-ated with renal vasoconstriction and a reduction in renal blood flow. Other potential mechanisms, such as a reduc-tion of the glomerular ultrafiltration coefficient and renal tubular toxic effects, have also been proposed.64

Obviously, a reduction in glomerular filtration rate fol-lowing treatment with amphotericin B can be associated with disturbances of the fluid and electrolyte balance. Owing to the effects of this drug on membrane per me-ability to monovalent cations, however, it can have a marked, direct effect on tubular function without con-comitant azotemia. A common renal tubular side effect of amphotericin B therapy is potassium wasting that leads to hypokalemia.66 Occasionally, hypokalemia can be so severe that it results in rhabdomyolysis.67

Amphotericin B increases membrane permeability to K+ in various tissues.64 As renin and aldosterone levels do not increase during amphotericin B treatment,68 alterations in the permeability of tubular cells in the distal nephron are likely, which cause a passive flux of K+ down its electro-chemical gradient. The induction of hypokalemia may further aggravate the renal tubular toxic effects induced by amphotericin B;69 consequently, the development of hypokalemia must be recognized early and potas-sium supplementation should be started if necessary. Amphotericin B nephrotoxic effects are likely to be worse in patients who have depletion of potassium69 or sodium68 before treatment with this agent is initiated. Both amiloride and spirono lactone reduce requirements for potassium supplementation in patients receiving amphotericin B.70,71 Patients who have marked proteinuria (>3 g/l) seem to have a reduced risk of renal tubular toxic effects caused by amphotericin B,73 an effect that may be related to a reduced concen tration of free amphotericin B in tubular fluid as a consequence of free protein binding to this drug.

This ionic ‘leakiness’ of the distal nephron is also presumed to cause the distal renal tubular acidosis in patients treated with amphotericin B (Figure 4). In studies that used turtle bladders, Steinmetz et al.73 demon strated that although H+ secretion was markedly reduced by administration of amphotericin B, it was not greatly affected when passive electrochemical transport

Lumen Interstitium

Collecting duct intercalated cell

H+

H+

H+

2K+

3Na+

Amphotericin B

H+ ATPase

Na+,K+-ATPase

Figure 4 | Antibiotics that affect collecting duct intercalated cells. Amphotericin B can create pores in the cell membrane. These pores allow a backflux of H+ into the cell, which inhibits urinary H+ excretion and, therefore, results in distal renal tubular acidosis. Abbreviations: H+, hydrogen ions; K+, potassium ions; Na+, sodium ions.

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Nierenschädigung durch Antibiotika

Nat Rev Nephrol 2009;5:209

200 | APRIL 2009 | VOLUME 5 www.nature.com/nrneph

REVIEWS

Rapid administration of large amounts of semi-synthetic penicillin derivates and amphotericin B has been associated with acute hyperkalemia.102,103 The underlying causes seem to be the potassium load in penicillin G and a shift from the intracellular to the extra cellular compartment, respectively.

Differential diagnosis and treatmentProximal and distal renal tubular acidosis fall into the cate-gory of metabolic acidosis that is not associated with an increased anion gap. When proximal renal tubular acidosis is part of Fanconi syndrome, in which hypo phosphatemia, hypouricemia and tubular glucosuria and proteinuria are also present, it can be easily distinguished from distal renal tubular acidosis. If proximal tubular acidosis is iso-lated, however, differentiation is more diffi cult and relies on calculation of fractional bicarbonate excretion during infusion. Treatment is generally with bicarbonate therapy, but this approach might worsen hypokalemia in proximal renal tubular acidosis because a bicarbonate diuresis can cause potassium wasting; potassium bicarbonate is another option.80 In all the causes of hypokalemia we have dis-cussed, renal potassium loss is central to the patho genesis.

Thus, assessment of urinary potassium excretion can be extremely useful; a (spot) urine potassium:creatinine ratio is the best indicator of renal potassium wasting. In patients with polyuria, a low urine osmolality and absence of a response to synthetic vasopressin is diagnostic for nephro genic diabetes insipidus.

ConclusionsSeveral groups of patients are at risk of developing renal side effects of antimicrobial agents, including those with an impairment of renal function or volume depletion. Here, we have reviewed the many electrolyte disturbances that can be induced by commonly prescribed anti microbial agents. Many of these adverse effects are dose-dependent and quite frequent (Table 1); consequently, the prudent physician should closely monitor serum electrolyte com-position and acid–base balance during the treatment of infections. Readily available parameters in serum and urine can be used in diagnosis of the different fluid, electro lyte and acid–base disorders. If one of these dis-orders is suspected, assessing a broad range of electrolytes, including levels of creatinine, urea, sodium, chloride, potassium, magnesium, calcium, phosphate, bicarbonate,

Table 2 | Diagnostic features and treatment of antibiotic-associated renal-tubule disorders

Antibiotics and relevant disorders

Diagnostic features Treatmenta

Aminoglycosides and tetracyclines

Proximal RTA or Fanconi syndrome

Non-anion-gap metabolic acidosis, hypokalemia with or without hypouricemia, hypophosphatemia, glucosuria, tubular proteinuria

Supplementation of potassium, bicarbonate and/or phosphate

Bartter-like syndrome Hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalcemia natriuresis

Supplementation of potassium, magnesium and/or calcium, isotonic saline

Amphotericin B

Distal RTA Non-anion-gap metabolic acidosis, hypokalemia Supplementation of bicarbonate and/or potassium

Hypokalemia Urinary potassium loss Supplementation of potassium, amiloride, spironolactone

Hyperkalemia Potassium shift out of cells (no speci!c diagnostic test available)

Calcium (with arrhythmia), glucose–insulin, cation-exchange resin, isotonic saline

Amphotericin B and demeclocycline

Nephrogenic diabetes insipidus

Synthetic-vasopressin-resistant polyuria, hypernatremia may be present

Thiazide diuretics, amiloride, low sodium and protein diet

Trimethoprim

ENaC blockade Hyperkalemia with or without hyponatremia Isotonic saline, alkalization of the urine

Distal RTA Non-anion-gap metabolic acidosis Bicarbonate

Penicillin

Hypokalemia Typically low urine chloride and high urine potassium Potassium supplementation

Hyperkalemia High potassium in drug in patient with impaired kaliuresis Calcium (with arrhythmia), glucose-insulin, cation-exchange resin, isotonic saline

Pyroglutamic acidosis High-anion-gap metabolic acidosis Discontinuation of the drug

Tetracyclines and linezolid

Lactic acidosis High-anion-gap metabolic acidosis with elevated lactate Discontinuation of the drugaDiscontinuation of the offending antibiotic should always be considered, depending on the severity of the renal tubular disorder. The choice to start the treatments listed below should also depend on the clinical significance and severity of the disorder. Abbreviations: ENaC, epithelial sodium channel; RTA, renal tubular acidosis.

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Rolle von Vasopressin bei Hyponatriämie

Nat Rev Nephrol 2013;9:37

40 | JANUARY 2013 | VOLUME 9 www.nature.com/nrneph

with increased mortality in heart failure patients occurs with an increase in serum creatinine as small as 27 μmol/l.62 Of interest, a rise in blood urea nitrogen cor-relates even better with mortality than does increased serum creatinine in patients with hyponatraemia.63 This correlation with blood urea nitrogen may be due to the effect of increased AVP increasing urea reabsorption in the renal collecting duct.63

Although substantial evidence is available to show that hyponatraemia in patients with heart failure is associated with a poor prognosis, less evidence exists to show that correction of the hyponatraemia has beneficial effects. Thus, hyponatraemia may be primarily a marker of more severe disease in patients with heart failure. In this regard, hyponatraemia is known to be associated with an increased plasma concentration of plasma renin and norepinephrine, which are also known risk factors for increased mortality in heart failure.64

In 1981, a sensitive radioimmunoassay was first used to measure levels of the antidiuretic hormone, AVP, in the plasma of hyponatraemic patients with heart failure.65 The results demonstrated that hypo-osmolar plasma levels, which would maximally suppress plasma AVP in healthy individuals, did not suppress plasma AVP concentration in hyponatraemic patients with heart failure. Subsequent studies have reported similar findings of a nonosmotic stimulation of AVP in heart failure.66,67 Experimental studies have demonstrated that

the osmotic regulation of AVP can be overridden by the nonosmotic baroreceptor pathway.68

When cardiac output decreases, the arterial stretch baroreceptors in the carotid sinus and aortic arch become unloaded (Figure 1).69 Thus, the normal tonic inhibitory effect to the central nervous system via the vagus and glossopharyngeal nerves is removed, with a resultant increase in sympathetic efferent activity. This increased sympathetic activity is associated with stimulation of the RAAS and the nonosmotic release of AVP.70 The resultant systemic and renal vasoconstriction, as well as the sodium and water retention, attenuates the arterial underfilling, but ultimately at the expense of the occur-rence of hyponatraemia, pulmonary congestion and diminished kidney function.

The prevalence of hyponatraemia in patients with high-output cardiac failure, as occurs in beriberi and thyrotoxicosis, has not been well studied. The initiating event in this setting, as occurs in patients with a large arterio-venous fistula, is a decrease in systemic vascu-lar resistance.71 As with a decrease in cardiac output, primary arterial vasodilatation leads to unloading of the arterial baroreceptors, with subsequent activation of the neurohumoral axis, including the sympathetic nervous system and RAAS, as well as the nonosmotic release of AVP (Figure 1).70 Thus, hyponatraemia would be expected to be associated with worse survival in both low-output and high-output cardiac failure. Evidence also exists to show that hyponatraemia is associated with increased mortality in patients with primary pulmonary hypertension and pulmonary embolism.72,73 In addition, preoperative hyponatraemia predicts an unfavourable outcome after cardiac surgery.74

The recent availability of vasopressin V2-receptor antagonists has been used to acutely reverse hypo-natraemia in patients with advanced cardiac failure.75 However, prospective studies are needed in patients with heart failure before and after correction of hypo natraemia to assess the effects on cognitive function, which is often impaired in these patients.76 In the EVEREST study, which investigated the safety of the V2-receptor antago-nist tolvaptan in patients with heart failure, only 7.7% of patients had hyponatraemia. This 9.9-month-long randomized study demonstrated the safety of tolvaptan in patients with heart failure, and showed a decrease in body weight and improved dyspnoea in the first week of therapy,77 but no effect on survival.27

Hyponatraemia in cirrhosis The pathophysiology of hyponatraemia in patients with cirrhosis is very similar to that observed in patients with high-output heart failure. The portal hypertension that occurs in patients with cirrhosis leads to primary splanchnic arterial vasodilatation, which is the main cause of the decreased systemic vascular resistance in these patients.78,79 Several vasodilators have been pro-posed as mediators of the splanchnic vasodilatation in cirrhosis, but the most convincing results implicate increased inducible and endothelial nitric oxide synthase leading to nitric-oxide-mediated arterial vasodilatation.80

Cardiac output Primary systemic arterial vasodilation

Heart failure

Cirrhosis

Arterial under!lling

Arterial baroreceptors unloaded

Sympathetic tone Nonosmotic vasopressin stimulation RAAS stimulation

Hyponatraemia

Figure 1 | The pivotal role of vasopressin in the pathophysiology of hyponatraemia. Stimulation of the sympathetic nervous system and the RAAS increases proximal sodium and water reabsorption and thus decreases fluid delivery to the distal diluting segment, but the primary defect in the pathophysiology of hyponatraemia is the inability to dilute the urine. Urine dilution is primarily mediated by suppression of vasopressin. Abbreviation: RAAS, renin–angiotensin–aldosterone system.

REVIEWS

© 2013 Macmillan Publishers Limited. All rights reserved

Freitag, 20. September 13

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Syndrom der unkorrekten ADH-Sekretion (SIADH)

NEJM 2007;356:20

Clinical Pr actice

n engl j med 356;20 www.nejm.org may 17, 2007 2065

The risk rises with increasing age and is espe-cially high among residents of nursing homes.4 Although the causes of SIAD are myriad, they can be categorized as related to malignant diseases, pulmonary diseases, and disorders of the central nervous system, among others (Table 1). In addi-tion, a variety of drugs can stimulate the release of arginine vasopressin or potentiate its action (Table 1); traditionally, some medical authorities include such drugs among the causes of SIADH,9,10 whereas others do not include them in this cat-egory.11

Severe hyponatremia (serum sodium <125 mmol per liter), especially when the condition develops rapidly (within 48 hours), has serious sequelae, including confusion, hallucinations, seizures, coma, decerebrate posture, and respiratory arrest, leading to death. Milder symptoms of hyponatre-mia include headache, difficulty concentrating, impaired memory, muscle cramps, and weakness; dysgeusia has also been reported. Patients with chronic hyponatremia may be asymptomatic, al-though some data suggest that neurologic deficits, such as those causing falls, may be more common in patients with chronic hyponatremia than in persons with normal serum sodium levels.12 The threshold serum sodium levels at which neuro-logic complications occur appear to be higher among women than among men.13

S tr ategies a nd E v idence

DiagnosisFormal criteria for the diagnosis of SIAD are sum-marized in Table 2.14 Serum osmolality must be measured to rule out pseudohyponatremia, a lab-oratory artifact occurring when levels of serum lip-ids or proteins are elevated and serum sodium lev-els are measured by means of common, indirect techniques.15 Hypertonic (or translocational) hy-ponatremia occurs when osmotically active solutes (glucose or mannitol) draw water from cells. For each increase of 100 mg per deciliter (5.6 mmol per liter) in plasma glucose levels, serum sodium de-clines by 1.6 to 2.4 mmol per liter. 16 (The tradi-tional correction factor of 1.6 mmol per liter may underestimate the actual change.) A normal or el-evated measured osmolality value, however, does not rule out hypotonic hyponatremia, because urea is an ineffective osmole. Thus, the effective osmo-lality (sometimes called tonicity) is equal to the

measured osmolality minus (blood urea nitrogen ÷ 2.8), with blood urea nitrogen measured in mil-ligrams per deciliter.17 For a diagnosis of hypo-tonic hyponatremia, the effective osmolality must be less than 275 mOsm per kilogram of water (Table 2).

To make the diagnosis of SIAD, the urinary osmolality must exceed 100 mOsm per kilogram of water when the effective plasma osmolality is low (Table 2). The presence of clinical euvolemia is considered to be essential, because depletion of the effective arterial blood volume stimulates the secretion of arginine vasopressin appropriately. When expansion of the volume of extracellular fluid is associated with depletion of the effective arterial blood volume (as in cirrhosis), edema is usually evident. Detecting extracellular-fluid vol-ume depletion as a cause of hyponatremia, how-ever, is more difficult than detecting volume expansion, because the sensitivity of clinical as-sessment is limited18; laboratory tests are often used to provide additional guidance. Hypourice-mia, low blood urea nitrogen, and a urinary sodi-um level greater than 40 mmol per liter in patients

16p6

4

8

00 120 130 140 150

Type C

Type A

Type B

Type D

12

AUTHOR:

FIGURE:

JOB: ISSUE:

4-CH/T

RETAKEICM

CASE

EMail LineH/TCombo

Revised

REG F

Enon

1st2nd3rd

Ellison

1 of 2

05-17-07

ARTIST: ts

35620

Figure 1. Types of the Syndrome of Inappropriate Antidiuresis (SIAD).

Patterns of plasma levels of arginine vasopressin (AVP; also known as the antidiuretic hormone), as compared with plasma sodium levels in patients with SIAD, are shown. Type A is characterized by unregulated secre-tion of AVP, type B by elevated basal secretion of AVP despite normal regulation by osmolality, type C by a “reset osmostat,” and type D by undetectable AVP. The shaded area represents normal values of plasma AVP. Adapted from Robertson,7 with the permission of the publisher.

The New England Journal of Medicine Downloaded from nejm.org by MARK DOMINIK ALSCHER on September 7, 2013. For personal use only. No other uses without permission.

Copyright © 2007 Massachusetts Medical Society. All rights reserved.

Verschiedene Sekretionstypen bei SIADH.

A: Unregulierte Sekretion.B: Erhöhte Basalsekretion bei erhaltener Sensivität auf Osmolarität.C: Reset Osmostat.D: Fehlender Nachweis von ADH.

Freitag, 20. September 13

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Syndrom der unkorrekten ADH-Sekretion (SIADH)

NEJM 2007;356:20

The n

ew

en

gl

an

d jo

ur

na

l of m

ed

icin

e

n en

gl j m

ed 356;20

ww

w.n

ejm.o

rg

may 17, 2007

2066

with hyponatrem

ia suggest SIAD, but are not di-agnostic 5; for exam

ple, a serum uric acid level of

less than 4 mg per deciliter (238 µ

mol per liter)

(in the presence of hyponatremia) has a positive

predictive value for SIAD of 73 to 100%

. 19-21 A uri-nary sodium

level of less than 30 mm

ol per liter has a positive predictive value of 71 to 100%

for an infusion of 0.9%

saline to increase the serum so-

dium level. 18,22

When diagnostic uncertainty rem

ains, volume

contraction of the extracellular fluid can be ruled out by infusing 2 liters of 0.9%

saline over a pe-riod of 24 to 48 hours. Even though 0.9%

saline is not the preferred treatm

ent for SIAD, it is usu-

ally safe when the baseline urinary osm

olality is less than 500 m

Osm

per kilogram of w

ater 17,22,23; correction of the hyponatrem

ia suggests underly-ing volum

e depletion of extracellular fluid. Mea-

surement of the serum

level of arginine vasopres-sin is not recom

mended routinely, because urinary

osmolality above 100 m

Osm

per kilogram of w

ater is usually sufficient to indicate excess of circulat-ing arginine vasopressin.

Man

agem

ent

The only definitive treatment of SIAD

is elimina-

tion of its underlying cause. Most cases caused by

malignant disease resolve w

ith effective antineo-plastic therapy, and m

ost of those due to medica-

tion resolve promptly w

hen the offending agent is discontinued. W

hen the hyponatremia is chronic

and asymptom

atic, a diagnosis can be pursued be-fore treatm

ent is initiated.

Acute Symptom

atic Hyponatrem

iaThe m

ost important factors dictating the m

anage-m

ent of SIAD are the severity of the hyponatrem

ia, its duration, and the presence or absence of sym

p-tom

s (Fig. 2). 11,24,25 For symptom

atic patients with

severe hyponatremia know

n to have developed w

ithin 48 hours, clinical experience suggests that rapid treatm

ent is warranted. 26 The goal is to raise

the serum sodium

level by 1 to 2 mm

ol per liter per hour by infusing 3%

saline; these recomm

ended rates are guided by data from

case series, in the absence of data from

randomized trials, but they

are widely accepted. 1 M

any authorities recomm

end concom

itant furosemide, 1 although som

e recom-

mend avoiding it 10 or reserving it for patients w

ith extracellular-fluid volum

e expansion. 9,27 Many ex-

perts believe that the magnitude of correction dur-

ing the first 24 hours of treatment should be no

Table 1. Causes of the Syndrome of Inappropriate Antidiuresis (SIAD).*

Malignant Diseases Pulmonary DisordersDisorders of the

Central Nervous System Drugs Other CausesCarcinoma

LungSmall-cellMesothelioma

OropharynxGastrointestinal tract

StomachDuodenumPancreas

Genitourinary tractUreterBladderProstateEndometrium

Endocrine thymomaLymphomasSarcomas

Ewing’s sarcoma

InfectionsBacterial pneumoniaViral pneumoniaPulmonary abscessTuberculosisAspergillosis

AsthmaCystic fibrosisRespiratory failure associat-

ed with positive-pres-sure breathing

InfectionEncephalitisMeningitisBrain abscessRocky Mountain spotted feverAIDS

Bleeding and massesSubdural hematomaSubarachnoid hemorrhageCerebrovascular accidentBrain tumorsHead traumaHydrocephalusCavernous sinus thrombosis

OtherMultiple sclerosisGuillain–Barré syndromeShy–Drager syndromeDelirium tremensAcute intermittent porphyria

Drugs that stimulate release of AVP or enhance its actionChlorpropramideSSRIsTricyclic antidepressantsClofibrate (Atromid-S, Wyeth–Ayerst)Carbamazepine (Epitol, Lemmon; Tegretol, Ciba–Geigy)Vincristine (Oncovin, Lilly; Vincasar, Pharmacia and

Upjohn)NicotineNarcoticsAntipsychotic drugsIfosfamide (Ifex, Bristol-Myers Squibb)Cyclophosphamide (Cytoxan, Bristol-Myers Squibb;

Neosar, Pharmacia and Upjohn)Nonsteroidal antiinflammatory drugsMDMA (“ecstasy”)

AVP analoguesDesmopressin (DDAVP, Rhone–Poulenc Rorer; Stimate,

Centeon)Oxytocin (Pitocin, Parke–Davis; Syntocinon, Novartis)Vasopressin

Hereditary (gain-of-function mutations in the vaso-pressin V2 receptor)

IdiopathicTransient

Endurance exerciseGeneral anesthesiaNauseaPainStress

* AIDS denotes the acquired immunodeficiency syndrome, AVP arginine vasopressin, SSRI selective serotonin-reuptake inhibitor, and MDMA 3,4-methylenedioxymethamphetamine.

The New

England Journal of Medicine

Dow

nloaded from nejm

.org by MA

RK D

OM

INIK

ALSCH

ER on September 7, 2013. For personal use only. N

o other uses without perm

ission. Copyright ©

2007 Massachusetts M

edical Society. All rights reserved.

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Syndrom der unkorrekten ADH-Sekretion (SIADH)

NEJM 2007;356:20

Clinical Pr actice

n engl j med 356;20 www.nejm.org may 17, 2007 2067

more than 8 to 10 mmol per liter, and during the first 48 hours no more than 18 to 25 mmol per liter, even when the hyponatremia is acute.1,9,27 One approach is to aim for the cessation of neurologic symptoms, such as seizures, and then reduce the correction rate.25 An increase in serum sodium levels of less than 10 mmol per liter is usually suf-ficient to reduce the symptoms and prevent com-plications.28 (Specific treatment regimens are dis-cussed below.)

Hyponatremia of Long or Unclear DurationMost cases of hyponatremia that occur out of the hospital are chronic and minimally symptomatic, except in marathon runners, users of 3,4-methy-lenedioxymethamphetamine (MDMA, also known as “ecstasy”), and people who drink water to ex-cess; in these groups, severe symptoms usually indicate acute hyponatremia and require rapid cor-rection.

The treatment of hyponatremia with an unclear duration and nonspecific symptoms or signs (e.g., headache or lethargy) is particularly challenging. Some reports suggest a high risk if patients are not treated aggressively29; others suggest that rapid correction increases morbidity or mortality.30 Un-like patients with acute hyponatremia, those with hyponatremia of longer duration have a docu-mented risk of osmotic demyelination if the serum sodium level is corrected by more than 12 mmol per liter over a period of 24 hours. This disorder, which includes both central pontine and extrapon-tine myelinolysis, begins with lethargy and affec-tive changes (generally after initial improvement of neurologic symptoms with treatment), followed by mutism or dysarthria, spastic quadriparesis, and pseudobulbar palsy.31 Case series and experi-mental data indicate that this complication may result from rapid correction of hyponatremia that has been present for more than 48 hours.31

To balance the risks of chronic hyponatremia against the risks of rapid correction, many au-thorities recommend a modest rate of correction (an increase in serum sodium of 0.5 to 1.0 mmol per liter per hour), using lower rates of saline infu-sion for patients with symptomatic hyponatremia of unknown duration. Many limit correction to 8 mmol per liter over a period of 24 hours and 18 mmol per liter over a period of 48 hours; close monitoring of the rate of correction (every 2 to 3 hours)25 is recommended to avoid overcorrec-tion. Some authorities recommend brain imaging

(e.g., CT or magnetic resonance imaging) to deter-mine whether cerebral edema is present and to gauge the urgency of the need for correction, al-though evidence that imaging improves outcomes is lacking.32

Asymptomatic patients with chronic hyponatre-mia have a low risk of serious neurologic sequelae but a well-described risk of osmotic demyelination with rapid correction.31 Therefore, treatment is aimed at correcting the hyponatremia very grad-ually. Fluid restriction, estimated on the basis of levels of urinary and plasma electrolytes (Fig. 2), is a cornerstone of therapy.6,33 The maximum tol-erated fluid intake is proportional to the oral os-motic load, so adequate intake of dietary protein and salt should be encouraged. Oral intake of urea (30 g per day) is effective but is poorly tolerated. Demeclocycline (Declomycin, Wyeth–Ayerst) (300 to 600 mg twice daily) reduces urinary osmolality and increases serum sodium levels, but its effects

Table 2. Diagnosis of SIAD.*

Essential features

Decreased effective osmolality (<275 mOsm/kg of water)

Urinary osmolality >100 mOsm/kg of water during hypotonicity

Clinical euvolemia

No clinical signs of volume depletion of extracellular fluid

No orthostasis, tachycardia, decreased skin turgor, or dry mucous membranes

No clinical signs of excessive volume of extracellular fluid

No edema or ascites

Urinary sodium >40 mmol/liter with normal dietary salt intake

Normal thyroid and adrenal function

No recent use of diuretic agents

Supplemental features

Plasma uric acid <4 mg/dl

Blood urea nitrogen <10 mg/dl

Fractional sodium excretion >1%; fractional urea excretion >55%

Failure to correct hyponatremia after 0.9% saline infusion

Correction of hyponatremia through fluid restriction

Abnormal result on test of water load (<80% excretion of 20 ml of water per kilogram of body weight over a period of 4 hours), or inadequate urinary dilution (<100 mOsm/kg of water)

Elevated plasma AVP levels, despite the presence of hypotonicity and clinical euvolemia

* AVP denotes arginine vasopressin. Data are adapted from Schwartz et al.6 and Janicic and Verbalis.9 The test for water load and measurement of AVP are rarely recommended. To convert the value for blood urea nitrogen to milli-moles per liter, multiply by 0.357.

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Syndrom der unkorrekten ADH-Sekretion (SIADH)

NEJM 2007;356:20

T h e n e w e ng l a nd j o u r na l o f m e dic i n e

n engl j med 356;20 www.nejm.org may 17, 20072068

can be variable and it can cause nephrotoxicity. Lithium (Eskalith, GlaxoSmithKline; Lithobid, Sol-vay Pharmaceuticals) is no longer recommended.

Vasopressin-Receptor Antagonist TherapyA more recent option for treating SIAD is conivap-tan (Vaprisol, Astellas Pharma), a vasopressin-receptor antagonist approved by the Food and Drug Administration in 2005 for intravenous treatment of euvolemic hyponatremia34 and approved in 2007 for intravenous treatment of hypervolemic hypo-natremia35 (Table 3). In a double-blind, random-ized trial, in patients assigned to conivaptan for

4 days, as compared with those assigned to place-bo, the serum sodium levels increased by 6 mmol per liter. Although hypotension has not been re-ported in association with conivaptan, it is a risk, because conivaptan is a nonselective vasopressin-receptor antagonist; blocking the vasopressin V1 receptor induces vasodilation. Currently, conivap-tan use is limited to the treatment of hospitalized patients; it might be considered particularly for those who have moderate-to-severe hyponatremia and symptoms but not seizures, delirium, or coma, which would warrant the use of hypertonic saline. Infusion-site reactions are common (occurring in

39p6

Severe hyponatremia, serum sodiumlevel <125 mmol/liter

Moderate symptoms andunknown duration

Begin diagnostic evaluation(Consider CT or MRI)

Rule out extracellular-fluid volumedepletion

If present, use 0.9% salineinfusion alone

Begin correction0.9% Saline infusion with

furosemide, 20 mgAim for increase of 0.5–2 mmol/

liter/hr Stop when serum sodium level

rises by 8–10 mmol/liter withinthe first 24 hr

Consider conivaptanCheck serum sodium level every

4 hr and adjust infusion rate

Restrict fluid intakeEncourage dietary intake of salt

and protein if hyponatremiacontinues

Demeclocycline, 300–600 mgtwice daily, or urea, 15–60 g daily

Vasopressin-receptor antagonists(if available)

Rule out or address correctablefactors

Documented as acute(duration <48 hr) or coma, seizures

Begin correction immediately3% Saline infusion at 1–2 ml/kg

of body weight/hrFurosemide, 20 mg intravenouslyAim for increase of 2 mmol/

liter/hr in serum sodium levelCheck serum sodium level every

2 hr and adjust infusion rateStop when symptoms improveBegin diagnostic evaluation

Asymptomatic

Begin diagnostic evaluation

AUTHOR:

FIGURE:

JOB: ISSUE:

4-CH/T

RETAKEICM

CASE

EMail LineH/TCombo

Revised

REG F

Enon

1st2nd3rd

Ellison

2 of 2

05-17-07

ARTIST: ts

35620

Urinary sodium+urinary potassiumplasma sodium

Recommendedfluid intake

<500 ml/day

500–700 ml/day

>1

~1

<1 <1 liter/day

Figure 2. Algorithm for the Treatment of Hyponatremia Associated with SIAD.

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Natriumsubstitution bei SIADHNotwendige Liter einer NaCl-Infusion 1,5% (= Isotonische NaCl-Infusion 0,9% + 6 Amp. 10% NaCl á 10ml) zum Ausgleich eines Natriummangels bis zu einem Ziel-Na 140 mmol/l. Unter Substitution müssen die Natriumwerte zunächst 2-stündlich bestimmt werden und der Anstieg darf nicht über 0,5 mmol/l/h liegen! Männer Frauen Gewicht 50kg 70kg 90kg 50kg 70kg 90kg S-Na 125 1,7l 2,5l 3,2l 1,5l 2,1l 2,7l S-Na 120 2,3l 3,3l 4,3l 1,9l 2,7l 3,5l S-Na 115 2,9l 4,1l 5,3l 2,5l 3,5l 4,4l S-Na 110 3,5l 4,9l 6,3l 2,9l 4,1l 5,3l S-Na 105 4,1l 5,8l 7,4l 3,5l 4,8l 6,2l S-Na 100 4,7l 6,6l 8,5l 3,9l 5,5l 7,1l

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Syndrom der unkorrekten ADH-Sekretion (SIADH)

NEJM 2007;356:20

Clinical Pr actice

n engl j med 356;20 www.nejm.org may 17, 2007 2069

as many as 50% of patients, according to the pack-age insert for the drug), and its metabolism by the 3A4 isoform of cytochrome P450 (CYP3A4) can re-sult in drug interactions.

Although not yet clinically available, oral vaso-pressin-receptor antagonists that are selective for the vasopressin V2 receptor have been developed (Table 3). In two randomized, controlled trials of tolvaptan, serum sodium levels rose from a mean baseline level of 129 mmol per liter within 24 hours after the administration of the first dose of active drug and remained significantly higher (by 4 mmol per liter) than the levels in the placebo group (P<0.001) 30 days after the start of treat-ment.4 The tolvaptan group also had a clinically and statistically significant improvement in the mental component of the Medical Outcomes Study 12-item Short-Form General Health Survey36 (P = 0.02). In an open-label study, in patients with SIAD, another long-acting oral vasopressin-recep-tor antagonist, satavaptan (Sanofi-Aventis), main-tained serum sodium levels within the normal range (135 to 147 mmol per liter) at 1 year, without major side effects.37 The appropriate clinical role of the vasopressin-receptor antagonists remains to be defined.

One theoretical concern is that vasopressin-receptor antagonists might increase serum sodium levels too rapidly, putting patients at risk for os-motic demyelination. To date, this complication has not been reported, but trials of these agents have involved very close monitoring and minimal or no water restriction. These agents frequently cause dry mouth and thirst,36 which stimulate water intake, slowing the rise in serum sodium levels. Use of these agents in practice would re-quire similarly close monitoring of serum sodium levels.

A r e a s of Uncerta in t y

Optimal Strategies for Correcting Serum Sodium Levels

There are no data from randomized trials to guide optimal strategies for correction of serum sodium levels in patients with either acute or chronic hypo-natremia, and the relative risks of osmotic demy-elination and of hyponatremic encephalopathy continue to be debated.24 Acute symptomatic hy-ponatremia is routinely treated with hypertonic sa-line; many authorities recommend concomitant use of furosemide. Although some suggest that complete correction may be safe,33 others note that osmotic demyelination might occur even in this setting25 and recommend that correction with 3% saline during the first 24 hours be limited to 8 to 12 mmol per liter.9 In patients with seizure and coma, it is reasonable to use 3% saline at a rate of 1 to 2 mmol per liter per hour, even if the hypo-natremia has been present for longer than 24 hours, keeping the maximal correction to 8 to 12 mmol per liter per day.1,9,10,25,27,33 When milder symptoms are present, correction is generally slower (rate, 0.5 mmol per liter per hour)9; some authorities avoid the use of 3% saline in this setting.

The best method for determining an initial rate for hypertonic saline infusion is also controver-sial38; Table 4 presents some suggested strategies. The traditional approach is to estimate a sodium deficit and is not physiologically based, because SIAD is characterized by a water excess, rather than a sodium deficit. Another approach is to cal-culate the effect of 1 liter of an infusate on the serum sodium level, then estimate the volume needed for infusion; this formula predicts actual changes in the serum sodium level reasonably well,38 but it involves two calculations, which can

Table 3. Vasopressin-Receptor Antagonists.*

Drug Dose of DrugVasopressin

ReceptorRoute of

AdministrationUrinary Volume

Urinary Osmolality

Sodium Excretion over 24 hr

Conivaptan (Vaprisol, Astellas Pharma)† 20–40 mg daily V1A and V2 Intravenous Increased Decreased �No change

Tolvaptan (Otsuka) 15–60 mg daily V2 Oral Increased Decreased �No change

Lixivaptan (CardioKine) 100–200 mg V2 Oral Increased Decreased �No change with low dose; increased with high dose

Satavaptan (Sanofi-Aventis) 12.5–50 mg V2 Oral Increased Decreased �No change

* Data are adapted from Lee et al.35

† Conivaptan was approved for clinical use in 2005 by the Food and Drug Administration.

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Vorgehen bei Hyponatriämie

Nat Rev Nephrol 2013;9:37

NATURE REVIEWS | NEPHROLOGY VOLUME 9 | JANUARY 2013 | 43

the results were compared to a reference standard of an experienced endocrinologist with expertise in hypo-natraemia. The inexperienced physicians using the algorithm had an overall agreement with the reference standard of 86%, whereas the senior intensive care phy-sicians not using the algorithm only had a 48% agree-ment with the reference standard. So, although such algorithms do have limitations in guiding the diagnos-tic approach to hyponatraemia, they do seem to be of considerable assistance to the practicing physician.

Hyponatraemia in strenuous exercise Another cause of acute hyponatraemia is endurance exercise such as marathons, ultra-marathons and tri-athlons.116–118 Among nonelite marathon runners, the reported incidence of hyponatraemia has varied from 3% to 13%.43–46 Hyponatraemia has been shown to cor-relate with increased weight gain during the race.117 Hyponatraemia in this setting can be associated with severe symptoms of cerebral oedema, convulsions, and even death.119 Evidence exists to indicate that the non-osmotic release of AVP occurs during marathons.120 This finding was demonstrated by directly measuring levels of AVP or copeptin120,121 in hyponatraemic marathon runners. Consumption of water in excess of insensible

losses (such as sweating and hyperventilation), in the presence of the nonosmotic stimulation of vaso pressin, explains why weight gain during the marathon runs correlates with hyponatraemia.43 In addition to exces-sive water intake and weight gain during the race, other risk factors for exercise-related hyponatraemia are female gender, a body mass index (BMI) of less than 20 kg/m2, and a slow race time.43

Hyponatraemia-induced encephalopathy due to strenuous exercise has been found to be associated with noncardiogenic pulmonary oedema. The noncardiogenic pulmonary oedema is a result of increased intracranial pressure, and resolution of brain oedema resolves the pulmonary oedema.122 The condition can be successfully treated with hypertonic saline.122

Hyponatraemia in cancer patients Hyponatraemia is one of the most common electro-lyte disorders associated with tumour-related condi-tions.123 Approximately 14% of cases of hyponatraemia in medical inpatients is associated with an underlying tumour-related condition.124 Such hyponatraemia usually accompanies, but can also precede, the diagnosis of the tumour.38 Hyponatraemia in patients with tumours may also be related to medical125 or surgical treatment.126

Hyponatraemia

Sodium and water de!cit Water excess Sodium and water excess

HypovolaemiaTotal body water

Total body sodium

Isotonic saline

Renal lossesDiuretic excess

Mineralocorticoidde!ciency

Salt-losing nephritisBicarbonaturia

Renal tubular acidosisKetonuria

Osmotic diuresis (glucose, urea, mannitol)

Extrarenal lossesVomitingDiarrhoea

“Third-space” burnsPancreatitis

Traumatized muscle

EuvolaemiaTotal body water

Normal total body sodium

HypervolaemiaTotal body water

Total body sodium

Water restriction Sodium and water restriction

Glucocorticoid de!ciencyHypothyroidism

PainPsychiatric disorders

DrugsSIADH

Nephrotic syndromeCardiac failure

Cirrhosis

Acute kidney injuryChronic renal failure

Urinary sodiumconcentration>30 mmol/l

Urinary sodiumconcentration<20 mmol/l

Urinary sodiumconcentration>30 mmol/l

Urinary sodiumconcentration<20 mmol/l

Urinary sodiumconcentration>30 mmol/l

Normonatraemia

Figure 2 | Diagnostic and therapeutic approach to the hypovolaemic, euvolaemic, and hypervolaemic patient with hyponatraemia. Urinary sodium concentrations in between 20 mmol/l and 30 mmol/l represent a ‘grey zone’. Abbreviation: SIADH, syndrome of inappropriate secretion of antidiuretic hormone. Permission obtained from American Society of Nephrology © Schrier, R. W. J. Am. Soc. Nephrol. 17, 1820–1832 (2006).1

REVIEWS

© 2013 Macmillan Publishers Limited. All rights reserved

Freitag, 20. September 13

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Agenda•Hypercalcämie

•Hyper- / Hyponatriämie- SIADH- Diarrhoen- Diabetes insipidus

•Hyper- / Hypokaliämie- Tumor-Lyse-Syndrom

•Hypomagnesiämie

Freitag, 20. September 13

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K+-Haushalt (70 kg schwerer Patient, 60 % H20)

K

Zellen (28 l H2O) EZR (14 l H2O)K = 140 mmol/l (98 %)

Na,K-ATPase

Na

K = 4-5 mmol/l (2 %)

Transzellulärer Shift Renale Exkretion

InsulinEpinephrinPlasma-K+

Plasma-K+

Distal-tubuläre K+-Sekretion (Aldo.)

80 mmol K+/Tag

Freitag, 20. September 13

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Ursachen für eine Hpokaliämie bei Krebs ITable 7. Cancer-specific causes of hypokalemia

Cause Mechanism Reference

PseudohypokalemiaMarked leukocytosis Transcellular shift into

white blood cellsduring blood storageat room temperature,typically in acutemyeloid leukemia

Polak R, Huisman A, Sikma MA, Kersting S:Spurious hypokalaemia and hypophosphataemiadue to extreme hyperleukocytosis in a patientwith a haematological malignancy. Ann ClinBiochem 47: 179–181, 2010

RedistributionGranulocyte-macrophagecolony-stimulating factor

Rapid uptake of potassiumduring robust myelopoiesis

Viens P, Thyss A, Garnier G, Ayela P, Lagrange M,Schneider M: GM-CSF treatment and hypokalemia.Ann Intern Med 111: 263, 1989

Nonrenal lossesVillous adenoma Chronic watery diarrhea Ashman N, Yaqoob M: Metabolic acidosis,

hypokalaemia and acute renal failure with anormal urine output. Nephrol Dial Transplant15: 1083–1085, 2000

Vasoactive intestinalpeptide-oma

Chronic watery diarrhea, maybe part of multipleendocrine neoplasia type 1

Kibria R, Ahmed S, Ali SA, Barde CJ: Hypokalemicrhabdomyolysis due to watery diarrhea,hypokalemia, achlorhydria (WDHA) syndromecaused by vipoma. South Med J 102: 761–764,2009

Zollinger-Ellisonsyndrome

Gastrin-induced profusediarrhea

Meko JB, Norton JA: Management of patients withZollinger-Ellison syndrome. Annu Rev Med 46:395–411, 1995

Renal lossesACTH secretingtumor

Mineralocorticoid excessinduces potassium secretion

Izzedine H, Besse B, Lazareth A, Bourry EF,Soria JC: Hypokalemia, metabolic alkalosis, andhypertension in a lung cancer patient. Kidney Int76: 115–120, 2009

Lysozymuria inmyelomonocyticleukemia

Lysozyme-induced tubularinjury

Perazella MA, Eisen RN, Frederick WG, Brown E:Renal failure and severe hypokalemia associatedwith acute myelomonocytic leukemia. Am J KidneyDis 22: 462–467, 1993

Anti-EGF receptorantibodies (Cetuximab,Panitumumab)

Inhibition of distal tubulemagnesium uptake causinghypomagnesemia-inducedhypokalemia

Groenestege WM, Thébault S, van der Wijst J, vanden Berg D, Janssen R, Tejpar S, van den Heuvel LP,van Cutsem E, Hoenderop JG, Knoers NV, Bindels RJ:Impaired basolateral sorting of pro-EGF causesisolated recessive renal hypomagnesemia. J Clin Invest117: 2260–2267, 2007

Ifosfamide Proximal tubule injury andpartial Fanconi syndrome

Glezerman IG, Latcha S: Fluid and electrolyte disordersassociated with cancer. In: Cancer and the Kidney:The Frontier of Nephrology and Oncology, edited byCohen EP, Oxford, UK, Oxford University Press, 2011,pp 21–52

Cisplatin Hypomagnesemia-inducedhypokalemia

Light chains Proximal tubule injury andpartial Fanconi syndrome

Ma CX, Lacy MQ, Rompala JF, Dispenzieri A,Rajkumar SV, Greipp PR, Fonseca R, Kyle RA,Gertz MA: Acquired Fanconi syndrome is an indolentdisorder in the absence of overt multiple myeloma.Blood 104: 40–42, 2004

56 Nephrology Self-Assessment Program - Vol 12, No 1, January 2013

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Ursachen für eine Hpokaliämie bei Krebs IITable 7. Cancer-specific causes of hypokalemia

Cause Mechanism Reference

PseudohypokalemiaMarked leukocytosis Transcellular shift into

white blood cellsduring blood storageat room temperature,typically in acutemyeloid leukemia

Polak R, Huisman A, Sikma MA, Kersting S:Spurious hypokalaemia and hypophosphataemiadue to extreme hyperleukocytosis in a patientwith a haematological malignancy. Ann ClinBiochem 47: 179–181, 2010

RedistributionGranulocyte-macrophagecolony-stimulating factor

Rapid uptake of potassiumduring robust myelopoiesis

Viens P, Thyss A, Garnier G, Ayela P, Lagrange M,Schneider M: GM-CSF treatment and hypokalemia.Ann Intern Med 111: 263, 1989

Nonrenal lossesVillous adenoma Chronic watery diarrhea Ashman N, Yaqoob M: Metabolic acidosis,

hypokalaemia and acute renal failure with anormal urine output. Nephrol Dial Transplant15: 1083–1085, 2000

Vasoactive intestinalpeptide-oma

Chronic watery diarrhea, maybe part of multipleendocrine neoplasia type 1

Kibria R, Ahmed S, Ali SA, Barde CJ: Hypokalemicrhabdomyolysis due to watery diarrhea,hypokalemia, achlorhydria (WDHA) syndromecaused by vipoma. South Med J 102: 761–764,2009

Zollinger-Ellisonsyndrome

Gastrin-induced profusediarrhea

Meko JB, Norton JA: Management of patients withZollinger-Ellison syndrome. Annu Rev Med 46:395–411, 1995

Renal lossesACTH secretingtumor

Mineralocorticoid excessinduces potassium secretion

Izzedine H, Besse B, Lazareth A, Bourry EF,Soria JC: Hypokalemia, metabolic alkalosis, andhypertension in a lung cancer patient. Kidney Int76: 115–120, 2009

Lysozymuria inmyelomonocyticleukemia

Lysozyme-induced tubularinjury

Perazella MA, Eisen RN, Frederick WG, Brown E:Renal failure and severe hypokalemia associatedwith acute myelomonocytic leukemia. Am J KidneyDis 22: 462–467, 1993

Anti-EGF receptorantibodies (Cetuximab,Panitumumab)

Inhibition of distal tubulemagnesium uptake causinghypomagnesemia-inducedhypokalemia

Groenestege WM, Thébault S, van der Wijst J, vanden Berg D, Janssen R, Tejpar S, van den Heuvel LP,van Cutsem E, Hoenderop JG, Knoers NV, Bindels RJ:Impaired basolateral sorting of pro-EGF causesisolated recessive renal hypomagnesemia. J Clin Invest117: 2260–2267, 2007

Ifosfamide Proximal tubule injury andpartial Fanconi syndrome

Glezerman IG, Latcha S: Fluid and electrolyte disordersassociated with cancer. In: Cancer and the Kidney:The Frontier of Nephrology and Oncology, edited byCohen EP, Oxford, UK, Oxford University Press, 2011,pp 21–52

Cisplatin Hypomagnesemia-inducedhypokalemia

Light chains Proximal tubule injury andpartial Fanconi syndrome

Ma CX, Lacy MQ, Rompala JF, Dispenzieri A,Rajkumar SV, Greipp PR, Fonseca R, Kyle RA,Gertz MA: Acquired Fanconi syndrome is an indolentdisorder in the absence of overt multiple myeloma.Blood 104: 40–42, 2004

56 Nephrology Self-Assessment Program - Vol 12, No 1, January 2013

Neph SAP 2013;12:56

Table 7. Cancer-specific causes of hypokalemia

Cause Mechanism Reference

PseudohypokalemiaMarked leukocytosis Transcellular shift into

white blood cellsduring blood storageat room temperature,typically in acutemyeloid leukemia

Polak R, Huisman A, Sikma MA, Kersting S:Spurious hypokalaemia and hypophosphataemiadue to extreme hyperleukocytosis in a patientwith a haematological malignancy. Ann ClinBiochem 47: 179–181, 2010

RedistributionGranulocyte-macrophagecolony-stimulating factor

Rapid uptake of potassiumduring robust myelopoiesis

Viens P, Thyss A, Garnier G, Ayela P, Lagrange M,Schneider M: GM-CSF treatment and hypokalemia.Ann Intern Med 111: 263, 1989

Nonrenal lossesVillous adenoma Chronic watery diarrhea Ashman N, Yaqoob M: Metabolic acidosis,

hypokalaemia and acute renal failure with anormal urine output. Nephrol Dial Transplant15: 1083–1085, 2000

Vasoactive intestinalpeptide-oma

Chronic watery diarrhea, maybe part of multipleendocrine neoplasia type 1

Kibria R, Ahmed S, Ali SA, Barde CJ: Hypokalemicrhabdomyolysis due to watery diarrhea,hypokalemia, achlorhydria (WDHA) syndromecaused by vipoma. South Med J 102: 761–764,2009

Zollinger-Ellisonsyndrome

Gastrin-induced profusediarrhea

Meko JB, Norton JA: Management of patients withZollinger-Ellison syndrome. Annu Rev Med 46:395–411, 1995

Renal lossesACTH secretingtumor

Mineralocorticoid excessinduces potassium secretion

Izzedine H, Besse B, Lazareth A, Bourry EF,Soria JC: Hypokalemia, metabolic alkalosis, andhypertension in a lung cancer patient. Kidney Int76: 115–120, 2009

Lysozymuria inmyelomonocyticleukemia

Lysozyme-induced tubularinjury

Perazella MA, Eisen RN, Frederick WG, Brown E:Renal failure and severe hypokalemia associatedwith acute myelomonocytic leukemia. Am J KidneyDis 22: 462–467, 1993

Anti-EGF receptorantibodies (Cetuximab,Panitumumab)

Inhibition of distal tubulemagnesium uptake causinghypomagnesemia-inducedhypokalemia

Groenestege WM, Thébault S, van der Wijst J, vanden Berg D, Janssen R, Tejpar S, van den Heuvel LP,van Cutsem E, Hoenderop JG, Knoers NV, Bindels RJ:Impaired basolateral sorting of pro-EGF causesisolated recessive renal hypomagnesemia. J Clin Invest117: 2260–2267, 2007

Ifosfamide Proximal tubule injury andpartial Fanconi syndrome

Glezerman IG, Latcha S: Fluid and electrolyte disordersassociated with cancer. In: Cancer and the Kidney:The Frontier of Nephrology and Oncology, edited byCohen EP, Oxford, UK, Oxford University Press, 2011,pp 21–52

Cisplatin Hypomagnesemia-inducedhypokalemia

Light chains Proximal tubule injury andpartial Fanconi syndrome

Ma CX, Lacy MQ, Rompala JF, Dispenzieri A,Rajkumar SV, Greipp PR, Fonseca R, Kyle RA,Gertz MA: Acquired Fanconi syndrome is an indolentdisorder in the absence of overt multiple myeloma.Blood 104: 40–42, 2004

56 Nephrology Self-Assessment Program - Vol 12, No 1, January 2013

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Tumor-Lyse-Syndrom: Diagnosekriterien

primates lack this enzyme, making less soluble uric acidthe final end product of adenine and guanine metabolism.Uric acid impairs kidney function via crystal-dependent

and crystal-independent mechanisms, with crystal-dependentprocesses generally considered to be more important (17).An acid urine pH favors production of poorly soluble uricacid over the more soluble urate, increasing the risk forprecipitation of intratubular uric acid crystals. Congerand Falk evaluated uric acid nephropathy in a rat model,demonstrating marked increases in proximal and distaltubular pressures in rats given exogenous uric acid loadsalong with a uricase inhibitor (18). In addition, peritubularcapillary pressures were increased two-fold, and vascular

resistance beyond the peritubular capillaries was in-creased by more than three-fold. These findings demon-strated that acute uric acid nephropathy is related notonly to tubular obstruction but also to marked hemody-namic changes in multiple renal vessels. Even at solubleconcentrations, uric acid may predispose to renal ische-mia. Uric acid can scavenge bioavailable nitric oxide, lead-ing to vasoconstriction (19). Vascular smooth muscle cellsexposed to dissolved uric acid release the inflammatorycytokines monocyte chemotactic protein-1, TNF-a, andother vasoactive mediators, leading to chemotaxis ofwhite cells and further inflammatory injury (20). Finally,uric acid may inhibit proximal tubule cell proliferation,prolonging the duration of kidney injury (21).

PotassiumThe intracellular concentration of potassium is as high

120 mEq/L (22,23). In the case of hematologic malignan-cies, much of the 2.6 kg of bone marrow in the averagehuman may be replaced by malignant cells. The rapid lib-eration of potassium into the extracellular fluid will lead tosevere hyperkalemia if it exceeds the normal homeostaticuptake of potassium into liver and muscle cells. In thesetting of CKD or AKI, renal clearance of potassium isreduced, increasing the severity of hyperkalemia (24). Hy-perkalemia can lead to weakness and death via cardiacarrhythmia.

Phosphorous and CalciumTLS can rapidly liberate a large volume of intracellular

phosphate. Hyperphosphatemia is less common in cases ofspontaneous TLS than in typical TLS, presumably becauseof the rapid uptake of extracellular phosphate by the remain-ing highly active residual tumor cells in the former condition(25–28). Hyperphosphatemia in patients with TLS will befurther exacerbated by any associated AKI.

Figure 1. | Metabolism of purine nucleic acids. In humans and apes, the end product is uric acid. Allopurinol inhibits metabolism of xanthineto uric acid. Recombinant urate oxidase catalyzes themetabolism of uric acid into themore soluble allantoin (55,94,95). Solubilities at a pH of7 are shown in parentheses.

Table 1. Cairo-Bishop classification of tumor lysis syndrome inadults

Laboratory TLS Clinical TLS

Uric acid: $8.0mg/dl

AKI (defined as creatinine.1.53 the upper limitof normal for patientage and sex)

Potassium: $6.0mEq/dl

Cardiac arrhythmia

Phosphorus:$4.6mg/dl

Seizure, tetany, or othersymptomatic hypocalcemia

Calcium: #7.0mg/dl

Patients must meet more than two of four laboratory criteria inthe same 24-hour period within 3 days before to 7 days afterchemotherapy initiation. A .25% increase from “baseline”laboratory values is also acceptable (13). Other causes of AKI(e.g., nephrotoxin exposure, obstruction) should be excluded.TLS, tumor lysis syndrome.

Clin J Am Soc Nephrol 7: 1730–1739, October, 2012 Tumor Lysis Syndrome, Wilson and Berns 1731

CJASN 2012;7:1730

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Tumor-Lyse-Syndrom: Pathophysiologie

NEJM 2011;364:19

current concepts

n engl j med 364;19 nejm.org may 12, 2011 1847

mia.5-8,29-32 Characteristics of patients that confer high risk include preexisting chronic renal insuf-ficiency, oliguria, dehydration, hypotension, and acidic urine.

The adequacy of f luid management affects both the development and the severity of the tu-mor lysis syndrome. Thus, disastrous cases of the tumor lysis syndrome occurred in patients with

Lysis of cancer cells

DNAase breaks down DNA, releasing purines

Adenosine

DNA

Guanosine Hypotension Inflammation

Inosine

Hypoxanthine

Xanthine

Phosphate Potassium

Acute kidney injury

Phosphate Potassium Cytokines

Uric acid

Urinary excretion AccumulationNo tumor lysis syndrome

Tumor lysis syndrome

Allantoin

Allopurinol

Rasburicase

Xanthine oxidase

Xanthine oxidase

Guanine

A

C

B

D

Release of cellular contents

1

CampionHastings

4/25/11

AUTHOR PLEASE NOTE:Figure has been redrawn and type has been reset

Please check carefully

AuthorFig #

Title

ME

DEArtist

Issue date

COLOR FIGURE

Draft 12Howard

Knoper

5/12/11

Figure 1. Lysis of Tumor Cells and the Release of DNA, Phosphate, Potassium, and Cytokines.

The graduated cylinders shown in Panel A contain leukemic cells removed by leukapheresis from a patient with T-cell acute lymphoblastic leukemia and hyperleukocytosis (white-cell count, 365,000 per cubic millimeter). Each cylinder con-tains straw-colored clear plasma at the top, a thick layer of white leukemic cells in the middle, and a thin layer of red cells at the bottom. The highly cellular nature of Burkitt’s lymphoma is evident in Panel B (Burkitt’s lymphoma of the appendix, hematoxylin and eosin). Lysis of cancer cells (Panel C) releases DNA, phosphate, potassium, and cytokines. DNA released from the lysed cells is metabolized into adenosine and guanosine, both of which are converted into xan-thine. Xanthine is then oxidized by xanthine oxidase, leading to the production of uric acid, which is excreted by the kid-neys. When the accumulation of phosphate, potassium, xanthine, or uric acid is more rapid than excretion, the tumor lysis syndrome develops. Cytokines cause hypotension, inflammation, and acute kidney injury, which increase the risk for the tumor lysis syndrome. The bidirectional dashed line between acute kidney injury and tumor lysis syndrome indi-cates that acute kidney injury increases the risk of the tumor lysis syndrome by reducing the ability of the kidneys to excrete uric acid, xanthine, phosphate, and potassium. By the same token, development of the tumor lysis syndrome can cause acute kidney injury by renal precipitation of uric acid, xanthine, and calcium phosphate crystals and by crystal-independent mechanisms. Allopurinol inhibits xanthine oxidase (Panel D) and prevents the conversion of hypoxanthine and xanthine into uric acid but does not remove existing uric acid. In contrast, rasburicase removes uric acid by enzymati-cally degrading it into allantoin, a highly soluble product that has no known adverse effects on health.

The New England Journal of Medicine Downloaded from nejm.org by MARK DOMINIK ALSCHER on September 7, 2013. For personal use only. No other uses without permission.

Copyright © 2011 Massachusetts Medical Society. All rights reserved.

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Tumor-Lyse-Syndrom: Kristalle

NEJM 2011;364:19

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 364;19 nejm.org may 12, 20111848

nonhematologic cancer who received effective anticancer treatment but no intravenous fluids or monitoring because the tumor lysis syndrome was not anticipated.5,32 In contrast, in many coun-tries, patients with a bulky Burkitt’s lymphoma who have a high potential for lysis have a low risk of clinical tumor lysis syndrome because they routinely receive aggressive treatment with hydra-tion and rasburicase, a recombinant urate oxidase enzyme that is a highly effective uricolytic agent (Table 1 in the Supplementary Appendix). Chil-dren with Burkitt’s lymphoma who received ras-buricase were a fifth as likely to undergo dialysis as those who received allopurinol, illustrating the

dramatic difference that supportive care can make, even when other risk factors for the tumor lysis syndrome are the same.33 This was seen in the 8-year-old boy in the vignette.

R isk a ssessmen t

Acute kidney injury is associated with high mor-bidity and mortality,34 and its prevention requires an awareness of the patient’s a priori risk of the tumor lysis syndrome and careful monitoring for early signs of it. Models that predict the risk of the tumor lysis syndrome have been developed for adults with acute myeloid leukemia35,36 and chil-

A B C

ED

2µm 100 µm

Figure 2. Crystals of Uric Acid, Calcium Phosphate, and Calcium Oxalate.

Crystallization of uric acid and calcium phosphate are the primary means of renal damage in the tumor lysis syndrome. The presence of crystals of one solute can promote crystallization of the other solutes. A scanning electron micrograph (Panel A) shows large uric acid crystals (arrowhead), which served as seeds for the formation of calcium oxalate crystals (arrows). Reprinted from Bouropoulos et al.21 with the permission of the publisher. In Panel B, a scanning electron micro-graph shows numerous small calcium oxalate crystals (arrows) formed on larger uric acid crystals (arrowheads). Reprinted from Grases et al.22 with the permission of the publisher. The kidney shown in Panel C was examined at the autopsy of a 4-year-old boy who had high-grade non-Hodgkin’s lymphoma and died of acute tumor lysis syndrome. Linear yellow streaks of precipitated uric acid in the renal medulla are shown in the left panel (arrows); a single tubule containing a uric acid crystal (arrowhead) is shown in the right panel. Reprinted from Howard et al.13 with the permission of the publisher. In Panel D, in the normal kidney on the left, the medullary pyramids are visible deep in the kidney (arrow-heads) and are surrounded by the renal cortex (arrows), which is darker than the collecting system and adjacent liver. The ultrasonographic image on the right shows a kidney from a patient with the tumor lysis syndrome, in which there is loss of the normal corticomedullary differentiation (arrowheads) and poor visualization of the renal pyramids. The brightness is similar to that of the adjacent liver (arrows), and the kidney is abnormally enlarged. Soft-tissue calcification of the dorsum of the distal forearm (Panel E) occurred in a 15-year-old boy with acute lymphoblastic leukemia and an initial white-cell count of 283,000 per cubic millimeter in whom tumor lysis syndrome, hyperphosphatemia, and symp-tomatic hypocalcemia developed. Several weeks after the treatment of hypocalcemia with multiple doses of intravenous calcium carbonate administered by means of a peripheral intravenous catheter in the dorsum of the hand, ectopic calci-fication was confirmed radiographically (arrows). Reprinted from Howard et al.13 with the permission of the publisher.

The New England Journal of Medicine Downloaded from nejm.org by MARK DOMINIK ALSCHER on September 7, 2013. For personal use only. No other uses without permission.

Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Freitag, 20. September 13

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Tumor-Lyse-Syndrom: Inzidenz

CJASN 2012;7:1730

The primary toxicity of hyperphosphatemia is the sec-ondary hypocalcemia that results from chelation of calciumby phosphate anions. Hypocalcemia can lead to cardiac ar-rhythmias, seizures, tetany, and death. Interestingly, pro-longed hypocalcemia has been described even after resolutionof hyperphosphatemia in TLS, presumably due to a deficiencyof 1,25-vitamin D (29).The precipitation of calcium-phosphate crystals within the

renal parenchyma, nephrocalcinosis, may also play a signif-icant role in the decreased GFR seen in this condition (30,31).The observation that TLS can cause AKI even in animalsthat are able to metabolize uric acid to allantoin points to apotentially important role for hyperphosphatemia in thepathogenesis of TLS-associated AKI (32).

EpidemiologyThe incidence of TLS varies widely, ranging from spo-

radic case reports in certain solid malignancies to the26.4% incidence described in high-grade B-cell acutelymphoblastic leukemia (33). Table 2 describes relativerisk for TLS in various hematologic and nonhematologicmalignancies. The highest risk for TLS is seen in large-volume, highly metabolic malignancies, such as B-cellacute lymphoblastic leukemia and Burkitt lymphoma,whereas solid tumors and slow-growing hematologicmalignancies (such as multiple myeloma) carry lowerrisks. Most, although not all, cases of TLS with multiplemyeloma have followed treatment with bortezomib (34).Spontaneous TLS is typically observed in high-grade he-matologic malignancies.

TLS in Solid TumorsThe true incidence of TLS in solid malignancies is not

well defined, perhaps because of a lack of significant sur-veillance for this complication of treatment. Case reportsexist across a variety of solid tumors, however, includingsmall-cell carcinoma, germ-cell tumors, neuroblastoma,

medulloblastoma, hepatoblastoma, breast carcinoma, non–small-cell lung cancer, vulvar carcinoma, thymoma, ovariancarcinoma, colorectal carcinoma, gastric carcinoma, mela-noma, hepatocellular carcinoma, and sarcoma (35).Although a recommendation to include routine measure-ment of serum uric acid, potassium, calcium, or phospho-rus during treatment of solid malignancies would bepremature, nephrologists should certainly consider this syn-drome in any differential diagnosis of AKI in a patient with asolid malignancy.

Identification of Individuals at RiskIn addition to type of malignancy, several other risk

factors for the development of TLS have been identified. Astudy at our institution retrospectively examined 194 pa-tients with acute myeloid leukemia, of whom 19 developedclinical or laboratory TLS. In univariate analysis, a strongassociation was demonstrated between baseline creatininelevel and the development of TLS {odds ratio (OR), 31.2(95% confidence interval [CI], 6.1–160.0); per mg/dl creat-inine}. Other predictors included pretreatment uric acidlevel (OR, 30.16 [95% CI, 6.12–148.63]), lactate dehydroge-nase (OR, 2.9 [95% CI, 1.6–5.2]), and male sex (OR, 4.8[95% CI, 1.5–15.0]) (36). Similar results have been seenacross a variety of tumor types (33,37–39). Table 3 summa-rizes these additional risks.

Effect of Kidney FunctionA reduced GFR compromises the ability to excrete ex-

cess solutes, potentially leading to elevated serum levelsof phosphorus and uric acid, which may further compro-mise renal function. The association between renal func-tion and development of TLS is strong and has been seenacross a variety of populations and tumor subtypes. Aprospective study of 1192 patients with non-Hodgkinlymphoma (of whom 63 developed TLS) revealed pre-existing renal dysfunction in 68% of those affected; however,

Table 2. Incidence of tumor lysis syndrome in various malignancies

Malignancy (Reference) Incidence (%) Risk

HematologicBurkitt lymphoma (33) 14.9 HighB cell ALL (33) 26.4 Highdiffuse large-B cell lymphoma (87) 6 IntermediateALL 5.2–23 May vary by WBC count,

with .100,000 cells/mm3

being highest riskAML: WBC count .75,000 cells/mm3 (37) 18 HighAML: WBC count 25,000–75,000 cells/mm3 (37) 6 IntermediateAML: WBC count ,25,000 cells/mm3 (37) 1 Lowchronic lymhocytic leukemia (88) 0.33 Low (higher with

WBC .100,000 cells/mm3)chronic myeloid leukemia (89) Case reports only Lowmultiple myeloma (90) 1 Low

Nonhematologicsolid tumors (35) Unknown Low

Many studies do not differentiate between laboratory and clinical tumor lysis syndrome. Risk category as per Cairo et al. (51). ALL,acute lymphocytic leukemia; AML, acute myeloid leukemia; WBC, white blood cell.

1732 Clinical Journal of the American Society of Nephrology

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Tumor-Lyse-Syndrom: Prädiktoren

CJASN 2012;7:1730

ruling out antecedent low-grade TLS was not possible inthis population (40). Among a group of 772 patients with anew diagnosis of acute myeloid leukemia, pretreatmentcreatinine concentration was strongly predictive of the de-velopment of clinical and laboratory TLS. Patients withpretreatment creatinine concentrations .1.4 mg/dl had10.7 times the odds of developing TLS (95% CI, 4.5–25.1)compared with those under that threshold (37). Furtherstudies using estimated GFR rather than creatinine concen-tration will help to better elucidate differences in riskamong varying degrees of kidney function while minimiz-ing potential confounding by sex and race.

Value of Urine Uric Acid-to-Creatinine RatioKelton et al. documented an increased spot urine uric

acid-to-creatinine ratio in 5 patients with acute uric acid ne-phropathy versus 27 patients with AKI from other causes. Acutoff of 1.0 was reported to be 100% sensitive and specific inthis small study (41). However, a subsequent study examin-ing the use of urine uric acid-to-creatinine ratio in non–malignancy-associated AKI demonstrated elevations.1.0 g/g in 12 of 23 patients (42). Thus, testing of urineuric acid and calculation of the urine uric acid-to-creatinineratio to predict the risk for or confirm the presence of TLS isnot recommended.

MortalityTLS is associated with higher tumor burden but also with

therapeutic efficacy, making inferences about TLS-specificmortality difficult. The presence of AKI, even after adjust-ment for other markers of severity of illness, seems to be apotent predictor of death in TLS (43). A recent retrospectivestudy of 63 patients with hematologic malignancies andTLS demonstrated a 6-month mortality rate of 21% in

the group without AKI and 66% in the group with AKI(44). This relationship persisted after multivariable adjust-ment, with AKI independently increasing the odds of 6-month mortality by 5.61 (95% CI, 1.64–54.66). PreventingAKI should be a primary therapeutic aim in patients at riskfor TLS.

Prophylaxis and TreatmentGoals of TLS therapy address the pathophysiologic

derangements discussed in the preceding section. Thus,therapy should be directed at increasing clearance of toxicintracellular contents. The choice of prophylactic therapydepends on the risk for TLS given specific patient and diseasecharacteristics (Table 4). We provide our algorithmic ap-proach to prophylaxis and therapy in Figure 2. In additionto specific therapies discussed in the following section,care should be taken also to avoid potentially nephrotoxicsubstances, including intravenous contrast and nonsteroidalanti-inflammatory agents, in patients at risk for TLS. Dis-continuation of angiotensin-converting enzyme inhibitorsand angiotensin-receptor blockers is also probably appro-priate in patients with TLS and AKI.

Volume ExpansionFluid resuscitation is a mainstay of therapy in TLS (45,46)

and is recommended as prophylaxis in any patient at riskof developing the syndrome (47). Crystalloid volume ex-pansion increases renal clearance of potassium, phosphate,and uric acid. In addition, distal delivery of sodium andchloride augment potassium secretion. Increased urineflow in the setting of volume expansion decreases boththe calcium-phosphate product in the urine as well asthe urine concentration of uric acid, potentially reducingobstructive crystal formation. Current consensus state-ments suggest fluid intake targets of 3 L/d using intrave-nous or oral therapy before the start of chemotherapy,provided pre-existing volume overload or oliguric AKIis not present (48).

DiureticsInsofar as diuretics enhance urinary flow, one would

expect decreased nephrotoxicity from urinary precipitationof uric acid or calcium-phosphate crystals. That said, thecytokine-mediated hemodynamic compromise seen in TLSmay be adversely affected by excessive volume depletiondue to diuretics (49). Because diuretics do not have a provenrole in reducing the incidence or severity of TLS, their routineuse is not recommended unless there are clinical signs orsymptoms of volume overload.

Table 3. Predictors of tumor lysis syndrome

Characteristic Risk Factor

Tumor burden Bulky lymphatic disease (.10 cm)Elevated lactate dehydrogenase(23 upper limit of normal)

Elevated white blood cell count(.25,000 cells/mm3)

Renal function Baseline creatinine. 1.4mg/dl (37)Baseline uric acid .7.5 mg/dlChemosensitivity Variable

Adapted from reference 91.

Table 4. Consensus recommendations for prophylaxis of tumor lysis syndrome (51)

Tumor Lysis Syndrome Risk Monitoring Volume Expansion Allopurinol Rasburicase

Low X XMedium X X XHigh X X X Xa

aContraindicated in patients with glucose-6-phosphate dehydrogenase deficiency.

Clin J Am Soc Nephrol 7: 1730–1739, October, 2012 Tumor Lysis Syndrome, Wilson and Berns 1733

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Tumor-Lyse-Syndrom: Behandlung I

primates lack this enzyme, making less soluble uric acidthe final end product of adenine and guanine metabolism.Uric acid impairs kidney function via crystal-dependent

and crystal-independent mechanisms, with crystal-dependentprocesses generally considered to be more important (17).An acid urine pH favors production of poorly soluble uricacid over the more soluble urate, increasing the risk forprecipitation of intratubular uric acid crystals. Congerand Falk evaluated uric acid nephropathy in a rat model,demonstrating marked increases in proximal and distaltubular pressures in rats given exogenous uric acid loadsalong with a uricase inhibitor (18). In addition, peritubularcapillary pressures were increased two-fold, and vascular

resistance beyond the peritubular capillaries was in-creased by more than three-fold. These findings demon-strated that acute uric acid nephropathy is related notonly to tubular obstruction but also to marked hemody-namic changes in multiple renal vessels. Even at solubleconcentrations, uric acid may predispose to renal ische-mia. Uric acid can scavenge bioavailable nitric oxide, lead-ing to vasoconstriction (19). Vascular smooth muscle cellsexposed to dissolved uric acid release the inflammatorycytokines monocyte chemotactic protein-1, TNF-a, andother vasoactive mediators, leading to chemotaxis ofwhite cells and further inflammatory injury (20). Finally,uric acid may inhibit proximal tubule cell proliferation,prolonging the duration of kidney injury (21).

PotassiumThe intracellular concentration of potassium is as high

120 mEq/L (22,23). In the case of hematologic malignan-cies, much of the 2.6 kg of bone marrow in the averagehuman may be replaced by malignant cells. The rapid lib-eration of potassium into the extracellular fluid will lead tosevere hyperkalemia if it exceeds the normal homeostaticuptake of potassium into liver and muscle cells. In thesetting of CKD or AKI, renal clearance of potassium isreduced, increasing the severity of hyperkalemia (24). Hy-perkalemia can lead to weakness and death via cardiacarrhythmia.

Phosphorous and CalciumTLS can rapidly liberate a large volume of intracellular

phosphate. Hyperphosphatemia is less common in cases ofspontaneous TLS than in typical TLS, presumably becauseof the rapid uptake of extracellular phosphate by the remain-ing highly active residual tumor cells in the former condition(25–28). Hyperphosphatemia in patients with TLS will befurther exacerbated by any associated AKI.

Figure 1. | Metabolism of purine nucleic acids. In humans and apes, the end product is uric acid. Allopurinol inhibits metabolism of xanthineto uric acid. Recombinant urate oxidase catalyzes themetabolism of uric acid into themore soluble allantoin (55,94,95). Solubilities at a pH of7 are shown in parentheses.

Table 1. Cairo-Bishop classification of tumor lysis syndrome inadults

Laboratory TLS Clinical TLS

Uric acid: $8.0mg/dl

AKI (defined as creatinine.1.53 the upper limitof normal for patientage and sex)

Potassium: $6.0mEq/dl

Cardiac arrhythmia

Phosphorus:$4.6mg/dl

Seizure, tetany, or othersymptomatic hypocalcemia

Calcium: #7.0mg/dl

Patients must meet more than two of four laboratory criteria inthe same 24-hour period within 3 days before to 7 days afterchemotherapy initiation. A .25% increase from “baseline”laboratory values is also acceptable (13). Other causes of AKI(e.g., nephrotoxin exposure, obstruction) should be excluded.TLS, tumor lysis syndrome.

Clin J Am Soc Nephrol 7: 1730–1739, October, 2012 Tumor Lysis Syndrome, Wilson and Berns 1731

CJASN 2012;7:1730

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Tumor-Lyse-Syndrom: Prophylaxe

CJASN 2012;7:1730

ruling out antecedent low-grade TLS was not possible inthis population (40). Among a group of 772 patients with anew diagnosis of acute myeloid leukemia, pretreatmentcreatinine concentration was strongly predictive of the de-velopment of clinical and laboratory TLS. Patients withpretreatment creatinine concentrations .1.4 mg/dl had10.7 times the odds of developing TLS (95% CI, 4.5–25.1)compared with those under that threshold (37). Furtherstudies using estimated GFR rather than creatinine concen-tration will help to better elucidate differences in riskamong varying degrees of kidney function while minimiz-ing potential confounding by sex and race.

Value of Urine Uric Acid-to-Creatinine RatioKelton et al. documented an increased spot urine uric

acid-to-creatinine ratio in 5 patients with acute uric acid ne-phropathy versus 27 patients with AKI from other causes. Acutoff of 1.0 was reported to be 100% sensitive and specific inthis small study (41). However, a subsequent study examin-ing the use of urine uric acid-to-creatinine ratio in non–malignancy-associated AKI demonstrated elevations.1.0 g/g in 12 of 23 patients (42). Thus, testing of urineuric acid and calculation of the urine uric acid-to-creatinineratio to predict the risk for or confirm the presence of TLS isnot recommended.

MortalityTLS is associated with higher tumor burden but also with

therapeutic efficacy, making inferences about TLS-specificmortality difficult. The presence of AKI, even after adjust-ment for other markers of severity of illness, seems to be apotent predictor of death in TLS (43). A recent retrospectivestudy of 63 patients with hematologic malignancies andTLS demonstrated a 6-month mortality rate of 21% in

the group without AKI and 66% in the group with AKI(44). This relationship persisted after multivariable adjust-ment, with AKI independently increasing the odds of 6-month mortality by 5.61 (95% CI, 1.64–54.66). PreventingAKI should be a primary therapeutic aim in patients at riskfor TLS.

Prophylaxis and TreatmentGoals of TLS therapy address the pathophysiologic

derangements discussed in the preceding section. Thus,therapy should be directed at increasing clearance of toxicintracellular contents. The choice of prophylactic therapydepends on the risk for TLS given specific patient and diseasecharacteristics (Table 4). We provide our algorithmic ap-proach to prophylaxis and therapy in Figure 2. In additionto specific therapies discussed in the following section,care should be taken also to avoid potentially nephrotoxicsubstances, including intravenous contrast and nonsteroidalanti-inflammatory agents, in patients at risk for TLS. Dis-continuation of angiotensin-converting enzyme inhibitorsand angiotensin-receptor blockers is also probably appro-priate in patients with TLS and AKI.

Volume ExpansionFluid resuscitation is a mainstay of therapy in TLS (45,46)

and is recommended as prophylaxis in any patient at riskof developing the syndrome (47). Crystalloid volume ex-pansion increases renal clearance of potassium, phosphate,and uric acid. In addition, distal delivery of sodium andchloride augment potassium secretion. Increased urineflow in the setting of volume expansion decreases boththe calcium-phosphate product in the urine as well asthe urine concentration of uric acid, potentially reducingobstructive crystal formation. Current consensus state-ments suggest fluid intake targets of 3 L/d using intrave-nous or oral therapy before the start of chemotherapy,provided pre-existing volume overload or oliguric AKIis not present (48).

DiureticsInsofar as diuretics enhance urinary flow, one would

expect decreased nephrotoxicity from urinary precipitationof uric acid or calcium-phosphate crystals. That said, thecytokine-mediated hemodynamic compromise seen in TLSmay be adversely affected by excessive volume depletiondue to diuretics (49). Because diuretics do not have a provenrole in reducing the incidence or severity of TLS, their routineuse is not recommended unless there are clinical signs orsymptoms of volume overload.

Table 3. Predictors of tumor lysis syndrome

Characteristic Risk Factor

Tumor burden Bulky lymphatic disease (.10 cm)Elevated lactate dehydrogenase(23 upper limit of normal)

Elevated white blood cell count(.25,000 cells/mm3)

Renal function Baseline creatinine. 1.4mg/dl (37)Baseline uric acid .7.5 mg/dlChemosensitivity Variable

Adapted from reference 91.

Table 4. Consensus recommendations for prophylaxis of tumor lysis syndrome (51)

Tumor Lysis Syndrome Risk Monitoring Volume Expansion Allopurinol Rasburicase

Low X XMedium X X XHigh X X X Xa

aContraindicated in patients with glucose-6-phosphate dehydrogenase deficiency.

Clin J Am Soc Nephrol 7: 1730–1739, October, 2012 Tumor Lysis Syndrome, Wilson and Berns 1733

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Tumor-Lyse-Syndrom: Vorgehen

Urinary AlkalinizationAlkalinization of the urine favors conversion of uric acid

to the more soluble urate salt, decreasing the potential forintra-tubular crystal formation. The solubility of urate inurine with a pH of 7 is 2.2 mg/ml, while that of uric acid inurine with a pH of 5 is only 0.15 mg/ml. However, animalstudies did not demonstrate a reduction in urate nephrop-athy with urine alkalinization compared with saline ad-ministration (18), and no controlled human studies exist toinform the decision of whether to attempt alkalinization.In addition, administering exogenous alkali decreasesthe solubility of calcium-phosphate salts, leading to increasedsoft-tissue and renal tubular deposition of calcium-phosphatecrystals. Further, alkalemia favors calcium binding toalbumin, decreasing ionized calcium concentration, whichmay precipitate tetany or arrhythmia in these patients whoare already prone to hypocalcemia. Finally, in the era of re-combinant urate oxidase treatment (see later discussion)the benefit of increased solubility of uric acid resultingfrom urinary alkalinization is probably largely attenuated.Therefore, urinary alkalinization for the prevention ortreatment of TLS is not generally recommended and maybe harmful.

AllopurinolAllopurinol is a purine analogue and structural isomer of

hypoxanthine. It is metabolized by xanthine oxidase tooxypurinol, its active form, which is a competitive xanthine

oxidase inhibitor. Oxypurinol is excreted by the kidneyswith a long half-life of up to 24 hours in normal individuals,making dosing complex in patients with CKD or AKI.Allopurinol decreases the generation of uric acid fromxanthine but does not have a direct effect on uric acid levels(50). As such, initiation of allopurinol therapy after markedhyperuricemia has already occurred and TLS has pro-gressed significantly is unlikely to alter the clinical course,and treatment with rasburicase, discussed later, may bemore appropriate. However, prophylactic use of allopuri-nol is generally recommended in patients with high- orintermediate-risk tumors (51).Allopurinol is associated with several potentially severe

adverse effects, including Stevens-Johnson syndrome, toxicepidermal necrolysis, hepatitis, bone marrow suppression,and the allopurinol hypersensitivity syndrome (a highlymorbid condition consisting of rash, acute hepatitis, andeosinophilia) (52). There has been concern that the renalexcretion of allopurinol predisposes patients with CKD orAKI to these adverse reactions, although it is unclearwhether these reactions are dose-related, or even whetherthe allergen is allopurinol or its metabolite oxypurinol.Thus, there may be a tendency to “underdose” allopurinolin an effort to reduce adverse events. A cohort study of 120patients, some of whom received allopurinol with dosingadjusted for their reduced GFR while others received stan-dard dosing, showed no increase in the rate of toxic reac-tions in the standard dosing group (53). A case-control

Figure 2. | Algorithmic approach to prophylaxis and treatment of tumor lysis syndrome (TLS). IV, intravenous; LDH, lactate dehydrogenase;PO, oral; RRT, renal replacement therapy.

1734 Clinical Journal of the American Society of Nephrology

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Tumor-Lyse-Syndrom: Rasburicase

CJASN 2012;7:1730

studyexam

iningrisk

factorsfor

allopurinolhypersensitiv-ity

syndromedid

notfind

anassociation

between

allopu-rinoldose

andthe

development

ofthis

syndrome,although

case-patientshad

ahigher

prevalenceof

CKD

(55%versus

21%;P,0.001)

(54).Skin

testingand

lymphocyte

culturemethods

haveproven

unsuccessfulatpredictingwhich

pa-tients

willdevelop

thesesevere

complications

(53).Becausethe

preponderanceofevidence

suggeststhatthese

reactionsare

notdose-related,allopurinol

dosingshould

beguided

bythe

uricacid

levelandTLS

risk.Treatm

entwith

allopurinolalso

increasesplasm

acon-

centrationsof

theuric

acidprecursors

hypoxanthineand

xanthine,which

themselves

inhibitenzym

esinvolved

inpurine

synthesis.Poorlysoluble,xanthine

hasbeen

demon-

stratedto

leadto

decreasesin

GFR

dueto

precipitationof

crystalsin

renaltubulesand

stoneform

ation(55,56).X

an-thine

crystalluriaor

stoneform

ationmay

thusbe

exacer-bated

ortriggered

bythe

administration

ofallopurinol.

Febuxo

statFebuxostat,a

novelxanthineoxidase

inhibitorthat

doesnot

havethe

hypersensitivitypro

fileof

allopurinoland

doesnotrequire

dosingadjustm

entsforreduced

GFR

,isan

attractiveconsideration

forprophylaxis

inpatients

atrisk

forTLS

with

impaired

kidneyfunction.H

owever,there

areno

activeor

completed

clinicaltrialsevaluating

theuse

offebuxostatfor

thisindication

(57).Febuxostatdoesseem

tobe

efficaciousin

thetreatm

entofhyperuricemia

associatedwith

gout(58,59).Because

itsmechanism

ofaction

issim

i-lar

tothat

ofallopurinol,febuxostat

would

notbe

expectedto

decreasethe

accumulation

ofxanthine

orthe

riskfor

xanthinestone

formation.Febuxostatm

aybe

areasonable,

albeitexpensive,

alternativeto

allopurinolin

theprophy-

laxisof

TLSin

patientswith

decreasedestim

atedGFR

,especially

ifthereisany

historyofallergy

orother

adversereactions

toallopurinol.

Reco

mbinan

tUrate

Oxid

aseRasburicase

isarecom

binantformofA

spergillus-derivedurate

oxidaseexpressed

inaSaccharom

ycescerevisiae

vec-tor.

Asdiscussed

earlier,urate

oxidase,although

presentin

many

mam

malian

species,is

notpresent

inhum

ans.Urate

oxidasemetabolizes

uricacid

tothe

much

more

sol-uble

allantoin,carbon

dioxide,and

hydrogenperoxide.

Theform

eris

readilyexcreted

bythe

kidneys.Thelibera-

tionof

hydrogenperoxide

canbe

devastatingin

patientswith

glucose-6-phosphatedehydrogenase

deficiency,

inwhom

theunchecked

oxidative

potentialof

H2 O

2can

leadto

methem

oglobinemia

andhem

olyticanem

ia(60).

Rasburicase

will

continueto

beactive

inblood

samples

exvivo,and

thusinappropriately

handledlaboratory

specimens

may

manifest

spuriouslylow

uricacid

levels.Samples

foruric

acidshould

beplaced

onice

immediately

afterphle-

botomyand

runas

quicklyas

possibleto

maxim

izereliable

approximation

ofin

vivouric

acidconcentration.

Rasburicase

isindicated

forasingle

courseof

treatment

forthe

initialmanagem

entof

elevateduric

acidlevels

inpediatric

andadult

patientswith

leukemia,lym

phoma,and

solidtum

ormalignancies

who

arereceiving

anticancertherapy

expectedto

resultin

TLS.Few

randomized

trialsexist

toinform

theuse

ofthis

agent(Table

5).Only

threerandom

ized,controlledtrials

havebeen

published.Ineach

Table 5. Randomized trials of rasburicase

Study Year Patients (n) Population Group 1 Group 2 End Point SuperiorGroup

Cortes et al. (61)a 2010 183 Adults at riskfor TLS

Rasburicase, 0.20mg/kg per d for 5 d

Allopurinol, 300mg/d for 5 d

Uric acid ,7.5 mg/dl at 3–7 d 1

Malaguarneraet al. (68)

2009 38 Hyperuricemicelderly patients

Rasburicase, 4.5 mgfor 1 dose

Placebo Change in uric acid at 1 wk 1

Kikuchi et al. (92) 2009 30 Japanese childrenat risk for TLS

Rasburicase, 0.20mg/kg per d for 5 d

Rasburicase, 0.15mg/kg per d for 5 d

Sustained reduction in uric acidto ,6.5 mg/dl (age ,13 yr)or ,7.5 mg/dl (age $13 yr)

1

Ishizawa et al. (93) 2009 50 Japanese adultsat risk for TLS

Rasburicase, 0.20mg/kg per d for 5 d

Rasburicase, 0.15mg/kg per d for 5 d

Sustained reductionof uric acid ,7.5 mg/dl

Equivalent

Goldman et al. (77) 2001 52 Children at riskfor TLS

Rasburicase, 0.20mg/kg per d for 5–7 d

Allopurinol, 300 mgevery 8 h for 5–7 d

Area under the uricacid curve over 5 d

1

TLS, tumor lysis syndrome.aStudy also contained a rasburicase and sequential allopurinol group (n592).

Clin

JAm

SocNep

hrol7:1730–1

739,Octo

ber,

2012

TumorLysis

Syndrome,

Wilso

nan

dBern

s1735

Freitag, 20. September 13

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Agenda•Hypercalcämie

•Hyper- / Hyponatriämie- SIADH- Diarrhoen- Diabetes insipidus

•Hyper- / Hypokaliämie- Tumor-Lyse-Syndrom

•Hypomagnesiämie

Freitag, 20. September 13

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Hypomagnesiämie bei Cetuximab

potassium balance is restored with discontinuation ofthe drug.

Hypomagnesemia

A vexing electrolyte disorder to manage in cancerpatients, hypomagnesemia is a common, may last foryears if caused by cisplatin, and can be difficult totreat. Drugs cause the majority of hypomagnesemiaseen clinically, with cisplatin topping the list. Morerecently, monoclonal inhibitors of EGFR have beenrecognized as a common cause of hypomagnesemia.Other drugs that cause hypomagnesemia includefoscarnet, carboplatin, and ifosfamide.

Cisplatinum-induced hypomagnesemia has beenrecognized ever since its clinical introduction in 1971(29). This side effect is dependent on the cumulativedose received, with 300 mg/m2 as the minimal cumu-lative dose required to induce hypomagnesemia in bothpediatric and adult patients (30,31). As a consequence,the incidence of cisplatinum-induced hypomagnesemia

varies with the amount of cisplatinum prescribed. Withmost regimens in use today, the incidence is about 50%of patients that develop magnesium ,1.8 mg/dl. Asubstantial fraction of these patients develop severehypomagnesemia of ,1.0 mg/dl. With higher dosingregimens, the incidence of all-grade hypomagnesemiaapproaches 90% (32). Although in many patientscisplatinum-induced hypomagnesemia resolves in theweeks after therapy is discontinued, in some it willpersist for years and may be permanent (33). Themechanism by which cisplatinum induces renal mag-nesium wasting is not clear, although cisplatinum isconcentrated in renal tubular cells and can induce celldeath, which may explain why some patients developpermanent hypomagnesemia after cisplatinum.

Treatment of cisplatinum-induced hypomagnese-mia requires repletion, but the exact method and dosevaries according to local practice. Oral repletion can beeffective, but may be limited by gastrointestinal sideeffects including diarrhea, which actually worsensmagnesium loss. Intravenous repletion is efficacious,

Figure 23. EGF regulates magnesium reabsorption in the distal convoluted tubule. Anti-EGF mAbs prevent EGF from bindingto its receptor on the basolateral membrane. This in turn prevents transient receptor potential M6 (TRPM6) insertion into theapical membrane. Because TRPM6 mediates magnesium reabsorption, the net effect of anti-EGFR antibodies is to induce renalmagnesium wasting. Reprinted with permission from Perazella MA: Onco-nephrology: Renal toxicities of chemotherapeuticagents. Clin J Am Soc Nephrol 7: 1713–1721, 2012.

Nephrology Self-Assessment Program - Vol 12, No 1, January 2013 57

Neph SAP 2013;12:57

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ZUSAMMENFASSUNG•Hypercalcämie

•Hyper- / Hyponatriämie- SIADH- Diarrhoen- Diabetes insipidus

•Hyper- / Hypokaliämie- Tumor-Lyse-Syndrom

•Hypomagnesiämie

Freitag, 20. September 13