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AUGUST 2010

Acute Kidney Injury Secondary to Bilateral Ureteral Obstruction

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49-year-old woman presentedith a 2-day history of severe ab-ominal pain, nausea, and vomit-ng. Her history included paranoidelusions and herniated lumbariscs, for which 16 months priorhe underwent decompressive lami-ectomy and diskectomy, with fu-ion of L5-S1. Topiramate therapyas started for neuropathy at a dosef 150 mg twice daily. Other medi-ations included olanzapine, atorva-tatin, aspirin, and esomeprazole.he was evaluated 3 days before

his presentation for a 3-week his-ory of paranoid delusions. Workupesults included the following values:erum sodium, 139 mEq/L (139mol/L); potassium, 3.4 mEq/L

3.4 mmol/L); chloride, 110 mEq/L v

American Journal of Kidney Diseases, Vol 5

110 mmol/L); bicarbonate, 17.9Eq/L (17.9 mmol/L); serum urea

itrogen, 16 mg/dL (5.7 mmol/L);erum creatinine, 0.8 mg/dL (71mol/L); estimated glomerular fil-

ration rate (eGFR), 81 mL/min/.73 m2 (1.35 mL/s/1.73 m2), andegative blood alcohol and toxicol-gy screen results. Her confusionas attributed to topiramate, and

he dose was decreased to 50 mgwice daily.

At this presentation, the patient’shysical examination was significantor lethargy, dry mucous membranes,nd diffuse abdominal tendernessith no rebound, guarding, or costo-ertebral tenderness. Serum chemis-ry tests now showed the following

alues: sodium, 128 mEq/L (128 p

6, No 2 (August), 2010: pp xxxiii-xxxv

mol/L); potassium, 4.2 mEq/L4.2 mmol/L); chloride, 106 mEq/L106 mmol/L); bicarbonate, 11Eq/L (11 mmol/L); serum urea

itrogen, 54 mg/dL (19.3 mmol/L);erum creatinine, 7.7 mg/dL (681mol/L); and eGFR, 6 mL/min/1.732 (0.02 mL/s/1.73 m2). Arterial

lood gas analysis showed pH 7.22;CO2, 20 mm Hg; and bicarbonate, 8Eq/L (8 mmol/L).Despite administration of 3 L of

ntravenous saline and Foley catheternsertion, the patient remained an-ric. Noncontrast abdominal com-uted tomography showed bilateraloderate hydroureternephrosis to the

evel of the bladder base (Fig 1). Anmergent percutaneous antegrade ne-

hrostogram was performed (Fig 2).

QU

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What is the cause of bilateral ureteral obstruction?

What electrolyte abnormalities are associated with this condition?

What is the underlying mechanism in the development of this condition?

igure 1. Computed tomography of the abdomen shows bilateraloderate hydronephrosis.

Figure 2. Percutaneous antegrade pyelogram.

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ISCUSSION

What is the causeof bilateralureteral obstruction?

his is a case of acute kidneynjury secondary to bilateral ob-tructing ureteral stones in the set-ing of topiramate use. Bilateralbstructing calculi (3 mm rightnd 5 mm left) were observedithin the distal ureters at the

evel of the bladder inlet (Fig 3).he percutaneous antegrade ne-hrostogram showed bilateral ab-ence of antegrade urine flow tohe bladder, consistent with bilat-ral ureterovesical junction ob-truction (Fig 2). Beyond long-erm topiramate use, no other riskactors for kidney stone forma-ion could be identified. The riskf kidney stone formation withopiramate is �2-4 times that ofhe untreated population,1,2 re-orted at an incidence of 1%-%.2

What electrolyteabnormalities areassociated withthis condition?

opiramate has an increased riskf metabolic acidosis. It showsarbonic anhydrase inhibitoryroperties similar to acetazol-mide, but is far less potent.3 Theechanism by which topiramate

auses metabolic acidosis haseen studied recently in a cross-ectional short-term longitudinaltudy.4 Inhibition of carbonic an-ydrase probably at both theroximal and distal tubule sites

nderlies its primary mode of ac- b

Axxxiv

ion. Typically, metabolic acido-is is of the hyperchloremic non–nion gap variety and is mild inature.2 No association betweencidosis and topiramate dose haseen identified because the re-orted cases vary in dosages from0-800 mg/d, and reported lengthsf therapy have been 1 week to 1ear.5,6 The patient we report hadrofound metabolic acidosis at theime of presentation (bicarbonate,1 mEq/L [11 mmol/L]), whichrobably reflects a combinationf chronic carbonic anhydrase in-ibition and acute obstructive kid-ey injury. On review of data from6 months ago, serum chemistryesults before initiation of topira-ate therapy were as listed inable 1, and eGFR was 95 mL/in/1.73 m2 (1.58 mL/s/1.73 m2).his confirms that she developedetabolic acidosis only after be-

ng started on topiramate therapy.

What is the underlyingmechanism in thedevelopment ofthis condition?

opiramate, a weak carbonic an-ydrase inhibitor, induces meta-

Figure 3. Computed tom

olic acidosis and concomitant c

merican Journal of Kidney Diseases, Vol 56

ypocitraturia, which was theikely underlying mechanism ofhis patient’s kidney stone forma-ion. The hypocitraturia observedn this setting most likely is conse-uent to carbonic anhydrase inhi-ition in that inhibition of thisnzyme promotes intracellularcidosis of the renal proximal tu-ule cell with resultant increasednflux of filtered citrate from theubular lumen. Jenkins et al7 havehown that rats rendered acidoticy placing ammonium chloride inhe drinking water develop pro-ound hypocitraturia compared withntreated animals. Using brush-order membrane vesicles, thesenvestigators showed that the ratef citrate uptake through the so-ium-dependent tricarboxylic acid-ntermediates transport pathwayas enhanced by �2-fold, and in-

rinsic changes in the brush-bor-er membrane of acidotic ani-als underlies this observation.he combination of carbonic an-ydrase inhibition and hypocitra-uria promotes urinary stone for-ation by increasing urinary pH

nd decreasing the amount ofitrate available to bind urinary

phy of the abdomen.

alcium.4 Hypocitraturia and alka-

, No 2 (August), 2010: pp xxxiii-xxxv

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ine urine increase calcium phos-hate supersaturation, resulting inalcium phosphate crystal precipi-ation. Our patient presented withbstructive uropathy, and we pre-ume, but cannot prove becausee were unable to isolate the cal-

uli, that the calculi were of thealcium phosphate variety.

Topiramate therapy was discon-inued, and no changes weremplemented in the patient’s other

edications. She was followedp in the nephrology clinic, anderial blood and urine chemistryests were performed at 1, 2, and

months after discontinuation ofopiramate therapy (Table 1). Athe 1-month period, metabolic aci-osis persisted (serum bicarbon-te, 18 mEq/L [18 mmol/L]) andrine citrate level remained low70 mg/d). However, by 4 months,etabolic acidosis had corrected

serum bicarbonate, 23 mEq/L [23mol/L]) and urinary citrate level

ad increased to the normal range

Table 1. Laboratory D

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erum chemistrySodium (mEq/L) 1Potassium (mEq/L)Chloride (mEq/L)Bicarbonate (mEq/L)Serum urea nitrogen (mg/dL)Creatinine (mg/dL)

reatinine clearancea (mL/min)

rine chemistrypHCitrate (mg/d)Ammonium (mEq/d)Calcium (mg/d)BrushiteUrine oxalate (mg/d)

Note: Conversion factors for units: s0.357. No conversion necessary for saCreatinine clearance calculated usin

641 mg/d). S

INAL DIAGNOSISopiramate-induced acute kidney

njury secondary to bilateral ob-tructing ureteral stones.

CKNOWLEDGEMENTSWe gratefully acknowledge the expert

ecretarial assistance of Sheryl Krulik.

EFERENCES1. Lamb EJ, Stevens PE, Nashef

. Topiramate increases biochemicalisk of nephrolithiasis. Ann Clin Bio-hem. 2004;41(pt 2):166-169.

2. Topamax (topiramate) [packagensert]. Titusville, NJ: Ortho-McNeil-anssen Pharmaceuticals Inc; 2009.

3. Sachdeo RC. Topiramate: clini-al profile in epilepsy. Clin Pharma-okinet. 1998;34(5):335-346.

4. Welch BJ, Graybeal D, MoeW, Maalouf NM, Sakhaee K. Bio-

hemical and stone-risk profiles withopiramate treatment. Am J Kidneyis. 2006;48(4):555-563.5. MathewsKD,StarkJE.Hyperchlo-

emic, normal anion-gap, metabolic aci-osis due to topiramate. Am J Health-

efore, During, and After Discontinuati

After16 mo

AtPresentation

1 moDiscon

139 128 1413.4 4.2 3

110 106 11217 11 1816 54 14

0.8 7.7 0

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creatinine in mg/dL to mol/L, �88.4;, potassium, chloride, and bicarbonat

hours urine collection.

ystem Pharm. 2008;65(15):1430-1434. F

6. Ozer Y, Ahunkaya H. Topira-ate induced metabolic acidosis. An-

esthesia. 2004;59(8):830.7. JenkinsAD, Dousa TP, Smith LH.

ransport of citrate across renal brushorder membrane: effects of dietarycid and alkali loading. Am Physioloc. 1985;249(4 pt 2):F590-595.

ASE PROVIDED AND AUTHORED BY

Jasmeet Kaur, MD, Edward P. Nord,MD, and Nand K. Wadhwa, MD,Division of Nephrology, Departmentof Medicine, School of Medicine,State University of New York at StonyBrook, Stony Brook, NY.

ddress correspondence to Nand K.Wadhwa, MD, Division of Ne-phrology, Department of Medi-cine, School of Medicine, HSCT-16 Rm-080, State University ofNY at Stony Brook, Stony Brook,NY 11794. E-mail: nwadhwa@notes.cc.sunysb.edu2010 by the National KidneyFoundation, Inc.

oi:10.1053/j.ajkd.2009.09.016UPPORT: None.

Topiramate Therapy

2 moAfter

4 moAfter

ReferenceRange

139 1353.8 4.6

103 10227 2310 12

0.75 0.83

96 151 92-128

5.6 6.1 5.5-7.0153 641 �32043 65 14-62

119 221 �2500.76 1.91 �2.00

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m urea nitrogen in mg/dL to mmol/L,Eq/L and mmol/L.

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INANCIAL DISCLOSURE: None. UIZ

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