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IDNEY BIOPSY TEACHING CASE

An Unusual Cause of Acute Renal Failure With Volume Depletion Due toRenal Losses

Lin Chong, MB,1 Shashidhar Baikunje, MD,1 David N. Poller, MD, FRCPath,1

Ian S.D. Roberts, MBChB, FRCPath,2 and Gopalakrishnan Venkat-Raman, MD, FRCP1

INDEX WORDS: Acute renal failure; volume depletion; hyponatremia; hypokalemia; juxtaglomerularapparatus hypertrophy; Bartter syndrome.

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cute renal failure caused by volume and electro-yte depletion mostly occurs due to gastrointestinalauses and only rarely due to renal losses. Weresent a case that illustrates an unusual cause of aommon syndrome, brought to light by histopatho-ogic appearances on a kidney biopsy specimen.

CASE REPORT

linical History

A 47-year-old white man was admitted to the hospitalith dysuria, generalized weakness, and volume depletion.hree days before admission, he was treated with amoxicil-

in for a urinary tract infection caused by Escherichia coli,hich was believed to be the precipitating cause of his acute

llness. He reported a 2-year history of polyuria and polydip-ia. There was no history of problems with blood pressure orther medical conditions. He had 8 siblings with no signifi-ant medical history, in addition to twins who were stillborn.e had attended a special-needs school as a child.On physical examination, he was clinically volume de-

leted with a pulse rate of 120 beats/min and supine systoliclood pressure of 70 mm Hg. He was in acute renal failureith a urea level of 84 mg/dL (30.1 mmol/L) and creatinine

evel of 3.3 mg/dL (293 �mol/L). He had severe hypokale-ic alkalosis with a potassium level of 1.4 mEq/L

1.4 mmol/L) and bicarbonate level of 41.1 mEq/L (41.1mol/L). He was also hyponatremic, with a sodium level of

25 mEq/L (125 mmol/L), and hypomagnesemic, with mag-esium level of 1.1 mg/dL (0.47 mmol/L), but serum cal-ium level was normal.

Urine dipstick results showed protein of ��� and a tracef blood. A 24-hour urine sample showed nephrotic-range

From the 1Wessex Renal & Transplant Service, Queenlexandra Hospital, Portsmouth; and 2Department of Cellu-

ar Pathology, John Radcliffe Hospital, Oxford, UK.Received March 19, 2008. Accepted in revised form April

2, 2008. Originally published online as doi:0.1053/j.ajkd.2008.04.025 on June 26, 2008.

Address correspondence to Gopalakrishnan Venkat-aman, MD, FRCP, Renal Unit, Queen Alexandra Hospital,ortsmouth Po6 3LY, UK. E-mail: gvr@porthosp.nhs.uk© 2008 by the National Kidney Foundation, Inc.0272-6386/08/5202-0021$34.00/0

tdoi:10.1053/j.ajkd.2008.04.025

American Journal of K66

roteinuria with protein of 6.48 g/24 h, but serum albuminevel was normal at 3.6 g/dL (36 g/L). A 24-hour urinaryollection showed inappropriately high excretion of potas-ium (180 mEq/L [180 mmol]), sodium (864 mEq/L [864mol]), and magnesium (42.3 mg/dL [17.4 mmol]), with

ery low phosphate excretion (1.08 mmol), but near-normalalcium (28.9 mg/dL [7.2 mmol]). Urine osmolality was lowt 208 mOsm/kg against serum osmolality of 280 mOsm/kg.rine myoglobin results were negative. Renal ultrasound

howed kidneys measuring 12 cm, with some loss of cortico-edullary differentiation. There were multiple simple cysts

n both kidneys (Fig 1) distributed throughout the cortex,anging in diameter from 10 to 17 mm.

idneyBiopsy andDiagnosis

The kidney biopsy specimen contained 48 glomeruli; 6 werelobally sclerosed and 13 showed complete collapse of theapillary tufts with an expanded Bowman’s space containingroteinaceous fluid (Fig 2A). The collapsed tufts did not showverlying podocyte hypertrophy, and there was no segmentalclerosis. There was striking hyperplasia of the cells of theuxtaglomerular apparatus (JGA), evident in 14 glomeruli inhich the section included the vascular pole (Fig 2B). Thereas moderately severe chronic tubulointerstitial damage, with5% of the cortex showing interstitial fibrosis and tubulartrophy. There was no evidence of active tubulointerstitialephritis. Small interlobular arteries and arterioles showededial hyperplasia and intimal thickening as a result of duplica-

ion of the elastica (Fig 2C and D), changes resembling chronicypertensive vascular disease. Immunohistochemistry resultsor immunoglobulin G, immunoglobulin A, immunoglobulin

, C3, and C1q were negative. Electron microscopy showedo evidence of electron-dense deposits. However, there wasvidence of podocyte injury with moderate effacement of footrocesses, microvillous transformation, and cytoplasmic vacu-lation with protein-resorption droplets (Fig 2E and F). Tubulesppeared normal ultrastructurally, with no evidence of lighthain crystalline tubulopathy.

linical Follow-up

On volume resuscitation, the patient became profoundlyolyuric, with daily urine output of 7 to 10 L. He neededarge amounts of potassium and magnesium supplements,nitially intravenous and later oral. With correction of potas-ium levels, polyuria improved. Kidney function improvedrogressively, with creatinine level decreasing to 1.5 mg/dL135 �mol/L) during the course of 2 weeks. With optimiza-

ion of fluid status and electrolytes, proteinuria dramatically

idney Diseases, Vol 52, No 2 (August), 2008: pp 366-369

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Acute Renal Failure Due to Renal Losses 367

mproved and 24-hour urine protein decreased to 0.73 g/24. Six months later, he remains well, with trivial proteinuria1� on dipstick) and stable, but mildly impaired, kidneyunction (serum creatinine, 1.6 mg/dL [144 �mol/L]) andild hypokalemia (potassium, 3 to 3.6 mmol/L) despite oral

upplementation with 336 mmol of potassium.Plasma renin and aldosterone concentrations (ambulant)

ere grossly increased at 1,637 mU/L (normal range, 3 to0) and 2,525 ng/L (normal range, 30 to 340), respectively.Gene analysis showed a homozygous mutation compatible

ith the diagnosis of Bartter syndrome type 3 in CLCNKB, aene encoding the chloride channel protein CLCNKB. Briefly,NA was extracted from whole blood in EDTA by using a

ommercial DNAisolation kit (Qiagen, Hilden, Germany). Thentire coding sequence (including all 20 exons) was sequencedully by using anABI Prism 310 automated sequencer (Appliediosystems, Foster City, CA). Results were interpreted accord-

ng the sequence data available for GenBank accession numberT_004873.16. Quantitative polymerase chain reaction usu-

lly used for detection of large duplications and deletions wasot applied.

DISCUSSION

Acute renal failure caused by profound fluidnd electrolyte loss is a common scenario, butarely caused by renal losses. Even in the latterase, it is usually caused by a “salt-losing ne-hropathy” secondary to tubulointerstitial dis-ase. In cases of acute renal failure caused byolume depletion (regardless of cause), the renin-ngiotensin-aldosterone system (RAAS) will bectivated, but is rarely, if ever, known to causeeavy proteinuria. In the case we describe, thereas no evidence of parenchymal or interstitial

enal disease but there was intense hypertrophyf the JGA, raising the likelihood of an underly-ng Gitelman/Bartter type of syndrome. These

Figure 1. Renal ultrasound shows kidney with multipleimple cysts.

yndromes are characterized by autosomal reces- c

ive inheritance, hypokalemia, metabolic alkalo-is, and hypomagnesemia. The primary defect ismpairment of sodium reabsorption caused byutations in the genes coding for 1 or more

ransporters in the loop of Henle or distal convo-uted tubule.1

The diagnosis usually is made in adulthooduring routine investigation.2 Although this con-ition traditionally is considered to be benign, itan be associated with serious clinical manifesta-ions3 as exemplified by this patient.

Multiple renal cysts have been documented inatients with chronic hypokalemia secondary toartter syndrome, primary aldosteronism, distal

ubular renal acidosis, Liddle disease, and apparentineralocorticoid excess.4-6 The underlying mecha-

ism for renal cyst formation in patients withhronic hypokalemia is unclear. Torres et al4 postu-ated that chronic hypokalemia is associated withncreased renal cytogenesis and enhanced prolifera-ion of tubular epithelial cells, thus leading to theevelopment of renal cysts.

Histological findings of chronic hypokalemianclude cytoplasmic vacuolation, dilatation ofroximal tubules, interstitial infiltration byhronic inflammatory cells, interstitial fibrosis,yst formation, and JGA hyperplasia.7,8 Animalnd human studies suggested that potassiumepletion and dehydration stimulated the secre-ion of transforming growth factor �2 and reninn renal arterioles and the JGA. This implies thatransforming growth factor �2 may be an impor-ant mediator in JGA hypertrophy.9-11 The arte-ial changes in our patient’s biopsy specimenesemble chronic hypertensive vascular diseaseespite his normal or low blood pressure. Thisupports recent animal studies indicating that theenovascular changes of hypertension are second-ry to overstimulation of the RAAS and directlyodulated by angiotensin/aldosterone, and not

ntirely by increased blood pressure.The typical patient with Bartter/Gitelman syn-

rome does not show a significant degree ofroteinuria. The finding of nephrotic proteinurian this patient during the acute phase and itsubsequent remission by correction of blood pres-ure and electrolyte status raises a fascinatingathophysiological conundrum. Podocyte injuryas a key role in the pathogenesis of glomerularroteinuria.12 A decrease in the number of podo-

ytes is directly linked to the development of

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roteinuria and glomerulosclerosis because ofhe relative inability of podocytes to proliferate,etachment, and apoptosis.13 The kidney biopsypecimen from our patient showed evidence of

Figure 2. Kidney biopsy specimen shows (A) glomeru200), (B) juxtaglomerular cell hyperplasia (hematoxylin a

hematoxylin and eosin; original magnification �400) wagnification �400). (E, F) Electron microscopy shows pod

odocyte injury with effacement of foot pro- s

esses and microvillous transformation. The rolef the RAAS in the development of these changesn podocyte structure and function is not fullynderstood, but experimental and clinical studies

t collapse (hematoxylin and eosin; original magnificationsin; original magnification �200), and (C) arteriosclerosis

reduplication of elastica (Elastic van Gieson; originalinjury with effacement of foot processes.

lar tufnd eoith (D)

howed that RAAS blockade reduced proteinuria

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Acute Renal Failure Due to Renal Losses 369

nd helped preserve podocyte structure and func-ion. Aldosterone has been implicated in endothe-ium remodeling by increasing the size and stiff-ess of endothelial cells, thus promoting proteineakage through intercellular gaps.14 Thus, argu-bly, the extreme generation of angiotensin II andldosterone could have produced sufficient podo-yte damage to cause heavy proteinuria, a processeversed by correction of the causative hemody-amic factors. Unfortunately, this will remain specu-ative because we did not measure those hormoneevels during the acute phase of the illness. Irrespec-ive of the exact pathogenesis, our case shows aikely link between hyper-reninemic hyperaldoste-onism and proteinuria. The initial polyuria can bexplained on the basis of hypokalemia, which isne of the known causes of tubular failure. Theefractory and ongoing hypokalemia requiring mas-ive supplementation, the typical finding of veryigh renin-aldosterone levels, and the kidney bi-psy findings together argue the case for this beingmember of the Bartter/Gitelman spectrum of

iseases.Interestingly, a similar case was reported15

n which hyponatremia, hypokalemia, poly-ria, and nephrotic syndrome were observedecondary to unilateral renal ischemia causedy renovascular disease. The features were alleversed by means of uninephrectomy andttributed to excessive activation of the RAAS.hus, overstimulation of the RAAS could be anal common pathway in the genesis of heavyroteinuria in such patients, regardless of pri-ary disease.The central teaching points of this case are as

ollows: (1) it is important to remember thatolume and electrolyte depletion may be causedy excessive renal losses; (2) extreme hypokale-ic alkalosis should trigger suspicion of such

nusual conditions as Bartter or Gitelman syn-romes; (3) heavy proteinuria may be a transienthenomenon, in association with extreme fluidnd electrolyte depletion, and not necessarilyaused by intrinsic glomerular disease; and (4)enovascular changes normally associated withypertension may be seen in the absence ofncreased blood pressure, reflecting direct ac-

ions of an overstimulated RAAS. 2

ACKNOWLEDGEMENTSSupport: None.Financial Disclosure: None.

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