Kidney Biopsy Teaching Case

Subclinical Celiac Disease and Crystal-Induced Kidney DiseaseFollowing Kidney Transplant

Giovanna Capolongo, MD,1 Sameh Abul-Ezz, MD,2 Orson W. Moe, MD,1,3,4 andKhashayar Sakhaee, MD1,3

Decreased kidney function from kidney deposition of calcium oxalate has been described previously ininflammatory bowel disease and after jejuno-ileal and Roux-en-Y gastric bypass surgeries. Although celiacdisease is the most prevalent bowel abnormality associated with intestinal malabsorption, its relationship tohigh kidney oxalate burden and decreased kidney function has not been established. We report a case ofsubclinical celiac disease and hyperoxaluria that presented with loss of kidney function as a result of highoxalate load in the absence of overt diarrhea, documented intestinal fat malabsorption, and nephrolithiasis.Subclinical celiac disease is commonly overlooked and hyperoxaluria is not usually investigated in kidneypatients. We propose that this entity should be suspected in patients with chronic kidney disease in which thecause of kidney damage has not been clearly established.Am J Kidney Dis. 60(4):662-667. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.This is a US Government Work. There are no restrictions on its use.

INDEX WORDS: Hyperoxaluria; calcium-oxalate crystals; celiac sprue; celiac disease.

INTRODUCTION

Enteric hyperoxaluria, a condition described ininflammatory bowel disease and after bowel resec-tion, is associated with an increased risk of kidneystones.1 Previous studies have shown that jejuno-ilealand Roux-en-Y gastric bypass surgeries, used for thetreatment of morbid obesity, are associated with en-teric hyperoxaluria, calcium oxalate nephrolithiasis,and oxalate-induced kidney disease.2-5 Celiac diseaseis the most prevalent enteric disease associated withintestinal malabsorption,6 and it has been shown thatthe degree of hyperoxaluria in celiac disease is associ-ated with fat malabsorption.7 In patients with un-treated celiac disease, hyperoxaluria from intestinaloxalate overabsorption increases the risk of nephroli-thiasis.8,9 However, the association between subclini-cal celiac disease and oxalate crystal–induced kidneydamage has not been established. This teaching casedescribes the association between untreated subclini-

From the 1Charles & Jane Pak Center for Mineral Metabolism& Clinical Research, University of Texas Southwestern MedicalCenter, Dallas, TX; 2Division of Nephrology, University of Arkan-sas for Medical Sciences, Little Rock, AR; and 3Departments ofInternal Medicine and 4Physiology, University of Texas Southwest-ern Medical Center, Dallas, TX.

Received August 31, 2011. Accepted in revised form February 29,2012. Originally published online June 27, 2012.

Address correspondence to Khashayar Sakhaee, MD, University ofTexas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas,TX 75390-8885. E-mail: khashayar.sakhaee@utsouthwestern.edu

Published by Elsevier Inc. on behalf of the National KidneyFoundation, Inc. This is a US Government Work. There are norestrictions on its use.

0272-6386/$0.00

http://dx.doi.org/10.1053/j.ajkd.2012.02.342

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cal celiac disease and kidney damage due to highoxalate burden in the absence of nephrolithiasis andovert fat malabsorption.

CASE REPORT

Clinical History and Initial LaboratoryData

A 57-year-old healthy white woman presented for a routineexamination. Her history was unremarkable except for mild hyper-tension and occasional diarrhea. Incidental abnormal laboratorydata showed a serum creatinine level of 2.0 mg/dL (177 �mol/L),corresponding to estimated glomerular filtration rate (eGFR) of 26mL/min/1.73 m2 (0.43 mL/s/1.73 m2, calculated using the 4-vari-able MDRD [Modification of Diet in Renal Disease] Study equa-tion),10 and mild anemia, with a hemoglobin level of 9.0 g/dL (90g/L) and hematocrit of 30.7%. Mean corpuscular volume was 89fL and mean corpuscular hemoglobin was 33 g/dL (330 g/L).Upper and lower gastrointestinal endoscopies disclosed no abnor-malities to account for anemia. There were no overt explanationsfor the decreased eGFR. On a follow-up examination 2 years later,she was found to have further deterioration of kidney function,with serum creatinine level of 5.3 mg/dL (469 �mol/L; eGFR, 9mL/min/1.73 m2 [0.15 mL/s/1.73 m2]) despite well-controlledhypertension.

KidneyBiopsy

A native kidney biopsy showed evidence of focal segmentalglomerulosclerosis, global sclerosis, and incidental calcium ox-alate crystal deposits (Fig 1A). Careful history excluded gastroin-testinal symptoms, overingestion of ascorbic acid or other oxalateprecursors, and family history suggestive of primary hyperox-aluria. Decreased kidney function therefore was attributed tohypertension. However, during the following months, kidney func-tion deteriorated further despite well-controlled hypertension, anddialysis therapy was initiated. After 3 months, she received a livingrelated donor kidney transplant.

The initial posttransplant course was uneventful, with a nadirserum creatinine level of 1.1 mg/dL (97 �mol/L; eGFR, 51mL/min/1.73 m2 [0.85 mL/s/1.73 m2]). However, over 8 weeks,

kidney function progressively decreased, with serum creatinine

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Crystal-Induced Kidney Failure in Celiac Disease

Figure 1. Native and transplant kidney biopsy specimens. (A) Light microscopy of native kidney biopsy shows 17 glomeruli, with 6globally sclerotic. (Left panel) No hypercellularity or crescent formation was seen. There was tubular atrophy and dropout withinterstitial fibrosis, and crystals were present in tubules. (Right panel) Under polarized light, crystals were birefringent, consistent withcalcium oxalate crystals. (B) Transplant biopsy specimen 3 weeks after kidney transplant: tubule shows occasional refractile acellulardeposits and birefringent crystals under a polarized lens. (C) Transplant biopsy specimen 8 weeks after kidney transplant: calciumoxalate crystals seen within tubular lumen and tubular epithelial cells with associated tubular injury. Birefringent calcium oxalatecrystals seen in many tubular lumens and tubular epithelial cells. (D) Transplant biopsy specimen 14 weeks after kidney transplant:large refractile acellular deposits in several tubular lumens with associated tubular injury. Extensive birefringent calcium oxalatecrystals within tubular lumina and within tubular epithelial cells. Left panels: hematoxylin and eosin stain (original magnification, �200);

right panels: polarized lens (original magnification, �100). Courtesy of Dr James Wellons.

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levels ranging from 1.8-2.8 mg/dL (159-248 �mol/L; Fig 2),corresponding to eGFR of 29-17 mL/min/1.73 m2 (0.48-0.28mL/s/1.73 m2), resulting in 3 successive kidney transplant biop-sies. The first biopsy, performed 3 weeks after transplant whenserum creatinine level was 6.0 mg/dL (530 �mol/L; eGFR, 7mL/min/1.73 m2 [0.12 mL/s/1.73 m2]), showed occasional cal-cium oxalate crystal deposits, which were irregular, laminated, orfan-shaped and colorless under ordinary light, but clearly birefrin-gent under polarized light (Fig 1B). Glomeruli and tubules wereintact and there was no evidence of cellular infiltrate to suggesttransplant rejection. The second percutaneous biopsy performed 8weeks posttransplant showed many more calcium oxalate crystalswith associated tubular injury, as well as areas of patchy interstitiallymphocytic infiltrate (Fig 1C). These findings were consideredconsistent with mild cellular rejection and/or oxalate kidney dis-ease. Despite antirejection treatment, serum creatinine level dete-riorated further. At 14 weeks posttransplant, a third biopsy showedevidence of extensive calcium oxalate deposition (Fig 1D). Two24-hour urine collections during this period showed urinary ox-alate excretion ranging from 97-130 mg/d (1,077-1,443 �mol/d;reference, �40 mg/d [�444 �mol/d]). At this time, oxalate kidneydisease was suspected.

Diagnosis

A metabolic evaluation was performed on a restricted metabolicdiet both before and after dietary gluten restrictions (Table 1).Normal urinary glycolate and L-glycerate levels ranging from19.7-33 �g/mg of creatinine (Cr; reference, �70 �g/mg Cr) and0-0.1 �g/mg Cr (reference, �19 �g/mg Cr), respectively, excludedprimary hyperoxaluria biochemically. Moreover, unclassified pri-mary hyperoxaluria was excluded because plasma glycolate levelwas normal at 26 �mol/L (reference, 21-193 �mol/L). Quantita-tive stool fat content during a 72-hour collection was 1.3 g(reference, �7 g), thus excluding fat malabsorption. However,stool quantity was markedly elevated at 1,369 g (reference, �500g). Serologic tests showed mildly elevated anti-gliadin immuno-globulin G (IgG) antibody at 28.5 EU (reference, �25 EU), normalanti-gliadin IgA antibody at 8.2 EU (reference, �25 EU), anduncertain anti-tissue transglutaminase antibodies at 7 U/mL (equivo-cal range, 5-8 U/mL). Due to the borderline level of serumanti-gliadin IgG, a small-intestine biopsy that was performedshowed normal mucosal architecture without the classic flattening

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Clinical Follow-up

The patient was started on dietary gluten restrictions, with adecrease in urinary oxalate excretion from 128 mg/d (1,421 �mol/d)to a normal level throughout follow-up, with the exception of ashort period (Table 1, Fig 2). Total urine volume, pH, and sodium,potassium, phosphorus, calcium, magnesium, and citrate levelsincreased with dietary gluten restrictions (Table 1). Commensuratewith the decrease in urinary oxalate level, serum creatinine leveldecreased from 1.7 mg/dL (150 �mol/L) to 1.2 mg/dL (106�mol/L), corresponding to an increase in eGFR from 31 to 46mL/min/1.73 m2 [0.52 to 0.77 mL/s/1.73 m2]). Based on these

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Figure 2. Clinical course of serum creat-inine concentrations and urinary oxalate ex-cretion rates in relationship to major clinicalevents. (A) Kidney transplant. (B) Oxalatecrystals on post–kidney transplant biopsies(first biopsy, 3 weeks posttransplant; sec-ond, 8 weeks; third, 14 weeks). (C) Oxalaterestriction. (D) Gluten-free diet started. (E)Nonadherence to diet. (F) Resumption ofgluten-free diet.

Table 1. Post–Kidney Transplant InpatientMetabolic Evaluation

24-h Urine Parameters Baseline4 mo After Gluten

Restriction P

Total volume (L/d) 2.8 � 0.9 3.5 � 0.4 0.4

pH 5.58 � 0.02 6.4 � 0.36 0.06

Sodium (mEq/d) 41 � 22 98 � 18 0.01

Potassium (mEq/d) 16.7 � 4.6 97.7 � 1.1 �0.001

Phosphorus (mg/d) 370 � 148 583 � 10 0.13

Calcium (mg/d) 66.7 � 46.3 109 � 18 0.1

Magnesium (mg/d) 26 � 18 57 � 4 0.06

Citrate (mg/d) 20 � 0 546 � 14 �0.001

Oxalate (mg/d) 128 � 21 68 � 6 0.04

Glycolate (�g/mg Cr)a 33 19.7 � 8.9 —

L-Glycerate (�g/mg Cr)b 0 0.91 � 0.36 —

Note: Values are expressed as mean � standard deviation.Results represent the mean of two or three 24-hour urine collec-tions with the exception of baseline glycolate and L-glyceratelevels. Laboratory data were collected during a 4-day constantmetabolic diet containing 400 mg of calcium, 100 mEq of sodium,100 mg of oxalate, and 800 mg of phosphorus daily. Conversionfactors for units: phosphorus in mg/d to mmol/d, �0.03229;calcium in mg/d to mmol/d, �0.02495; magnesium in mg/d tommol/d, �0.041; citrate in mg/d to mmol/d, �0.00521; oxalate inmg/d to �mol/d, �11.11.

Abbreviation: Cr, creatinine.

aReference, �70 �g/mg Cr; breference, �19 �g/mg Cr.

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findings, the diagnosis of kidney transplant failure due to calciumoxalate crystal deposition as a result of celiac disease was reached.

DISCUSSION

This is an instructive case describing the relation-ship between subclinical celiac disease and oxalate-induced kidney disease in both native and transplantkidneys. Previous studies also have shown overt en-teric hyperoxaluria in association with increased tis-sue oxalate burden and consequent GFR loss.11-13

Celiac disease can present as a subclinical ratherthan overt disorder, with its late diagnosis leading tosignificant morbidity and mortality.14-17 In our pa-tient, the typical clinical manifestations of celiac dis-ease were masked and an early diagnosis was missed.This case highlights the notion that subclinical celiacdisease and its accompanying hyperoxaluria shouldbe explored carefully as causes of unexplained kidneytransplant failure.

The gold standard for the diagnosis of celiacdisease is abnormal intestinal mucosal architecture.However, it has been proposed that the small-bowelmucosal lesion of celiac disease is heterogeneous,

Figure 3. Architecture and SLC26A6 expression in the smunaffected control (bottom row). (Left panels) Intestinal biopsy shoeosin stain; original magnification, �100). (Middle and right panels(green), differential interference contrast image, merged image, and

ranging from normal mucosa and increased intraepi-

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thelial lymphocytes to the classic finding of flatmucosal lining.18 The normal intestinal biopsy speci-men in this patient (Fig 3, top row) may reflect thisheterogeneous distribution and sampling error. Asingle intestinal biopsy specimen may not be suffi-cient to establish the diagnosis because stringentdiagnostic criteria require multiple biopsies.19 An-other possible complication is that abnormal mu-cosa may normalize shortly after a decrease (per-haps unintended) in gluten intake. Althoughsubsequent intestinal biopsies were not indicated orperformed after the patient started dietary glutenrestrictions, in this case, a concomitant decrease inserum creatinine and urinary oxalate levels stronglysuggests that dietary gluten restrictions resolved thehyperoxaluria and kidney disease (Fig 2). Fourmonths after dietary gluten restrictions, total fecalweight decreased from 1,369 to 539 g, and totalfecal lipid content did not change significantly.

One curious finding is that high stool volume wasnot associated with increased fecal fat content. Awidely perceived mechanism for increased urinaryoxalate excretion is enhanced binding of luminal fat

testine in biopsy specimens from the patient (top row) and anormal mucosal architecture in patient and control (hematoxylin andh cluster of 4 images shows (clockwise from top left) villin staining26A6 staining (red) (original magnification, �100).

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absorption.7,12 The finding of increased stool volumesuggests impaired salt and water transport throughoutthe intestine from either defective absorption and/orsecretion. Hyperoxaluria conceivably could have oc-curred due to the altered permeability of the intestinalepithelia to oxalate, resulting in absorption. Bothparacellular and transcellular pathways are believedto contribute to oxalate movement in the gut, yet therelative significance of these pathways has not beenfully elucidated. A recent study has speculated that netdietary oxalate absorption is governed by the relativebalance between absorption and transcellular secre-tion governed by the oxalate transporter SLC26A6.20

In rodents, SLC26A6 previously has been describedto mediate intestinal oxalate secretion, and gene dele-tion results in inhibition of intestinal oxalate secre-tion, hyperoxalemia, and secondary “spill-over” hyper-oxaluria.21-23 One could hypothesize that damagedepithelium in our patient with celiac disease mayresult in lower protein expression of SLC26A6, favor-ing intestinal oxalate absorption. It also is plausiblethat subclinical celiac disease with an inflammatoryresponse may have stimulated intestinal oxalate ab-sorption through a cytokine-mediated paracellular“leak pathway.” 20 Therefore, we used immunofluores-cence staining to examine the protein expression ofSLC26A6 in the small bowel of our patient and anunaffected control (Fig 3). In the control, SLC26A6signal was evident on the surface of the microvilli andintracellularly (bottom row). Although villin stainingwas preserved, SLC26A6 staining appeared to bemuch reduced in our patient (top row). We are cogni-zant that immunohistochemistry is not quantitative,but in our view, the difference in staining is remark-able. This raises the possibility that reduction ofintestinal oxalate secretion may also be a mechanismof hyperoxaluria in humans. This finding will need tobe examined further in patients with intestinal hyper-oxaluria.

In our case, the possibility of increased tissueoxalate burden caused by diminished kidney excre-tion is remote. Although serum oxalate concentrationsincrease in patients with end-stage kidney disease,24,25

this increase is not associated with significant tissueaccumulation of oxalate because the increase in uri-nary oxalate excretion after transplant is transient.25-27

This situation is unlike that of our patient, in whomhyperoxaluria and crystal-induced decrease in kidneyfunction occurred several weeks after transplant. Cal-cium oxalate deposition was reported in 4% of unse-lected kidney biopsy specimens from one study.13,28

Interstitial calcium oxalate deposit is not a prominentfeature in patients with calcium oxalate stones.28 Ahigher incidence is shown in transplant biopsy and

transplant nephrectomy specimens.28-30

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Unlike oxalate kidney disease complicating Roux-en-Y gastric bypass,5 kidney function in our patientimproved and was sustained within a normal rangeduring the 52-month follow-up. One major differencebetween this case and oxalate burden detected injejuno-ileal or Roux-en-Y gastric bypass is that adher-ence to dietary gluten restrictions leads to a fullrecovery of kidney function.

In conclusion, the diagnosis of calcium oxalate-induced kidney failure from enteric hyperoxaluria dueto subclinical celiac disease may be cumbersome anddifficult because intestinal biopsy, a gold standard forthe diagnosis of celiac disease, is invasive and sam-pling may be heterogeneous. However, practicingnephrologists must be aware that hyperoxaluria andresultant kidney oxalate deposition is a reversiblecause of kidney failure and intestinal hyperoxaluriacan exist with minimal or no intestinal symptoms. Theaddition of urinary oxalate measurements and carefulserologic investigations should be considered to ex-plore this possibility in patients with unexplainedkidney failure.

ACKNOWLEDGEMENTSThe authors thank Dr Shmuel Muallem (National Institutes of

Health [NIH]) for kind provision of the anti-SLC26A6 antiserum,Dr James Wellons for provision of kidney biopsy slides, Dr Xin J.Zhou for interpretation of kidney biopsy results, Dr JianningZhang for intestinal biopsy immunostaining, Dr Naim Maalouf forconstructive criticism on the manuscript, and Ms Hadley Palmerfor her role in the preparation of the manuscript.

Support: The authors were supported by NIH grants M01-RR00633, P01-DK20543, and R01-DK081423. Dr Capalongo wassupported by a fellowship grant from the Pak Center of MineralMetabolism and Beauticontrol Cosmetics Inc Professorship inMineral Metabolism & Osteoporosis.

Financial Disclosure: The authors declare that they have norelevant financial interests.

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