Case Report Acute Oxalate Nephropathy Associated With Clostridium difficile Colitis Abraham Cohen-Bucay, MD,1 Pranav Garimella, MD, MPH,2 Chukwudi Ezeokonkwo, MD, PhD,1 Vanesa Bijol, MD,3 James A. Strom, MD,4 and Bertrand L. Jaber, MD, MS4 We report the case of a 69-year-old man who presented with acute kidney injury in the setting of communityacquired Clostridium difficile–associated diarrhea and biopsy-proven acute oxalate nephropathy. We discuss potential mechanisms, including increased colonic permeability to oxalate. We conclude that C difficile– associated diarrhea is a potential cause of acute oxalate nephropathy. Am J Kidney Dis. 63(1):113-118. ª 2013 by the National Kidney Foundation, Inc. INDEX WORDS: Acute oxalate nephropathy; Clostridium difficile; acute kidney injury (AKI); acute renal failure; calcium oxalate; acute diarrhea; case report.
H
yperoxaluria, although a frequent cause of nephrolithiasis, is an uncommon but welldocumented cause of acute kidney injury (AKI), known as acute oxalate nephropathy.1 Hyperoxaluria can result in the crystallization and deposition of calcium oxalate in the renal tubules, causing acute tubular injury.1 Under normal circumstances, 10%-15% of the oxalate load originates from enteric absorption, whereas the rest is derived from the endogenous metabolism of glycine, glycolate, glyoxylate, and ascorbic acid.1,2 Although chronic diarrheal illnesses producing fat malabsorption have been associated with acute oxalate nephropathy,3 to our knowledge, there are no reported cases of acute oxalate nephropathy in the setting of acute diarrhea. We report a case of AKI due to biopsy-proven acute oxalate nephropathy in the setting of community-acquired acute Clostridium difficile–associated diarrhea and discuss potential underlying mechanisms.
CASE REPORT A 69-year-old Haitian man with a history of myelodysplastic syndrome presented with nausea and watery diarrhea for 6 days, associated with 1 day of dizziness. His primary care provider had empirically started him on metronidazole therapy 3 days prior to admission. At presentation, serum creatinine (SCr) level was 6.3 mg/dL (corresponding to estimated glomerular filtration rate [eGFR] by the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation4 of 11 mL/min/1.73 m2), compared to 1.4 mg/dL (eGFR . 60 mL/min/1.73 m2) 3 months earlier. He denied prior use of antibiotics, over-the-counter medications, or herbal supplements. Physical examination findings were unremarkable and urinalysis showed no blood or protein. Urine sediment was bland without evidence of casts or crystals. Serum complement levels were low (C3, 64 [reference range, 79-152] mg/dL; C4, 12 [reference range, 16-38] mg/dL). Other serologic workup results were unrevealing. After 24 hours, given a persistently elevated SCr level despite hydration, the patient underwent ultrasound-guided percutaneous kidney biopsy, which revealed prominent oxalate deposition in Am J Kidney Dis. 2014;63(1):113-118
the renal tubules associated with acute tubular necrosis, interstitial inflammation, and edema (Fig 1). The 24-hour urine collection performed on day 4 showed an oxalate excretion rate of 26 mg/d (within the reference range of ,45 mg/d), but a low citrate excretion rate of 46 mg/d (reference, . 320 mg/d). He was treated with oral citrate supplements, intravenous fluids containing sodium bicarbonate, and empirically with pyridoxine to increase the metabolism of oxalate precursors. The diarrhea resolved by day 2, and stool examination for ova and parasites was unrevealing. Evaluation for malabsorption, including serum anti-tissue transglutaminase immunoglobulin A, small-bowel series, and serum levels of vitamin B12 and folate, was unrevealing, except for a decreased fecal elastase level at 158 mg per gram of stool (reference, . 200 mg per gram of stool). The patient was discharged on day 8 with an SCr level of 4.9 mg/dL (eGFR, 14 mL/min/1.73 m2). The patient presented 2 days later with profuse watery diarrhea, abdominal cramping, and nausea. Computed tomography of the abdomen showed diffuse colitis extending from the cecum to the rectum and no evidence of chronic pancreatitis. Stool polymerase chain reaction for C difficile, which had not been tested initially, was positive. His SCr level was 4.4 mg/dL (eGFR, 16 mL/min/ 1.73 m2) at the time of hospital readmission. He was treated with
From the 1Department of Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine; 2Division of Nephrology, Tufts Medical Center; 3Kidney Pathology Service, Department of Pathology, Brigham and Women’s Hospital; and 4 Division of Nephrology, Department of Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA. Received June 24, 2013. Accepted in revised form September 6, 2013. Originally published online November 1, 2013. Because an author of this manuscript is an editor for AJKD, the peer-review and decision-making processes were handled entirely by an Associate Editor (Holly Kramer, MD, MPH) who served as Acting Editor-in-Chief. Details of the journal’s procedures for potential editor conflicts are given in the Editorial Policies section of the AJKD website. Address correspondence to Abraham Cohen-Bucay, MD, St. Elizabeth’s Medical Center, Department of Medicine, 736 Cambridge St, Boston, MA 02135. E-mail: [email protected] 2013 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.09.010 113
Cohen-Bucay et al
Figure 1. Acute oxalate nephropathy. Kidney biopsy specimen shows (A) nonspecific glomerular changes and frequent deposits of oxalate crystals within the tubular lumens, with (B) characteristic bright birefringence when viewed under polarized light (hematoxylin and eosin; original magnification 3200). (C) Deposits consist of needle-like crystals packed in rosettes or fanlike arrangements, causing tubular damage and eliciting an inflammatory reaction in the surrounding interstitium; frequent eosinophils, interstitial edema, and degenerative changes of the tubular epithelium also are noted (hematoxylin and eosin; original magnification 3400).
oral metronidazole and a probiotic Lactobacillus formulation. The diarrhea resolved and he was discharged 3 days later. He remained symptom free and at the 3-month follow-up, SCr level was down to 2.4 mg/dL (eGFR, 31 mL/min/1.73 m2).
DISCUSSION Acute oxalate nephropathy can be caused by an increase in endogenous production or intestinal absorption of oxalate. The former is associated with ingestion of oxalate precursors such as ethylene glycol5 or excessive vitamin C,5,6 vitamin B6 (pyridoxine) deficiency,1 and primary hyperoxalurias, which are rare autosomal recessive enzymatic deficiencies that lead to oxalate overproduction.5 Increased intestinal absorption of oxalate can be caused by 3 different mechanisms: (1) increased dietary oxalate intake, which has been described after ingestion of large amounts of peanuts,7 rhubarb,8 Chaga mushroom,9 and starfruit or carambola juice10,11; (2) increased oxalate availability in the colon due to fat malabsorption (Crohn disease, celiac sprue, jejunoileal bypass, ileal resection, or chronic pancreatitis)1,3 or decreased enteric colonization by oxalate-degrading bacteria1,12; and (3) increased colonic permeability to oxalate.3,13 No obvious cause for the acute oxalate nephropathy was identified in our patient. He specifically denied ingestion of high-oxalate–containing foods or oxalate precursors such as vitamin C or ethylene glycol. Primary hyperoxaluria was unlikely because this inherited condition presents earlier in life and our 114
patient had a normal 24-hour urine oxalate excretion rate.3 Despite a low fecal elastase level, he did not meet the diagnostic criteria for chronic pancreatitis.14,15 We postulate that this patient’s initial presentation likely was due to community-associated C difficile infection that was partially treated before admission, resulting in resolution of the diarrhea on the initial presentation. However, the resulting colitis involving the entire colon may have led to an acute hyperoxaluric state that resulted in acute oxalate nephropathy. Ingested oxalate binds to calcium in the intestinal lumen and forms an insoluble calcium oxalate complex, therefore limiting the absorption to 10%-12% of ingested oxalate.2 In pathologic states of fat malabsorption, calcium preferentially binds to free fatty acids, thereby increasing intestinal soluble oxalate content, leading to increased colonic oxalate absorption.1,3 This mechanism has been described in patients with inflammatory bowel disease affecting the small bowel,3,13 Roux-en-Y gastric bypass surgery,16 and following therapy with orlistat (a gastrointestinal lipase inhibitor).17-19 Other mechanisms, such as increased colonic permeability to oxalate, also have been proposed.3,13 Because dietary oxalate is absorbed through the paracellular pathway by simple diffusion, its absorption is accelerated under conditions associated with increased permeability of the tight junctions of the colonic cells. The C difficile toxin disrupts the epithelial barrier function by altering the tight junction Am J Kidney Dis. 2014;63(1):113-118
SCr (mg/dL) Reference
Treatment
Outcome & f/u SCr (mg/dL)
Baseline
At Presentation
Mandel et al26 (1980)
36/F
0.5-1.0
10.1
Crohn disease
Yes
HD
Recovery, 1.2
Canos et al27 (1981)
56/F
1.1
2.4
Jejunoileal bypass
No
Supportive medical therapy, reversal of bypass
Recovery, NA
69/F
1.2
3.3
Partial gastric resection/ steatorrhea
No
Supportive medical therapy
Recovery, NA
Wharton et al37 (1990)
GI Disorder
Recent Antibiotic Use
Age (y)/Sex
72/M
2.0-2.5
24
Small-bowel resection
No
HD
ESRD
57/M
2.6
13
Chronic pancreatitis
No
PD
ESRD
Fakhouri et al28 (2002)
69/M
0.9
6.3
Chronic pancreatitis
Yes
HD
ESRD
Cuvelier et al29 (2002)
37/M
NAa
7.3
Chronic pancreatitis
No
HD
Recovery, 2.1
Mpofu et al30 (2003)
78/F
NA
4.6
Systemic sclerosis/pancreatic insufficiency
No
Supportive medical therapy
Recovery, 3.6
Lefaucheur et al31 (2006)
17/M
NA
9.2
Cystic fibrosis (lung-liver Tx recipient)
Yes
HD, kidney Tx
Recovery, 1.0
33/M
0.8
NA
Cystic fibrosis (lung Tx recipient)
Yes
HD
ESRD
Singh et al18 (2007) Courtney et al32 (2007)
57/F 55/F
2.5 1.6
5.8 7.1
Orlistat treatment Orlistat treatment
No No
Supportive medical therapy HD
Recovery, 2.5 ESRD
Rankin et al33 (2008)
70/M
1.1-1.4a
5.4
Chronic pancreatitis
No
HD
Recovery, 2.1
16
69/F
1.2
6.5
Roux-en-Y gastric bypass
NA
HD
ESRD
56/M
NA
8.8
Roux-en-Y gastric bypass
NA
HD
ESRD
45/M
1.4
9.2
Roux-en-Y gastric bypass
NA
HD
ESRD
55/M
1.5
7.6
Roux-en-Y gastric bypass
NA
HD
ESRD
63/F
1.3
3.5
Roux-en-Y gastric bypass
NA
HD
Recovery, 2.0
59/F 55/F
1.2 1.4
5.1 3.4
Roux-en-Y gastric bypass Roux-en-Y gastric bypass
NA NA
HD Supportive medical therapy
ESRD Recovery, 3.0
Nasr et al
(2008)
Karamadoukis et al17 (2009)
59/F
1.7
4.2
Roux-en-Y gastric bypass
NA
Supportive medical therapy
Recovery, 4.4
77/M
0.9
10.0
Total gastrectomy/Roux-en-Y gastric bypass
NA
HD
ESRD
79/M
2.5
6.0
NA
HD
ESRD
57/F
1.6
7.5
NA
HD
ESRD
66/M
NA
4.6
Total gastrectomy/Roux-en-Y gastric bypass Total gastrectomy/Roux-en-Y gastric bypass Orlistat treatment
No
HD
Death
(Continued)
Acute Oxalate Nephropathy
Am J Kidney Dis. 2014;63(1):113-118
Table 1. Clinical and Laboratory Features of 45 Patients Presenting With Biopsy-Proven Acute Oxalate Nephropathy Associated With GI Disorders
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116
Table 1 (Cont’d). Clinical and Laboratory Features of 45 Patients Presenting With Biopsy-Proven Acute Oxalate Nephropathy Associated With GI Disorders SCr (mg/dL) Reference
GI Disorder
Recent Antibiotic Use
Treatment
Outcome & f/u SCr (mg/dL)
Age (y)/Sex
Baseline
At Presentation
Beloncle et al34 (2011)
66/M
0.7
4.1
Pancreatic insufficiency (liver Tx recipient)
No
HD
ESRD
Sentis et al35 (2011)
59/NA
NA
9.6
Surgery-induced fat malabsorption
No
Supportive medical therapy
Recovery, 2.0
Cartery et al13 (2011)
56/M
2.0
3.6
Exocrine pancreatic insufficiency
Yes
Supportive medical therapy
ESRD ESRD
62/F
1.2
7.8
Chronic pancreatitis
No
Supportive medical therapy
50/F
0.8
3.3
Chronic pancreatitis
Yes
CVVH
Recovery, 1.1
90/M
1.3
8.3
Chronic pancreatitis
No
Supportive medical therapy
Recovery, 2.3
83/M
1.4
4.8
Chronic pancreatitis
No
HD
Recovery, 4.2
76/M
1.3
9.0
Chronic pancreatitis
No
HD
ESRD
67/M
0.9
4.6
Chronic pancreatitis
No
Supportive medical therapy
Recovery, 2.4
69/M 41/M
1.1 1.5
9.6 6.6
Chronic pancreatitis Chronic pancreatitis
No Yes
Supportive medical therapy Supportive medical therapy
Recovery, 4.6 Recovery, 2.6
80/F
1.0
3.9
Chronic pancreatitis
No
Supportive medical therapy
Recovery, 2.0
56/M
1.0
7.4
Chronic pancreatitis
No
HD
Recovery, 2.1
73/M 48/F
1.1 2
8.5 6
Chronic pancreatitis Roux-en-Y gastric bypass
Yes No
HD HD
Recovery, 3.7 ESRD
57/F
2.0
5.3
Celiac disease
No
Recovery, 1.2
Dheda et al39 (2012)
29/M
NA
NA
Cystic fibrosis (lung-liver Tx recipient)
Yes
Supportive medical therapy, kidney Tx HD, kidney Tx
Kwan et al19 (2013)
60/F
1.1
8.2
Orlistat treatment
No
HD
Recovery, NA
Troxell et al40 (2013)
70/F
1.1-1.2
1.8
Gastric bypass surgery (kidney Tx recipient)
No
Supportive medical therapy
Recovery, 1.4
67/M
1.5-2.2
6.0
Roux-en-Y gastric bypass (kidney Tx recipient)
Yes
HD
ESRD
Moutzouris et al36 (2011) Capolongo et al38 (2012)
Recovery, 1.4
Cohen-Bucay et al
Am J Kidney Dis. 2014;63(1):113-118
Note: Conversion factor for units: SCr in mg/dL to mmol/L, 388.4. Abbreviations: CVVH, continuous venovenous hemofiltration; ESRD, end-stage renal disease; f/u, follow-up; GI, gastrointestinal; HD, hemodialysis; NA, not available; PD, peritoneal dialysis; SCr, serum creatinine; Tx, transplant. a Post kidney Tx.
Acute Oxalate Nephropathy
proteins,20 which theoretically can increase the colon’s permeability to oxalate. C difficile–associated diarrhea affects mainly the colon, but there have been cases with evidence of small-bowel involvement,21-23 which theoretically could lead to fat malabsorption, as well as increased colonic permeability to oxalate by the same mechanisms as inflammatory bowel disease. Our patient did not have evidence of smallbowel disease based on the small-bowel series. Enteric oxalate is degraded by normal intestinal flora, including Oxalobacter formigenes and certain strains of Enterococcus faecalis, Lactobacillus, and Bifidobacterium.1,12 Because C difficile–associated diarrhea is related to alterations in normal intestinal flora, we hypothesize that this change, along with a possible decrease in oxalate-degrading bacteria, resulted in increased intestinal intraluminal oxalate content in our patient. The fact that O formigenes is sensitive to metronidazole24 might have contributed to impaired intestinal oxalate degradation. The use of multiple successive antibiotic treatments over a prolonged period has been identified as a risk factor for acute oxalate nephropathy,25 which supports this hypothesis. We identified 45 reported cases of biopsy-proven acute oxalate nephropathy associated with gastrointestinal disorders (Table 1).13,16-19,26-40 Mean age was 60 years. Baseline mean SCr level was 1.4 (range, 0.7-2.6) mg/dL, and at presentation, 6.8 (range, 1.8-24) mg/dL. Four cases involved kidney transplant recipients. Thirty (66%) patients required acute dialysis, of whom 17 (55%) progressed to end-stage kidney disease, 2 (6%) received a kidney transplant, and 1 (2%) died. Of the other 15 patients who received supportive medical therapy, 2 (13%) progressed to end-stage kidney disease, 1 (6%) received a kidney transplant, and none died. Supportive medical therapy included intravenous fluids, pyridoxine, diet modifications, citrate supplementation, and treatment of the underlying gastrointestinal disorder. Only 35 cases provided information regarding recent antibiotic exposure. Eleven (31%) patients had recent antibiotic exposure. None of the cases reported testing for C difficile. This case report is limited by the lack of hyperoxaluria. We can only speculate as to whether the decreased GFR from AKI at the time of the kidney biopsy resulted in decreased urinary oxalate excretion. In addition, the 24-hour urine collection for oxalate measurement occurring nearly 4 days after the initial insult might have missed the transient hyperoxaluric state. We also were unable to document a decrease in oxalate-degrading bacteria intestinal colonization. Also confounding is the fact that our patient had mildly decreased fecal elastase levels, but Am J Kidney Dis. 2014;63(1):113-118
no other features of chronic pancreatitis or pancreatic insufficiency. In conclusion, to our knowledge, this is the first case reporting a possible link between C difficile– associated diarrhea and the development of acute oxalate nephropathy. Studies are needed to identify risk factors for the development of acute oxalate nephropathy in patients with C difficile–associated diarrhea and elucidate its potential underlying mechanisms, with the hope of designing preventive and treatment strategies. A high index of suspicion for acute oxalate nephropathy is required in patients with unexplained AKI in the setting of acute or chronic diarrheal syndromes, exocrine pancreatic insufficiency, and prolonged antibiotic therapy.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
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Cohen-Bucay et al understanding the rarity of urolithiasis in the black group. J Appl Microbiol. 2012;113(2):418-428. 13. Cartery C, Faguer S, Karras A, et al. Oxalate nephropathy associated with chronic pancreatitis. Clin J Am Soc Nephrol. 2011;6(8):1895-1902. 14. Schneider A, Löhr JM, Singer MV. The M-ANNHEIM classification of chronic pancreatitis: introduction of a unifying classification system based on a review of previous classifications of the disease. J Gastroenterol. 2007;42(2):101-119. 15. Shimosegawa T, Kataoka K, Kamisawa T, et al. The revised Japanese clinical diagnostic criteria for chronic pancreatitis. J Gastroenterol. 2010;45(6):584-591. 16. Nasr SH, D’Agati VD, Said SM, et al. Oxalate nephropathy complicating Roux-en-Y gastric bypass: an underrecognized cause of irreversible renal failure. Clin J Am Soc Nephrol. 2008;3(6): 1676-1683. 17. Karamadoukis L, Shivashankar GH, Ludeman L, Williams AJ. An unusual complication of treatment with orlistat. Clin Nephrol. 2009;71(4):430-432. 18. Singh A, Sarkar SR, Gaber LW, Perazella MA. Acute oxalate nephropathy associated with orlistat, a gastrointestinal lipase inhibitor. Am J Kidney Dis. 2007;49(1):153-157. 19. Kwan TK, Chadban SJ, McKenzie PR, Saunders JR. Acute oxalate nephropathy secondary to orlistat-induced enteric hyperoxaluria. Nephrology (Carlton). 2013;18(3):241-242. 20. Nusrat A, von Eichel-Streiber C, Turner JR, Verkade P, Madara JL, Parkos CA. Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins. Infect Immun. 2001;69(3):1329-1336. 21. Jacobs A, Barnard K, Fishel R, Gradon JD. Extracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of the literature. Medicine. 2001;80(2):88-101. 22. Vesoulis Z, Williams G, Matthews B. Pseudomembranous enteritis after proctocolectomy: report of a case. Dis Colon Rectum. 2000;43(4):551-554. 23. Hayetian FD, Read TE, Brozovich M, Garvin RP, Caushaj PF. Ileal perforation secondary to Clostridium difficile enteritis: report of 2 cases. Arch Surg. 2006;141(1):97-99. 24. Lange JN, Wood KD, Wong H, et al. Sensitivity of human strains of Oxalobacter formigenes to commonly prescribed antibiotics. Urology. 2012;79(6):1286-1289. 25. Gariani K, de Seigneux S, Courbebaisse M, Lévy M, Moll S, Martin P-Y. Oxalate nephropathy induced by octreotide treatment for acromegaly: a case report. J Med Case Rep. 2012;6(1):215. 26. Mandell I, Krauss E, Millan JC. Oxalate-induced acute renal failure in Crohn’s disease. Am J Med. 1980;69(4):628-632. 27. Canos HJ, Hogg GA, Jeffery JR. Oxalate nephropathy due to gastrointestinal disorders. Can Med Assoc J. 1981;124(6): 729-733.
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28. Fakhouri F, Chauveau D, Touam M, Noël L-H, Grünfeld J-P. Crystals from fat. Acute oxalate nephropathy. Nephrol Dial Transplant. 2002;17(7):1348-1350. 29. Cuvelier C, Goffin E, Cosyns J-P, Wauthier M, de Strihou C van Y. Enteric hyperoxaluria: a hidden cause of early renal graft failure in two successive transplants: spontaneous late graft recovery. Am J Kidney Dis. 2002;40(1):E3. 30. Mpofu S, Rhodes JM, Mpofu CMA, Moots RJ. An unusual cause of acute renal failure in systemic sclerosis. Ann Rheum Dis. 2003;62(12):1133-1134. 31. Lefaucheur C, Hill GS, Amrein C, et al. Acute oxalate nephropathy: a new etiology for acute renal failure following nonrenal solid organ transplantation. Am J Transplant. 2006;6(10): 2516-2521. 32. Courtney AE, O’Rourke DM, Maxwell AP. Rapidly progressive renal failure associated with successful pharmacotherapy for obesity. Nephrol Dial Transplant. 2007;22(2):621-623. 33. Rankin AC, Walsh SB, Summers SA, Owen MP, Mansell MA. Acute oxalate nephropathy causing late renal transplant dysfunction due to enteric hyperoxaluria. Am J Transplant. 2008;8(8):1755-1758. 34. Beloncle F, Sayegh J, Duveau A, et al. An unexpected cause of progressive renal failure in a 66-year-old male after liver transplantation: secondary hyperoxaluria. Int Urol Nephrol. 2012;45(4):1209-1213. 35. Sentís A, Quintana LF, Massó E, Peréz NS, Botey Puig A, Campistol Plana JM. Acute renal failure due to oxalate crystal deposition and enteric hyperoxaluria. Nefrología. 2011;31(1):121-123. 36. Moutzouris D-A, Skaneli G, Margellos V, Apostolou T, Petraki C, Nikolopoulou N. Oxalate nephropathy in a diabetic patient after gastric by-pass. Clin Nephrol. 2011;75(suppl 1): 16-19. 37. Wharton R, D’Agati V, Magun AM, Whitlock R, Kunis CL, Appel GB. Acute deterioration of renal function associated with enteric hyperoxaluria. Clin Nephrol. 1990;34(3): 116-121. 38. Capolongo G, Abul-Ezz S, Moe OW, Sakhaee K. Subclinical celiac disease and crystal-induced kidney disease following kidney transplant. Am J Kidney Dis. 2012;60(4): 662-667. 39. Dheda S, Swaminathan R, Musk M, Sinniah R, Lawrence S, Irish A. Acute irreversible oxalate nephropathy in a lung transplant recipient treated successfully with a renal transplant. Nephrology (Carlton). 2012;17(suppl 1):12-15. 40. Troxell ML, Houghton DC, Hawkey M, Batiuk TD, Bennett WM. Enteric oxalate nephropathy in the renal allograft: an underrecognized complication of bariatric surgery. Am J Transplant. 2013;13(2):501-509.
Am J Kidney Dis. 2014;63(1):113-118
H
yperoxaluria, although a frequent cause of nephrolithiasis, is an uncommon but welldocumented cause of acute kidney injury (AKI), known as acute oxalate nephropathy.1 Hyperoxaluria can result in the crystallization and deposition of calcium oxalate in the renal tubules, causing acute tubular injury.1 Under normal circumstances, 10%-15% of the oxalate load originates from enteric absorption, whereas the rest is derived from the endogenous metabolism of glycine, glycolate, glyoxylate, and ascorbic acid.1,2 Although chronic diarrheal illnesses producing fat malabsorption have been associated with acute oxalate nephropathy,3 to our knowledge, there are no reported cases of acute oxalate nephropathy in the setting of acute diarrhea. We report a case of AKI due to biopsy-proven acute oxalate nephropathy in the setting of community-acquired acute Clostridium difficile–associated diarrhea and discuss potential underlying mechanisms.
CASE REPORT A 69-year-old Haitian man with a history of myelodysplastic syndrome presented with nausea and watery diarrhea for 6 days, associated with 1 day of dizziness. His primary care provider had empirically started him on metronidazole therapy 3 days prior to admission. At presentation, serum creatinine (SCr) level was 6.3 mg/dL (corresponding to estimated glomerular filtration rate [eGFR] by the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation4 of 11 mL/min/1.73 m2), compared to 1.4 mg/dL (eGFR . 60 mL/min/1.73 m2) 3 months earlier. He denied prior use of antibiotics, over-the-counter medications, or herbal supplements. Physical examination findings were unremarkable and urinalysis showed no blood or protein. Urine sediment was bland without evidence of casts or crystals. Serum complement levels were low (C3, 64 [reference range, 79-152] mg/dL; C4, 12 [reference range, 16-38] mg/dL). Other serologic workup results were unrevealing. After 24 hours, given a persistently elevated SCr level despite hydration, the patient underwent ultrasound-guided percutaneous kidney biopsy, which revealed prominent oxalate deposition in Am J Kidney Dis. 2014;63(1):113-118
the renal tubules associated with acute tubular necrosis, interstitial inflammation, and edema (Fig 1). The 24-hour urine collection performed on day 4 showed an oxalate excretion rate of 26 mg/d (within the reference range of ,45 mg/d), but a low citrate excretion rate of 46 mg/d (reference, . 320 mg/d). He was treated with oral citrate supplements, intravenous fluids containing sodium bicarbonate, and empirically with pyridoxine to increase the metabolism of oxalate precursors. The diarrhea resolved by day 2, and stool examination for ova and parasites was unrevealing. Evaluation for malabsorption, including serum anti-tissue transglutaminase immunoglobulin A, small-bowel series, and serum levels of vitamin B12 and folate, was unrevealing, except for a decreased fecal elastase level at 158 mg per gram of stool (reference, . 200 mg per gram of stool). The patient was discharged on day 8 with an SCr level of 4.9 mg/dL (eGFR, 14 mL/min/1.73 m2). The patient presented 2 days later with profuse watery diarrhea, abdominal cramping, and nausea. Computed tomography of the abdomen showed diffuse colitis extending from the cecum to the rectum and no evidence of chronic pancreatitis. Stool polymerase chain reaction for C difficile, which had not been tested initially, was positive. His SCr level was 4.4 mg/dL (eGFR, 16 mL/min/ 1.73 m2) at the time of hospital readmission. He was treated with
From the 1Department of Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine; 2Division of Nephrology, Tufts Medical Center; 3Kidney Pathology Service, Department of Pathology, Brigham and Women’s Hospital; and 4 Division of Nephrology, Department of Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA. Received June 24, 2013. Accepted in revised form September 6, 2013. Originally published online November 1, 2013. Because an author of this manuscript is an editor for AJKD, the peer-review and decision-making processes were handled entirely by an Associate Editor (Holly Kramer, MD, MPH) who served as Acting Editor-in-Chief. Details of the journal’s procedures for potential editor conflicts are given in the Editorial Policies section of the AJKD website. Address correspondence to Abraham Cohen-Bucay, MD, St. Elizabeth’s Medical Center, Department of Medicine, 736 Cambridge St, Boston, MA 02135. E-mail: [email protected] 2013 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.09.010 113
Cohen-Bucay et al
Figure 1. Acute oxalate nephropathy. Kidney biopsy specimen shows (A) nonspecific glomerular changes and frequent deposits of oxalate crystals within the tubular lumens, with (B) characteristic bright birefringence when viewed under polarized light (hematoxylin and eosin; original magnification 3200). (C) Deposits consist of needle-like crystals packed in rosettes or fanlike arrangements, causing tubular damage and eliciting an inflammatory reaction in the surrounding interstitium; frequent eosinophils, interstitial edema, and degenerative changes of the tubular epithelium also are noted (hematoxylin and eosin; original magnification 3400).
oral metronidazole and a probiotic Lactobacillus formulation. The diarrhea resolved and he was discharged 3 days later. He remained symptom free and at the 3-month follow-up, SCr level was down to 2.4 mg/dL (eGFR, 31 mL/min/1.73 m2).
DISCUSSION Acute oxalate nephropathy can be caused by an increase in endogenous production or intestinal absorption of oxalate. The former is associated with ingestion of oxalate precursors such as ethylene glycol5 or excessive vitamin C,5,6 vitamin B6 (pyridoxine) deficiency,1 and primary hyperoxalurias, which are rare autosomal recessive enzymatic deficiencies that lead to oxalate overproduction.5 Increased intestinal absorption of oxalate can be caused by 3 different mechanisms: (1) increased dietary oxalate intake, which has been described after ingestion of large amounts of peanuts,7 rhubarb,8 Chaga mushroom,9 and starfruit or carambola juice10,11; (2) increased oxalate availability in the colon due to fat malabsorption (Crohn disease, celiac sprue, jejunoileal bypass, ileal resection, or chronic pancreatitis)1,3 or decreased enteric colonization by oxalate-degrading bacteria1,12; and (3) increased colonic permeability to oxalate.3,13 No obvious cause for the acute oxalate nephropathy was identified in our patient. He specifically denied ingestion of high-oxalate–containing foods or oxalate precursors such as vitamin C or ethylene glycol. Primary hyperoxaluria was unlikely because this inherited condition presents earlier in life and our 114
patient had a normal 24-hour urine oxalate excretion rate.3 Despite a low fecal elastase level, he did not meet the diagnostic criteria for chronic pancreatitis.14,15 We postulate that this patient’s initial presentation likely was due to community-associated C difficile infection that was partially treated before admission, resulting in resolution of the diarrhea on the initial presentation. However, the resulting colitis involving the entire colon may have led to an acute hyperoxaluric state that resulted in acute oxalate nephropathy. Ingested oxalate binds to calcium in the intestinal lumen and forms an insoluble calcium oxalate complex, therefore limiting the absorption to 10%-12% of ingested oxalate.2 In pathologic states of fat malabsorption, calcium preferentially binds to free fatty acids, thereby increasing intestinal soluble oxalate content, leading to increased colonic oxalate absorption.1,3 This mechanism has been described in patients with inflammatory bowel disease affecting the small bowel,3,13 Roux-en-Y gastric bypass surgery,16 and following therapy with orlistat (a gastrointestinal lipase inhibitor).17-19 Other mechanisms, such as increased colonic permeability to oxalate, also have been proposed.3,13 Because dietary oxalate is absorbed through the paracellular pathway by simple diffusion, its absorption is accelerated under conditions associated with increased permeability of the tight junctions of the colonic cells. The C difficile toxin disrupts the epithelial barrier function by altering the tight junction Am J Kidney Dis. 2014;63(1):113-118
SCr (mg/dL) Reference
Treatment
Outcome & f/u SCr (mg/dL)
Baseline
At Presentation
Mandel et al26 (1980)
36/F
0.5-1.0
10.1
Crohn disease
Yes
HD
Recovery, 1.2
Canos et al27 (1981)
56/F
1.1
2.4
Jejunoileal bypass
No
Supportive medical therapy, reversal of bypass
Recovery, NA
69/F
1.2
3.3
Partial gastric resection/ steatorrhea
No
Supportive medical therapy
Recovery, NA
Wharton et al37 (1990)
GI Disorder
Recent Antibiotic Use
Age (y)/Sex
72/M
2.0-2.5
24
Small-bowel resection
No
HD
ESRD
57/M
2.6
13
Chronic pancreatitis
No
PD
ESRD
Fakhouri et al28 (2002)
69/M
0.9
6.3
Chronic pancreatitis
Yes
HD
ESRD
Cuvelier et al29 (2002)
37/M
NAa
7.3
Chronic pancreatitis
No
HD
Recovery, 2.1
Mpofu et al30 (2003)
78/F
NA
4.6
Systemic sclerosis/pancreatic insufficiency
No
Supportive medical therapy
Recovery, 3.6
Lefaucheur et al31 (2006)
17/M
NA
9.2
Cystic fibrosis (lung-liver Tx recipient)
Yes
HD, kidney Tx
Recovery, 1.0
33/M
0.8
NA
Cystic fibrosis (lung Tx recipient)
Yes
HD
ESRD
Singh et al18 (2007) Courtney et al32 (2007)
57/F 55/F
2.5 1.6
5.8 7.1
Orlistat treatment Orlistat treatment
No No
Supportive medical therapy HD
Recovery, 2.5 ESRD
Rankin et al33 (2008)
70/M
1.1-1.4a
5.4
Chronic pancreatitis
No
HD
Recovery, 2.1
16
69/F
1.2
6.5
Roux-en-Y gastric bypass
NA
HD
ESRD
56/M
NA
8.8
Roux-en-Y gastric bypass
NA
HD
ESRD
45/M
1.4
9.2
Roux-en-Y gastric bypass
NA
HD
ESRD
55/M
1.5
7.6
Roux-en-Y gastric bypass
NA
HD
ESRD
63/F
1.3
3.5
Roux-en-Y gastric bypass
NA
HD
Recovery, 2.0
59/F 55/F
1.2 1.4
5.1 3.4
Roux-en-Y gastric bypass Roux-en-Y gastric bypass
NA NA
HD Supportive medical therapy
ESRD Recovery, 3.0
Nasr et al
(2008)
Karamadoukis et al17 (2009)
59/F
1.7
4.2
Roux-en-Y gastric bypass
NA
Supportive medical therapy
Recovery, 4.4
77/M
0.9
10.0
Total gastrectomy/Roux-en-Y gastric bypass
NA
HD
ESRD
79/M
2.5
6.0
NA
HD
ESRD
57/F
1.6
7.5
NA
HD
ESRD
66/M
NA
4.6
Total gastrectomy/Roux-en-Y gastric bypass Total gastrectomy/Roux-en-Y gastric bypass Orlistat treatment
No
HD
Death
(Continued)
Acute Oxalate Nephropathy
Am J Kidney Dis. 2014;63(1):113-118
Table 1. Clinical and Laboratory Features of 45 Patients Presenting With Biopsy-Proven Acute Oxalate Nephropathy Associated With GI Disorders
115
116
Table 1 (Cont’d). Clinical and Laboratory Features of 45 Patients Presenting With Biopsy-Proven Acute Oxalate Nephropathy Associated With GI Disorders SCr (mg/dL) Reference
GI Disorder
Recent Antibiotic Use
Treatment
Outcome & f/u SCr (mg/dL)
Age (y)/Sex
Baseline
At Presentation
Beloncle et al34 (2011)
66/M
0.7
4.1
Pancreatic insufficiency (liver Tx recipient)
No
HD
ESRD
Sentis et al35 (2011)
59/NA
NA
9.6
Surgery-induced fat malabsorption
No
Supportive medical therapy
Recovery, 2.0
Cartery et al13 (2011)
56/M
2.0
3.6
Exocrine pancreatic insufficiency
Yes
Supportive medical therapy
ESRD ESRD
62/F
1.2
7.8
Chronic pancreatitis
No
Supportive medical therapy
50/F
0.8
3.3
Chronic pancreatitis
Yes
CVVH
Recovery, 1.1
90/M
1.3
8.3
Chronic pancreatitis
No
Supportive medical therapy
Recovery, 2.3
83/M
1.4
4.8
Chronic pancreatitis
No
HD
Recovery, 4.2
76/M
1.3
9.0
Chronic pancreatitis
No
HD
ESRD
67/M
0.9
4.6
Chronic pancreatitis
No
Supportive medical therapy
Recovery, 2.4
69/M 41/M
1.1 1.5
9.6 6.6
Chronic pancreatitis Chronic pancreatitis
No Yes
Supportive medical therapy Supportive medical therapy
Recovery, 4.6 Recovery, 2.6
80/F
1.0
3.9
Chronic pancreatitis
No
Supportive medical therapy
Recovery, 2.0
56/M
1.0
7.4
Chronic pancreatitis
No
HD
Recovery, 2.1
73/M 48/F
1.1 2
8.5 6
Chronic pancreatitis Roux-en-Y gastric bypass
Yes No
HD HD
Recovery, 3.7 ESRD
57/F
2.0
5.3
Celiac disease
No
Recovery, 1.2
Dheda et al39 (2012)
29/M
NA
NA
Cystic fibrosis (lung-liver Tx recipient)
Yes
Supportive medical therapy, kidney Tx HD, kidney Tx
Kwan et al19 (2013)
60/F
1.1
8.2
Orlistat treatment
No
HD
Recovery, NA
Troxell et al40 (2013)
70/F
1.1-1.2
1.8
Gastric bypass surgery (kidney Tx recipient)
No
Supportive medical therapy
Recovery, 1.4
67/M
1.5-2.2
6.0
Roux-en-Y gastric bypass (kidney Tx recipient)
Yes
HD
ESRD
Moutzouris et al36 (2011) Capolongo et al38 (2012)
Recovery, 1.4
Cohen-Bucay et al
Am J Kidney Dis. 2014;63(1):113-118
Note: Conversion factor for units: SCr in mg/dL to mmol/L, 388.4. Abbreviations: CVVH, continuous venovenous hemofiltration; ESRD, end-stage renal disease; f/u, follow-up; GI, gastrointestinal; HD, hemodialysis; NA, not available; PD, peritoneal dialysis; SCr, serum creatinine; Tx, transplant. a Post kidney Tx.
Acute Oxalate Nephropathy
proteins,20 which theoretically can increase the colon’s permeability to oxalate. C difficile–associated diarrhea affects mainly the colon, but there have been cases with evidence of small-bowel involvement,21-23 which theoretically could lead to fat malabsorption, as well as increased colonic permeability to oxalate by the same mechanisms as inflammatory bowel disease. Our patient did not have evidence of smallbowel disease based on the small-bowel series. Enteric oxalate is degraded by normal intestinal flora, including Oxalobacter formigenes and certain strains of Enterococcus faecalis, Lactobacillus, and Bifidobacterium.1,12 Because C difficile–associated diarrhea is related to alterations in normal intestinal flora, we hypothesize that this change, along with a possible decrease in oxalate-degrading bacteria, resulted in increased intestinal intraluminal oxalate content in our patient. The fact that O formigenes is sensitive to metronidazole24 might have contributed to impaired intestinal oxalate degradation. The use of multiple successive antibiotic treatments over a prolonged period has been identified as a risk factor for acute oxalate nephropathy,25 which supports this hypothesis. We identified 45 reported cases of biopsy-proven acute oxalate nephropathy associated with gastrointestinal disorders (Table 1).13,16-19,26-40 Mean age was 60 years. Baseline mean SCr level was 1.4 (range, 0.7-2.6) mg/dL, and at presentation, 6.8 (range, 1.8-24) mg/dL. Four cases involved kidney transplant recipients. Thirty (66%) patients required acute dialysis, of whom 17 (55%) progressed to end-stage kidney disease, 2 (6%) received a kidney transplant, and 1 (2%) died. Of the other 15 patients who received supportive medical therapy, 2 (13%) progressed to end-stage kidney disease, 1 (6%) received a kidney transplant, and none died. Supportive medical therapy included intravenous fluids, pyridoxine, diet modifications, citrate supplementation, and treatment of the underlying gastrointestinal disorder. Only 35 cases provided information regarding recent antibiotic exposure. Eleven (31%) patients had recent antibiotic exposure. None of the cases reported testing for C difficile. This case report is limited by the lack of hyperoxaluria. We can only speculate as to whether the decreased GFR from AKI at the time of the kidney biopsy resulted in decreased urinary oxalate excretion. In addition, the 24-hour urine collection for oxalate measurement occurring nearly 4 days after the initial insult might have missed the transient hyperoxaluric state. We also were unable to document a decrease in oxalate-degrading bacteria intestinal colonization. Also confounding is the fact that our patient had mildly decreased fecal elastase levels, but Am J Kidney Dis. 2014;63(1):113-118
no other features of chronic pancreatitis or pancreatic insufficiency. In conclusion, to our knowledge, this is the first case reporting a possible link between C difficile– associated diarrhea and the development of acute oxalate nephropathy. Studies are needed to identify risk factors for the development of acute oxalate nephropathy in patients with C difficile–associated diarrhea and elucidate its potential underlying mechanisms, with the hope of designing preventive and treatment strategies. A high index of suspicion for acute oxalate nephropathy is required in patients with unexplained AKI in the setting of acute or chronic diarrheal syndromes, exocrine pancreatic insufficiency, and prolonged antibiotic therapy.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
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