Acute oxalate nephropathy associated with Clostridium difficile infection

Abstract

Acute oxalate nephropathy has been associated with chronic diarrheal illness and only one case has been reported due to acute diarrhea secondary to Clostridium difficile colitis. To the best of our knowledge, this is the second case report of acute oxalate nephropathy due to C. difficile colitis. A 75-year-old man with a medical history of hypertension, type 2 diabetes mellitus, chronic kidney disease stage IV, recent C. difficile colitis was admitted for acute kidney injury with a creatinine (Cr) of 8.54 mg/dL (baseline Cr, 2.3–2.6 mg/dL). His urinalysis did not show any eosinophils, casts or crystals. Antinuclear antibody, antineutrophil cytoplasmic antibody, complement levels (C3 and C4) and hepatitis screen were negative; a renal ultrasound visualized no hydronephrosis. A kidney biopsy showed widespread tubular oxalate crystal deposition suggestive of hyperoxaluria as the cause of acute kidney injury. In conclusion, an acute diarrheal illness like C. difficile colitis can cause acute oxalate nephropathy.

Background

Acute oxalate nephropathy can be caused by either increased endogenous production or increased intestinal absorption of oxalate. The former includes primary hyperoxaluria which is a group of autosomal recessively inherited enzyme deficiencies that lead to the increased urinary excretion of oxalate or secondary hyperoxaluria due to ingestion of oxalate precursors—excessive vitamin C, ethylene glycol ingestion and vitamin B₆ deficiency.^{1 2} The latter is associated with increased dietary oxalate intake (ingestion of rhubarb, chug mushroom, starfruit), increased oxalate availability due to fat malabsorption (chronic pancreatitis, Crohn’s disease, celiac sprue and bariatric surgery) or reduction in oxalate degrading bacteria and, increased colonic permeability such as in inflammatory bowel diseases.^3–6 Acute oxalate nephropathy has been associated with chronic diarrheal illness, and only one case has been reported due to acute diarrhea secondary to Clostridium difficile colitis.⁷ To the best of our knowledge, this is the second case report of acute oxalate nephropathy due to C. difficile colitis.

Case presentation

A 75-year-old man with medical history of hypertension, coronary artery disease, heart failure with preserved ejection fraction (HFpEF), atrial fibrillation, type 2 diabetes mellitus, peripheral vascular disease and chronic kidney disease (CKD) stage IV, presumed secondary to hypertensive nephrosclerosis, was admitted for acute kidney injury (AKI) with a creatinine (Cr) of 8.54 mg/dL, value corresponding to an estimated glomerular filtration rate (eGFR) of 5 mL/min/1.73 m² by the Modification of Diet in Renal Disease Study (MDRD) equation. His baseline Cr was 2.3–2.6 mg/dL until 2 months back. Five weeks ago, he was admitted to an outside hospital for profuse diarrhea secondary to C. difficile colitis. During that hospitalization, he had an episode of non-oliguric ischaemic acute tubular necrosis in the setting of C. difficile infection. His Cr at the time of admission was 8 mg/dL which did not improve with the intravenous fluid. He was discharged 2 weeks later. On repeat basic metabolic panel as an outpatient, his Cr improved to a minimum of 6.16 mg/dL before rising to 8 mg/dL again, when he was referred to the emergency department. He did not have any complaints this time. His diarrhea had resolved. He was taking oral vancomycin but denied recent use of any other antibiotics, nonsteroidal anti-inflammatory drug (NSAID), herbal supplements and over-the-counter medications. Physical examination findings were unremarkable.

Investigations

His laboratory reports were remarkable for Cr—8.54 mg/dL, blood urea nitrogen—62 and bicarbonate—19. Urinalysis did not show any eosinophils, casts or crystals. Further workup including antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), complement levels (C3 and C4) and hepatitis screen were negative; a renal ultrasound visualized no hydronephrosis. Given persistent elevated Cr, he underwent kidney biopsy which showed widespread tubular oxalate crystal deposition suggestive of hyperoxaluria as the cause of AKI (figures 1–3). It also showed severe arterial and arteriolar sclerosis, with diffuse glomerular hypoperfusion and diffuse interstitial fibrosis, suggesting significant primary vascular disease, early diffuse and nodular diabetic glomerulosclerosis, tubular atrophy and mild immunoglobulin A nephropathy. Twenty-four hours urine for oxalate quantification was not done, as the glomerular filtration rate (GFR) was very low.

Figure 1.

Oxalosis with intratubular oxalate crystals seen on H&E stain.

Figure 2.

Oxalate crystals with bright birefringence under polarised light (H&E stain).

Figure 3.

Intratubular oxalate crystals are positive on alizarin red stain.

Treatment

Dialysis was discussed but it was deferred per patient wishes. Pyridoxine was tried empirically with no improvement.

Outcome and follow-up

He was admitted again after 3 weeks for altered mental status secondary to hospital-acquired pneumonia and uremia. He was treated with antibiotics and eventually initiated on dialysis with improvement in mental status. His renal function did not recover.

Discussion

Hyperoxaluria can result in calcium oxalate precipitation in renal tubules causing direct tubular injury. We believe that our patient had AKI related to secondary hyperoxaluria caused by C. difficile colitis. There was no other obvious cause for his acute oxalate nephropathy. There was no history of increased intake of oxalate-rich foods including spinach, rhubarb, chug mushrooms, black tea, peanuts and, almonds; increased intake of oxalate precursors—vitamin C and ethylene glycol intake; or malabsorption syndrome. He was not evaluated for malabsorption as his diarrhea had resolved. He had recent C. difficile infection which might have caused increased oxalate absorption (enteric hyperoxaluria) by following possible mechanisms:

1. As oxalate is absorbed through the paracellular pathway by simple diffusion, its absorption can be accelerated by increased permeability of the tight junctions of colonic cells.⁶ C. difficile toxins A and B can disrupt the tight junction between epithelial cells, and can potentially lead to increased oxalate absorption.⁸

2. C. difficile infection usually affects the colon, but cases have been reported with small bowel involvement, which can lead to increased oxalate absorption due to fat malabsorption.⁹ In fat malabsorption, calcium preferentially binds to free fatty acids (FFA), increasing intestinal soluble oxalate level and FFA along with bile salts induces colonic hyperpermeability.^{6 10}

3. Also, alteration of intestinal flora in C. difficile infection can potentially cause a reduction in oxalate degrading bacteria—Oxalobacter formigenes—leading to increased oxalate availability in the colon for absorption.²

In the first case report on acute oxalate nephropathy associated with C. difficile colitis, by Cohen-Bucay et al,⁷ the patient had stage I CKD unlike our patient with stage IV. In our patient, volume depletion due to diarrhea along with metabolic acidosis in the setting of CKD might have contributed further to oxalate precipitation in the kidney. In conclusion, an acute diarrheal illness like C. difficile colitis can potentially cause acute oxalate nephropathy and patients with CKD are at an increased risk for hyperoxaluric AKI.

Learning points.

• Acute diarrheal illness especially Clostridium difficile infection can cause acute kidney injury due to oxalate crystal deposition.

• Enteric hyperoxaluria can occur with C. difficile colitis possibly due to increased permeability of the tight junctions of colonic cells; due to fat malabsorption if there is small bowel involvement and by alteration in intestinal flora leading to a reduction in oxalate degrading bacteria.

• Chronic kidney disease patients are at increased risk of acute oxalate nephropathy due to C. difficile colitis.