Cashew-Induced Oxalate Nephropathy: A Rare Cause of Acute Renal Failure

ABSTRACT

We present a rare case of cashew-induced oxalate nephropathy in a 69 year old veteran male with history of type 2 diabetes mellitus, nephrolithiasis, and undiagnosed chronic kidney disease (CKD). Oxalate nephropathy is a rare cause of acute renal failure with poor prognosis. The various causes of oxalate nephropathy are categorized as primary or secondary hyperoxaluria. Primary hyperoxaluria is caused by genetic mutation in genes involved in the metabolism of glyoxylate. Secondary hyperoxaluria is caused by mal-absorptive state, excessive intake of oxalate-rich diet, inflammatory diseases, and medications such as orlistat and antibiotics. Diet-induced oxalate nephropathy is often identified after unexplained acute kidney injury in patients with underlying CKD. Definitive diagnosis requires renal biopsy as laboratory tests are non-specific. A simple dietary history in CKD patients during routine primary care visit may lead to early diagnosis and lead to prevention of acute renal failure and progression of renal disease.

INTRODUCTION

Common causes of acute kidney injury (AKI) in the hospitalized setting include pre-renal azotemia, acute tubular necrosis, and acute interstitial nephritis. Diet-induced oxalate nephropathy was previously thought of as rare entity, but has become more recognized with increasing case reports describing AKI secondary to an oxalate-rich diet such as vitamin C, spinach, and nuts.^1–4 Oxalate nephropathy is often identified in patients with an unexplained AKI or chronic kidney disease (CKD). Diagnosing oxalate nephropathy can be challenging as most of the laboratory tests for oxalate nephropathy are nonspecific. A recent systemic review reported that mean 24-h urinary oxalate excretion was 85.4 mg/d (Normal < 40 mg/d) and urinary oxalate crystals were seen in 26% of the cases,⁵ which may provide clinical suspicion, but tissue analysis is needed for definitive diagnosis. The treatment for acute oxalate nephropathy is mainly supportive and has poor prognosis due to frequent residual renal injury. Early recognition of diet-induced oxalate nephropathy and dietary changes in patients with unexplained CKD can prevent progression to end-stage renal disease (ESRD) and AKI. Here, we present a case of acute oxalate nephropathy requiring renal replacement therapy that may have been preventable with early diagnosis of unexplained CKD during routine follow-up.

CASE

A 69 year old Caucasian male with history of hypertension, poorly controlled type 2 diabetes mellitus, nephrolithiasis, and undiagnosed CKD stage 2 was presented to the emergency department with 2 days of anuria, accompanied by profound malaise, nausea, and vomiting. Physical exam was unremarkable. Labs at initial presentation revealed serum creatinine 9.5 mg/dL, BUN 70 mg/dL, bicarbonate 15 mEq/L, and anion gap 20 mEq/L. Record review showed routine labs from one-month prior demonstrating a serum creatinine 1.1 mg/dL and eGFR 72 mL/min. Urinalysis showed specific gravity 1.014 with WBC 14/HPF, 2+ protein, and epithelial cells < 1 HPF. The protein-to-creatinine ratio was 0.78 mg/gm, and peripheral smear was unremarkable without schistocytes. Other significant labs include a C-reactive protein of 4.21 mg/L and an ESR of 46 mm/h. CBC, liver function test, and creatine kinase were within the normal range. Renal CT showed multiple bilateral renal cysts and single renal stone within the inferior pole of the left kidney without obstructive uropathy or hydronephrosis. His medications include metformin, lisinopril, atenolol, gabapentin, ergocalciferol, and hydrochlorothiazide. At the time of his admission, the differential diagnosis included acute glomerulonephritis, acute interstitial nephritis, and acute tubular necrosis.

On admission, 2L of crystalloid fluid was given for possible pre-renal cause; however, renal function worsened with an increase in creatinine level to 11.3 mg/dL and a decrease in urine output to <100 mL per 24 h. Due to concern for possible glomerulonephritis and acute interstitial nephritis, 500 mg of IV solumedrol was administered for 3 days followed by 1 mg/kg/d of prednisone. Despite this, creatinine continued to uptrend and peaked at 16 mg/dL. Concurrently, the workup for glomerulonephritis was unremarkable and included anti-nuclear antibody, streptococcus pneumonia antigen, anti-neutrophilic cytoplasmic autoantibody panel, anti-GBM antibody, complements, SPEP/UPEP, HIV, and hepatitis serology.

On hospital day 4, renal replacement therapy was initiated and renal biopsy was obtained revealing oxalate crystal nephropathy (Figure 1). The biopsy showed extensive acute tubular injury with intraluminal proteinaceous casts; flattening and blebbing of tubular epithelial cells; and intratubular oxalate crystals. The possibility of enteric hyperoxaluria was considered given his age and no known family history of primary hyperoxaluria; however, he lacked history of Roux-en-Y surgery (or any abdominal surgery), Crohn’s disease, celiac disease, recent antibiotic use, or chronic pancreatitis. Further interview regarding his dietary habits elucidated consumption of 17 ounces (480 g) of cashew nuts 2 days prior to presentation that correlates with the onset of symptoms. We estimate he consumed approximately 1,257 mg of oxalate during this meal as every 100 g of cashew nut contains about 262 mg of oxalate.⁶

FIGURE 1.

Extensive acute tubular necrosis with dilated tubules, flattening of epithelial cells (leftwards arrow (←)), proteinaceous casts (leftwards double arrow (⇐)), blebbing of tubular epithelial cells (long leftwards arrow (←)), and frequent intra-tubular oxalate crystals (long leftwards double arrow (⇐)).

At the time of discharge, creatinine improved to 8.25 mg/dL with urine output of about 800 mL/d. He continued to transiently require hemodialysis as an outpatient for few months. Today, he is no longer on hemodialysis and his new baseline creatinine is 2 mg/dL with eGFR of 30 mL/min.

DISCUSSION

Oxalate nephropathy is characterized by renal tubular deposition of calcium oxalate crystals that leads to acute and chronic tubular injury causing progressive renal insufficiency.⁷ The various underlying causes that increase risk of oxalate nephropathy are categorized as primary or secondary hyperoxaluria.

Primary hyperoxaluria type 1, 2, and 3 involves mutations in AGT, GRHPR, and DHDPSL, respectively. These enzymes are involved in the metabolism of glyoxylate and oxalate.⁸ Secondary hyperoxaluria is the more common mechanism and involves increased intestinal absorption and excessive intake of oxalate. This often occurs as a consequence of malabsorptive states, such as inflammatory bowel disease, small bowel or gastric surgery, chronic pancreatitis, and systemic sclerosis with bowel involvement. Malabsorptive states promote excessive intraluminal free fatty acids that bind to and saponify calcium within the intestine, thereby inhibiting the formation of calcium oxalate. As a result, the soluble oxalate is more readily absorbed by the colonic mucosa.⁹ Also, free fatty acids and bile salts enhance the permeability of the colonic mucosa to oxalate.¹⁰ Secondary hyperoxaluria can also be caused by consumption of large amounts of oxalate rich foods, such as nuts, fruit juice (kiwi or starfruit), and leafy greens (spinach, parsley, and collard greens).^3,11 Lastly, antibiotics can result in altered gut flora (decreased colonization of Oxalobacter formigenes) that increases enteric absorption and leads to increased renal excretion of oxalate.¹² According to a recently published systematic review, fat malabsorption (75%) was the most attributed cause of secondary oxalate nephropathy, followed by excessive dietary oxalate consumption (30%) and then a decrease of intestinal oxalate degradation (0.9%).⁵

The mean oxalate intake of a usual Western diet is approximately 100–150 mg/d.^13,14 A larger amount would be necessary to induce acute renal failure, but the exact amount required to induce damage is unknown. Getting et al. described a case of oxalate nephropathy in a patient who kept a detailed record of his diet, which revealed an approximate oxalate ingestion of 10–1,035 mg per meal.¹¹ Our patient ingested about 480 g of cashews (1,257 mg of oxalate) in one setting 2 days prior to presentation that led to anuric AKI, but we suspect that he had acute on CKD from years of excess intake of oxalate. It is unclear why some patients with hyperoxaluria develop recurrent nephrolithiasis without renal injury, while others develop oxalate nephropathy; however, based on pathophysiology, oxalate nephropathy is chronic condition because calcium oxalate crystals take months to years to develop. Lumlertgul et al. reports that the most common presentation of oxalate nephropathy was AKI (35%), followed by acute on CKD (29%), CKD with stones (26%), and CKD (10%). We suspect based on what we know about the clinical course of oxalate nephropathy that even patients that present solely with AKI, likely had some element of unrecognized CKD leading up to their presentation. In patients with primary hyperoxaluria, mean time to symptom onset is 9.5 years,⁵ which further supports the idea that oxalate nephropathy is chronic condition.

Case reports of diet-induced oxalate nephropathy demonstrate a wide range of oxalate amount, duration of excess oxalate intake, and severity of AKI. Garland et al. reports a 59 year old female with underlying CKD3 of unknown etiology who ingested approximately 1 g of oxalate per day for 1 year who incurred an AKI with creatinine rising from 1.34 to 1.8 mg/dL.⁴Bernandino et al. also describes a 63 year old female without history of renal insufficiency or nephrolithiasis who developed biopsy-proven oxalate nephropathy with increase in creatinine from 0.8 to 1.94 mg/dL after ingesting about 339–409 mg of oxalate per day in cashew intake over 4 months. Another case report demonstrated a patient who was on an “antioxidant diet” (about 1,500 mg oxalate in nuts and seeds) for unknown periods of time, developed an AKI, and whose renal biopsy revealed oxalate nephropathy.¹⁵ In all these cases, the patients demonstrated partial recovery after transitioning to a low-oxalate diet.^1–4 In Garland et al., the patient had underlying CKD3, consumed 1 g of oxalate for more than a 1 year, and incurred stage 1 AKI compared to a stage 3 AKI in our patient. These cases illustrate that oxalate nephropathy is a chronic process that may be preventable with early intervention and recent study suggests that oxalate nephropathy may be an underdiagnosed condition among patients with CKD.¹⁶

There are also case reports that demonstrate rapid progression of acute oxalate nephropathy. Lawton et al. reported a patient who received 45 g of IV Vitamin C as an adjuvant therapy for primary amyloidosis with nephrotic syndrome and developed acute oxalate nephropathy leading to death.¹⁷ It is estimated that the patient received about 22.5 g of oxalate, which is 150 times the recommended daily oxalate amount.¹⁸ Diet-induced oxalate nephropathy has been described in patients with lower and shorter courses of oxalate intake with predisposing conditions, such as bariatric surgery and recent antibiotic use. Makkapati et al. reported a 65 year old female with history of Roux-en-Y gastric bypass and recent antibiotic use who developed AKI that progressed to ESRD after increasing spinach intake (1.3 g of oxalate for 10 days). Patients with predisposing conditions should be particularly cautious about oxalate intake.

Diet-induced oxalate nephropathy is preventable condition. Our patient had undiagnosed stage 2 CKD and nephrolithiasis with no records of 24-h oxalate/calcium measurements, stone analysis, or further evaluation for his unexplained CKD. While his CKD may have been due to poorly controlled type 2 diabetes mellitus and age, our case questions whether detailed dietary history for his CKD in routine primary care visits could have prevented his acute oxalate nephropathy.

Management of chronic oxalate nephropathy involves limiting oxalate intake (<50 mg per day), calcium acetate supplementation (to bind intestinal oxalate and decreases absorption), and adequate hydration. Table I describes some of the common foods that have high oxalate content. Proposed pharmaceutical therapy still requires more investigation and includes anti-inflammatory drugs that targets inflammasome NLRP3, such as glyburide, parthenolide, dimethyl sulfoxide, methylsulfonylmethane, 3,4-methylenedioxy-b-nitrostyrene, and cytokine release inhibitory drug CP-456,773.¹⁹ In acute renal failure secondary to oxalate nephropathy, treatment remains mainly supportive therapy.

TABLE I.

Common Foods that Have High Oxalate Content

Food high in oxalate
Foods (100 g)	Oxalate (mg)
Nuts
Almond, roasted	469
Cashews, roasted	262
Hazelnuts, roasted	222
Soy nuts	392
Peanuts, raw	142
Leafy vegetable
Amaranth leaves, raw	1,090
Beet leaves, raw	610
Brussels sprouts, raw	360
Chives, raw	1,480
Parsley, raw	1,700
Purslane, raw	1,310
Spinach, raw	970
Cassava root, raw	1,260
Miscellaneous foods
Rhubarb	800
Black pepper	419
Cocoa powder	623
Soy protein	496
Tofu	275

Sources: Reference [6].

CONCLUSION

Diet-induced oxalate nephropathy is a devastating renal disease with poor prognosis that may be preventable with early recognition. Often, oxalate nephropathy is identified after experiencing AKI in patients with underlying CKD without clear etiology. Even then, diagnosis is challenging as renal biopsy is required for definitive diagnosis since most laboratory tests are nonspecific. Even after diagnosis, treatment is mainly supportive in acute renal failure secondary to oxalate nephropathy. Our case demonstrated the importance of recognizing diet-induced oxalate nephropathy in patients with unexplained CKD, as early diagnosis may lead to prevention of acute renal failure and progression of renal disease. A simple dietary history in CKD patients during routine primary care visit may improve clinical outcome.

ACKNOWLEDGMENTS

The authors would like to thank the patient for their cooperation and the clinicians and technicians involved in this case.

FUNDING

None declared.

CONFLICT OF INTEREST STATEMENT

None declared.

Author notes

Podium Presentation at: American College of Physicians, Tri-service Chapter Meeting, September 10–12, 2020.

The views expressed are solely those of the authors and do not reflect the official policy or position of the US Army, US Navy, US Air Force, the Department of Defense, or the US Government.