Don't Eat the Leaves

Hyperoxaluria is an important risk factor for kidney stones, approximately 80% of which are primarily composed of calcium oxalate. Hyperoxaluria is typically diagnosed by performing a 24 hour urine collection and levels above 45 mg/day are considered abnormal although, depending on the other urine constituents, the risk of CaOx stones increases when the urinary oxalate level is above 20 mg/dl. It is important to distinguish between hyperoxaluria that results from increased oxalate production (endogenous) and increased oxalate ingestion (enteric).

The classic disease associated with increased oxalate production is primary hyperoxaluria. There are 3 identified types although all result from defects in glycoxylate metabolism leading to oxalate accumulation. At first, the manifestations are primarily renal leading to nephrolithiasis and nephrocalcinosis. However, as the disease progresses,  the serum oxalate concentration increases eventually resulting in extra-renal oxalate deposition. Vitamin C is metabolized to oxalate also so that patients with oxalate-containing kidney stones should probably avoid excess vitamin C supplementation as this could increase the risk of stones.

Enteric hyperoxaluria results from increased absorption of oxalate in the large bowel. In general, there are 3 ways in which this might occur:

• Increased dietary oxalate ingestion
• Decreased dietary calcium intake - calcium binds oxalate in the gut and reduces absorption. This is why low calcium diets are not recommended in patients with idiopathic kidney stones. Calcium supplements are a different issue as they may contribute to hypercalciuria and not decrease oxalate ingestion, particularly if they are not taken at mealtimes
• In the setting of malabsorption syndromes and GI disease. This occurs in patients following bariatric surgery, fat malabsorption and inflammatory bowel disease. The mechanism is thought to be related to binding of calcium to fatty acids thus reducing the availability of calcium for oxalate-binding, along with increased large bowel permeability. There have been multiple cases of patients developing severe oxalosis following jejuno-ileal bypass surgery.

The treatment of hyperoxaluria depends on the cause. For all patients, increasing fluid intake is good advice. Some patients with primary hyperoxaluria respond to treatment with pyridoxine which promotes conversion of glycoxylate to glycine instead of oxalate. Recently, a bacterium has been identified that metabolizes oxalate in the gut and this has been proposed as a potential treatment for hyperoxaluria. Interestingly, antibiotic treatment has been shown to decrease oxalobacter colonization in individuals with peptic ulcer disease.

Of course, all patients with hyperoxaluria should be advised to reduce oxalate consumption in the diet. Foods high in oxalate include spinach, rhubarb, tea, chocolate, star fruit and soy products. A full list can be found here.

Rhubarb is an interesting case. In the First World War because of the lack of access to fresh vegetables, the British government recommended that families supplement their diets with rhubarb leaves which were not traditionally eaten. It turns out that this was very bad advice. Rhubarb leaves contain considerably more oxalate than the stalks and there was a flurry of case reports towards the end of the war detailing cases of oxalate poisoning from rhubarb leaf consumption (see also and this). The toxicity of the leaves was probably increased by advice to cool the leaves with soda which increases the solubility of oxalate. Although the MD50 of oxalate would require the ingestion of about 5kg of rhubarb leaves, one could imagine that much lower doses would be toxic in patients with chronic kidney disease.

One last point about oxalate. It is a terminal metabolite and was thought to not have any positive role. However, recent data have suggested that oxalate is important for chloride transport in the proximal tubule where it acts similarly to formate..

What are you smoking?

I recently saw an interesting case series published in CJASN where they reported four cases of oliguric AKI  associated with synthetic cannabinoids use. Renal biopsy revealed acute tubular injury in three of them and calcium oxalate crystals  in two.

Interestingly, around the same period of time I was rotating in nephrology consult service and had an elderly patient with history of paraplegia and neurogenic bladder (on intermittent self-catheterization), who was brought to the ER with altered mental status for which he was intubated for airway protection. On presentation, he was found to have acute kidney injury (Cr 6.0). His renal function continued to deteriorate with no specific etiology for his renal failure, so he had a renal biopsy which showed evidence of an active tubulointerstitial nephritis with marked tubular injury and calcium oxalate crystals present within the tubular lumina. Remarkable findings in his history included the recent use of cannabinoids. He never had history of renal stones. His home medication includes: methadone, oxycodone, nortriptyline and pregabalin. Admission labs showed normal osmolar gap and negative toxicology analysis. Urine microscopy showed muddy brown casts with no identifiable crystals.  Abdominal ultrasound did not reveal any renal calculi. Renal replacement therapy was started for uremic symptoms and he continued to require replacement therapy after his discharge.

The use of these synthetic cannabinoid preparations has increased significantly in the United States over the past few years, and the incidence of acute kidney injury (AKI) from use of these agents  is underestimated. CDC investigators have identified 16 patients (15 males; median age, 18.5 years) from 6 states who presented to emergency departments in 2012 with acute kidney injury after smoking a synthetic cannabinoid product.  Six patients had acute tubular injury and three had acute interstitial nephritis. Even though we can relate tubular injury and interstitial nephritis to the use of cannabinoids  , presence of calcium oxalate crystals was perplexing. In the case series reported in CJASN, they mentioned the presence of calcium oxalate crystals in two patients, but the mechanism of development of these crystals was not fully elucidated . We are hypothesizing that synthetic cannabinoids could be the potential cause for calcium oxalate deposition in this patient (after all causes of secondary hyperoxaluria were excluded). One possible explanation is that synthetic cannabinoids contain additional compounds which are plant in origin and these may be oxalogenic

Synthetic cannabinoids use should be in our differential diagnosis for unexplained AKI in young adult population as it can cause either ATN or AIN or both. A high index of suspicion is required as they may not be detected on routine urine drug screens.

Posted by Mahmoud Kamel

Enteric Hyperoxalosis following Roux-En-Y Bypass

Recently, I evaluated an older gentleman with diabetic nephropathy who had undergone a living related kidney transplant from a family member. He underwent Roux-en-Y bypass with an approximate 80 lbs. weight loss prior to his transplant to achieve a BMI of 30. His post transplant allograft function was initially stable with a serum creatinine of 1.5 mg/dl.

Approximately 1.5 years after his transplant he was lost to follow up and ceased his surveillance laboratory testing. He then developed worsening edema and fatigue and returned to our center for evaluation of his symptoms. On routine laboratory testing his serum creatinine was elevated at 6.8 mg/dl. He underwent an ultrasound guided transplant biopsy which revealed the findings seen in the biopsy on the left.

Pathology noted severe chronic interstitial fibrosis with evidence of oxalate deposition (shiny deposits under polarized light) within his allograft supportive of secondary oxalate nephropathy. Secondary oxalosis can occur from either high oxalate consumption (e.g. mega-doses of vitamin C, large consumption of star fruit or rhubarb) or increased enteric absorption of oxalate from either malabsorption or alterations in enteric flora (see nice editorial in the July 2012 nephsap).

In this particular case, enteric hyperabsorption following Roux-en-Y bypass was suspected as the underlying cause of the secondary oxalosis. In a case series performed at the Mayo Clinic Roux-en-Y bypass resulted in enteric fat malabsorption (from 4 grams per day to 9 grams per day, normal reference 2-7 grams/day) and an increase in serum oxalate levels for 12 months, the length of the evaluation. Urinary oxalate levels were also elevated, and enteric hyperabsorption was shown by providing an oxalate load and demonstrating an increase in serum oxalate levels.

Our patient was found to have severe fat malabsorption by timed fecal fat quantification with elevated serum and urinary oxalate levels.  Unfortunately given the chronicity of renal injury, recovery of his allograft was unlikely and he restarted maintenance hemodialysis. 

Author: Erik Lum, MD