Nephrology-Endocrinology conference

Anti-obesity drug and Acute Renal Failure

Ma. Lourdes Josefina A.Dueñas, M.D.

Makati Medical Center

Renal Failure with anti obesity drug• Crystalluria and acute kidney injury are known

complications of certain types of drugs.• Calcium oxalate crystalluria and acute oxalate

nephropathy are described in the setting of exposure to several substances– ethylene glycol poisoning – diethylene glycol– paracetamol elixirs– intravenous administration– ingestion of megadoses of vitamin C, pyridoxilate– Ingestion star fruit (carambola)

• Orlistat is used as therapy to reduce weight and maintain weight loss in obese patients.

• It is a potent inhibitor of gastric and pancreatic lipase in humans, resulting in fat malabsorption

• It promotes clinically significant weight loss and reduces weight regain in obese patients, in conjunction with appropriate dietary modifications.

• It is licensed for use in patients with a BMI of 30 kg/m2 or more, or of 28 kg/m2 or more in the presence of other risk factors.

• The side-effect profile reflects gastrointestinal fat malabsorption with oily stools, faecal urgency, faecal incontinence and flatulence.

• In combination with a hypocaloric diet, it improves metabolic parameters and decreases the risk for developing type 2 diabetes mellitus.

• Understanding the effects of orlistat in the gastrointestinal tract provides insight into the mechanism of acute oxalate nephropathy as a cause of acute kidney injury by orlistat.

• Orlistat has the undesirable potential to enhance gastrointestinal oxalate absorption by inducing a fat malabsorption syndrome and increase urinary oxalate concentrations, similar to other secondary forms of enteric hyperoxaluria.

• Animals treated with orlistat increased urinary oxalate concentrations

• In a meta-analysis of 9 clinical trials, the most commonly reported gastrointestinal events were fatty/oily stool, fecal urgency, and oily spotting, occurring at frequency rates of 15% to 30% in most studies.Increased gastrointestinal oxalate absorption and the resulting increased urinary oxalate excretion (enteric hyperoxaluria) occurs with various gastrointestinal disorders (short-bowel syndrome).

• Orlistat, a lipase inhibitor, seems to recreate the "enteric hyperoxaluria" induced by pathologic fat and bile salt malabsorption.

• According to researchers, unabsorbed bile acids and fatty acids react with calcium forming "soaps" in the intestinal lumen that limit the amount of free calcium binding with oxalate. Hence, more oxalate is available to be absorbed and eventually excreted with urine.

• Enteric hyperoxaluria from fat malabsorption results from complexing of dietary calcium with unabsorbed fat present in the intestinal lumen.

• This same physiological state applies to orlistat.

• Ferraz et al7 studied effects of orlistat on urinary oxalate excretion in 39 adult male Wistar rats administered orlistat with various diets. They showed that orlistat led to a 30% increase in urinary oxalate in these experimental animals.

• Although the study did not show oxalate crystal deposition within renal tissue, a significant increase in calcium-oxalate activity product, a marker of risk for renal stone formation, was noted.

• In a rodent study, the addition of orlistat significantly increased the urinary excretion of oxalate.Hyperoxaluria is one of the major risk factors for calcium oxalate stone formation, as urinary oxalate concentration correlates directly with urinary supersaturation of calcium oxalate.

• Hyperoxaluria is classified as primary or secondary.

• Primary hyperoxaluria is very rare and is due to the overproduction of oxalic acid, most commonly when there is low or absent activity of the liver enzyme alanine/glyoxylate aminotransferase.

• Increased intestinal absorption of oxalate, usually due to upper gastrointestinal pathology, causes secondary hyperoxaluria.

• Enteric hyperoxaluria occurs when there is absence or non-function of the small bowel, (e.g. small bowel resection, bypass surgery), or defective absorption of fat or bile acids, (e.g. biliary cirrhosis, pancreatic failure).

• The increased intraluminal free fatty acids complex with intraluminal calcium ions, competitively inhibiting the precipitation of oxalate with calcium. The increase in soluble uncomplexed oxalate facilitates oxalate absorption.

• Further absorption can occur in the colon which has increased permeability to oxalate in the presence of excess bile salts and free fatty acids

• induction of increased fat malabsorption from inhibition of pancreatic and gastric lipase by orlistat, followed by “soaping” out of calcium, allowing free oxalate to be absorbed by the more permeable large bowel (from fat and bile acids).

• This mimics other secondary forms of enteric hyperoxaluria, such as small-bowel resection (severe Crohn’s disease) and intestinal bypass for morbid obesity, which have been associated with acute oxalate nephropathy.

Increase urinary oxalate == inc enteric absorption of dietary oxalate

Ca + Oxalate =insoluble complex(intestinal lumen)

Malabsorption/steatorrhea

Ca + Fatty acids== more soluble oxalate for absorption---excreted via urinary tract

Hypercalciuria/hyperoxaluria

Ca oxalate crystals + renal tubular epithelial cells

endocytosis

renal interstitium

Inflammatory interstitial response

Tissue injury and sclerosis

• The combination of underlying stage 3 CKD and mild volume depletion from drug-induced steatorrhea (and concurrent furosemide) likely further increased the risk for calcium oxalate crystal precipitation within renal tubules.

• Underlying kidney disease should be emphasized as a predisposition to acute oxalate nephropathy because decreased renal excretion of oxalate from the lower glomerular filtration rate promotes additional crystal deposition.

• acute on chronic renal failure (fall in eGFR of over 30 ml/min/1.73m2 in 5 months) was triggered by intrarenal precipitation of calcium oxalate in the setting of a gastrointestinal lipase inhibitor. The rapidity of deterioration far exceeded the natural history of decline of function in diabetic nephropathy.

• The absence of other causes of acute kidney injury on clinical history and kidney biopsy, as well as the presence of calcium oxalate crystals within renal tubules, supports the diagnosis of acute oxalate nephropathy from orlistat use.

• Oxalate is a metabolic end-product of limited solubility in physiologic solution. Thus, the organism is highly dependent on urinary excretion, which involves net secretion. Normal urine is supersaturated with respect to calcium oxalate.

• Crystallization is prevented by a number of endogenous inhibitors, including citrate. A mild excess of oxalate load, as occurs with excessive dietary intake, contributes to nephrolithiasis.

• Because the kidney is the main excretory route for oxalate, in the face of excessive oxalate production even mild degrees of renal insufficiency can lead to systemic deposition of oxalate in a wide variety of tissues.

• Secondary causes of hyperoxaluria include dietary excess, enteric hyperabsorption, and enhanced endogenous production resultingfrom either exposure to metabolic precursors of oxalate or pyridoxine deficiency.

• Intestinal absorption of oxalate can be enhanced markedly in patients with bowel disease, particularly inflammatory bowel disease or after extensive bowel resection or jejunoileal bypass.

• In the setting of acute exposure to large quantities of metabolic precursors, such as ingestion of ethylene glycol or administration of glycine or methoxyflurane, tubular obstruction by calcium oxalate crystals can lead to acute renal failure.

Haematoxylin and eosin staining (magnification 100) of renal biopsy specimen showing intratubular deposition of calciumoxalate crystals (arrowhead) with mild interstitial inflammation (white arrow), on a background of chronic changes of diabetic nephropathy (black arrow).

Haematoxylin and eosin staining (magnification 200) under polarized light showing the characteristic birefringement of calcium oxalate crystals.

Photomicrograph of a representative field shows the presence of birefringent crystals (calcium oxalate lodged in the lumen of a renal tubule. The affected portion o the tubule is dilated, and the epithelial lining is flattened (Hematoxylin and eosin stain; original magnification 200.)

• All patients with renal impairment who are prescribed gastrointestinal lipase inhibitors have their renal function monitored, particularly where there is a high degree of compliance and substantial weight loss. Early detection of rapidly deteriorating renal function would allow discontinuation of the medication before irreversible end-stage renal disease is reached.