Severe Hyperoxaluria Can Irreversibly Damage the Kidneys
Oxalate is endogenously produced as an end product of normal cellular metabolism and is also absorbed through the GI tract from a typical diet. Humans lack the innate capacity to digest oxalate and primarily depend on renal excretion to eliminate it from the body. Although oxalate has no identified biological function, it is known to damage the kidney when present in excess amounts, a condition called hyperoxaluria. Hyperoxaluria is characterized by significantly elevated oxalate levels in the urine, or urinary oxalate excretion.
There are two types of hyperoxaluria:
- Primary hyperoxaluria is due to a genetic defect that results in overproduction of oxalate by the liver.
- Secondary hyperoxaluria results from over absorption of oxalate from the diet and is further characterized either as enteric, resulting from a chronic and unremediable underlying GI disorder associated with malabsorption, such as bariatric surgery complications or Crohn’s disease, which predisposes patients to excess oxalate absorption, or idiopathic, meaning the underlying cause is unknown. Enteric hyperoxaluria is the more severe type of secondary hyperoxaluria.
The first clinical manifestation of hyperoxaluria is often a kidney stone; however, the disorder can be variable in its presentation. Patients with severe hyperoxaluria may have recurrent kidney stones or experience infrequent or no kidney stones, yet still develop CKD and end-stage renal disease, which can be fatal. The risk for kidney stones and kidney damage increases with progressively elevated levels of urinary oxalate excretion.1- 5 Patients with hyperoxaluria are often diagnosed after a single complicated kidney stone episode (i.e. requiring surgical removal) or a recurrent kidney stone episode. Given the often painful and debilitating nature of kidney stones, patients suffering from recurrent kidney stones bear significant social and financial burdens and are therefore highly motivated to seek treatment.
There are approximately 200,000 to 250,000 patients in the United States with enteric hyperoxaluria and kidney stones.6 Enteric hyperoxaluria is most commonly seen as a complication of malabsorptive bariatric surgical procedures, such as Roux-en-Y gastric bypass, and can also be related to inflammatory bowel disease, such as Crohn’s disease, or other conditions associated with GI malabsorption, including cystic fibrosis, pancreatic insufficiency, celiac disease or short bowel syndrome following surgical resection of the bowel. Enteric hyperoxaluria is the more severe type of secondary hyperoxaluria since the underlying GI disorder predisposes patients to chronic excess oxalate absorption.7 Given this hyperabsorption, patients with enteric hyperoxaluria can have markedly high levels of urinary oxalate excretion. Consequently, these patients tend to have more frequent and more complicated kidney stone episodes8-10 and other kidney disorders including progressive calcium oxalate (CaOx) deposits in the kidney, or nephrocalcinosis, systemic oxalosis, CKD and ESRD.11-13
Primary hyperoxaluria, a type of severe hyperoxaluria, is a rare genetic disorder that can result in kidney stone disease, kidney damage, and kidney failure, which may lead to death. Primary hyperoxaluria has three main types, PH1, PH2, and PH3, which each categorization representing the particular genetic enzyme deficiency that drives the overproduction of oxalate, mainly in the liver, and massive excretion of oxalate in the urine. The most severe and common type of primary hyperoxaluria is PH1. These patients typically develop recurrent kidney stones with progressive nephrocalcinosis and end stage renal disease by 20-30 years of age. Among patients with primary hyperoxaluria, about 50 percent will have kidney failure by age 15, and about 80 percent will have kidney failure by age 30.14 Primary hyperoxaluria is estimated to affect approximately 1 in 58,000, or approximately 5,000 patients in the United States.15
There is no approved pharmacologic therapy for the reduction of urinary oxalate excretion in patients with hyperoxaluria, either primary or secondary. Existing treatment options for hyperoxaluria generally are non- specific and include high fluid intake to increase urine output to more than two to three liters per day, a diet low in salt and oxalate, oral citrate and/or calcium and/or magnesium supplementation and, exclusively for the subset of responsive patients with the most severe form of primary hyperoxaluria (PH1), orthophosphate and Vitamin B6 supplementation. Despite these strategies, many patients continue to experience hyperoxaluria with recurrent kidney stones and continued risk for long-term kidney damage.
1. Parvin M et al. The Most Important Metabolic Risk Factors in Recurrent Urinary Stone Formers. Urol J. 2011;8(2):99-106.
2. Robertson WG et al. The Cause of Idiopathic Calcium Stone Disease: Hypercalciuria or Hyperoxaluria? Nephron. 1980;26(3):105-1Q.
3. Curhan GC et al, 24-h Uric Acid Excretion and the Risk of Kidney Stones. Kidney Int. 2008;73(4):489-496.
4. Milliner D. Treatment of the Primary Hyperoxalurias: A New Chapter. Kidney Int. 2006;70(7):1198-1200.
5. Zhao F et al. Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure Clin Am J Soc Nephrol. 2016;11(1):119-126.
6. Company data.
7. Bhasin B et al. 2015. Primary and Secondary Hyperoxaluria: Understanding the Enigma World J Nephrol. 2015;4(2):235-244.
8. Lieske JC et al. Kidney Stones are Common After Bariatric Surgery. Kidney Int. 87(4):839-845.
9. Nightingale JM et al. Colonic Preservation Increases Incidence of Renal Stone in Patients with a Short Bowel. Gut. 1992;33(11):1493-1497.
10. Matlaga BR et al. Effect of Gastric Bypass Surgery on Kidney Stone Disease. J Urol. 2009;181(6);2573-2577.
11. Nasr SH 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.
12. Nazzal L et al. Enteric Hyperoxaluria: an Important Cause of End Stage Kidney Disease. Nephrol Dial Transplant. 2016;31(3):375-382.
13. Demoulin N et al. Enteric Hyperoxaluria in Chronic Pancreatitis. Medicine. 2017;96(19):e6758.
14. Cochat P, Rumsby G. Primary Hyperoxaluria. N Engl J Med. 2013;369(7):649-658.
15. Hopp K et al. Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. J Am Soc Nephrol. 2015;26(10):2559-2570.