Improving our understanding of oxalate disorders may provide an opportunity to target the gut to treat kidney stone disease.
by Dr Annamaria Kausz and Dr Zhiqun Zhang
Hyperoxaluria, or excess urinary oxalate excretion, is an under-recognised metabolic disorder that can lead to kidney stones and progressive kidney damage, as well as systemic complications associated with extra-renal oxalate deposition.
The gastrointestinal (GI) tract plays a significant role in the development of secondary hyperoxaluria, where the hyperoxaluria is due to excess absorption of oxalate from the GI tract.
The role of the GI tract in the pathophysiology of systemic disorders is becoming increasingly recognised, and therapeutic interventions utilising the gut to target metabolic disorders have existed for some time. Examples include orally administered non-absorbable drugs which act within the GI tract, such as polymeric resins to bind potassium or phosphate (to treat hyperkalemia or hyperphosphatemia, respectively) or enzymes in pancreatic insufficiency. Degradation of oxalate within the gut offers a potential novel approach to the treatment of hyperoxaluria.
What is oxalate?
Oxalate (C2O42-) is an end product of normal cellular metabolism and is also absorbed from the diet. Certain foods like green leafy vegetables, fruits and nuts have particularly high oxalate content. Plants use oxalate to store calcium, but oxalate does not have a known role in normal human physiology. Humans lack the innate capacity to degrade or metabolise oxalate. It is mostly excreted unchanged by the kidneys in urine. It is also reported that some oxalate is secreted into the intestine, and secretion may be adaptively modulated under some pathological conditions (e.g. increased in chronic kidney disease or obesity).1
Hyperoxaluria: A “new” metabolic disorder
Persistently elevated oxalate in urine (hyperoxaluria) is a relatively underdiagnosed metabolic disorder. Although hyperoxaluria is typically suspected in patients with recurrent kidney stones, hyperoxaluria is also associated with an increased risk for kidney damage due to oxalate deposition in the kidneys (oxalate nephropathy) with or without a prior history of kidney stones. In severe cases, systemic oxalosis, chronic kidney disease (CKD) and end-stage renal disease (ESRD) may ensue.2
Hyperoxaluria is due to either overproduction of oxalate by the liver from a genetic defect, called primary hyperoxaluria, or from over-absorption of oxalate from the GI tract, called secondary hyperoxaluria.
A number of physiological parameters influence the absorption of dietary oxalate, including intestinal pH and transit time, type of diet, and the presence of other compounds, such as calcium and magnesium, in the GI tract.
Secondary hyperoxaluria is further characterised either as enteric, resulting from a chronic and irremediable underlying GI disorder associated with fat malabsorption, or idiopathic, meaning the underlying cause is unknown.
Enteric hyperoxaluria is commonly seen as a complication of a malabsorptive disorder; it is a common complication following bariatric surgery (such as Roux-en-Y gastric bypass) and in patients with short bowel syndrome, and can also be related to inflammatory bowel diseases (IBD) such as Crohn’s disease, or other conditions associated with GI malabsorption, including cystic fibrosis, pancreatic insufficiency, and celiac disease. It is the more severe type of secondary hyperoxaluria because the underlying GI disorder predisposes patients to chronic excess oxalate absorption; patients with enteric hyperoxaluria often have levels of urinary oxalate excretion approaching those seen with primary hyperoxaluria.3
The diagnosis and subsequent management of hyperoxaluria is based on measurement of 24-hour urinary oxalate excretion. In general, patients are considered to have hyperoxaluria if urinary oxalate excretion is greater than 40 mg/24 hour. The scientific literature suggests that sustained urinary oxalate excretion above 30-40 mg/24 hour is associated with an increased risk of kidney stone formation; even small incremental increases in the range of 5-10 mg/24 hour can be associated with a higher risk of kidney stones.4
Kidney stone disease in enteric hyperoxaluria
Kidney stones affect approximately 1 in 11 people in the United States at some point in their lives and the likelihood of recurrence has been estimated to be as high as 50 percent within five years of the initial event. The incidence and prevalence of kidney stones is increasing globally and is seen across sex, race, and age.5
Typically, kidney stones present with sudden onset of intense flank pain, and in some cases nausea and vomiting; gross or microscopic hematuria are also common. Patients who experience a kidney stone typically go to the emergency room for treatment due to this intense physical pain, and the kidney stone may take hours or even days to pass. In some cases, patients require interventional surgical procedures to remove a stone if it is too large to pass on its own.
Hyperoxaluria is one of the identified risk factors for kidney stones, with high urine oxalate levels leading to precipitation of calcium oxalate crystals in the urinary tract. In patients who underwent bariatric surgery for weight loss (excluding restrictive procedures), reported kidney stone incidence at 10 months to 6 years post-operatively ranged from 0.02 to 18 percent across the studies.6,7,8 In studies with pre-operative and non-operative control data reported, kidney stone incidence was higher post-operatively compared with pre-operative and control subjects who did not undergo surgery.8 The prevalence of hyperoxaluria is reported to be 5 to 24 percent among patients with GI diseases associated with malabsorption.9
Progressive kidney disease in enteric hyperoxaluria
While the typical clinical manifestation of hyperoxaluria is kidney stones, the disorder can be variable in its presentation. Hyperoxaluria can also lead to calcium oxalate (CaOx) crystal deposition in kidney tissue; this can lead to obstruction and inflammation resulting in oxalate nephropathy and progressive loss of kidney function.10,11 Acute kidney injury from oxalate nephropathy, which can occur after ingestion of ethylene glycol (hepatically metabolised to oxalate) and fruits such as rhubarb and star fruit (both contain high amount of oxalate) dramatically illustrates the nephrotoxic potential of CaOx crystals. The CaOx crystals and associated tubular and interstitial injury seen on kidney biopsy serve as direct evidence of the pathophysiologic role of oxalate.12
It is important to note that progressive kidney damage may be the only manifestation of hyperoxaluria, and can frequently lead to ESRD and even death. In a systematic review of cases with biopsy-proven oxalate nephropathy, only 26 percent of patients presented with kidney disease and stones; over a mean follow-up of 12.9 months, renal replacement therapy (dialysis) was required in more than half of the patients and the overall mortality rate was 33 percent.2 The authors reported that oxalate crystal deposition was universally found in the kidneys and suggested a causal role for the oxalate crystals.
Patients with hyperoxaluria who develop advanced CKD begin to accumulate oxalate in the blood as their capacity for renal excretion of oxalate diminishes. With persistently elevated plasma oxalate (can also be referred to as hyperoxalemia), oxalate may deposit in tissues throughout the body including the bones, joints, eyes and heart, resulting in a condition called systemic oxalosis. Patients with ESRD may require more frequent hemodialysis to prevent or limit systemic oxalosis, especially prior to (and immediately after) kidney transplantation in order to avoid development of oxalate nephropathy in the new allograft.13
A need for effective and targeted treatment options
Patients suffering from recurrent kidney stones bear significant physical, social and financial burdens and would likely be highly motivated to prevent recurrences. This is especially true in patients with enteric hyperoxaluria because they tend to have more frequent and more complicated kidney stone episodes.
There are currently no approved pharmacologic therapies 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 (to bind oxalate) and, exclusively for the subset of patients with the most severe form of primary hyperoxaluria type 1 (PH1), Vitamin B6 supplementation.
Despite these strategies, many patients continue to experience hyperoxaluria with recurrent kidney stones and carry significant risk for long-term kidney damage.14
Patients with enteric hyperoxaluria may find it particularly difficult to consistently ingest the quantities of fluid required to maintain adequate urine volume due to their underlying GI condition. In addition, recommendations for a low oxalate diet are somewhat in conflict with general recommendations for a healthy diet of largely plant-based foods for these patients. The limited options to treat calcium oxalate kidney stones have suboptimal efficacy, are not targeted to oxalate, and may be difficult to tolerate in patients with GI disorders.
Given the lack of approved and effective therapies for patients suffering from enteric hyperoxaluria, there is a significant unmet need for a safe and effective therapy that reliably lowers urine oxalate levels. Novel approaches to reduce oxalate absorption and its metabolic burden on the kidney via the GI tract are currently in clinical development.
Providing oxalate-degrading bacteria orally has been studied for the treatment of enteric hyperoxaluria,15 and there are ongoing clinical trials in primary hyperoxaluria.16 Allena Pharmaceuticals is developing reloxaliase, an orally-administered, crystalline oxalate decarboxylase enzyme that remains stable in the GI tract and specifically degrades oxalate in the GI tract. It is currently being evaluated in a Phase 3 trial in patients with enteric hyperoxaluria.17
The general therapeutic approach of deploying a non-absorbed drug into the GI tract to reduce metabolic disease burden in patients with kidney disease has proven successful (examples include sevelamer to bind phosphate, or patiromer to bind potassium). Reloxaliase is not a binder, rather it is a crystallised enzyme that specifically degrades oxalate present within the GI tract. As such it has the potential to directly address the underlying pathophysiology of enteric hyperoxaluria, which is excess absorption of oxalate. If successful, the reloxaliase trials may deliver a targeted treatment option for patients with enteric hyperoxaluria, as well as advance our understanding of oxalate and its role in kidney stone recurrence and progressive kidney disease.
- Whittamore, J.M. and M. Hatch, The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man. Urolithiasis, 2017. 45(1): p. 89-108.
- Lumlertgul, N., et al., Secondary Oxalate Nephropathy: A Systematic Review. Kidney International Reports, 2018. 3(6): p. 1363-1372.
- Asplin, J.R., The management of patients with enteric hyperoxaluria. Urolithiasis, 2016. 44(1): p. 33-43.
- Curhan, G.C. and E.N. Taylor, 24-h uric acid excretion and the risk of kidney stones. Kidney Int, 2008. 73(4): p. 489-96.
- Romero, V., H. Akpinar, and D.G. Assimos, Kidney stones: a global picture of prevalence, incidence, and associated risk factors. Rev Urol, 2010. 12(2-3): p. e86-96.
- Lieske, J.C., et al., Kidney stones are common after bariatric surgery. Kidney Int, 2015. 87(4): p. 839-45.
- Gonzalez, R.D. and B.K. Canales, Kidney stone risk following modern bariatric surgery. Curr Urol Rep, 2014. 15(5): p. 401.
- Valezi, A.C., et al., Urinary evaluation after RYGBP: a lithogenic profile with early postoperative increase in the incidence of urolithiasis. Obes Surg, 2013. 23(10): p. 1575-80.
- Nazzal, L., S. Puri, and D.S. Goldfarb, Enteric hyperoxaluria: an important cause of end-stage kidney disease. Nephrol Dial Transplant, 2016. 31(3): p. 375-82.
- Knauf, F., et al., NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy. Kidney Int, 2013. 84(5): p. 895-901.
- Kurts, C., A crystal-clear mechanism of chronic kidney disease. Kidney Int, 2013. 84(5): p. 859-61.
- Glew, R.H., et al., Nephropathy in dietary hyperoxaluria: A potentially preventable acute or chronic kidney disease. World J Nephrol, 2014. 3(4): p. 122-42.
- Roodnat, J.I., et al., A Successful Approach to Kidney Transplantation in Patients With Enteric (Secondary) Hyperoxaluria. Transplant Direct, 2017. 3(12): p. e331.
- 14.Dhondup, T., et al., Risk of ESRD and Mortality in Kidney and Bladder Stone Formers. Am J Kidney Dis, 2018.
- Lieske, J.C., et al., Use of a probiotic to decrease enteric hyperoxaluria. Kidney Int, 2005. 68(3): p. 1244-9.
- Milliner, D., B. Hoppe, and J. Groothoff, A randomised Phase II/III study to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria. Urolithiasis, 2018. 46(4): p. 313-323.
- ClinicalTrials.gov Identifier: NCT03456830
Dr Annamaria Kausz is a nephrologist and vice president of clinical development at Allena Pharmaceuticals USA
Dr Zhiqun Zhang is a nephrologist and clinical scientist at Allena Pharmaceuticals USA