Pathophysiology and Treatment of Enteric Hyperoxaluria

Abstract

Enteric hyperoxaluria is a distinct entity that can occur as a result of a diverse set of gastrointestinal disorders that promote fat malabsorption. This, in turn, leads to excess absorption of dietary oxalate and increased urinary oxalate excretion. Hyperoxaluria increases the risk of kidney stones and, in more severe cases, CKD and even kidney failure. The prevalence of enteric hyperoxaluria has increased over recent decades, largely because of the increased use of malabsorptive bariatric surgical procedures for medically complicated obesity. This systematic review of enteric hyperoxaluria was completed as part of a Kidney Health Initiative–sponsored project to describe enteric hyperoxaluria pathophysiology, causes, outcomes, and therapies. Current therapeutic options are limited to correcting the underlying gastrointestinal disorder, intensive dietary modifications, and use of calcium salts to bind oxalate in the gut. Evidence for the effect of these treatments on clinically significant outcomes, including kidney stone events or CKD, is currently lacking. Thus, further research is needed to better define the precise factors that influence risk of adverse outcomes, the long-term efficacy of available treatment strategies, and to develop new therapeutic approaches.

Introduction

Hyperoxaluria is an important pathogenic factor in the formation of calcium oxalate kidney stones (hereafter referred to simply as stones), the most common type that occur in humans. Marked hyperoxaluria can result from genetic causes of hepatic overproduction (primary hyperoxaluria), or through gastrointestinal (GI) conditions causing fat malabsorption and increased oxalate absorption in the GI tract (enteric hyperoxaluria). Both primary hyperoxaluria and enteric hyperoxaluria are associated not only with stone formation, but may progress to crystal nephropathy, CKD, and kidney failure. Novel treatments for both conditions are rapidly emerging, but, because both are relatively rare conditions, there is a paucity of clinical trial data at this time. A workgroup within the Oxalosis and Hyperoxaluria Foundation (OHF), in coordination with the Kidney Health Initiative (KHI), was formed in 2017 to define possible trial end points, with the objective of expanding treatment options for enteric hyperoxaluria. As a first step in that process, a multidisciplinary workgroup performed a systematic review of the literature on the pathophysiology and current treatment options for enteric hyperoxaluria; this document is a summary of this initial endeavor.

Pathophysiology of Enteric Hyperoxaluria

Oxalate arises from a variety of dietary and endogenous sources and is an end product of human metabolism. While a small fraction of ingested oxalate is absorbed under normal circumstances (typically 5%–10%), the majority of urine oxalate is derived from endogenous hepatic production (1,2). Any oxalate absorbed from the diet or endogenously produced is delivered to the kidney, where it is freely filtered and excreted as urinary oxalate (3). An increase in either GI oxalate absorption or hepatic oxalate production increases plasma oxalate and thus urinary oxalate, and contributes to the risk of stone formation and other adverse kidney outcomes, such as nephrocalcinosis (Figure 1) (4).

Figure 1.

Urinary oxalate is derived from a combinaiton of hepatic metabolism and gastrointestinal absorption in enteric hyperoxaluria. (A) Oxalate is an end product of glyoxalate metabolism in the liver. The remainder of systemic oxalate comes from ingestion of certain fruits and vegetables. The oxalate in these plants is in the form of relatively insoluble calcium oxalate crystals. Hence, under normal conditions, only 5%–10% of ingested oxalate is absorbed and the remainder passes into the stool. However, in patients with fat malabsorption of any cause (enteric hyperoxaluria), undigested fatty acids reach the large intestine where they can combine with calcium; (B) the net effect is to release more free oxalate into the intestinal lumen. It is thought that this free oxalate is largely absorbed paracellularly in the large intestine. Due to the fat malabsorption, among patients with enteric hyperoxaluria, the net percentage of ingested oxalate that ends up being absorbed can increase to ≥30%. Any oxalate that comes from the liver or is absorbed from the diet is delivered by (C) the blood to (D) the kidneys, where it is excreted via a combination of glomerular filtration and proximal tubular secretion. The increased delivery of oxalate to the kidneys leads to (E) increased urinary oxalate excretion, which in turn places these patients at risk of calcium oxalate kidney stones, corticomedullary nephrocalcinosis, and oxalate nephropathy.

Enteric hyperoxaluria can result from increased bioavailability of dietary oxalate or increased GI oxalate permeability. Decreased intestinal secretion of oxalate into the gut lumen has also been associated with hyperoxaluria in animal models (5,6). The bioavailability of dietary oxalate is, in part, determined by the calcium content of ingested food because calcium can form insoluble calcium oxalate salts in the intestine lumen that are eliminated in the stool. An increase in the dietary intake of free fatty acids, or their malabsorption in the small intestine, can result in increased fat delivery to the colon where it can bind dietary calcium, thus increasing free oxalate that can be absorbed into the bloodstream. Bile salts and fatty acids not only determine the bioavailability of soluble oxalate in the intestine, they can also increase the local membrane permeability in the bowel and thereby facilitate oxalate absorption (7). Thus, the net effect of fat malabsorption from any cause is increased absorption of luminal oxalate into the blood.

Oxalate homeostasis could potentially be affected by the gut microbiota and genetic anomalies. Research over the past 20 years has established the role of the gut microbiome in oxalate homeostasis (8,9). Certain bacterial strains, including Oxalobacter spp., Bifidobacterium spp., and Lactobacillus spp., can degrade oxalate and may be capable of modulating intestinal oxalate secretion (6,10). Additionally, animal studies suggest that inherited defects in the SLC6 family of anion exchangers could predispose to enteric hyperoxaluria (11,12). However, the role of either in human disease remains to be defined.

Causes of Enteric Hyperoxaluria

Enteric hyperoxaluria is frequently observed in conjunction with digestive diseases that affect fat absorption such as Crohn's disease, cystic fibrosis, chronic biliary disease, pancreatic pathologies, and short bowel syndrome (13). Chronic diarrhea associated with fat malabsorption may result in a low urine volume, hypocitraturia, and hypomagnesuria, which further increases the risk for stone formation.

Surgical procedures used for weight loss have been linked with enteric hyperoxaluria and higher stone risk due to altered fat absorption. The jejunoileal bypass procedure was almost universally associated with enteric hyperoxaluria but, due to this and other complications, was abandoned by the early 1980s (14). In the intervening years, that procedure was largely replaced by the Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion procedures, which can also result in enteric hyperoxaluria, calcium oxalate kidney stones, and oxalate nephropathy. Nondiverting procedures for bariatric surgery (i.e., restrictive), such as sleeve gastrectomy, appear to only rarely cause enteric hyperoxaluria and are not associated with a markedly higher risk of kidney stones (15). Over the last 10 years, use of sleeve gastrectomy has increased and RYGB has decreased; consequently, the incidence of enteric hyperoxaluria associated with bariatric surgery may fall over time. Nevertheless, tens of thousands of RYGB surgeries are still performed annually, and the numbers of at-risk patients previously treated with RYGB and other malabsorptive procedures will be substantial for decades to come.

A recent study demonstrated a higher risk for nephrolithiasis associated with use of antibiotics (16) that can alter the gut microbiome (17). Because good observational evidence backs up the potential role of Oxalobacter, Bifidobacterium, Lactobacillus, and other gut microbiota in maintaining oxalate homeostasis, this correlation has validity, but more studies are needed to establish the cause and effect of this relationship and the exact mechanism(s) involved.

Prevalence of Enteric Hyperoxaluria in the United States

The prevalence of enteric hyperoxaluria and its major complications (kidney stones and CKD) remains poorly defined. The total prevalence of patients in the United States in 2019 with enteric conditions associated with kidney failure and/or recurrent kidney stones is estimated at 250,000. The most common causes were RYGB surgery for obesity (approximately 60%), inflammatory bowel disease (approximately 20%), celiac disease (8%), and chronic pancreatitis (4%).

Nephrolithiasis in Enteric Hyperoxaluria

Kidney stones are a well-recognized complication of enteric hyperoxaluria (18), and urinary oxalate excretion appears to correlate with stone risk. In a study of 762 patients after RYGB, urinary oxalate increased over time and was highest in patients who developed stones (63 mg/d in stone formers compared with 42 mg/d in non-stone formers, P<0.001) (15). In another series, stone formation risk was also increased after RYGB (odds ratio, 1.4; 95% confidence interval [95% CI], 1.1 to 1.8; P=0.006), and those with stones had a greater increase in urinary oxalate excretion (19). Finally, an analysis of seven studies including 277 patients before and after RYGB identified a 50% increase in urinary oxalate as one of the key lithogenic risk factors after RYGB (20).

The reported stone incidence 10 months to 6 years after RYGB ranges from 0.02% to 18% (Table 1). In studies where preoperative and nonoperative control data were reported, stone incidence was up to 7% higher postoperatively compared with preoperatively, and 3%–7% higher compared with subjects who were obese and who did not undergo surgery. A recent meta-analysis reported the pooled relative risk of stone formation from RYGB to be 1.79 (95% CI, 1.54 to 2.10) (21). After procedures that cause more pronounced malabsorption (i.e., very long limb RYGB or biliopancreatic diversion), patients have a five-fold greater risk of stones compared with nonoperative controls who are obese (15). In a detailed literature review of 24 studies that, in aggregate, included 6777 patients who had undergone bariatric surgery and had a stone history and 7089 non–stone forming controls, the incidence of stones was two-fold higher in the non-stone formers (9%) and four-fold higher in those with a previous history of stones (17%) (20).

Table 1.

Published studies reporting kidney stone rates in patients with enteric hyperoxaluria due to bariatric surgery

Article	Population	Stone Incidence
		Bariatric Surgery	Comparison Group	P Value
Prospective
Valezi et al. (19)	151 obese patients who underwent RYGB	1 yr postop, 18%	Preop, 11%	0.001
Retrospective
Lieske et al. (15)	762 patients who underwent bariatric surgery and matched control individuals, who were equally obese, without surgery	6 yr postop, 11%	No surgery, 4%	<0.001
Matlaga et al. (83)	4639 patients who underwent RYGB surgery, and a control group of 4639 patients who were obese and who did not have surgery, in a national private insurance claims database in a 5-year period (2002–2006)	4.6 yr postop, 8%	No surgery, 5%	<0.001
Costa-Matos et al. (84)	58 Brazilian patients who underwent RYGB between 2000 and 2005	10 mo to 6 yr postop, 0.02%	Preop, 0.02%	N/A
Durrani et al. (85)	972 patients who underwent RYGB	2.4 yr postop, 6% overall, 3% de novo, and 31% of patients with prior stones	Preop, 9%	N/A

RYGB, Roux-en-Y gastric bypass; postop, postoperative; preop, preoperative; N/A, not applicable.

Malabsorptive conditions other than bariatric surgery are also associated with kidney stone risk, with the reported stone incidence ranging from 2% to 38% across studies (Table 2). Stone incidence is 35% in patients with inflammatory bowel disease and hyperoxaluria, compared with 23% in patients with inflammatory bowel disease who have normal urinary oxalate excretion (22). Among patients who undergo bowel resection, the incidence of stones correlated with the length of resection (23,24). However, the segment of bowel removed is important, because loss of small intestine favors fat malabsorption, whereas the pathologic oxalate absorption associated with enteric hyperoxaluria occurs largely in the colon. Thus, patients who have resection of the colon, for example for ulcerative colitis, are at low risk for enteric hyperoxaluria.

Table 2.

Published studies reporting kidney stone rates in patients with enteric hyperoxaluria associated with other malabsorptive conditions

Article	Population	Stone Incidence
Prospective
Caudarella et al. (86)	66 patients with Crohn's disease or ulcerative colitis. Patients with Crohn's disease had ileal resection and right hemicolectomy with end-end ileotransversostomy. Patients with ulcerative colitis had proctocolectomy with ileal pouch anal anastomosis	Preop, 8%
		Postop, 12%
Anderson et al. (23)	107 patients with Crohn's disease receiving various bowel resections	Preop, 2%
		Postop, 10%
Hylander et al. (22)	87 patients with chronic IBD, stratified by kidney oxalate excretion. 26 patients had increased urinary oxalate, while 61 patients had normal urinary oxalate	Normal urinary oxalate, 23%
		Hyperoxaluric, 35%
Retrospective
McAuliffe et al. (87)	33,386 patients with IBD, stratified by severity of disease, followed for at least 6 mo	Incidence per 1000 person-years (95% CI):
		Mild IBD, 13.5 (12.5 to 14.6)
		Moderate-severe IBD, 10.8 (8.80 to 13.2)
Cury et al. (88)	168 Brazilian patients with IBD (93 with Crohn's disease, 75 with ulcerative colitis)	Crohn's disease, 38%
		Ulcerative colitis, 38%
Siener et al. (64)	51 patients with fat malabsorption due to intestinal diseases such as Crohn's disease, exocrine pancreatic insufficiency, short bowel syndrome, and primary biliary cholangitis	Overall, 20%
		Pancreatic insufficiency, 29%
		Crohn's disease, 13%
Hueppelshaeuser et al. (89)	27 children and 19 adults with Crohn's disease	28%
Mukewar et al. (90)	218 patients with ileal pouch anal anastomosis	37%
Repiso et al. (91)	157 patients diagnosed with Crohn's disease in Spain	8%
Ben-Ami et al. (92)	312 patients with Crohn's disease in Israel, followed for 7.2 yr	4%
Christodoulou et al. (93)	256 patients with IBD in Greece, followed for 8.1 yr	Crohn's disease, 5%
		Ulcerative colitis, 6%
Nightingale et al. (94)	86 patients with <200 cm of residual small bowel after resection, followed for 22 mo	With colon, 24%
		Without colon, 0%
Trnka et al. (95)	113 patients with IBD after resections, followed for 19.8 yr	19%
Bambach et al. (24)	426 patients after bowel surgery, stratified by procedure, followed for 8 yr	Overall, 9%
		Resection with intact colon, 7%
		Ileostomy only, 9%
		Ileostomy with resection, 15%
Knudsen et al. (96)	228 patients with chronic IBD	15%
Maratka et al. (97)	512 patients with ulcerative colitis in Czechoslovakia	Overall, 2%
		After resection, 13%

95% confidence interval, 95% CI; preop, preoperative; postop, postoperative; IBD, inflammatory bowel disease.

Compared with age-matched controls without cystic fibrosis (1%–2%), 3%–6% of patients with cystic fibrosis have nephrolithiasis. Suggested mechanisms include hyperoxaluria due to fat malabsorption, hypocitraturia, antibiotic exposure, and lack of Oxalobacter formigenes colonization (25). Most recently, in a mouse model of cystic fibrosis, SLC26A6 expression and SLC26A6-mediated intestinal oxalate secretion was defective and was associated with a 2.5-fold increase in urine oxalate excretion and plasma oxalate concentration (26).

Other Kidney Complications and Natural History

It is increasingly apparent that urinary oxalate is a risk factor for other kidney pathologies, including AKI and CKD (27–30). AKI occurs after patients consume ethylene glycol, which is hepatically metabolized to oxalate, or with heavy consumption of fruits such as rhubarb and star fruit (both very oxalate rich) (31).

Calcium oxalate crystals can precipitate within kidney tubules, bind to epithelial cells, and cause obstruction. Attached crystals can be phagocytosed and transcytosed into the kidney interstitium (32). The resulting release of inflammatory mediators can contribute to oxalate nephropathy and the potential for progressive loss of kidney function (33). Evidence in animal studies suggests that the inflammation induced by calcium oxalate crystals could be mediated by the NLRP3 inflammasome, the same pathway of crystal-induced inflammation observed in gout (uric acid) and arteriosclerosis (cholesterol) (34). Stimulation of TGF-β release by NLRP3 is associated with kidney fibrosis and progressive loss of kidney function in animal models of hyperoxaluria (35). Similarly, kidney biopsy specimens of patients after RYGB show diffuse tubular degenerative changes, abundant tubular calcium oxalate deposits, and various degrees of tubulointerstitial scarring (28).

Oxalate nephropathy in enteric hyperoxaluria can lead to progressive kidney deterioration and, eventually, kidney failure requiring dialysis (27–29,36,37). Patients with obesity syndromes necessitating bariatric surgery often suffer from underlying CKD (27,38). Thus, postoperative hyperoxaluria and kidney stone formation place this population at further long-term risk for kidney failure. Patients with pancreatic insufficiency, as can occur in cystic fibrosis, can also develop kidney failure due to oxalate nephropathy, particularly if they are nonadherent with pancreatic enzyme replacement therapy (39).

When GFR falls below 30–40 ml/min per 1.73 m², plasma oxalate levels increase. This, in turn, can promote calcium oxalate crystallization and deposition in extrarenal tissues, a process termed systemic oxalosis (40). Rarely, patients with CKD and severe secondary hyperoxaluria can present with systemic crystal deposition in the retina, joints, and skin, particularly when consuming high oral doses of vitamin C, which is metabolized to oxalate (41,42).

After patients receive a kidney transplant for kidney failure due to oxalate nephropathy, they remain at risk for recurrent oxalate nephropathy in the allograft (43). In a small report of three patients with enteric hyperoxaluria who developed kidney failure requiring transplantation, two developed recurrent oxalate nephropathy and one required a second transplant (37).

Finally, in addition to the attendant kidney risks, there is increasing evidence that hyperoxaluria may be a factor in the pathogenesis of cardiovascular complications. Elevated plasma oxalate has been associated with reactive cardiac fibrosis, increased vascular calcification, and hemodynamic effects such as reduced pulse wave velocity and central aortic BPs (44–47). Thus, the effect of enteric hyperoxaluria likely extends far beyond stones.

Current Therapies

There are no specific therapies for enteric hyperoxaluria. Current management includes treating the underlying disease with the goal of reducing fat malabsorption. Because that is not always possible or sufficient, measures to reduce GI absorption of oxalate (and hence its excretion through kidneys) and/or measures to reduce calcium oxalate crystallization in the urine and tubular fluid are needed. Examples include reducing dietary consumption of fat or oxalate, using calcium supplements to bind oxalate in the gut, and increasing daily fluid intake to reduce calcium oxalate concentration. Finally, other treatments such as bile acids or bile acid sequestrants, probiotics, oxalate-degrading enzymes, and calcium supplements have also been studied.

Treatment of the Underlying Disease

Whenever possible, treatment of the underlying GI disease is critical for reducing fat malabsorption and resultant enteric hyperoxaluria. There are a large number of patients with morbid obesity who underwent malabsorptive bariatric surgery over the last 3 decades and are at risk for developing profound hyperoxaluria and kidney failure (29,48). If oxalate nephropathy develops, reversal of the bypass may result in improved kidney function and reduction in oxalate excretion, although reversal can carry significant risks and is rarely done (49,50).

In patients with celiac disease, treatment with a gluten-free diet lowers stone incidence comparably to control levels (51). Among patients with pancreatic insufficiency, such as secondary to cystic fibrosis, sustained use of pancreatic enzyme therapy reduces steatorrhea and thus may prevent stone formation (52). In inflammatory bowel disease, enteric hyperoxaluria can be prevented both by medical therapy to reduce disease activity, and avoiding, if possible, surgical resection of the small intestine (53).

Dietary Measures

Increased fluid intake, a general stone-prevention tool, is a standard component of enteric hyperoxaluria treatment. However, patients with enteric hyperoxaluria may have short gut or diarrhea, which limits the amount of fluid intake they may tolerate. Low-oxalate diets are an obvious treatment strategy (50,54). Although studies that used a low-oxalate diet (<50 mg, or 0.57 mmol, per day) are small, many (55,56), but not all (54,57), suggest this strategy reduces urinary oxalate excretion. Most studies also incorporated other diet interventions, such as lower protein or sodium intake, which limits the ability to combine them for analysis. Although a low-fat, low-oxalate, moderate-protein, and normal-calcium diet has been demonstrated to reduce calcium oxalate supersaturation in enteric hyperoxaluria, this diet can be difficult for patients to maintain and may have a minimal effect on urinary oxalate excretion (50,54). One current recommendation is to lower daily oxalate intake to 50 mg with maintenance of normal dietary calcium, although this may be difficult to chronically maintain and accurate information about food oxalate content is not readily available (58).

Urinary oxalate excretion in enteric hyperoxaluria also correlates directly with the fat content of stool, and limiting fat intake has been shown to reduce urinary oxalate (59,60). A low-fat diet also improves steatorrhea, leading to less fecal fluid loss, which further diminishes the risk of stone formation.

Calcium supplements have been used to bind oxalate in the gut and thus promote excretion in the stool. Multiple small studies in the 1970s demonstrated this treatment reduced urinary oxalate in patients with diverse causes of enteric hyperoxaluria, without a significant increase in urinary calcium (61,62). Although this has theoretic benefit to reduce risk for oxalate nephropathy, the effectiveness of calcium supplementation to reduce stone formation in enteric hyperoxaluria remains to be demonstrated. Treatment algorithms currently suggest administration of elemental calcium, primarily when consuming oxalate-rich foods, and monitoring 24-hour urine oxalate and calcium excretion. Calcium citrate has superior bioavailability and a potential advantage for bone health compared with calcium carbonate (63), and patients with enteric hyperoxaluria often manifest hypocitraturia and may benefit from oral citrate therapy (59,64). However, it is unclear which calcium salt is a more effective oxalate binder (59,60).

Other Approaches

The use of natural, conjugated bile acids may benefit those with significant terminal ileum resection who are known to be deficient in bile acids, although definitive evidence is lacking for this approach (65). Older studies have demonstrated variable efficacy for the use of bile acid sequestrants (e.g., cholestyramine) to reduce urinary oxalate excretion in enteric hyperoxaluria (66–69).

Enzymatic degradation of oxalate in the GI tract using an oral preparation of oxalate decarboxylase is a newer potential treatment strategy (70). A phase 2, open-label trial in 16 participants with idiopathic and enteric hyperoxaluria found that oral oxalate decarboxylase taken for 4 days decreased urinary oxalate excretion by 14 mg/d, with a greater reduction observed in patients with enteric (−22.0 mg/d) versus idiopathic (−10.2 mg/d) hyperoxaluria (71). A phase 3 randomized controlled trial in patients with enteric hyperoxaluria treated for 28 days was recently completed, and a follow-up phase 3 randomized controlled trial will evaluate the effect of oral oxalate decarboxylase on stone recurrence in patients with enteric hyperoxaluria (NCT03847090). Future research may identify methods to manipulate oxalate transport in the colon and small intestine, but much work remains to better understand these pathways (72–74).

Future Directions and Knowledge Gaps

Although much has been learned about oxalate absorption from the GI tract over the last 50 years, many gaps remain. Overall, the literature is limited, and the majority of clinical studies have been small, single center, and nonrandomized. Further, there is no definitive evidence that reducing urinary oxalate decreases stone formation or preserves kidney function, despite the known pathophysiologic mechanisms that would suggest this should be beneficial. Enteric hyperoxaluria also has many different underlying etiologies, and controlled trials are limited. Hence, there is a significant gap in data on existing treatments for enteric hyperoxaluria, and future studies should aim to include larger populations in randomized controlled trials.

Mechanisms of Intestinal Oxalate Transport

Over the last 20 years, major progress has been made regarding the molecular identification of oxalate transporters. Several investigators have confirmed the SLC26A6 protein can actively secrete oxalate at the apical membrane of enterocytes, and loss of SLC26A6 results in hyperoxaluria and oxalate nephrolithiasis in animal models (11,12). Similar to SLC26A6, functional expression in Xenopus oocytes revealed that SLC26A1 can mediate oxalate transport (75,76). Moreover, one line of SLC26A1-knockout mice developed hyperoxalemia, hyperoxaluria, and calcium oxalate nephrolithiasis analogous to SLC26A6-knockout mice (77), whereas another strain did not (78). It has also been proposed that active, transcellular oxalate absorption occurs at the apical membrane via SLC26A3 (79). However, heterologous expression studies have demonstrated poor oxalate affinity of human SLC26A3 (80), and the lower urinary oxalate excretion of SLC23A3-knockout mice may be due to the diarrhea these mice manifest, rather than reduced transcellular oxalate absorption. Overall, to date, the exact molecular mechanisms of oxalate transport in the human intestine remain incompletely understood. Further studies are needed to identify the molecular identity and physiologic function of oxalate transporters and their importance in humans with enteric hyperoxaluria.

Potential Role of the Intestinal Microbiome in Oxalate Metabolism and Transport

Work over the last 2 decades has identified O. formigenes as an obligate anaerobe that degrades oxalate and stimulates oxalate absorption in the gut (5,81). However, use of O. formigenes as a therapeutic agent in humans has not reduced urine oxalate excretion or plasma oxalate concentration in clinical trials of patients with primary hyperoxaluria (5), and has not been extensively studied in patients with enteric hyperoxaluria. Humans are variably colonized, and epidemiologic evidence suggests associations of colonization with kidney stone risk in various patient populations. Emerging evidence suggests other elements of the intestinal microbiome might also participate in oxalate degradation, and maintaining biodiversity of the microbiome is important to maintain adequate oxalate metabolism (81,82).

Conclusion

Multiple GI disorders associated with fat malabsorption can cause oxalate overabsorption and result in enteric hyperoxaluria. This disorder is most commonly recognized in short bowel syndrome and after malabsorptive bariatric procedures (most often RYGB), but can also occur in inflammatory bowel disease and with pancreatic insufficiency of any cause. Enteric hyperoxaluria is associated with a higher risk of kidney stones and, less often, CKD. However, there is limited published literature to suggest uniformly effective measures to mitigate the consequences of enteric hyperoxaluria. Clearly more research and novel therapeutic approaches are needed, as well as careful analysis of appropriate end points for clinical trials.

Disclosures

M. Allain reports employment at the American Society of Nephrology. D. Assimos has been on editorial boards for Journal of Endourology, Journal of Urology, and Urolithiasis. M.A. Baum is on the scientific advisory boards for Dicerna, Dent Disease Foundation, Oxalosis/Hyperoxaluria Foundation, and Retrophin, and is a consultant for Retrophin. A. Kausz is employed by and has ownership interest in Allena Pharmaceuticals, Inc, which is developing a product for the treatment of enteric hyperoxalura. She is also on the KHI Board of Directors. F. Knauf is a consultant for Allena Pharmaceuticals, Alnylam Pharmaceuticals, and OxThera Pharmaceuticals, and receives funding from Dicerna Pharmaceuticals and Fresenius Medical Care. C.B. Langman is a consultant for Alexion Pharmaceuticals, Allena Pharmaceuticals, and Dicerna Pharmaceuticals, and receives researching funding from Lurie Children’s Hospital, Achillion and Alexicon Pharmaceuticals; Lurie Children’s Hospital of Chicago, Alexion; and Lurie Children’s Hospital, Ultragenyx. J.C. Lieske reports receiving grants and other from Allena, and reports serving on the advisory boards of Novobiom and Synlogic, during the conduct of the study. He is a consultant for Allena, Alnylam, American Board of Internal Medicine, Dicerna, Orfan, OxThera, Retrophin, and Siemens; receives funding from Allena, Alnylam, Dicerna, OxThera, Retrophin, and Siemens; and serves on the advisory board for Orfan. D. Milliner reports serving as consultant (contracts paid directly to Mayo Clinic) for Allena Pharmaceuticals, consultant (contracts paid directly to Mayo Clinic) and on the advisory committee for Alnylam Pharmaceuticals, consultant and chair of Data Safety and Monitoring Committtee (contracts paid directly to Mayo Clinic) for Dicerna Pharmaceuticals, consultant and chair of the Data Safety and Monitoring Board (contracts paid directly to Mayo Clinic) for OxThera Pharmaceuticals, member of Synologic Medical Advisory Panel (contracts paid directly to Mayo Clinic) for Synlogic, and on the editorial board for Urolithiasis. D. Milliner also reports receiving National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant U54-DK083908, outside the submitted work. G. Tasian is a consultant for Allena Pharmaceuticals; reports receiving grants from the Patient-Centered Outcomes Research Institute and NIDDK; and reports receiving personal fees from Allena Pharmaceuticals, Dicerna, and Novome, outside the submitted work. M. West reports employment at the American Society of Nephrology, serving as the Director of the KHI. KHI is a public-private partnership with the US Food and Drug Administration. M. West received no direct financial compensation. E. Worcester is a consultant for Allena, Alnylam, Dicerna, and OxThera. All remaining authors have nothing to disclose.

Funding

None.