Enteric hyperoxaluria: an important cause of end-stage kidney disease

Abstract

Hyperoxaluria is a frequent complication of inflammatory bowel diseases, ileal resection and Roux-en-Y gastric bypass and is well-known to cause nephrolithiasis and nephrocalcinosis. The associated prevalence of chronic kidney disease and end-stage kidney disease (ESKD) is less clear but may be more consequential than recognized. In this review, we highlight three cases of ESKD due to enteric hyperoxaluria following small bowel resections. We review current information on the pathophysiology, complications and treatment of this complex disease.

INTRODUCTION

Enteric hyperoxaluria (EH) is a frequent complication of inflammatory bowel diseases (IBD), ileal resection and Roux-en-Y gastric bypass (RYGB) and is well-known to cause nephrolithiasis and nephrocalcinosis. Less well-known, and highlighted here, is that it also contributes to chronic kidney disease (CKD) and end-stage kidney disease (ESKD). The urinary solubility product of calcium oxalate (CaOx), a determinant of the tendency of urine to yield crystals, is 10 times more affected by a rise of urinary oxalate concentration than an equimolar rise in urinary calcium concentration [1]. The prevalence of hyperoxaluria has been estimated at 5–24% of all patients with gastrointestinal diseases associated with malabsorption [2, 3]. Hyperoxaluria is becoming more common secondary to an increase in IBD [4] and bariatric surgery. The associated prevalence of CKD and ESKD is less clear but may be more consequential than recognized. Here we highlight three cases of ESKD due to hyperoxaluria and review the relatively sparse literature on treatment.

CASE 1

A 33-year-old woman was diagnosed with Crohn's disease at age 17, her course complicated by small bowel infarction due to a volvulus requiring small bowel resection. She developed short bowel syndrome with chronic diarrhea. She had her first stone 7 years later, attributed to EH. She developed recurrent stones and progressive CKD. On presentation, her serum creatinine was 2.3 mg/dL, with mild metabolic acidosis. A 24-h urine collection showed hyperoxaluria (135 mg/day), low calcium (49 mg/day), pH 5.8 and hypocitraturia (137 mg/day). For 3 years, she was treated with potassium citrate, sodium citrate, calcium citrate, lactobacillus, vitamin B6 and magnesium. The use of potassium citrate and magnesium was limited due to diarrhea which decreased urine output. Her renal function worsened until hemodialysis (HD) was initiated at age 38. She underwent a living donor kidney transplant 6 months later. Six months following her transplant, she had an episode of renal obstruction due to a CaOx stone requiring ureteroscopy. Hyperoxaluria persisted, with progressive increase in serum creatinine to 2.5 mg/dL 5 years after her transplant. A graft biopsy showed calcium oxalate crystal deposition, mild-to-moderate interstitial fibrosis with tubular atrophy and inflammatory infiltrates without rejection. Despite cholestyramine, calcium supplements, citrate and bicarbonate supplements, dialysis was resumed 6 years after the transplant.

She received a second transplant from an altruistic donor less than a year later. Her most recent serum creatinine was 1.1 mg/dL 1 year post-transplantation. Urinary oxalate excretion remains high at 131 mg/day, with urine volume 1.1 L/day, low calcium of 17 mg/day and a high SS CaOx (calcium oxalate supersaturation). Her current medications are sodium citrate, calcium citrate, loperamide, opium extract, sodium bicarbonate, pancreatic enzymes, mycophenolate, tacrolimus, lactobacilli and vitamin D.

CASE 2

A 48-year-old man had Crohn's disease 20 years prior to presentation and required two small bowel resections. IBD did not recur but he had chronic diarrhea. His first CaOx stone occurred a year following his first small bowel resection. Serum creatinine was 2.3 mg/dL and he had metabolic acidosis. His 24-h urine collection revealed severe hyperoxaluria with hypocalciuria, hypocitraturia and low urine volume. Computed tomography and ultrasound showed nephrocalcinosis. Medical therapy failed to prevent stone recurrence and CKD culminated in initiation of HD. He received a cadaveric kidney transplant 1 year later. His renal function remained stable at 1.1–1.2 mg/dL post-transplantation with improved hyperoxaluria, higher urine pH and citrate levels but his urine volume remained low. Three years after his transplant, his serum creatinine is 1.2 mg/dL without radiologic recurrence of stones.

CASE 3

A 47-year-old woman with a history of Crohn's disease required extensive small bowel resection resulting in short bowel syndrome, recurrent kidney stones and CKD. Her serum creatinine at presentation was 2.9 mg/dL and a 24-h urine collection showed risk factors for CaOx stones. Her clinical course was complicated by recurrent obstructive uropathy, and the need for bilateral nephrectomies for repeated stone-related infections. After nephrectomy, she underwent a cadaveric renal transplant. Allograft function remained stable for 2 years despite hyperoxaluria and hypocitraturia. She then had progressive CKD with graft biopsy showing sheaves of birefringent crystals in the cortical tubules consistent with CaOx, with glomerulosclerosis and tubular atrophy. Tubular epithelial cells showed moderate injury with loss of brush border, fibrosis and necrosis. Her serum creatinine peaked at 6.5 mg/dL and improved modestly to 2.9 mg/dL with intravenous saline and NaHCO₃ infusion.

These three cases illustrate (Table 1) the potentially severe consequences of EH, with progressive CKD leading to ESKD despite medical therapy and urologic interventions. In this review of the literature, we will highlight the pathophysiology, current treatment options and newer drug targets for this complex disease.

Table 1.

Summary of the cases

Patient	Primary pathology	Yrs to ESRD	Initial Uox (mg/day)	Post-transplant Uox (mg/day)	Initial CaOx SS	Post-transplant CaOx SS
1	Crohn's disease	20	135	86	12.7	3.6
2	Crohn's disease	29	110	64	5.8	14.5
3	Crohn's disease	NA	114	135	4.8	6.5

Yrs, years; ESRD, end stage renal disease; SS, supersaturation; UOx, urinary oxalate excretion; NA, not available.

The epidemiology of ESKD due to EH remains unreported. Case reports have highlighted individual cases of short bowel syndrome and bariatric surgery leading to ESKD but no registries of this phenomenon have been developed [5]. Several studies disclose the risk of CKD and ESKD associated with kidney stones but none have detailed the contribution of EH to the total of affected cases [6, 7]. In one report, 8 of 11 patients with oxalate nephropathy presenting with acute kidney injury progressed to ESKD [5]. EH is also an important risk for recurrence of CKD in patients undergoing kidney transplantation, but again, incidence and prevalence are not known [8]. Therefore, the true prevalence of EH-mediated ESKD is uncertain.

OXALATE METABOLISM

Oxalate is produced endogenously as an end product of the metabolism of amino acids and is also absorbed by the stomach, small bowel and colon from dietary sources [9]. The exact mechanism of oxalate absorption in the intestine is not fully elucidated [10]. In healthy individuals, up to half of urinary oxalate is derived from the diet [11]. Oxalate can be excreted, dissolved in the urine, precipitated with calcium in the stool or metabolized by gut microbiota [9]. Under normal conditions, all oxalate absorbed from the diet and produced endogenously is excreted in the urine. Normal urinary oxalate excretion is variable but a value above 40–45 mg/day (0.45 mmol) is considered hyperoxaluria.

ETIOLOGY OF HYPEROXALURIA

Most patients with calcium stones and hyperoxaluria have idiopathic hyperoxaluria. It is not a well-characterized condition and is presumed to be secondary to dietary choices in most instances with a possible component of hyperabsorption [12].

EH, as seen in the cases presented here, is a form of secondary hyperoxaluria, caused by increased intestinal absorption of oxalate due to malabsorption syndromes. EH is a form of secondary hyperoxaluria attributable to various digestive diseases, such as Crohn's disease [13], Hirschsprung's disease, cystic fibrosis and chronic biliary or pancreatic pathology. It has also been observed more recently as a result of bariatric surgery and ileal resection [5].

Primary hyperoxaluria (PH) is caused by three genetic disorders affecting proteins important in the hepatic metabolism of glyoxalate, leading to high endogenous oxalate production, increased urinary oxalate excretion and, eventually, to accumulation of oxalate in tissues [14]. Kidney stones are often a presenting sign, and renal failure due to nephrocalcinosis often ensues, particularly with Type I PH. In contrast to PH where systemic oxalate deposition (heart, joints, bones and peripheral nerves) has been described, such occurrences have rarely been described in secondary hyperoxalosis, barring a case of bone marrow infiltration with oxalate [15, 16], facial papules, vasculitis and subungual deposits [17–19]. This difference in presentation is possibly due to lower systemic oxalate load in secondary hyperoxaluria. In our cases we did not note manifestations of systemic oxalosis, although we did not actively seek them. The patients were transplanted relatively soon after developing ESKD.

PATHOPHYSIOLOGY OF EH

The pathogenesis of EH is complex (Figure 1). It is thought to be secondary to an increase in oxalate solubility in the intestinal lumen and a concomitant rise in bowel permeability to oxalate due to bile salts and colonic mucosal inflammation as seen in IBD [20]. Under normal conditions, dietary calcium binds dietary oxalate to form insoluble CaOx that is excreted in the stool. In EH, non-absorbed fatty acids instead bind calcium in the small intestine rendering it unavailable to precipitate oxalate. Soluble oxalate is consequently present in relatively high concentration in the lumen and can diffuse passively out of the colon into the blood, from where it can be excreted by the kidneys. The colon also has a role in the etiology of hyperoxaluria. In one series, none of five patients with steatorrhea and ileostomies had hyperoxaluria, whereas 8 of 11 patients with steatorrhea and intact colons had hyperoxaluria [20]. Such studies suggest that the colon is the dominant site of intestinal oxalate absorption.

FIGURE 1:

Pathophysiology of enteric hyperoxaluria. Fat malabsorption increases (1) oxalate solubility in the intestinal lumen and (2) bowel permeability to oxalate. Malabsorption also causes deficiency of pyridoxine or vitamin B6 leading to the accumulation of peroxisomal glyoxylate that is eventually oxidized to oxalate in the liver. High levels of oxalate excreted in the urine can lead to nephrocalcinosis and calcium oxalate kidney stones.

In addition, high concentrations of bile acids, as well as colonic inflammation, are thought to enhance colonic permeability to oxalate. An exaggerated passive, paracellular absorption of oxalate ensues [21]. In a study of 81 patients with Crohn's disease, the degree of hyperoxaluria was related to the length of ileum resected. When bowel disease is well treated in Crohn's disease, hyperoxaluria resolves [13].

Hyperoxaluria in malabsorption syndromes is also attributed to deficiency of pyridoxine or vitamin B6, a cofactor of the liver enzyme alanine:glyoxylate aminotransferase. B6 deficiency can lead to higher endogenous oxalate production and accumulation of peroxisomal glyoxylate which is eventually oxidized to oxalate. Although a recent prospective trial in PH1 patients showed a decrease of urinary oxalate excretion in a subset of patients treated with oral vitamin B6 [22], particularly those homozygous for Gly170Arg mutation, the efficacy of B6 treatment in EH has not been satisfactorily examined in prospective trials.

Another potential variable in the pathophysiology of hyperoxaluria is the intestinal microbiome. Colonization of the colon with Oxalobacter formigenes, a Gram-negative anaerobic bacterium that depends on oxalate, was shown to be low in patients with IBD [23]. A lack of such oxalate-degrading bacteria in the colon is hypothesized to lead to an increase in intestinal oxalate absorption. The change in colonization status could be due to the disease state, changes in diet or an effect of administered antibiotics [24]. A role for other intestinal oxalate-degrading bacterial populations on the risk of hyperoxaluria is possible.

With the prevalence of obesity exceeding 30% globally, bariatric surgery has become more common. RYGB is the most commonly used surgical approach to treat obesity. The procedure limits food intake by creating a gastric pouch that reduces caloric absorption, bypassing the proximal intestine with a Roux limb. The standard Roux limb bypasses the distal stomach, duodenum and a small segment of the jejunum. By inducing malabsorption, the prevalence of obesity-associated comorbidities secondary to abnormalities in carbohydrate and lipid metabolism decreases and life expectancy rises [25–27].

Despite the advantages of RYGB, it causes hyperoxaluria, resulting in nephrolithiasis and nephrocalcinosis [28]. In rats, RYGB or ileal resection result in steatorrhea and hyperoxaluria when rats were fed a low fat and high oxalate diet [29, 30]. In one large study, 4369 subjects underwent RYGB between 2002 and 2006 [31]. When compared with obese controls, the subjects who underwent RYGB had a significantly higher incidence of nephrolithiasis (7.6 versus 4.6%, P < 0.0001). Restrictive surgery, such as gastric banding and sleeve gastrectomy, was not associated with increased risk for kidney stones disease [32, 33].

At 6 and 12 months following RYGB, plasma oxalate and urine CaOx supersaturation increase significantly compared with pre-surgical levels of both variables [34]. Urine chemistry of 132 patients with kidney stones who underwent bariatric surgery was compared with that of patients with jejunoileal bypass, those with routine kidney stones and normal subjects (jejunoileal bypass is currently not performed due to the subsequent risk of CKD). Patients with jejunoileal bypass had the highest level of urine oxalate excretion (102 mg/day, P < 0.001), followed by patients with bariatric surgery (83 mg/day, P < 0.001) as compared with normal controls (34 mg/day) [35].

The prevalence of CaOx stones post-intestinal resection in adults and children with Crohn's disease has been estimated at 28% with many experiencing recurrent stones [36]. Stone incidence in patients with jejunoileal bypass is also high at 20–30% [37].

In addition to hyperoxaluria, other factors promote CaOx crystallization. Chronic diarrhea leads to low urine volume and metabolic acidosis. Patients with bowel disease and stones were divided into five groups: those with bypass surgery, with colon and small bowel surgery, colon only surgery, small bowel only surgery and no surgery. They were compared with people with stones and normal bowel. Urine volume was low in most bowel groups, except the patients with bypass, compared with stone-forming control patients without bowel surgery (P = 0.0001). Urine oxalate excretion was modestly high after small bowel resection but very high with bypass (P < 0.0001). Citrate and magnesium, crystallization inhibitors, were present in only low levels in urine in the setting of chronic diarrhea [38].

In addition to nephrolithiasis, nephrocalcinosis is not an uncommon complication of EH and the major contributor to CKD. EH prevalence rates have not been systematically determined and are in the range of 29 and 74% in post-RYGB patients. Time to onset is 3–24 months after the procedure [39]. In 11 patients presenting with acute kidney injury, median onset was 1 year after RYGB. Eight progressed to ESKD [5]. Of note, all patients in this group were hypertensive and nine were diabetic, with diabetic glomerulopathy also evident on biopsy.

Toxic effects of oxalate on epithelial and tubular cells can induce oxalate nephropathy with persistent hyperoxaluria New animal data suggest a role of CaOx crystals in stimulating inflammation, resulting in interstitial fibrosis and CKD. Two recent studies have implicated the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome pathway in the pathogenesis of kidney injury due to CaOx. The NLRs are a set of intracellular pattern recognition receptors involved in identification of pathogen-associated molecular patterns and host-derived danger signals. NLR assemble to form caspase-1 activating platforms called ‘inflammasomes’ which control the maturation and secretion of interleukin (IL)-1β and IL-18. In one model, acute hyperoxaluria was induced with an intraperitoneal injection and oral ingestion of sodium oxalate. In a second model, mice were fed a diet high in soluble oxalate and low in calcium. Both models showed calcium oxalate crystal deposition in the kidneys with activation of the NLRP3/inflammasome and over-expression of IL-1β. Pharmacological IL-1β blockade with anakinra prevented the kidney injury [40, 41].

Crystals may also induced tubular damage via activation of reactive oxygen species (ROS) [42]. Hyperoxaluria induces ROS via the activation of the renin angiotensin system (RAS) leading to kidney injury and inflammation. NADPH oxidase is also a major source of ROS, especially in the presence of angiotensin II [43]. Blocking of the RAS and inhibiting NADPH oxidase reduced oxalate-induced injury in tissue culture and in animal models. Targeting this pathway presents a potential therapeutic approach [44, 45]. Apocyanin is a plant-derived phytochemical used in Ayurvedic practice that may reduce ROS and inhibit NADPH oxidase. In animal models, its administration was associated with a reduction in crystal deposits, kidney inflammation and expression of a number of markers of renal injury [45]. It has not been studied in humans with kidney stones or with EH but may be worth testing [46].

TREATMENT OF EH

Several approaches have been used to treat EH but none have been tested in randomized controlled trials (Table 2). The most important strategy is a high fluid intake in order to increase urine output to more than 2–3 L per day. A high urine output lowers the CaOx supersaturation, which correlates positively with oxalate nephropathy. Increased oral intake of fluids does not always lead to increased urine output in some patients with loose stool.

Table 2.

Summary of available therapies

Therapy	Target	Effect in vivo	References
Calcium supplements	Increasing oxalate precipitation in gut	Reduce Uox in humans	[47]
		Reduce CaOx SS with no change in Uox	[48]
Cholestyramine	Decreasing bile acids	Reduce Uox in animals	[49]
		Contradicting results in humans	[21]
			[50]
Oxalate-binding agents	Decreasing oxalate concentration in colon	OMH reduced Uox in humans	[51]
		Sevelamer did not reduce Uox in humans	[52]
Citrate supplements	Inhibiting calcium oxalate crystallization	Potassium citrate and citrus juice reduced Uox in humans	[53]
		Sodium citrate and sodium bicarbonate may also be appropriate	[54]
Microbiome manipulation	Increasing oxalate degradation in the gut	No reduction in Uox in humans	[55]
Oxalate-degrading enzymes	Increasing oxalate degradation in the gut	Reduce Uox in animals	[56]
		Prelim data in healthy subject showed decreased in Uox
NLRP3/Inflammasomes inhibitors	Blocking CaOx induced inflammation	Reduce inflammation in animal experiments	[40]
		No human studies	[41]
Reversal of bariatric surgery	Treating malabsorption	Only reported in cases of jejunoileal bypass	[57]
			[58]
Kidney and intestinal transplant	Treating malabsorption	Only cases reports	[59]

CaOx, calcium oxalate; NLRP3, NOD-like receptor family, pyrin domain containing 3; OMH, organic marine hydrocolloid; SS, supersaturation; UOx, urinary oxalate excretion.

Dietary therapy has focused on reducing fat malabsorption. Oxalate reabsorption from the colon is markedly enhanced by the presence of luminal unconjugated bile acids [60]. In in vitro studies, cholestyramine reduced oxalate absorption in various segments of rat intestine by blocking binding of oxalate to bile acids, rather than by directly binding to oxalate [49]. However, a reduction in colonic oxalate absorption was not observed in human subjects [21, 50]. Increasing dietary calcium intake has been shown to be effective. Eight patients with EH were kept on a standardized diet with a fixed supply of fat (70 g), calcium (800 mg) and oxalate (200 mg) and given additional calcium supplementation (calcium glubionate and calcium lactobionate) of 1 g/day [47]. Renal oxalate excretion fell from 119 mg/24 h to 60 mg/24 h with a corresponding decrease in colonic absorption of C¹⁴-labeled oxalate from 28 to 9%. No increase in urinary calcium excretion was noted. In another recent study, nine bariatric surgery patients with EH and a history of CaOx stones were kept on a controlled metabolic diet consisting of low oxalate (70–80 mg), low fat (<25%) and 1 g/day of elemental calcium. The average daily calcium intake was 2.5 ± 0.84 g/day including supplements. This diet significantly reduced urinary CaOx supersaturation (from 1.97 to 1.13, P = 0.01) without affecting urinary oxalate excretion [48]. A risk of high dose calcium supplementation is the potential for worsening urinary CaOx supersaturation if patients are not consistently able to maintain a high urine output.

Studies using oxalate-binding agents included a study in which patients with EH were given an oral seaweed-derived organic marine hydrocolloid, charged with calcium. The preparation significantly reduced urinary oxalate excretion at 2 weeks and at 6 months [51]. Due to short periods of follow-up, none of these studies examined the effect of these agents on stone formation or CKD.

In a nonrandomized and open label trial, sevelamer hydrochloride, a cationic resin, usually used as a phosphate binder, was used in the treatment of hyperoxaluria. The medication resulted in a non-significant reduction of the mean urinary oxalate (0.84–0.70 mmol/day). CaOx supersaturation did not change significantly because of a countervailing effect of increasing urinary calcium and decreasing urinary citrate [52]. Alternatively, sevelamer carbonate could increase citrate excretion but has not been tested.

Hypocitraturia is also a common finding in EH due to bicarbonate loss from chronic diarrhea, often with subsequent metabolic acidosis. Lower plasma pH stimulates proximal tubular reabsorption of citrate resulting in hypocitraturia, a risk factor for stone formation. Citrate inhibits CaOx nucleation and crystallization by lowering urinary ionized calcium. Potassium citrate has been shown to decrease stone formation in idiopathic hypocitraturic calcium stone formers [53] but has not been tested specifically in EH. Citrus juices, high in citrate, are an alternative in some cases if potassium citrate is not tolerated [54]. However, their intake includes the ingestion of significant calories, which is obviously undesirable in patients after bariatric surgery and overweight stone formers.

Sodium citrate and sodium bicarbonate are not usually considered first-line agents in management of calcium stones because increasing sodium excretion is associated with increasing calcium excretion. However in patients with bowel disease, urinary sodium excretion may be low due to enteric sodium losses. In that case, sodium salts may be safely used and not expected to increase calcium excretion. Some patients may have better gastrointestinal tolerance of sodium than potassium salts, and the risk of hyperkalemia in patients with CKD is avoided. Correction of metabolic acidosis and urinary citrate excretion are addressed equally by citrate and bicarbonate salts.

Manipulation of the gut microbiome to reduce hyperoxaluria has been a recent area of therapeutic interest. A probiotic, composed of various lactic acid bacteria, was given to 10 patients with EH [55]. Urinary oxalate excretion was significantly reduced after 1 and 2 months (19 and 24%, respectively) but at the third month, oxalate excretion increased to baseline. No study has looked at stone formation as the result of administration of lactic acid bacteria. Administration of Oxalobacter formigenes is an attractive possible therapy but has not yet been tested in EH.

An additional potential therapy for EH is the oral administration of oxalate-degrading enzymes in a form that delivers them to the intestinal lumen in an active form. Preliminary work was done with mice knocked-out for the hepatic enzyme alanine:glyoxylate aminotransferase, a model of primary hyperoxaluria type I [56]. Oxalate decarboxylase, bound in a protective, crystalline, cross-linked form, was administered. Urinary and fecal oxalate excretion rates were significantly reduced when compared with controls. Similarly, when mice were challenged with ethylene glycol, which augments urinary oxalate excretion, the preparation led to a 30–50% reduction in hyperoxaluria, and prevention of nephrocalcinosis and nephrolithiasis.

More recently, a similar preparation called ALLN-177, using oxalate decarboxylase, was administered in a double-blind, randomized, placebo-controlled crossover study of 30 healthy volunteers who developed hyperoxaluria when placed on a high oxalate diet. The result was a significant reduction in oxalate levels compared with placebo. The results of further testing of this preparation in stone-forming patients with EH are awaited.

In many cases, consideration of reversal of bariatric surgery, something not available for those with IBD and bowel resections, may be considered. Some study subjects with CKD following jejunoileal bypass, a common bariatric procedure in the past, improved their kidney function after reversal of the intestinal bypass [57, 58]. Reversal of RYGB, however, has significant risk.

With respect to renal replacement therapy, the risk of recurrent oxalate nephropathy and de novo oxalate nephropathy persists after renal transplantation. Such cases may present with unexplained graft failure. Diagnosis is usually made on allograft biopsy [61, 62]. Clinical suspicion for oxalate nephropathy and prompt recognition are key to early diagnosis.

In a recent case report, two patients with EH due to short bowel syndrome secondary to Crohn's disease received both kidney and intestinal transplants [59]. Both patients did well with excellent long-term kidney function, had normalized urinary oxalate excretion and were able to become free of parenteral nutrition. While intestinal transplantation remains available in only a few centers, this is a logical response to recurrent EH in the setting of short bowel syndrome. It may be a preferable option for patients such as Case 1, after the first kidney transplant failed due to hyperoxaluria, which could not be corrected with medical management.

CKD is a risk factor for oxalosis and measurement of plasma oxalate concentrations are indicated. Hemodialysis should be prescribed to maintain lower plasma oxalate levels [63]. Vitamin C supplementation should be avoided as ascorbate metabolism to oxalate is a risk factor for oxalosis and oxalate nephropathy [64]. In pediatric PH patients HD with high flux membranes and high blood flow is effective in clearing plasma, but not tissue, oxalate. [65] However, rebound rates of plasma levels were high due to endogenous production. While HD is preferred, with peritoneal dialysis, a 3 h equilibration of 95% could be achieved, hence shorter dwells may be more effective in patients with oxalosis.

CONCLUSIONS

EH is a complex disease with significant implications for patients' quality of life. Complications, including nephrolithiasis and nephrocalcinosis, can result in CKD and ESKD. With a rising incidence of IBD and obesity leading to bariatric surgery, we expect the burden of this disease to increase. While treatment options remain limited, the new interest in oxalate-degrading bacteria and the discovery of pathways of injury involving inflammation in calcium oxalate nephropathy offer promising new targets for therapy.

CONFLICT OF INTEREST STATEMENT

The results presented in this article have not been published previously in whole or part. D.S.G: consultant, Astra Zeneca; CME speaker, Mission Pharmacal; owner, Ravine Group.