Pathophysiology and management of enteric hyperoxaluria.

Enteric hyperoxaluria is a metabolic disorder resulting from conditions associated with fatty acid malabsorption and characterized by an increased urinary output of oxalate. Oxalate is excessively absorbed in the gut and then excreted in urine where it forms calcium oxalate crystals, inducing kidney stones formation and crystalline nephropathies. Enteric hyperoxaluria is probably underdiagnosed and may silently damage kidney function of patients affected by bowel diseases. Moreover, the prevalence of enteric hyperoxaluria has increased because of the development of bariatric surgical procedures. Therapeutic options are based on the treatment of the underlying disease, limitation of oxalate intakes, increase in calcium salts intakes but also increase in urine volume and correction of hypocitraturia. There are few data regarding the natural evolution of kidney stone events and chronic kidney disease in these patients, and there is a need for new treatments limiting kidney injury by calcium oxalate crystallization.

Resolution of Crystalline Retinopathy After Kidney Transplant for Hyperoxaluria.

This case report discusses the evolution of crystalline retinopathy secondary to systemic hyperoxalosis after kidney transplant for hyperoxaluria was performed.

Oxalate: from physiology to pathology / Oxalate : de la physiologie à la pathologie

Hyperoxaluria is defined by an increase of urinary oxalate, leading to kidney stones, nephrocalcinosis and/or chronic kidney disease. There are different diseases related to hyperoxaluria: (1) kidney stones, 50% of them being explained by intermittent hyperoxaluria, secondary to dietary mistakes such as low hydration, excess of oxalate consumption and/or low calcium consumption; (2) primary hyperoxaluria, a genetic orphan disease inducing a massive production of oxalate by the liver, leading to increased plasma oxalate increase and saturation, and further systemic oxalosis with oxalate deposition, nephrocalcinosis and ultimately kidney failure, the management of this disease being currently dramatically modified by the onset of new therapeutic tools such as RNA interference; and (3) enteric hyperoxaluria, resulting from increased intestinal oxalate absorption because of intestinal malabsorption (short bowel syndrome, bariatric surgery, exocrine pancreatic insufficiency, etc.). Diagnosis and therapeutic management of these diseases require a full understanding of oxalate physiology that we detail in this review.

L'hyperoxalurie, définie par une élévation de l'oxalate urinaire, favorise la survenue d'une maladie lithiasique, d'une néphrocalcinose et/ou d'une insuffisance rénale chronique. L'hyperoxalurie peut témoigner de différentes maladies : (1) l'hyperoxalurie diététique, responsable de 50 % de la maladie lithiasique par le biais d'erreurs alimentaires (hydratation insuffisante, consommation excessive d'oxalate et/ou consommation insuffisante de calcium) ; (2) les hyperoxaluries primaires, maladies génétiques orphelines responsables d'une production massive d'oxalate aboutissant à des dépôts tissulaires précoces (dès l'enfance) et sévères (à l'origine d'une insuffisance rénale terminale puis d'une thésaurismose avec atteinte multiviscérale) et dont le pronostic est aujourd'hui transformé par les nouvelles thérapies (ARN interférents) ; (3) l'hyperoxalurie entérique, résultant d'une augmentation de l'absorption digestive de l'oxalate dans une situation de malabsorption (syndrome du grêle court, chirurgie bariatrique, insuffisance pancréatique exocrine, etc.). La physiologie de l'oxalate, détaillée dans cet article, permet d'appréhender la prise en charge diagnostique et thérapeutique de ces maladies.

Stiripentol and Lumasiran as a Rescue Therapy for Oxalate Nephropathy Recurrence After Kidney Transplantation in an Adult Patient With Primary Hyperoxaluria Type 1.

Primary hyperoxaluria type 1 is a rare cause of kidney failure. Stiripentol, an inhibitor of lactate dehydrogenase A, and lumasiran, a small interfering RNA targeting glycolate oxidase, have been proposed as therapeutic options, but clinical data are scarce, especially in adults and transplanted patients. We describe the case of a 51-year-old patient with a biopsy-proven recurrence of oxalate nephropathy after a kidney-only transplantation. He received stiripentol and lumasiran without adverse events. Fourteen months after transplantation, graft function, serum, and urinary oxalate levels have remained stable, and kidney biopsy showed a complete regression of oxalate crystals. Further studies are needed to assess whether this strategy is effective and could replace liver-kidney transplantation.

Secondary oxalate nephropathy and kidney transplantation.

PURPOSE OF REVIEW: Secondary hyperoxaluria is associated with poor kidney allograft outcomes after the kidney transplant. Calcium oxalate (CaOx) deposition is common in early allograft biopsies leading to acute tubular necrosis and poor kidney allograft function. Though treatment options for secondary hyperoxaluria are limited, it is crucial to identify patients at increased risk of oxalate nephropathy after the transplant. RECENT FINDINGS: Recent data suggest that significant changes in renal replacement therapies and dietary modifications in high-risk patients can prevent kidney allograft damage from the calcium oxalate deposition leading to improve allograft outcomes. SUMMARY: The accurate and timely diagnosis of secondary oxalate nephropathy in kidney transplant recipients is paramount to preserving graft function in the long-term. This review will discuss the incidence, risk factors, prevention, and management of oxalate nephropathy in the kidney allograft.

Role of insulin resistance and the gut microbiome on urine oxalate excretion in ob/ob mice.

Ob/ob mice have recently emerged as a model for obesity-related hyperoxaluria as they are obese and excrete more urine oxalate compared to wild type mice. Ob/ob mice are deficient of leptin and develop obesity with hyperphagia and hyperinsulinemia. We hypothesized that insulin resistance and the gut microbiome contribute to hyperoxaluria in ob/ob mice. We developed a new liquid chromatography-mass spectrometry assay for urine oxalate and first compared urine oxalate excretion in ob/ob mice before and after ablation of intestinal bacteria with a standard antibiotic cocktail. We then compared urine oxalate excretion in ob/ob mice before and after leptin replacement or pioglitazone treatment, two maneuvers that reduce insulin resistance in ob/ob mice. Ob/ob mice excreted more oxalate into the urine in a 24-h period compared to wild type mice, but antibiotic, leptin, or pioglitazone treatment did not change urine oxalate excretion in ob/ob mice. Unexpectedly, we found that when food intake was carefully matched between ob/ob and wild type mice, the amount of 24-h urine oxalate excretion did not differ between the two mouse strains, suggesting that ob/ob mice excrete more urine oxalate because of hyperphagia. Since the level of urine oxalate excretion in wild type mice in our study was higher than those reported in prior studies, future work will be needed to standardize the measurement of urine oxalate and to define the range of urine oxalate excretion in wild type mice so that accurate and valid comparisons can be made between wild type mice and ob/ob mice or other mouse models.

Small-molecule inhibitor of intestinal anion exchanger SLC26A3 for treatment of hyperoxaluria and nephrolithiasis.

Nephrolithiasis is a common and recurrent disease affecting 9% of the US population. Hyperoxaluria is major risk factor for calcium oxalate kidney stones, which constitute two-thirds of all kidney stones. SLC26A3 (DRA, downregulated in adenoma) is an anion exchanger of chloride, bicarbonate, and oxalate thought to facilitate intestinal oxalate absorption, as evidenced by approximately 70% reduced urine oxalate excretion in knockout mice. We previously identified a small-molecule SLC26A3 inhibitor (DRAinh-A270) that selectively inhibited SLC26A3-mediated chloride/bicarbonate exchange (IC50 ~ 35 nM) and, as found here, oxalate/chloride exchange (IC50 ~ 60 nM). In colonic closed loops in mice, luminal DRAinh-A270 inhibited oxalate absorption by 70%. Following oral sodium oxalate loading in mice, DRAinh-A270 largely prevented the 2.5-fold increase in urine oxalate/creatinine ratio. In a mouse model of oxalate nephropathy produced by a high-oxalate low-calcium diet, vehicle-treated mice developed marked hyperoxaluria with elevated serum creatinine, renal calcium oxalate crystal deposition, and renal injury, which were largely prevented by DRAinh-A270 (10 mg/kg twice daily). DRAinh-A270 administered over 7 days to healthy mice did not show significant toxicity. Our findings support a major role of SLC26A3 in intestinal oxalate absorption and suggest the therapeutic utility of SLC26A3 inhibition for treatment of hyperoxaluria and prevention of calcium oxalate nephrolithiasis.

An engineered bacterial therapeutic lowers urinary oxalate in preclinical models and in silico simulations of enteric hyperoxaluria.

Enteric hyperoxaluria (EH) is a metabolic disease caused by excessive absorption of dietary oxalate leading to the formation of chronic kidney stones and kidney failure. There are no approved pharmaceutical treatments for EH. SYNB8802 is an engineered bacterial therapeutic designed to consume oxalate in the gut and lower urinary oxalate as a potential treatment for EH. Oral administration of SYNB8802 leads to significantly decreased urinary oxalate excretion in healthy mice and non-human primates, demonstrating the strain's ability to consume oxalate in vivo. A mathematical modeling framework was constructed that combines in vitro and in vivo preclinical data to predict the effects of SYNB8802 administration on urinary oxalate excretion in humans. Simulations of SYNB8802 administration predict a clinically meaningful lowering of urinary oxalate excretion in healthy volunteers and EH patients. Together, these findings suggest that SYNB8802 is a promising treatment for EH.

Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence, risk factors, and effect on renal allograft function.

Primary hyperoxaluria (PH) is a metabolic defect that results in oxalate overproduction by the liver and leads to kidney failure due to oxalate nephropathy. As oxalate tissue stores are mobilized after transplantation, the transplanted kidney is at risk of recurrent disease. We evaluated surveillance kidney transplant biopsies for recurrent calcium oxalate (CaOx) deposits in 37 kidney transplants (29 simultaneous kidney and liver [K/L] transplants and eight kidney alone [K]) in 36 PH patients and 62 comparison transplants. Median follow-up posttransplant was 9.2 years (IQR: [5.3, 15.1]). The recurrence of CaOx crystals in surveillance biopsies in PH at any time posttransplant was 46% overall (41% in K/L, 62% in K). Higher CaOx crystal index (which accounted for biopsy sample size) was associated with higher plasma and urine oxalate following transplant (p < .01 and p < .02, respectively). There was a trend toward higher graft failure among PH patients with CaOx crystals on surveillance biopsies compared with those without (HR 4.43 [0.88, 22.35], p = .07). CaOx crystal deposition is frequent in kidney transplants in PH patients. The avoidance of high plasma oxalate and reduction of CaOx crystallization may decrease the risk of recurrent oxalate nephropathy following kidney transplantation in patients with PH. This study was approved by the IRB at Mayo Clinic.

The three biological gaps and hyperoxaluria in ethylene glycol poisoning: case presentation and review.

Ethylene glycol is a toxic alcohol which may induce significant toxicity when ingested accidentally or intentionally. The main clinical complications of EG poisoning include central nervous system depression, cardiorespiratory instability and renal failure, which may be lethal if improperly treated. Although the demonstration of high plasma levels of ethylene glycol confirms the intoxication, such measurements are generally not obtained in the acute setting and can be misleading due to the rapid metabolism of EG. This implies the need for alternative, indirect, diagnostic methods, which reflect the metabolic fate of EG. These include an early and transient osmolar gap, followed by an anion gap metabolic acidosis and hyperoxaluria. Another frequent finding is a lactate gap between various methods of lactate measurements. An appropriate knowledge of these laboratory findings is essential for the diagnosis of EG poisoning, and for the initiation of antidote therapy (fomepizole) and hemodialysis in selected cases. These features are illustrated by the presentation of a prototypical case of EG poisoning, in which an incomplete diagnostic workup on hospital admission resulted in an unnecessary laparotomy and a significant delay in the management of the intoxication.

Clinical Outcomes and Histological Patterns in Oxalate Nephropathy due to Enteric and Nonenteric Risk Factors.

INTRODUCTION: Current knowledge of risk factors and renal histologic patterns of oxalate nephropathy (ON) not due to primary hyperoxaluria (PH) has been limited to small case series and case reports. Thus, we analyzed and compared clinical risk factors, histologic characteristics, and renal outcomes of patients with biopsy-confirmed ON among a cohort of patients with enteric and nonenteric risk factors. METHODS: A clinical data repository of native kidney pathology reports from 2009 to 2020 at all Mayo Clinic sites was used to identify 421 ON cases. RESULTS: After excluding cases in transplanted kidneys or due to PH, 64 cases remained. Enteric risk factors were present in 30 and nonenteric in 34. Roux-en-Y gastric bypass (17) and pancreatic insufficiency (6) were most common in the enteric hyperoxaluria group. In the nonenteric group, vitamin C (7) and dietary oxalate (7) were common, while no apparent risk was noted in 16. Acute kidney injury (AKI) stage III at the time of diagnosis was present in 60%, and 40.6% required dialysis. Patients in the nonenteric group had more interstitial inflammation (p = 0.01), and a greater number of tubules contained intratubular calcium oxalate (CaOx) crystals (p = 0.001) than the nonenteric group. Patients in the enteric group were more likely to have baseline chronic kidney disease (CKD) (p = 0.02) and moderate-to-severe tubulointerstitial fibrosis and atrophy (IFTA) (OR 3.49, p = 0.02). After a median follow-up of 10 months, 39% were dialysis dependent, 11% received a kidney transplant, and 32% died. On univariate analysis, >10 tubules with CaOx crystals, baseline CKD, and AKI requiring dialysis correlated with the risk of dialysis, transplant, or death. On multivariate analysis, only AKI requiring dialysis correlated with adverse renal outcomes. CONCLUSION: This is the largest cohort study of ON not due to PH. Histologic features differ in patients with enteric versus nonenteric risks. Patients in the enteric group are more likely to have baseline CKD and significant IFTA, while patients in the nonenteric group were more likely to have a greater number of tubules with CaOx crystals and corresponding interstitial inflammation. AKI requiring dialysis at the time of diagnosis was the single most significant predictor of adverse renal outcome.

A Sodium Oxalate-Rich Diet Induces Chronic Kidney Disease and Cardiac Dysfunction in Rats.

Chronic kidney disease (CKD) is a worldwide public health issue affecting 14% of the general population. However, research focusing on CKD mechanisms/treatment is limited because of a lack of animal models recapitulating the disease physiopathology, including its complications. We analyzed the effects of a three-week diet rich in sodium oxalate (OXA diet) on rats and showed that, compared to controls, rats developed a stable CKD with a 60% reduction in glomerular filtration rate, elevated blood urea levels and proteinuria. Histological analyses revealed massive cortical disorganization, tubular atrophy and fibrosis. Males and females were sensitive to the OXA diet, but decreasing the diet period to one week led to GFR significance but not stable diminution. Rats treated with the OXA diet also displayed classical CKD complications such as elevated blood pressure and reduced hematocrit. Functional cardiac analyses revealed that the OXA diet triggered significant cardiac dysfunction. Altogether, our results showed the feasibility of using a convenient and non-invasive strategy to induce CKD and its classical systemic complications in rats. This model, which avoids kidney mass loss or acute toxicity, has strong potential for research into CKD mechanisms and novel therapies, which could protect and postpone the use of dialysis or transplantation.

Effect of Vitamin B2-Deficient Diet on Hydroxyproline- or Obesity-Induced Hyperoxaluria in Mice.

SCOPE: Hyperoxaluria is a major cause of kidney stone disease. Around half of the oxalate in mammals is supplied from the diet and the other half is endogenously synthesized from glyoxylate. Reduction of hepatic glycolate oxidase (GO) activity is one approach to reduce endogenous production of oxalate. However, there are currently few effective dietary approaches to reduce hepatic GO activity. METHODS AND RESULTS: In the present study, it is investigated whether restriction of dietary vitamin B2 (VB2) can reduce hepatic GO activity and oxalate excretion in mice with hyperoxaluria induce by hydroxyproline (Hyp) or obesity. It is found that VB2 restriction significantly reduces hepatic GO activity in both the Hyp- and obesity-induced model of hyperoxaluria in mice. However, VB2 restriction reduces urinary oxalate excretion only in the Hyp-treated mice and not the obese mice. This difference could be due to the contribution of endogenous oxalate production that manifests as increased hepatic GO activity in Hyp-treated mice but not obese mice. CONCLUSION: Together these results suggest that VB2 restriction could be a new dietary approach to improve hyperoxaluria when endogenous production of oxalate is increased.

Subsequent urinary stone events are predicted by the magnitude of urinary oxalate excretion in enteric hyperoxaluria.

Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone events in those with enteric hyperoxaluria (EH) are limited. Therefore, we assessed the relationship between UOx excretion and risk of kidney stone events in a retrospective population-based EH cohort. In all, 297 patients from Olmsted County, Minnesota were identified with EH based upon having a 24-h UOx ≥40 mg/24 h preceded by a diagnosis or procedure associated with malabsorption. Diagnostic codes and urologic procedures consistent with kidney stones during follow-up after baseline UOx were considered a new stone event. Logistic regression and accelerated failure time modeling were performed as a function of UOx excretion to predict the probability of new stone event and the annual rate of stone events, respectively, with adjustment for urine calcium and citrate. Mean ± standard deviation age was 51.4 ± 11.4 years and 68% were female. Median (interquartile range) UOx was 55.4 (46.6-73.0) mg/24 h and 81 patients had one or more stone event during a median follow-up time of 4.9 (2.8-7.8) years. Higher UOx was associated with a higher probability of developing a stone event (P < 0.01) and predicted an increased annual risk of kidney stones (P = 0.001). Estimates derived from these analyses suggest that a 20% decrease in UOx is associated with 25% reduction in the annual odds of a future stone event. Thus, these data demonstrate an association between baseline UOx and stone events in EH patients and highlight the potential benefit of strategies to reduce UOx in this patient group. BACKGROUND: Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone events in those with enteric hyperoxaluria (EH) are limited. METHODS: We assessed the relationship between UOx excretion and risk of kidney stone events in a retrospective population-based EH cohort. In all, 297 patients from Olmsted County, Minnesota were identified with EH based upon having a 24-h UOx ≥40 mg/24 h preceded by a diagnosis or procedure associated with malabsorption. Diagnostic codes and urologic procedures consistent with kidney stones during follow-up after baseline UOx were considered a new stone event. Logistic regression and accelerated failure time modeling were performed as a function of UOx excretion to predict the probability of new stone event and the annual rate of stone events, respectively, with adjustment for urine calcium and citrate. RESULTS: Mean ± SD age was 51.4 ± 11.4 years and 68% were female. Median (interquartile range) UOx was 55.4 (46.6-73.0) mg/24 h and 81 patients had ≥1 stone event during a median follow-up time of 4.9 (2.8-7.8) years. Higher UOx was associated with a higher probability of developing a stone event (P < 0.01) and predicted an increased annual risk of kidney stones (P = 0.001). Estimates derived from these analyses suggest that a 20% decrease in UOx is associated with 25% reduction in the annual odds of a future stone event. CONCLUSIONS: These data demonstrate an association between baseline UOx and stone events in EH patients and highlight the potential benefit of strategies to reduce UOx in this patient group.

Pathophysiology and Treatment of Enteric Hyperoxaluria.

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.

Unusual cause of irreversible acute kidney injury postgastrectomy.

A 56-year-old male was diagnosed to have carcinoma stomach following evaluation of lack of appetite and weight loss. He underwent neoadjuvant chemotherapy and gastrectomy. Following surgery he developed progressive renal failure. A renal biopsy led to the diagnosis of oxalate nephropathy. Despite treatment his renal functions never recovered. Oxalate nephropathy is an underappreciated cause of renal failure postgastrectomy. It can cause irreversible renal failure unless detected and treated early.

Medical Management of Advanced Oxalate Nephropathy Secondary to Gastric Bypass Surgery.

A 73-year-old Caucasian female with a history of obesity status post Roux-en-Y gastric bypass (RYGB) surgery presented with generalized weakness and was found to have acute kidney injury (AKI) with a creatinine peak of 9.1 mg/dL above her baseline of 1.2 mg/dL, and anemia with hemoglobin 5.7 g/dl. Kidney biopsy revealed oxalate nephropathy likely related to gastric bypass surgery four years prior. RYGB is a strong risk factor for hyperoxaluria, nephrolithiasis, and oxalate nephropathy which often progresses to end-stage renal disease (ESRD). Meaningful treatment strategies for this disease entity are lacking. We present a case in which dietary and pharmacological management without the use of renal replacement therapy resulted in stabilization of chronic kidney disease (CKD) stage 5 for seven years at the time of this writing.

Diet-induced oxalate nephropathy from excessive nut and seed consumption.

Oxalate is a metabolite consumed in nuts, beans and leaves, and excreted in urine. Oxalosis can cause nephropathy. We describe a rare case of a high-oxalate diet intended for irritable bowel syndrome (IBS) treatment causing oxalate nephropathy. A 59-year-old woman with a history of controlled hypertension presented with creatinine 1.8 mg/dL, increased from baseline 1.3 mg/dL. She denied recent illness, urinary stones, medication adjustments, herbal supplements and non-steroidal anti-inflammatory drugs use. Diet included six tablespoons of chia seeds and five handfuls of almonds daily to manage IBS symptoms. Her electrolytes, urinalysis and renal ultrasound were unremarkable. Her 24-hour urine output revealed increased oxalate and low citrate. Renal biopsy showed glomerulosclerosis, fibrosis and calcium oxalate deposition. She switched to a low-oxalate diet, with improvement in laboratory markers. An earlier dietary history could have raised concern for oxalosis prior to renal biopsy. Providers should be trained to identify at-risk patients and provide appropriate dietary counselling.