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Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1.This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged6 years with PH1 and an estimated glomerular filtration rate45 mL/min/1.73 mAll patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions.Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.

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

Introduction Because of phenotypic overlap between monogenic urinary stone diseases (USD), gene-specific analyses can result in missed diagnoses. We used targeted next generation sequencing (tNGS), including known and candidate monogenic USD genes, to analyze suspected primary hyperoxaluria (PH) or Dent disease (DD) patients genetically unresolved (negative; N) after Sanger analysis of the known genes. Cohorts consisted of 285 PH (PHN) and 59 DD (DDN) families. Methods Variants were assessed using disease-specific and population databases plus variant assessment tools and categorized using the American College of Medical Genetics (ACMG) guidelines. Prior Sanger analysis identified 47 novel PH or DD gene pathogenic variants. Results Screening by tNGS revealed pathogenic variants in 14 known monogenic USD genes, accounting for 45 families (13.1%), 27 biallelic and 18 monoallelic, including 1 family with a copy number variant (CNV). Recurrent genes included the following: SLC34A3 (n = 13), CLDN16 (n = 8), CYP24A1 (n = 4), SLC34A1 (n = 3), SLC4A1 (n = 3), APRT (n = 2), CLDN19 (n = 2), HNF4A1 (n = 2), and KCNJ1 (n = 2), whereas ATP6V1B1, CASR, and SLC12A1 and missed CNVs in the PH genes AGXT and GRHPR accounted for 1 pedigree each. Of the 48 defined pathogenic variants, 27.1% were truncating and 39.6% were novel. Most patients were diagnosed before 18 years of age (76.1%), and 70.3% of biallelic patients were homozygous, mainly from consanguineous families. Conclusion Overall, in patients suspected of DD or PH, 23.9% and 7.3% of cases, respectively, were caused by pathogenic variants in other genes. This study shows the value of a tNGS screening approach to increase the diagnosis of monogenic USD, which can optimize therapies and facilitate enrollment in clinical trials., Graphical abstract

Introduction Loss-of-function variants in the CYP24A1 gene cause a rare hereditary disease characterized by reduced 24-hydroxylase enzyme activity, increased serum 1,25-dihydroxycholecalciferol levels, hypercalcemia, hypercalciuria, and nephrocalcinosis and/or nephrolithiasis. Kidney cysts in patients with CYP24A1 deficiency were first reported in a single case study from our center. However, a possible association between CYP24A1 deficiency and kidney cysts has not been described. Methods Retrospective analysis of patients with confirmed or suspected CYP24A1 deficiency and available kidney imaging. Results Among 16 patients with confirmed pathogenic variants, 38% were male and 31% were children, the median age at genetic confirmation was 38 years (range 1–66), and none had a family history of cystic kidney disease. Medullary and/or corticomedullary junction cysts were present in all cases. The median age at first detected cyst was 37 years (range 3–60). The mean and median number of cysts per patient were 5.3 and 2.5 (range 1–37), respectively. Four of 5 further patients with suspected but unconfirmed pathogenic variants had cysts. The number of cysts ≥5 mm in size was above the 97.5th percentile of an age- and sex-matched control population in 55% and 67% of patients with confirmed and suspected pathogenic variants, respectively. At least 1 cyst (≥5 mm in size) was found in 80% of children with confirmed CYP24A1 deficiency. Conclusions These observations strongly suggest an association between CYP24A1 deficiency and kidney cysts. Further studies are needed to evaluate the role of CYP24A1, vitamin D metabolism, and/or hypercalciuria in cyst formation, and whether cysts exacerbate chronic kidney disease or modify nephrocalcinosis and stone risk.

Background Primary hyperoxaluria (PH) type 3 (PH3) is caused by mutations in the hydroxy-oxo-glutarate aldolase 1 gene. PH3 patients often present with recurrent urinary stone disease in the first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. This study characterized clinical manifestations of PH3 across the decades of life in comparison with PH1 and PH2. Methods Clinical information was obtained from the Rare Kidney Stone Consortium PH Registry (PH1, n = 384; PH2, n = 51; PH3, n = 62). Results PH3 patients presented with symptoms at a median of 2.7 years old compared with PH1 (4.9 years) and PH2 (5.7 years) (P = 0.14). Nephrocalcinosis was present at diagnosis in 4 (7%) PH3 patients, while 55 (89%) had stones. Median urine oxalate excretion was lowest in PH3 patients compared with PH1 and PH2 (1.1 versus 1.6 and 1.5 mmol/day/1.73 m2, respectively, P Conclusions Patients with all forms of PH experience lifelong stone events, often beginning in childhood. Kidney failure is common in PH1 but rare in PH3. Longer-term follow-up of larger cohorts will be important for a more complete understanding of the PH3 phenotype.

Primary hyperoxaluria is a rare monogenic disorder characterized by excessive hepatic production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive kidney damage. Most patients with primary hyperoxaluria are diagnosed after clinical suspicion based on symptoms. Since some patients are detected by family screening following detection of an affected family member, we compared the clinical phenotype of these two groups. Patients with primary hyperoxaluria types 1, 2, and 3 enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry were retrospectively analyzed following capture of clinical and laboratory results in the Registry. Among 495 patients with primary hyperoxaluria, 47 were detected by family screening. After excluding 150 patients with end stage kidney disease at diagnosis, 300 clinical suspicion and 45 family screening individuals remained. Compared to patients with clinical suspicion, those identified by family screening had significantly fewer stones at diagnosis (mean 1.2 vs. 3.6), although initial symptoms occurred at a similar age (median age 6.1 vs. 7.6 years). Urinary oxalate did not differ between these groups. The estimated glomerular filtration rate at diagnosis and its decline over time were similar for the two groups. Altogether, five of 45 in family screening and 67 of 300 of clinical suspicion individuals developed end stage kidney disease at last follow-up. Thus, patients with primary hyperoxaluria identified through family screening have significant disease despite no outward clinical suspicion at diagnosis. Since promising novel treatments are emerging, genetic screening of family members is warranted because they are at significant risk for disease progression.

An amendment to this paper has been published and can be accessed via the original article.

Background Adenine phosphoribosyltransferase (APRT) deficiency is a rare, hereditary cause of kidney stones and chronic kidney disease (CKD) which is characterized by 2,8-dihydroxyadenine renal parenchymal crystal deposition. The aim of this study was to examine outcomes of kidney transplantation in APRT deficiency patients. Methods Included were 13 patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, 2 from Westmead Hospital in Sydney, Australia, and 2 from Necker Hospital in Paris, France. The CKD-EPI and CKiD equations were used to calculate glomerular filtration rate estimates. Allograft survival was analyzed employing the Kaplan-Meier method. The Wilcoxon-Mann-Whitney test was used to compare alllograft outcomes according to xanthine oxidoreductase (XOR) inhibitor treatment status at transplantation. Results Seventeen patients (9 females) received 22 kidney transplants. Age at first transplantation was 47.2 (14.9-67.0) years. Ten patients received XOR inhibitor therapy pretransplant (11 allografts), while 8 patients did not receive such treatment before transplantation (11 allografts). Two-year allograft survival was 91% and 55% in the 2 groups, respectively (P = 0.16). The median (range) estimated glomerular filtration rate at 2 years posttransplant was 61.3 (24.0-90.0) mL/min/1.73 m when XOR inhibitor therapy was initiated before transplantation, and 16.2 (10.0-39.0) mL/min/1.73 m (P = 0.009) when such treatment was not administered pretransplant. Conclusions Kidney allograft outcomes are good in APRT deficiency patients beginning XOR inhibitor therapy pretransplant. Delay in such treatment is a major cause of premature graft loss in these patients. Increased awareness among clinicians is imperative, promoting early diagnosis of APRT deficiency and pharmacotherapy initiation before kidney transplantation.

International audience; BACKGROUND AND OBJECTIVES: In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. RESULTS: Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal. CONCLUSIONS: Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.

Background In patients with primary hyperoxaluria (PH), endogenous oxalate overproduction increases urinary oxalate excretion, leading to compromised kidney function and often kidney failure. Highly elevated plasma oxalate (Pox) is associated with systemic oxalate deposition in patients with PH and severe chronic kidney disease (CKD). The relationship between Pox and estimated glomerular filtration rate (eGFR) in patients with preserved kidney function, however, is not well established. Our analysis aimed to investigate a potential correlation between these parameters in PH patients from three randomized, placebo-controlled trials (studies OC3-DB-01, OC3-DB-02, and OC5-DB-01). Methods Baseline data from patients with a PH diagnosis (type 1, 2, or 3) and eGFR > 40 mL/min/1.73 m2 were analyzed for a correlation between eGFR and Pox using Spearman’s rank and Pearson’s correlation coefficients. Data were analyzed by individual study and additionally were pooled for Studies OC3-DB-02 and OC5-DB-01 in which the same Pox assay was used. Results A total of 106 patients were analyzed. A statistically significant inverse Spearman’s correlation between eGFR and Pox was observed across all analyses; correlation coefficients were − 0.44 in study OC3-DB-01, − 0.55 in study OC3-DB-02, − 0.51 in study OC5-DB-01, and − 0.49 in the pooled studies (p Conclusions Baseline evaluations showed a moderate and statistically significant inverse correlation between eGFR and Pox in patients with PH already at early stages of CKD (stages 1–3b), demonstrating that a correlation is present before substantial loss in kidney function occurs. Graphical 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.

Primary hyperoxaluria type 1 (PH1) is a genetic disorder characterized by overproduction of oxalate and eventual kidney failure. Kidney failure is usually irreversible in PH1. However, in patients with PH1 homozygous for the G170R mutation (in which the glycine at amino acid 170 is replaced by an arginine), pyridoxine is an enzyme cofactor and decreases urinary oxalate excretion by reducing hepatic oxalate production. We report recovery from dialysis in 3 patients with PH1 homozygous for the G170R mutation in response to pharmacologic-dose pyridoxine treatment. Median age at initiation or resumption of pyridoxine treatment was 37 (range, 20-53) years, and median daily pyridoxine dose was 8.8 (range, 6.8-14.0) mg per kilogram of body weight. Duration of hemodialysis before recovery of kidney function was 10 (range, 5-19) months. Plasma oxalate concentration improved after recovery of kidney function. At a median of 3 (range, 2-46) months following discontinuation of hemodialysis, estimated glomerular filtration rate was 34 (range, 23-52) mL/min/1.73m2, plasma oxalate concentration was 8.8 (range, 4.6-11.3) μmol/L, and urinary oxalate excretion was 0.93 (range, 0.47-1.03) mmol/d. Kidney function was maintained during a median of 3.2 (range, 1.3-3.8) years of follow-up. These observations suggest that kidney failure may be reversible in a subset of patients with PH1 homozygous for the G170R mutation treated with pharmacologic-dose pyridoxine.

Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, scientists, patients with primary hyperoxaluria, industry, and United States regulators critically examined the published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end points. Kidney stones affect how patients with primary hyperoxaluria feel and function, but standards for measurement and monitoring are lacking. Primary hyperoxaluria registry data suggest that eGFR decline in most patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate and long-term kidney function loss. Urine oxalate is reasonably likely to predict clinical benefit, due to its causal role in stone formation and kidney damage in CKD stages 1-3a, and plasma oxalate is likely associated with risk of systemic oxalosis in CKD 3b-5. Change in slope of eGFR could be considered the equivalent of a clinically meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary hyperoxaluria type 1 and CKD stages 1-3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary hyperoxaluria and CKD stages 3b-5. Primary hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary hyperoxaluria.

Background Primary hyperoxaluria type 1 (PH1) is associated with nephrocalcinosis (NC) and calcium oxalate (CaOx) kidney stones (KS). Populations of urinary extracellular vesicles (EVs) can reflect kidney pathology. The aim of this study was to determine whether urinary EVs carrying specific biomarkers and proteins differ among PH1 patients with NC, KS or with neither disease process. Methods Mayo Clinic Rare Kidney Stone Consortium bio-banked cell-free urine from male and female PH1 patients without (n = 10) and with NC (n = 6) or KS (n = 9) and an eGFR > 40 mL/min/1.73 m2 were studied. Urinary EVs were quantified by digital flow cytometer and results expressed as EVs/ mg creatinine. Expressions of urinary proteins were measured by customized antibody array and results expressed as relative intensity. Data were analyzed by ANCOVA adjusting for sex, and biomarkers differences were considered statistically significant among groups at a false discovery rate threshold of Q Results Total EVs and EVs from different types of glomerular and renal tubular cells (11/13 markers) were significantly (Q Conclusions These results imply activation of distinct renal tubular and interstitial cell populations and processes associated with KS and NC, and suggest specific populations of urinary EVs and proteins are potential biomarkers to assess the pathogenic mechanisms between KS versus NC among PH1 patients.

Primary hyperoxalurias (PHs) are rare inherited disorders characterized by an increased endogenous synthesis of oxalate caused by a deficiency in one of several liver and kidney enzymes involved in glyoxylate metabolism. The excess oxalate is eliminated from the body by the kidneys. High concentrations of oxalate in the urine increase the risk of calcium oxalate deposition in the kidney (resulting in nephrocalcinosis) and in the urinary tract (leading to urinary stones). Primary hyperoxaluria is characterized by recurring calcium oxalate stones, presenting from early childhood to late adult life. Over time, deposition of calcium oxalate crystals in kidney tissue leads to kidney damage with progressive loss of kidney function. Primary hyperoxaluria type 1 is the most severe form with a median age at end-stage renal failure reached during young adulthood. Patients with PH type 2 and PH type 3 may show preservation of kidney function well into adulthood. Systemic deposition of calcium oxalate (oxalosis) can follow kidney failure and increased plasma oxalate levels. Diagnosis is made by DNA analysis of peripheral blood samples, or more rarely by enzyme assay of liver biopsy tissue. Treatment relies on high fluid intake, inhibitors of calcium oxalate crystallization, and, when required, urological procedures for stone removal. Some patients with PH1 respond to vitamin B6 treatment. Management of end-stage renal failure is difficult as dialysis, whether haemo- or peritoneal, cannot match oxalate production. Isolated kidney transplantation places patients at risk of recurring oxalate deposition in the graft in PH1 patients not responsive to vitamin B6. Liver transplantation, usually combined with kidney transplantation, is a curative treatment for PH1 but carries significant risks.

INTRODUCTION AND OBJECTIVES:PH1 is a genetic disorder characterized by hepatic overproduction of oxalate, which crystalizes with calcium in the urinary system to become toxic; this manifests with r...

Context Urolithiasis has a high prevalence and recurrence rate. Prevention is key to patient management, but risk stratification is challenging. In particular, genetic predisposition for urinary stones is not fully understood. Objective To review current evidence of potential causative genes for idiopathic urolithiasis and map their relationships to one another. This evidence is essential for future establishment of molecular targeted therapy. Evidence acquisition A systematic literature review from 2007 to 2017 was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. The search was restricted to human studies conducted as either case–control or genome-wide association studies, and published in English. We also performed a causal network analysis of candidate genes gained from the systematic review using Ingenuity Pathway Analysis (IPA). Evidence synthesis During the systematic screening of literature, 30 papers were selected for the review. A total of 20 genes with 42 polymorphisms/variants were found to be associated with urolithiasis risk. Their functional roles were mainly categorized as stone matrix, calcium and phosphate regulation, urinary concentration and constitution, and inflammation/oxidative stress. IPA network analysis revealed that these genes connected via signaling pathways and a proinflammatory/oxidative environment. Conclusions This systematic review provides an updated gene list and novel causal networks for idiopathic urolithiasis risk. Although some genes such as SPP1, CASR, VDR, CLDN14, and SLC34A1 were identified by several studies and recognized by prior reviews, further investigation elucidating their roles in stone formation will be essential for future studies. Patient summary In this review, we summarized recent literature regarding genes responsible for kidney stone risk. Based on a detailed review of 30 articles and computational network analysis, we concluded that disorder of mineral regulation with local inflammation in the kidney may cause kidney stone disease.

Summary Background: The 2013 American College of Cardiology / American Heart Association Guidelines for the Treatment of Blood Cholesterol emphasize treatment based on cardiovascular risk. But finding time in a primary care visit to manually calculate cardiovascular risk and prescribe treatment based on risk is challenging. We developed an informatics-based clinical decision support tool, MayoExpertAdvisor, to deliver automated cardiovascular risk scores and guideline-based treatment recommendations based on patient-specific data in the electronic heath record. Objective: To assess the impact of our clinical decision support tool on the efficiency and accuracy of clinician calculation of cardiovascular risk and its effect on the delivery of guideline-consistent treatment recommendations. Methods: Clinicians were asked to review the EHR records of selected patients. We evaluated the amount of time and the number of clicks and keystrokes needed to calculate cardiovascular risk and provide a treatment recommendation with and without our clinical decision support tool. We also compared the treatment recommendation arrived at by clinicians with and without the use of our tool to those recommended by the guidelines. Results: Clinicians saved 3 minutes and 38 seconds in completing both tasks with MayoExpertAd-visor, used 94 fewer clicks and 23 fewer key strokes, and improved accuracy from the baseline of 60.61% to 100% for both the risk score calculation and guideline-consistent treatment recommendation. Conclusion: Informatics solution can greatly improve the efficiency and accuracy of individualized treatment recommendations and have the potential to increase guideline compliance.

Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.

This retrospective analysis investigated plasma oxalate (POx) as a potential predictor of end-stage kidney disease (ESKD) among primary hyperoxaluria (PH) patients. PH patients with type 1, 2, and 3, age 2 or older, were identified in the Rare Kidney Stone Consortium (RKSC) PH Registry. Since POx increased with falling estimated glomerular filtration rate (eGFR), patients were stratified by chronic kidney disease (CKD) subgroups (stages 1, 2, 3a, and 3b). POx values were categorized into quartiles for analysis. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of ESKD were estimated using the Cox proportional hazards model with a time-dependent covariate. There were 118 patients in the CKD1 group (nine ESKD events during follow-up), 135 in the CKD 2 (29 events), 72 in CKD3a (34 events), and 45 patients in CKD 3b (31 events). During follow-up, POx Q4 was a significant predictor of ESKD compared to Q1 across CKD2 (HR 14.2, 95% CI 1.8&ndash, 115), 3a (HR 13.7, 95% CI 3.0&ndash, 62), and 3b stages (HR 5.2, 95% CI 1.1&ndash, 25), p &lt, 0.05 for all. Within each POx quartile, the ESKD rate was higher in Q4 compared to Q1&ndash, Q3. In conclusion, among patients with PH, higher POx concentration was a risk factor for ESKD, particularly in advanced CKD stages.

Primary hyperoxaluria (PH) is caused by genetic mutations resulting in oxalate overproduction leading to nephrolithiasis, nephrocalcinosis, extrarenal manifestations, chronic kidney disease, and end-stage renal disease. Advances in genetic testing techniques have improved our ability to efficiently and effectively obtain a definitive diagnosis of PH as well as easily screen at-risk family members. Similarly, advances in technologies related to intervening at the genetic and molecular level promise to change the way we treat patients with PH. In this review, we provide an update regarding the identification of underlying molecular and biochemical causes of inherited hyperoxalurias, clinical manifestations, and treatment strategies.

We report a case of systemic oxalosis involving the eyes and joints due to long-term use of high-dose vitamin C in a patient receiving maintenance peritoneal dialysis (PD). This 76-year-old woman with autosomal dominant polycystic kidney disease underwent living unrelated kidney transplantation 10 years earlier. The transplant failed 6 months before presentation, and she initiated hemodialysis therapy before transitioning to PD therapy 4 months later. During the month before presentation, the patient noted worsening arthralgias and decreased vision. Ophthalmologic examination revealed proliferative retinopathy and calcium oxalate crystals. Plasma oxalate level was markedly elevated at 187 (reference range, 1.7) μmol/L, and urine oxalate-creatinine ratio was high (0.18mg/mg). The patient reported taking up to 4g of vitamin C per day for several years. Workup for causes of primary and secondary hyperoxaluria was otherwise negative. Vitamin C use was discontinued, and the patient transitioned to daily hemodialysis for 2 weeks. Plasma oxalate level before the dialysis session decreased but remained higher (30-53μmol/L) than typical for dialysis patients. Upon discharge, the patient remained on thrice-weekly hemodialysis therapy with stabilized vision and improved joint symptoms. This case highlights the risk of high-dose vitamin C use in patients with advanced chronic kidney disease, especially when maintained on PD therapy.

BACKGROUND: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments. METHODS: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n=112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n=96) and Novel therapies for resistant FSGS Trial (FONT) (n=30). Urinary α(1)-microglobulin (α(1)-M), albumin (A), total protein (TP) and creatinine (Cr) were assessed from CKiD subjects (n=104); DD1 patients (n=14) and DD1 carriers (DC; n=8). TP/Cr, α1M/Cr, α1M/TP and A/TP from the CKiD cohort were compared with DD1 and DC. RESULTS: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than DD1 and CKiD with glomerular disease (P < 0.002). α(1)M/Cr was higher in DD1 than CKiD and DC (P < 0.001). A/TP was lower in DD1, DC and CKiD with tubulointerstitial disease, higher in CKiD with glomerular disease (P < 0.001). Thresholds for A/TP of ≤ 0.21 and α(1)-M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease. CONCLUSIONS: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cut off of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. α(1)-M/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.

Since plasma oxalate (POx) concentrations increase at lower glomerular filtration rate (GFR) levels, even among those without enteric (EH) or primary hyperoxaluria (PH), the appropriate thresholds for considering a disorder of oxalate metabolism are poorly defined. The current study was completed to establish relationships between POx, GFR, and urine oxalate excretion (UOx) among patients with PH, EH, and routine urinary stone disease (USD).The most recent POx measurement on all Mayo Clinic patients between 2005 and 2015 were electronically pulled from the Lab Information System together with the closest serum creatinine within 14days and 24h urine study within 60days. After exclusion of patients not in steady state at the time of blood draw, 270 patients were available for study. Records were reviewed for clinical diagnoses to categorize patients as PH, EH, or USD. Waste plasma for Pox was also obtained from controls without USD undergoing clinical GFR testing.In all 3 groups POx increased as eGFR fell. For any given eGFR, POx was highest in the PH group and lowest in the USD and control groups (p0.0001). POx was also influenced by UOx excretion (reflecting total body oxalate burden, absorption from diet and endogenous production). Generalized estimating equations of POx vs eGFR revealed higher average POx levels in PH compared to EH,USD or control, and for EH compared to USD or control. GEE prediction models were created that use POx, UOx, age, and serum creatinine to estimate the probability of a PH diagnosis.New models were developed to help interpret POx when considering PH in clinical practice even when it was not previously suspected and/or eGFR is reduced.

Background: Primary hyperoxaluria type 1 (PH1) and idiopathic hypercalciuria (IHC) are stone-forming diseases that may result in the formation of calcium (Ca) oxalate (Ox) stones, nephrocalcinosis, and progressive chronic kidney disease (CKD). Poorer clinical outcome in PH1 is segregated by the highest urine (Ur)-Ox (UrOx), while IHC outcomes are not predictable by UrCa. We hypothesized that differences would be found in selected Ur-protein (PRO) patterns in PH1 and IHC, compared to healthy intra-familial sibling controls (C) of PH1 patients. We also hypothesized that the PRO patterns associated with higher UrOx levels would reflect injury, inflammation, biomineralization, and abnormal tissue repair processes in PH1. Methods: Twenty four-hour Ur samples were obtained from 3 cohorts: PH1 (n = 47); IHC (n = 35) and C (n = 13) and were analyzed using targeted platform-based multi-analyte profile immunoassays and for UrOx and UrCa by biochemical measurements. Results: Known stone matrix constituents, osteopontin, calbindin, and vitronectin were lowest in PH1 (C > IHC > PH1; p < 0.05). Ur-interleukin-10; chromogranin A; epidermal growth factor (EGF); insulin-like growth factor-1 (IGF-1), and macrophage inflammatory PRO-1α (MIP-1α) were higher in PH1 > C (p = 0.03 to p < 0.05). Fetuin A; IGF-1, MIP-1α, and vascular cell adhesion molecule-1 were highest in PH1 > IHC (p < 0.001 to p = 0.005). Conclusion: PH1 Ur-PROs reflected overt inflammation, chemotaxis, oxidative stress, growth factors (including EGF), and pro-angiogenic and calcification regulation/inhibition compared to the C and IHC cohorts. Many of the up- and downregulated PH1-PROs found in this study are also found in CKD, acute kidney injury, stone formers, and/or stone matrices. Further data analyses may provide evidence for PH1 unique PROs or demonstrate a poorer clinical outcome.

Background Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known. Methods To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [(15)N,(13)C(5)]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary (13)C(2)-oxalate and (13)C(2)-glycolate formed using ion chromatography coupled to mass detection. Results The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and

Primary hyperoxaluria (PH) patients overproduce oxalate because of rare genetic errors in glyoxylate metabolism. Recurrent urolithiasis and/or progressive nephrocalcinosis are PH hallmarks and can lead to kidney damage, systemic oxalosis and death. Based on previous studies, we hypothesised that treatment with the oxalate-metabolizing bacterium Oxalobacter formigenes would mediate active elimination of oxalate from the plasma to the intestine of PH patients, thereby reducing urinary oxalate excretion (Uox). The efficacy and safety of O. formigenes (Oxabact™ OC3) were evaluated for 24 weeks in a randomised, placebo-controlled, double-blind study. The primary endpoint was reduction in Uox. Secondary endpoints included change in plasma oxalate (Pox) concentration, frequency of stone events, number of responders, and Uox in several subgroups. Additional post hoc analyses were conducted. Thirty-six patients were randomised; two patients withdrew from placebo treatment. Both OC3 and placebo groups demonstrated a decrease in Uox/urinary creatinine ratio, but the difference was not statistically significant. No differences were observed with respect to change in Pox concentration, stone events, responders’ number or safety measures. In patients with estimated glomerular filtration rate (eGFR)

Objective To present our experience with surgical management of nephrolithiasis in patients with primary hyperoxaluria (PH). Methods A retrospective chart review from 1994 to 2012 was performed to identify patients with diagnosis of PH. Results A total of 14 patients with PH were identified with a median follow-up of 18.6 years (range, 0.9-51 years). Median ages at initial symptom and subsequent diagnosis were 6.7 years (range, 1.1-35.5 years) and 0.42 years (range, 0-33.25 years), respectively. Patients underwent a total of 54 procedures at our institution, including ureteroscopy (27 [50%]), percutaneous nephrolithotomy (15 [28%]), shock wave lithotripsy (8 [15%]), and combined procedures (4 [7%]). Overall nonintraparenchymal stone-free rate after the first, second, and third procedures were 59%, 76%, and 78%, respectively. On average, 1.6 procedures (range, 1-4) were required to rid patients of symptomatic stones, which subsequently afforded them a mean of 3.62 years (range, 0.25-21.5 years) without the need for additional intervention. There were 6 Clavien grade ≥III complications in 4 patients, including immediate postoperative end-stage renal disease in 3 patients. Conclusion Despite optimal medical and surgical management, patients experience recurrent acute stone events requiring multiple urologic interventions. Significant complications such as end-stage renal disease can occur secondary to surgical intervention.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a mutation in the alanine-glyoxalate aminotransferase (AGXT) gene which encodes the hepatic enzyme alanine-glyoxylate aminotransferase (AGT). AGT is responsible for converting glyoxylate into glycine. When the enzyme is deficient or defective, glyoxylate accumulates and is converted to oxalate. Oxalate cannot be metabolized and is excreted by the kidneys 4. In PH1, high urinary levels of oxalate lead to kidney stones and deposition of calcium oxalate crystals within the renal tubules and parenchyma, which results in progressive renal fibrosis. As kidney function declines, oxalate production increasingly exceeds renal oxalate clearance. Plasma oxalate levels rise, and insoluble calcium oxalate crystals are deposited in tissues throughout the body, including the kidney, heart, bone, blood vessels, retina, muscle, skin, and nerve. Hemodialysis is needed to remove oxalate from the body, but removal is incomplete, and even when it is intensive, dialysis is often insufficient to prevent progressive systemic oxalate deposition 5,6,7. Because oxalate removal with dialysis is incomplete, the treatment of choice for patients with PH1 and poor kidney function, is combined liver/ kidney transplantation. Liver transplantation is required in the majority of PH type 1 patients to restore the hepatic enzyme defect and protect the renal allograft from recurrent oxalate nephropathy. Significant neurologic improvement in patients with neuropathy has been noted following combined liver and kidney transplantation 8. Only a few case reports have described the nerve pathology associated with primary hyperoxaluria type 1. Demyelination (particularly at the internodes) and axonal degeneration have been reported,1 and some case reports describe crystals in nerve 1,3. The characterization and location of these crystals within nerve has not been well described, and their pathological significance has remained unclear 1,3. In each of these case reports, the patient had significant systemic oxalosis with deposition of oxalate into multiple tissues, whereas the patient we describe had oxalosis affecting peripheral nerve preferentially without other clinically discernible extrarenal manifestations. Approval by our Institutional Review Board and Biospecimens Committee was received for this study.

Combined liver/kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) since orthotopic liver transplantation replaces the deficient liver-specific AGT enzyme, thus restoring normal metabolic oxalate production. However, primary hyperoxaluria type 2 (PH2) is caused by deficient glyoxylate reductase/hydroxypyruvate reductase (GRHPR), and this enzyme is widely distributed throughout the body. Though the relative abundance and activity of GRHPR in various tissues is not clear, some evidence suggests that the majority of enzyme activity may indeed reside within the liver. Thus the effectiveness of liver transplantation in correcting this metabolic disorder has not been demonstrated. Here we report a case of 44-year-old man with PH2, frequent stone events, and end-stage renal disease; he received a combined liver/kidney transplant. Although requiring confirmation in additional cases, the normalization of plasma oxalate, urine oxalate, and urine glycerate levels observed in this patient within a month of the transplant that remain reduced at the most recent follow-up at 13 months suggests that correction of the GRHPR deficiency in PH2 can be achieved by liver transplantation.

Obesity, a risk factor for kidney stones and chronic kidney disease (CKD), is effectively treated with bariatric surgery. However, it is unclear whether surgery alters stone or CKD risk. To determine this we studied 762 Olmsted County, Minnesota residents who underwent bariatric surgery and matched them with equally obese control individuals who did not undergo surgery. The majority of bariatric patients underwent standard Roux-en-Y gastric bypass (RYGB; 78%), with the remainder having more malabsorptive procedures (very long limb RYGB or biliopancreatic diversion/duodenal switch; 14%) or restrictive procedures (laparoscopic banding or sleeve gastrectomy; 7%). The mean age was 45 years with 80% being female. The mean preoperative body mass index (BMI) was 46.7 kg/m(2) for both cohorts. Rates of kidney stones were similar between surgery patients and controls at baseline, but new stone formation significantly increased in surgery patients (11.0%) compared with controls (4.3%) during 6.0 years of follow-up. After malabsorptive and standard surgery, the comorbidity-adjusted hazard ratio of incident stones was significantly increased to 4.15 and 2.13, respectively, but was not significantly changed for restrictive surgery. The risk of CKD significantly increased after the malabsorptive procedures (adjusted hazard ratio of 1.96). Thus, while RYGB and malabsorptive procedures are more effective for weight loss, both are associated with increased risk of stones, while malabsorptive procedures also increase CKD risk.

Combined kidney liver transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) given that it removes the hepatic source of oxalate production and improves renal allograft survival. However, PH1 patients homozygous for the G170R mutation can develop normal urine oxalate levels with pyridoxine therapy and may be candidates for kidney alone transplant. We examined the efficacy of pyridoxine therapy following kidney alone transplant in five patients homozygous for G170R transplanted between 9/1999 and 7/2013. All patients were maintained on pyridoxine post-transplant. Median age at transplant was 39 years (range 33–67 years). Median follow-up post-transplant was 8.5 years (range 0.2–13.9 years). At the end of follow-up, 4 grafts were functioning. One graft failed 13.9 years post-transplant due to recurrent oxalate nephropathy following an acute medical illness. After tissue oxalate stores had cleared, post-transplant urine oxalate levels were < 0.5 mmol/24 hr the majority of times checked. Calcium oxalate crystals were noted in only 3/13 allograft biopsies. This series suggests that a subgroup of PH1 patients demonstrate sustained response to pyridoxine therapy following kidney alone transplant. Therefore, pyridoxine combined with kidney alone transplantation should be considered for PH1 patients with a homozygous G170R mutation.

The original version of this article unfortunately contained a mistake. On page 84, the dose for oral potassium citrate is incorrectly written as "0.1 mg/kg/day divided BID-QID for children, 30-60 mg per day divided BID-QID for adults".

The sequence of events by which primary hyperoxaluria type 1 (PH1) causes renal failure is unclear. We hypothesize that proximal tubule (PT) is vulnerable because oxalate secretion raises calcium oxalate (CaOx) supersaturation (SS) there, leading to crystal formation and cellular injury. We studied cortical and papillary biopsies from two PH1 patients with preserved renal function, and seven native kidneys removed from four patients at the time of transplant, after short-term ( 2 ) or longer term ( 2 ) dialysis. In these patients, and another five PH1 patients without renal failure, we calculated oxalate secretion, and estimated PT CaOx SS. Plasma oxalate was elevated in all PH1 patients and inverse to creatinine clearance. Renal secretion of oxalate was present in all PH1 but rare in controls. PT CaOx SS was >1 in all nonpyridoxine-responsive PH1 before transplant and most marked in patients who developed end stage renal disease (ESRD). PT from PH1 with preserved renal function had birefringent crystals, confirming the presence of CaOx SS, but had no evidence of cortical inflammation or scarring by histopathology or hyaluronan staining. PH1 with short ESRD showed CaOx deposition and hyaluronan staining particularly at the corticomedullary junction in distal PT while cortical collecting ducts were spared. Longer ESRD showed widespread cortical CaOx, and in both groups papillary tissue had marked intratubular CaOx deposits and fibrosis. CaOx SS in PT causes CaOx crystal formation, and CaOx deposition in distal PT appears to be associated with ESRD. Minimizing PT CaOx SS may be important for preserving renal function in PH1.

An electronic health record (EHR) can assist the delivery of high-quality patient care, in part by providing the capability for a broad range of clinical decision support, including contextual references (e.g., Infobuttons), alerts and reminders, order sets, and dashboards. All of these decision support tools are based on clinical knowledge; unfortunately, the mechanisms for managing rules, order sets, Infobuttons, and dashboards are often unrelated, making it difficult to coordinate the application of clinical knowledge to various components of the clinical workflow. Additional complexity is encountered when updating enterprise-wide knowledge bases and delivering the content through multiple modalities to different consumers. We present the experience of Mayo Clinic as a case study to examine the requirements and implementation challenges related to knowledge management across a large, multi-site medical center. The lessons learned through the development of our knowledge management and delivery platform will help inform the future development of interoperable knowledge resources.

Introduction The pace of medical discovery is accelerating to the point where caregivers can no longer keep up with the latest diagnosis or treatment recommendations. At the same time, sophisticated and complex electronic medical records and clinical systems are generating increasing volumes of patient data, making it difficult to find the important information required for patient care. To address these challenges, Mayo Clinic established a knowledge management program to curate, store, and disseminate clinical knowledge. Methods The authors describe AskMayoExpert, a point-of-care knowledge delivery system, and discuss the process by which the clinical knowledge is captured, vetted by clinicians, annotated, and stored in a knowledge content management system. The content generated for AskMayoExpert is considered to be core clinical content and serves as the basis for knowledge diffusion to clinicians through order sets and clinical decision support rules, as well as to patients and consumers through patient education materials and internet content. The authors evaluate alternative approaches for better integration of knowledge into the clinical workflow through development of computer-interpretable care process models. Results Each of the modeling approaches evaluated has shown promise. However, because each of them addresses the problem from a different perspective, there have been challenges in coming to a common model. Given the current state of guideline modeling and the need for a near-term solution, Mayo Clinic will likely focus on breaking down care process models into components and on standardization of those components, deferring, for now, the orchestration. Conclusion A point-of-care knowledge resource developed to support an individualized approach to patient care has grown into a formal knowledge management program. Translation of the textual knowledge into machine executable knowledge will allow integration of the knowledge with specific patient data and truly serve as a colleague and mentor for the physicians taking care of the patient.