Rationale & Objective:Characterize the natural history of advanced primary hyperoxaluria type 1 (PH1) in a multinational patient cohort. Study Design:A retrospective chart review. Setting & Participants:Patients, from participating medical centers in North America, Europe, and the Middle East, had ≥ 4 health care visits related to PH1 spanning ≥ 6 months (except deceased patients) on/after January 1, 2000, and ≥ 2 estimated glomerular filtration rate (eGFR) values ≤ 45 mL/min/1.73m2 (if age < 12 months, 2 serum creatinine values elevated for age) were included. Exposure:None (retrospective observational study). Outcomes:Kidney function, liver and/or kidney transplantation, death, plasma oxalate, systemic oxalosis, emergent clinical events, and abnormal clinical laboratory values. Analytical Approach:Patients were categorized as not on dialysis (Cohort A) and receiving hemodialysis (Cohort B). Patients could be in more than one cohort, but not during the same time. Results:Seventy patients were analyzed (up to 21 years of data; Cohort A, n = 54; Cohort B, n = 53). The median age at entry was 11.8 years (Cohort A) and 12.2 years (Cohort B). The eGFR slope was -2.8 mL/min/1.73m2/year (Cohort A). Patients underwent hemodialysis a median of 6 days/week (range, 3-7; Cohort B). Forty-two patients underwent liver and/or kidney transplantation (median age at first transplant, 15.3 years). Nineteen patients died (median age at death, 3.9 years [range, 2.2-34.9]), including 8 who received liver or liver-kidney transplants. Death occurred in 11 of 28 (39.3%) patients without transplant and 8 of 42 (19.0%) patients with transplant. Improvement in skeletal oxalosis after liver-kidney transplantation generally took > 1 year. Limited plasma oxalate and cardiac oxalosis data were available. The most common emergent clinical events were nephrolithiasis (Cohort A [nondialysis]) and fracture (Cohort B [hemodialysis]). The most commonly reported abnormal clinical laboratory values were bicarbonate, creatinine, and eGFR. Limitations:Minimal follow-up in some patients; small sample for some endpoints. Conclusions:Advanced PH1 is associated with high morbidity and mortality rates.

Background Urinary stone disease with a clear genetic cause, monogenic stone disease (MSD), is increasingly recognized as a significant proportion of the total population. When MSD is suspected, genetic testing provides a firm diagnosis that can alter management and treatment. Here, we present testing results from a large cohort with suspected MSD. Methods Patients with features suggestive of MSD (early onset, family history, frequent stones, nephrocalcinosis [NC], and/or CKD) were recruited by the Rare Kidney Stone Consortium and genotyped for up to 160 known or candidate MSD genes via a targeted massively parallel sequencing panel. We compared clinical and biochemical features between genetically resolved MSD and unresolved individuals. Results Of 426 families (657 patients) enrolled, 145 (34%) were resolved with identified disease associated variants in 22 known MSD genes. Ninety-nine families were biallelic, 37 monoallelic, and two digenic. An additional 21 of the 231 screened family members were resolved. Genes identified in ten or more families include the following: AGXT, HOGA1, SLC34A3, CYP24A1, SLC3A1, and CLCN5. Compared with the unresolved group, MSD probands had a lower baseline and last visit eGFR, earlier age of stone presentation, and more stone events and procedures/year of life. The resolve rate was higher in those <16 years, and NC was seen earlier in the MSD group. Overall, NC was a risk factor for lower eGFR. Among the specific disorders, patients with primary hyperoxaluria had the earliest age of stone and NC diagnosis, and as expected, the highest urinary oxalate level. Conclusions Our study emphasizes the value of selecting patients enriched for factors associated with MSD, and comprehensive genetic testing to achieve a high yield of genetic diagnoses. Significant clinical and biochemical characteristics of patients with MSD were defined. A definitive MSD diagnosis facilitates individualized management and strategies to delay disease progression in probands and affected family members.

Introduction: Hyperoxaluria is a risk factor for kidney stone formation and chronic kidney disease progression. The microbiome is an important protective factor against oxalate accumulation through the activity of its oxalate-degrading enzymes (ODEs). In this cross-sectional study, we leverage multiomics to characterize the microbial community of participants with primary and enteric hyperoxaluria, as well as idiopathic calcium oxalate kidney stone (CKS) formers, focusing on the relationship between oxalate degrading functions of the microbiome. Methods: Patients diagnosed with type 1 primary hyperoxaluria (PH), enteric hyperoxaluria (EH), and CKS were screened for inclusion in the study. Participants completed a food frequency questionnaire recording their dietary oxalate content while fecal oxalate levels were ascertained. DNA and RNA were extracted from stool samples and sequenced. Metagenomic (MTG) and metatranscriptomic (MTT) data were processed through our bioinformatics pipelines, and microbiome diversity, differential abundance, and networks were subject to statistical analysis in relationship with oxalate levels. Results: A total of 38 subjects were recruited, including 13 healthy participants, 12 patients with recurrent CKS, 8 with PH, and 5 with EH. Urinary and fecal oxalate were signi fi cantly higher in the PH and the EH population compared to healthy controls. At the community level, alpha-diversity and beta-diversity indices were similar across all populations. The respective contributions of single bacterial species to the total oxalate degradative potential were similar in healthy and PH subjects. MTT-based network analysis identi fi ed the most interactive bacterial network in patients with PH. Patients with EH had a decreased abundance of multiple major oxalate degraders. Conclusion: The composition and inferred activity of oxalate-degrading microbiota were differentially associated with host clinical conditions. Identifying these changes improves our understanding of the relationships between dietary constituents, microbiota, and oxalate homeostasis, and suggests new therapeutic approaches protecting against hyperoxaluria.

The primary hyperoxalurias (PH 1, 2, and 3) are rare autosomal recessive disorders of glyoxylate metabolism resulting in hepatic overproduction of oxalate. Clinical presentations that should prompt consideration of PH include kidney stones, nephrocalcinosis, and kidney failure of unknown etiology, especially with echogenic kidneys on ultrasound. PH1 is the most common and severe of the primary hyperoxalurias with a high incidence of kidney failure as early as infancy. Until the recent availability of a novel RNA interference (RNAi) agent, PH care was largely supportive of eventual need for kidney/liver transplantation in PH1 and PH2. Together with the Oxalosis and Hyperoxaluria Foundation, the authors developed a diagnostic algorithm for PH1 and in this report outline best clinical practices related to its early diagnosis, supportive treatment, and long-term management, including the use of the novel RNAi. PH1-focused approaches to dialysis and kidney/liver transplantation for PH patients with progression to chronic kidney disease/kidney failure and systemic oxalosis are suggested. Therapeutic advances for this devastating disease heighten the importance of early diagnosis and informed treatment.

Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive oxalate production because of specific gene defects. PH1 is the most prevalent type, causing recurrent kidney stone disease and often leading to chronic kidney disease and kidney failure. Our previous study suggested that pregnancy did not adversely affect kidney function in female patients with PH. In this study, we identified 4 PH1 cases with urinary oxalate (UOx) measurements during pregnancy from the Rare Kidney Stone Consortium and Oxalosis and Hyperoxaluria Foundation PH registry to investigate UOx levels during pregnancy in patients with PH1. The PH Registry is approved by the Institutional Review Board of Mayo Clinic (Rochester, MN). All 4 showed a decrease in UOx during pregnancy when compared with before pregnancy and after delivery. These findings contrast with those of the general population, in which the UOx tends to increase during pregnancy because of a simultaneous physiological increase in the glomerular filtration rate. Elucidating the mechanism underlying reduced UOx during pregnancy in PH1 could suggest novel PH therapies. These findings could also affect the clinical management and have implications regarding the safety of withholding novel PH1-directed molecular therapies that currently have uncertain safety profiles during pregnancy. We highlight the need for additional data on urinary changes in patients with PH and other populations while pregnant to clarify changes in UOx throughout pregnancy.

Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion due to increased gastrointestinal oxalate absorption. Causative features include fat malabsorption and/or increased intestinal permeability to oxalate. Enteric hyperoxaluria has long been known to cause nephrolithiasis and nephrocalcinosis, and, more recently, an association with CKD and kidney failure has been shown. Currently, there are no US Food and Drug Administration-approved therapies for enteric hyperoxaluria, and it is unclear what end points should be used to evaluate the efficacy of new drugs and biologics for this condition. This study represents work of a multidisciplinary group convened by the Kidney Health Initiative to review the evidence supporting potential end points for clinical trials in enteric hyperoxaluria. A potential clinical outcome is symptomatic kidney stone events. Potential surrogate end points include ( 1 ) an irreversible loss of kidney function as a surrogate for progression to kidney failure, ( 2 ) asymptomatic kidney stone growth/new stone formation observed on imaging as a surrogate for symptomatic kidney stone events, ( 3 ) urinary oxalate and urinary calcium oxalate supersaturation as surrogates for the development of symptomatic kidney stone events, and ( 4) plasma oxalate as a surrogate for the development of the clinical manifestations of systemic oxalosis. Unfortunately, because of gaps in the data, this Kidney Health Initiative workgroup was unable to provide definitive recommendations. Work is underway to obtain robust information that can be used to inform trial design and medical product development in this space.

Primary hyperoxaluria type 2 (PH2) is a rare autosomal recessive disorder of endogenous oxalate overproduction caused by variants of the GRHPR gene. Deficiency of GRHPR enzyme activity leads to the accumulation of glyoxylate and hydroxypyruvate upstream of the deficient enzyme, resulting in hyperoxaluria. PH2 is characterized by recurrent nephrolithiasis, nephrocalcinosis, and chronic kidney disease. Progression to kidney failure has been reported in in up to 25% to 35% of patients in several large cohorts.

Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis, and often progressive chronic kidney disease. Little is known about the natural history of urine and plasma oxalate values over time in children with PH1. For this retrospective observational study, we analyzed data from genetically confirmed PH1 patients enrolled in the Rare Kidney Stone Consortium PH Registry between 2003 and 2018 who had at least 2 measurements before age 18 years of urine oxalate-to-creatinine ratio (Uox:cr), 24-h urine oxalate excretion normalized to body surface area (24-h Uox), or plasma oxalate concentration (Pox). We compared values among 3 groups: homozygous G170R, heterozygous G170R, and non-G170R AGXT variants both before and after initiating pyridoxine (B6). Of 403 patients with PH1 in the registry, 83 met the inclusion criteria. Uox:cr decreased rapidly over the first 5 years of life. Both before and after B6 initiation, patients with non-G170R had the highest Uox:cr, 24-h Uox, and Pox. Patients with heterozygous G170R had similar Uox:cr to homozygous G170R prior to B6. Patients with homozygous G170R had the lowest 24-h Uox and Uox:cr after B6. Urinary oxalate excretion and Pox tend to decrease over time during childhood. eGFR over time was not different among groups. Children with PH1 under 5 years old have relatively higher urinary oxalate excretion which may put them at greater risk for nephrocalcinosis and kidney failure than older PH1 patients. Those with homozygous G170R variants may have milder disease.

PURPOSE:Hallmarks of primary hyperoxaluria type 3 are nephrolithiasis and hyperoxaluria. However, little is known about factors influencing stone formation in this disease. We characterized stone events and examined associations with urine parameters and kidney function in a primary hyperoxaluria type 3 population.MATERIALS AND METHODS:We retrospectively analyzed clinical, and laboratory data of 70 primary hyperoxaluria type 3 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry.RESULTS:Kidney stones occurred in 65/70 primary hyperoxaluria type 3 patients (93%). Among the 49 patients with imaging available, the median (IQR) number of stones was 4 (2, 5), with largest stone 7 mm (4, 10) at first imaging. Clinical stone events occurred in 62/70 (89%) with median number of events per patient 3 (2, 6; range 1-49). Age at first stone event was 3 years (0.99, 8.7). Lifetime stone event rate was 0.19 events/year (0.12, 0.38) during follow-up of 10.7 (4.2, 26.3) years. Among 326 total clinical stone events, 139 (42.6%) required surgical intervention. High stone event rates persisted for most patients through the sixth decade of life. Analysis was available for 55 stones: pure calcium oxalate accounted for 69%, with mixed calcium oxalate and phosphate in 22%. Higher calcium oxalate supersaturation was associated with increased lifetime stone event rate after adjusting for age at first event (IRR [95%CI] 1.23 [1.16, 1.32]; P < .001). By the fourth decade, estimated glomerular filtration rate was lower in primary hyperoxaluria type 3 patients than the general population.CONCLUSIONS:Stones impose a lifelong burden on primary hyperoxaluria type 3 patients. Reducing urinary calcium oxalate supersaturation may reduce event frequency and surgical intervention.

FEATURE EDITORDaniel E. WeinerADVISORY BOARDL. Ebony BoulwareKevin EricksonEduardo Lacson JrBruce M. RobinsonWolfgang WinkelmayerPolicy Forum highlights aspects of nephrology relating to payment and social policy, legislation, regulation, demographics, politics, and ethics, contextualizing these issues as they relate to the lives and practices of members of the kidney community, including providers, payers, and patients. FEATURE EDITOR Daniel E. Weiner ADVISORY BOARD L. Ebony Boulware Kevin Erickson Eduardo Lacson Jr Bruce M. Robinson Wolfgang Winkelmayer Policy Forum highlights aspects of nephrology relating to payment and social policy, legislation, regulation, demographics, politics, and ethics, contextualizing these issues as they relate to the lives and practices of members of the kidney community, including providers, payers, and patients. Over the last decade, many exciting developments and treatment approaches for kidney disease have emerged.1Jhaveri K.D. Warp speed nephrology drug development.Kidney News. 2021; 13: 13Google Scholar There are many underlying reasons for this, including rapid advances in understanding the pathogenesis for specific kidney diseases. The increased availability of high-throughput genetic sequencing, single-cell gene expression analysis, and ever more powerful bioinformatic techniques are just a few of the contributing factors. Equally important are efficient yet rigorous methods to conduct clinical trials to assure the safety and efficacy of new treatments in a cost-efficient and timely manner. Clinical trial design has been particularly important in kidney disease, given the relatively long time it takes to progress to clinically meaningful end points such as kidney failure. Clinical trials in rare diseases pose additional challenges in identification of end points that are achievable in small patient populations. It is equally important to consider the views of the target patient population for any given treatment, since for many diseases with potentially serious and painful outcomes, patients may be willing to assume greater uncertainty about the ultimate safety and efficacy of new treatment approaches.2Lawrence J.E. Wattenberg D.J. Primary hyperoxaluria: the patient and caregiver perspective.Clin J Am Soc Nephrol. 2020; 15: 909-911Google Scholar The US Food and Drug Administration (FDA) recognizes the importance of balancing rigorous evaluation of novel therapeutics and the impact that delay of any effective treatments will have on families and patients, many of whom are children, and thus the role of patient-focused drug development (PFDD) has evolved.3CDER Patient-Focused Drug Development.https://www.fda.gov/drugs/development-approval-process-drugs/cder-patient-focused-drug-developmentDate accessed: October 3, 2021Google Scholar For kidney diseases overall, there have been careful considerations of what changes—ie, estimated glomerular filtration rate, slope of estimated glomerular filtration rate decline, or change in albuminuria—would be acceptable for traditional or accelerated drug approval.4Thompson A. Carroll K. Inker L.A. et al.Proteinuria reduction as a surrogate end point in trials of IgA nephropathy.Clin J Am Soc Nephrol. 2019; 14: 469-481Google Scholar Oxalate is a small 2-carbon molecule found in certain plants in the form of calcium oxalate crystals. Oxalate is also produced in the human liver as a product of metabolism. Since humans have no enzyme to degrade oxalate, whatever oxalate is absorbed from dietary sources or produced by the liver must be excreted, primarily by the kidneys.5Worcester E.M. Evan A.P. Coe F.L. et al.A test of the hypothesis that oxalate secretion produces proximal tubule crystallization in primary hyperoxaluria type I.Am J Physiol Renal Physiol. 2013; 305: F1574-F1584Google Scholar Within the urinary tract, oxalate can combine with calcium to form calcium oxalate crystals and kidney stones. Extreme hyperoxaluria can result from 2 major causes: primary hyperoxaluria due to hepatic overproduction of oxalate because of a defect in 1 of 3 known genes,6Milliner D.S. McGregor T.L. Thompson A. et al.End points for clinical trials in primary hyperoxaluria.Clin J Am Soc Nephrol. 2020; 15: 1056-1065Google Scholar and enteric hyperoxaluria due to gastrointestinal fat malabsorption that causes increased intestinal absorption of dietary oxalate.7Witting C. Langman C.B. Assimos D. et al.Pathophysiology and treatment of enteric hyperoxaluria.Clin J Am Soc Nephrol. 2021; 16: 487-495Google Scholar In both cases the excess oxalate markedly increases the risk of kidney stones and chronic kidney disease.6Milliner D.S. McGregor T.L. Thompson A. et al.End points for clinical trials in primary hyperoxaluria.Clin J Am Soc Nephrol. 2020; 15: 1056-1065Google Scholar, 7Witting C. Langman C.B. Assimos D. et al.Pathophysiology and treatment of enteric hyperoxaluria.Clin J Am Soc Nephrol. 2021; 16: 487-495Google Scholar, 8Tang X. Bergstralh E.J. Mehta R.A. Vrtiska T.J. Milliner D.S. Lieske J.C. Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria.Kidney Int. 2015; 87: 623-631Google Scholar, 9Zhao F. Bergstralh E.J. Mehta R.A. et al.Predictors of incident ESRD among patients with primary hyperoxaluria presenting prior to kidney failure.Clin J Am Soc Nephrol. 2016; 11: 119-126Google Scholar, 10Garrelfs S.F. Rumsby G. Peters-Sengers H. et al.Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up.Kidney Int. 2019; 96: 1389-1399Google Scholar, 11D’Costa M.R. Kausz A.T. Carroll K.J. et al.Subsequent urinary stone events are predicted by the magnitude of urinary oxalate excretion in enteric hyperoxaluria.Nephrol Dial Transplant. 2021; 36: 2208-2215Google Scholar In primary hyperoxaluria, the more extreme and persistent hyperoxaluria is frequently associated with kidney failure, and if kidney failure ensues systemic oxalosis can occur.12Sas D.J. Enders F.T. Gunderson T.M. et al.Natural history of clinical, laboratory, and echocardiographic parameters of a primary hyperoxaluria cohort on long term hemodialysis.Front Med (Lausanne). 2021; 8: 592357Google Scholar Continued hyperoxaluria following kidney transplantation can lead to transplant failure in both primary and enteric forms of the disease. Fortunately, novel therapies are in the pipeline for both primary and enteric hyperoxaluria; however, clinical trials in rare diseases such as these are challenging. The number of affected individuals is small for trial recruitment. In genetic diseases there is added complexity for conducting studies in a pediatric population. In enteric and primary hyperoxaluria kidney stone events are a key clinical end point, but since stone events generally occur every 2-3 years in an active patient, the number of patients necessary for traditional placebo-controlled trials is quite large and trial duration long. Kidney failure is an important clinically significant outcome, but even for primary hyperoxaluria the number of patients and time they would need to be followed using this end point in a trial is daunting. Regulatory authorities recognize these obstacles. Thus, although patient-centered clinical outcomes are always most important, surrogate end points can often support efficacy of a given therapy. In general, for a surrogate end point to be acceptable for approval of a therapy, even as a contingent approval, evidence linking that surrogate to patient outcome must be available.6Milliner D.S. McGregor T.L. Thompson A. et al.End points for clinical trials in primary hyperoxaluria.Clin J Am Soc Nephrol. 2020; 15: 1056-1065Google Scholar The Oxalosis and Hyperoxaluria Foundation (OHF; www.ohf.org/) is a donor-funded, 501(c)(3) not-for-profit dedicated to finding treatments and a cure for all forms of hyperoxaluria that supports research and spreads awareness about the disease among patients, medical professionals, government officials, the general public, and industry. This passionate and forward-looking patient advocacy group recognized imminent opportunities for novel treatments, as well as the potential barriers to confirming their efficacy and getting these therapies to hyperoxaluria patients as soon as possible. Thus a group of scientists, clinicians, industry representatives, patients, and their families were brought together 5 years ago to examine barriers to rapid implementation of novel treatments. This group worked to develop a shared understanding of patient experiences with hyperoxaluria, the current treatment options, gaps in those approaches, and patient willingness to adopt novel approaches. Definition of clinically meaningful and potential surrogate end points for clinical trials and identification of data gaps were identified as critical needs in order to approach regulatory agencies. Thus, the OHF work group approached the Kidney Health Initiative (KHI), a public-private partnership between the American Society of Nephrology (ASN), the FDA, and over 100 member companies and organizations including those that represent industry and kidney patients. KHI fosters a precompetitive collaborative environment to address regulatory issues that can ultimately expedite the development and approval of promising therapies. The KHI endorsed a project in 2017 and charged a workgroup with identifying surrogate end points for trials in enteric and primary hyperoxaluria. Well-developed patient registries based in Europe and the United States and several relevant peer-reviewed publications already existed for primary hyperoxaluria.8Tang X. Bergstralh E.J. Mehta R.A. Vrtiska T.J. Milliner D.S. Lieske J.C. Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria.Kidney Int. 2015; 87: 623-631Google Scholar, 9Zhao F. Bergstralh E.J. Mehta R.A. et al.Predictors of incident ESRD among patients with primary hyperoxaluria presenting prior to kidney failure.Clin J Am Soc Nephrol. 2016; 11: 119-126Google Scholar, 10Garrelfs S.F. Rumsby G. Peters-Sengers H. et al.Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up.Kidney Int. 2019; 96: 1389-1399Google Scholar Thus subgroups were immediately formed around potential primary hyperoxaluria clinical trial end points, including kidney stone events, and surrogate markers urine oxalate, kidney function, and plasma oxalate. After a systematic review of the literature and available data, the subgroups compiled a single document that was reviewed and further edited in collaboration with patients, clinicians, industry, and the FDA. The final product was subsequently published and serves as a roadmap for biotech companies interested in potential therapies for primary hyperoxaluria.6Milliner D.S. McGregor T.L. Thompson A. et al.End points for clinical trials in primary hyperoxaluria.Clin J Am Soc Nephrol. 2020; 15: 1056-1065Google Scholar In parallel with this work, patients and their caregivers, led by OHF, reported their experiences and perspectives on living with primary hyperoxaluria and their hopes for future treatments.2Lawrence J.E. Wattenberg D.J. Primary hyperoxaluria: the patient and caregiver perspective.Clin J Am Soc Nephrol. 2020; 15: 909-911Google Scholar Ongoing collaborations with the KHI culminated in a primary hyperoxaluria PFDD meeting on October 5, 2020. Altogether, more than 300 persons attended this virtual meeting held at the height of the COVID-19 pandemic, over half being patients and caregivers, with the remainder representing the FDA, academia, industry, and patient advocates. This forum allowed patients to openly share their life experience with primary hyperoxaluria and discuss their willingness to accept novel treatments and their risk tolerance for receiving them. Key patient messages are highlighted in Box 1, and a Voice of the Patient document summarizing this event is in preparation and will be published on the FDA’s PFDD website.3CDER Patient-Focused Drug Development.https://www.fda.gov/drugs/development-approval-process-drugs/cder-patient-focused-drug-developmentDate accessed: October 3, 2021Google ScholarBox 1Patient and Caregiver Perspectives on Living With Primary HyperoxaluriaTabled 1Common symptoms/manifestations•Kidney stones (80%)•Pain (57%)•UTI/dysuria (54%)•CKD/kidney failure (50%)•Nausea/vomiting (47%)•Anxiety/depression (44%)Most troublesome symptoms/manifestations•Kidney stones (76%)•CKD/kidney failure (53%)•Pain (24%)•Anxiety/depression (23%)•UTI/dysuria (23%)Current and recent major interventions•Ureteroscopy (37%)•Percutaneous nephrolithotomy (24%)•Shock wave lithotripsy (18%)•Dialysis (18%)Current medical treatments•Very high fluid intake (91%)•Prescription medications, including pyridoxine (80%)•Low-oxalate diet (67%)•CKD diet (low sodium, potassium, and protein) (55%)•Counseling (15%)Therapeutic priorities•Prevent kidney stones (61%)•Prevent CKD/kidney failure (47%)•Decrease treatment burden (23%)•Prevent organ transplantationaNo polling data available, but frequently mentioned in the final discussion session.•Willing to participate in clinical trials and incur study burden and potential risksaNo polling data available, but frequently mentioned in the final discussion session.Data based upon responses at FDA externally led Patient Focussed Drug Development meeting held October 5, 2020. Percentages based upon live polling at the meeting. Abbreviations: CKD, chronic kidney disease; UTI, urinary tract infection.a No polling data available, but frequently mentioned in the final discussion session. Open table in a new tab Tabled 1Common symptoms/manifestations•Kidney stones (80%)•Pain (57%)•UTI/dysuria (54%)•CKD/kidney failure (50%)•Nausea/vomiting (47%)•Anxiety/depression (44%)Most troublesome symptoms/manifestations•Kidney stones (76%)•CKD/kidney failure (53%)•Pain (24%)•Anxiety/depression (23%)•UTI/dysuria (23%)Current and recent major interventions•Ureteroscopy (37%)•Percutaneous nephrolithotomy (24%)•Shock wave lithotripsy (18%)•Dialysis (18%)Current medical treatments•Very high fluid intake (91%)•Prescription medications, including pyridoxine (80%)•Low-oxalate diet (67%)•CKD diet (low sodium, potassium, and protein) (55%)•Counseling (15%)Therapeutic priorities•Prevent kidney stones (61%)•Prevent CKD/kidney failure (47%)•Decrease treatment burden (23%)•Prevent organ transplantationaNo polling data available, but frequently mentioned in the final discussion session.•Willing to participate in clinical trials and incur study burden and potential risksaNo polling data available, but frequently mentioned in the final discussion session.Data based upon responses at FDA externally led Patient Focussed Drug Development meeting held October 5, 2020. Percentages based upon live polling at the meeting. Abbreviations: CKD, chronic kidney disease; UTI, urinary tract infection.a No polling data available, but frequently mentioned in the final discussion session. Open table in a new tab Data based upon responses at FDA externally led Patient Focussed Drug Development meeting held October 5, 2020. Percentages based upon live polling at the meeting. Abbreviations: CKD, chronic kidney disease; UTI, urinary tract infection. The KHI workgroup pursued the same general process for enteric hyperoxaluria. Unfortunately, a mature patient registry and robust publications regarding the natural history of enteric hyperoxaluria were lacking. Thus, completion of a systematic review was an essential first step.7Witting C. Langman C.B. Assimos D. et al.Pathophysiology and treatment of enteric hyperoxaluria.Clin J Am Soc Nephrol. 2021; 16: 487-495Google Scholar The next step will be evaluation of potential end points for clinical trials based upon this literature, expert opinion, and other background information, working in close concert with the FDA. Developing novel therapies for rare diseases remains a challenge owing to the small number of patients and the limitations this imposes on clinical trials. Prerequisites include detailed knowledge of the natural history of the disease as well as input from patients to help gauge their willingness to participate in clinical trials and the level of risk they would be willing to take to embark upon novel therapies. The experience of OHF shepherding these processes over the course of the last 5 years provides a paradigm for other rare diseases. Development of a community of scientists, caregivers, patients, and industry partners with a common purpose is fundamental to success. This diverse working group brought complementary expertise and viewpoints as well as efficient collation of data and literature, which was followed by the development of rigorous scientific documents that incorporated the patient perspective. The partnership with KHI was an additional important feature that drove the work efficiently, including facilitating interactions with the FDA through the process. The effort was a good example of PFDD in a rare disease, including a well-attended and impactful meeting with the FDA that amplified the concerns of this patient community.2Lawrence J.E. Wattenberg D.J. Primary hyperoxaluria: the patient and caregiver perspective.Clin J Am Soc Nephrol. 2020; 15: 909-911Google Scholar Importantly, in large part owing to the hard work and collaboration of this group, in late 2020 a small inhibitory RNA against hepatic glycolate oxidase was approved by the FDA and the European Medicines Agency as a treatment of primary hyperoxaluria type based upon a significant reduction in urinary oxalate excretion.13Scott L.J. Keam S.J. Lumasiran: first approval.Drugs. 2021; 81: 277-282Google Scholar Parallel work is ongoing in enteric hyperoxaluria to facilitate cost-effective trials for emerging and novel therapies directed at this disorder. The important documents generated by this KHI-led effort are serving as road maps for other researchers and biotech companies looking at novel therapies for primary and enteric hyperoxaluria.6Milliner D.S. McGregor T.L. Thompson A. et al.End points for clinical trials in primary hyperoxaluria.Clin J Am Soc Nephrol. 2020; 15: 1056-1065Google Scholar,7Witting C. Langman C.B. Assimos D. et al.Pathophysiology and treatment of enteric hyperoxaluria.Clin J Am Soc Nephrol. 2021; 16: 487-495Google Scholar John C. Lieske, MD, Meaghan A. Malley, BA, Melissa West, BA, Kim Hollander, BS, and Dawn S. Milliner, MD. The authors were partially supported by the Rare Kidney Stone Consortium (RKSC; U54DK83908), which is part of Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), R21TR003174, and the Mayo Foundation. The Patient Focussed Drug Development meeting was funded by the OHF. The KHI is funded by the ASN and is a public-private partnership between the ASN, the FDA, and over 100 member companies and organizations. Dr Milliner has received consulting fees from OxThera, Dicerna, Allena, Synlogic, and Alnylam, and grant funding from OxThera and Alnylam. Dr Lieske has received consulting fees from Alnylam, OxThera, Dicerna, Synlogic, Orfan-Bridgebio, and Novobiome, and grant support from Alnylam, Allena, Retrophin, OxThera, and Dicerna. Meaghan Malley and Melissa West are employed by the ASN. Kim Hollander is Executive Director of the OHF. Received April 1, 2021 in response to an invitation from the journal. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form September 9, 2021.

Primary hyperoxaluria (PH) is an autosomal recessive disorder of oxalate metabolism caused by pathogenic variants in either of three genes ( AGXT , GRHPR or HOGA1 ). The study aimed at characterizing the clinical phenotypes as well as the genotypic spectrum of PH in Egypt. We screened 25 Egyptian patients suspected of PH for the three responsible genes by Sanger sequencing. We diagnosed 20 patients from 18 unrelated families, in which the natural history, family history, clinical features and genotypes were evaluated. PH patients were 15 males and 5 females ranging in age from 4 months to 31 years (median 8 years). Fifteen families were consanguineous (83%) and familial clustering was reported in six families (33%). Pathogenic variants in all 40 alleles were in AGXT , with none detected in GRHPR or HOGA1 . We detected two novel pathogenic variants c.166-1_172dupGATCATGG (p.Asp58Glyfs*65) and c.766delC (p.Gln256fs*16) and seven previously reported variants in our cohort. This is the first study reporting the genotype of a considerable number of PH1 patients from Egypt. Our detected variants in the AGXT gene could form the basis for future genetic counseling and prenatal diagnosis in Egypt and surrounding populations.

Rationale & Objective: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare monogenic disorder caused by SLC34A3 pathogenic variants. HHRH is characterized by kidney phosphate wasting, hypophosphatemia, hypercalciuria, an elevated 1,25-dihydroxyvitamin D level, nephrocalcinosis, and urinary stone disease. Previously, we reported a 100% prevalence of kidney cysts in the related CYP24A1 deficiency. Thus, in the current study, we characterized cysts’ presence in HHRH, another monogenic cause of hypercalciuria, nephrocalcinosis, and urinary stone disease. Study Design: Case series. Setting & Participants: Medical records from the Mayo Clinic and the Rare Kidney Stone Consortium monogenic stone disease database were queried for patients with a genetically confirmed HHRH diagnosis. The number, sizes, and locations of kidney cysts in each patient were recorded. Results: Twelve patients with SLC34A3 pathogenic variants were identified (7 monoallelic, 5 biallelic). Of these, 5 (42%) were males, and the median (Q1, Q3) ages were 16 years (13, 35 years) at clinical presentation and 42 years (20, 57 years) at genetic confirmation. Kidney cysts were present in 9 of 12 (75%) patients, and the median (Q1, Q3) age at first cyst detection was 41 years (13, 50 years). The median number of cysts per patient was 2.0 (0.5, 3.5). Fifty percent of adult patients had a cyst number that exceeded the 97.5th percentile of an age- and sex-matched control population. All children had at least 2 or more total cysts. None had a family history of cystic kidney disease. Limitations: Retrospective study, possible selection bias, single-center experience. Conclusions: A strong association between HHRH and kidney cysts was observed. Similarities in the biochemical profiles of HHRH and CYP24A1 deficiency suggest elevated active vitamin D and hypercalciuria may be potential cystogenic factors. Further studies are needed to understand how genetic changes in SLC34A3 favor cyst formation.

Rationale & Objective: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism that results in early -onset kidney stone disease, nephrocalcinosis, and kidney failure. There is an unmet need for reliable markers of disease progression to test effectiveness of new treatments for patients with PH. In this study, we assessed the rate of estimated glomerular filtration rate (eGFR) decline across chronic kidney disease (CKD) glomerular filtration rate (GFR) categories (CKD G2-G5) in a cohort of patients with PH1. Study Design: Retrospective observational study. Setting & Participants: Patients with PH1 enrolled in the Rare Kidney Stone Consortium (RKSC) registry who did not have kidney failure at diagnosis and who had at least 2 eGFR values recorded from within 1 month of diagnosis until their last contact date or incident kidney failure event. Predictors: CKD GFR category, baseline patient and laboratory characteristics. Outcome: Annualized rate of eGFR decline.Analytical Approach: Generalized estimating equations and linear regression were used to evaluate the associations between CKD GFR category, baseline patient and laboratory characteristics, and annual change in eGFR during follow-up. Results: Compared with the slope in CKD G2 (-2.3 mL/min/1.73 m2 per year), the mean annual eGFR decline was nominally steeper in CKD G3a (-5.3 mL/min/1.73 m2 per year) and statistically significantly more rapid in CKD G3b and G4 (-14.7 and -16.6 mL/min/1.73 m(2) per year, respectively). In CKD G2, older age was associated with a more rapid rate of eGFR decline (P = 0.01). A common PH1-causing variant of alanine glyoxylate aminotransferase, a glycine to arginine substitution at amino acid 170 (G170R), appeared to be associated with less severe annual decline in eGFR. Limitations: Data at regular time points were not available for all patients due to reliance on voluntary reporting in a retrospective rare disease registry. Conclusions: The eGFR decline was not uniform across CKD GFR categories in this PH1 population, with a higher rate of eGFR decline in CKD G3b and G4. Thus, CKD GFR category needs to be accounted for when analyzing eGFR change in the setting of PH1.

Primary hyperoxaluria (PH) is a rare monogenic disorder of glyoxylate metabolism with three phenotypes [1]. PH1 accounts for 70–80% of all diagnosed cases; PH2 and PH3 each account for approximately 10–15%. Increased oxalate production leads to hyperoxaluria, recurrent urolithiasis, and accumulation of oxalate in the kidneys, which can result in chronic kidney disease and eventually kidney failure [2]. Information on maternal and infant outcomes from pregnancy in women with PH is limited, and data about disease progression in women with PH in relation to pregnancy are lacking. * Andrea Kattah Kattah.Andrea@mayo.edu

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 m(2), respectively, P < 0.001) while urine calcium was highest in PH3 (112 versus 51 and 98 mg/day/1.73 m(2) in PH1 and PH2, respectively, P < 0.001). Stone events per decade of life were similar across the age span and the three PH types. At 40 years of age, 97% of PH3 patients had not progressed to end-stage kidney disease compared with 36% PH1 and 66% PH2 patients. 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.

Abstract Background: Time-dependent Cox proportional hazards regression is a popular statistical method used in kidney disease research to evaluate associations between biomarkers collected serially over time with progression to kidney failure. Typically, biomarkers of interest are considered time-dependent covariates being updated at each new measurement using last observation carried forward (LOCF). Recently, joint modeling has emerged as a flexible alternative for multivariate longitudinal and time-to-event data. This study describes and demonstrates multivariate joint modeling using as an example the association of serial biomarkers (plasma oxalate [POX] and urinary oxalate [UOX]) and kidney function among patients with primary hyperoxaluria in the Rare Kidney Stone Consortium Registry. Methods: Time-to-kidney failure was regressed on serially measured biomarkers in two ways: time-dependent LOCF Cox proportional hazards regression and multivariate joint models. Results: In time-dependent LOCF Cox regression, higher POX was associated with increased risk of kidney failure (HR = 2.20 per doubling, 95% CI = [1.38-3.51], p < 0.001) whereas UOX was not (HR = 1.08 per doubling, [0.66–1.77], p = 0.77). In multivariate joint models, estimates suggest higher UOX may be associated with lower risk of kidney failure (HR = 0.42 per doubling [0.15–1.04], p = 0.066), though not statistically significant, since impaired urinary excretion of oxalate may reflect worsening kidney function. Conclusions: Multivariate joint modeling is more flexible than LOCF and may better reflect biological plausibility since biomarkers are not steady-state values between measurements. While LOCF is preferred to naïve methods not accounting for changes in biomarkers over time, results may not accurately reflect flexible relationships that can be captured with multivariate joint modeling.

Background: Primary hyperoxaluria type 1 (PH1) is a rare monogenic disorder characterized by excessive hepatic production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive kidney damage, often requiring renal replacement therapy (RRT). Though systemic oxalate deposition is well-known, the natural history of PH1 during RRT has not been systematically described. In this study, we describe the clinical, laboratory, and echocardiographic features of a cohort of PH1 patients on RRT. Methods: Patients with PH1 enrolled in the Rare Kidney Stone Consortium PH Registry who progressed to require RRT, had ≥2 plasma oxalate (pOx) measurements 3–36 months after start of RRT, and at least one pair of pOx measurements between 6 and 18 months apart were retrospectively analyzed. Clinical, echocardiographic, and laboratory results were obtained from the Registry. Results: The 17 PH1 patients in our cohort had a mean total HD hours/week of 17.4 (SD 7.9; range 7.5–36) and a range of age of RRT start of 0.2–75.9 years. The average change in plasma oxalate (pOx) over time on RRT was −0.74 [−2.9, 1.4] μmol/L/month with the mean pOx never declining below 50 μmol/L. Over time on RRT, oxalosis progressively developed in multiple organ systems. Echocardiography performed on 13 subjects showed worsening of left ventricular global longitudinal strain correlated with pOx (p < 0.05). Conclusions: Even when a cohort of PH1 patients were treated with intensified RRT, their predialysis pOx remained above target and they developed increasing evidence of oxalosis. Echocardiographic data suggest that cardiac dysfunction could be related to elevated pOx and may worsen over time.

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

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 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