American Board of Internal Medicine Nephrology Procedure Requirements for Initial Certification: Time for a Change and Pursuing Consensus in the Nephrology Community.

In 1988, the American Board of Internal Medicine (ABIM) defined essential procedural skills in nephrology, and candidates for ABIM certification were required to present evidence of possessing the skills necessary for placement of temporary dialysis vascular access, hemodialysis, peritoneal dialysis, and percutaneous renal biopsy. In 1996, continuous renal replacement therapy was added to the list of nephrology requirements. These procedure requirements have not been modified since 1996 while the practice of nephrology has changed dramatically. In March 2021, the ABIM Nephrology Board embarked on a policy journey to revise the procedure requirements for nephrology certification. With the guidance of nephrology diplomates, training program directors, professional and patient organizations, and other stakeholders, the ABIM Nephrology Board revised the procedure requirements to reflect current practice and national priorities. The approved changes include the Opportunity to Train standard for placement of temporary dialysis catheters, percutaneous kidney biopsies, and home hemodialysis which better reflects the current state of training in most training programs, and the new requirements for home dialysis therapies training will align with the national priority to address the underuse of home dialysis therapies. This perspective details the ABIM process for considering changes to the certification procedure requirements and how ABIM collaborated with the larger nephrology community in considering revisions and additions to these requirements.

Clinicopathologic Characteristics, Etiologies, and Outcome of Secondary Oxalate Nephropathy.

OBJECTIVE: To report the clinicopathologic characteristics, prognostic indicators, prognosis, and transplant outcome of secondary oxalate nephropathy (ON). PATIENTS AND METHODS: We performed a retrospective analysis of 113 consecutive patients with secondary ON diagnosed at Mayo Clinic in Rochester, Minnesota, between January 1, 2001, and March 1, 2023. RESULTS: The incidence of secondary ON among all native biopsies from Mayo Clinic patients over the study period (n=11,617) was 0.97%. ON was attributed to enteric hyperoxaluria in 60% of the 113 patients (68; most commonly Roux-en-Y gastric bypass), excessive ingestion of foods high in oxalate or oxalate precursors in 23% (26) (most commonly vitamin C), and idiopathic in 17% (19). Most patients presented with acute kidney injury (AKI) (particularly in the ingestion group) or AKI on chronic kidney disease, and 53% (60 of 113) were diabetic. Calcium oxalate crystals were accompanied by acute tubular injury, inflammation, and interstitial fibrosis and tubular atrophy. Concurrent pathologic conditions were present in 53% of the patients (60 of 113), most commonly diabetic nephropathy. After a median follow-up of 36 months, 27% of the patients (30 of 112) had kidney recovery, 19% (21 of 112) had persistent kidney dysfunction, 54% (61 of 112) had development of kidney failure, and 29% (32 of 112) died. The mean kidney survival was worse for patients with a concurrent pathologic lesion (30 months vs 96 months for those without a concurrent pathologic lesion; P<.001). Independent predictors of kidney failure were the degree of interstitial fibrosis and tubular atrophy and nadir estimated glomerular filtration rate but not the degree of crystal deposition. After a median follow-up of 58 months in 23 patients who received kidney transplant, 4 had graft loss (due to ON in 3). The 2-, 5-, and 10-year graft survivals were 90% (18 of 20), 79% (11 of 14), and 50% (6 of 12). CONCLUSION: ON is a rare cause of AKI or AKI on chronic kidney disease. Most patients have comorbid pathologic conditions, particularly diabetic nephropathy, which worsen the prognosis. Recurrence in the renal allograft and graft loss may occur if hyperoxaluria is not controlled.

Natural history of urine and plasma oxalate in children with primary hyperoxaluria type 1.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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. A higher resolution version of the Graphical abstract is available as Supplementary information.

Assessing GFR With Proenkephalin.

Introduction: In clinical practice, kidney (dys)function is monitored through creatinine-based estimations of glomerular filtration rate (eGFR: Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). Creatinine is recognized as a late and insensitive biomarker of glomerular filtration rate (GFR). The novel biomarker proenkephalin (PENK) may overcome these limitations, but no PENK-based equation for eGFR is currently available. Therefore, we developed and validated a PENK-based equation to assess GFR. Methods: In this international multicenter study in 1354 stable and critically ill patients, GFR was measured (mGFR) through iohexol or iothalamate clearance. A generalized linear model with sigmoidal nonlinear transfer function was used for equation development in the block-randomized development set. Covariates were selected in a data-driven fashion. The novel equation was assessed for bias, precision (mean ± SD), and accuracy (eGFR percentage within ±30% of mGFR, P30) in the validation set and compared with MDRD and CKD-EPI. Results: Median mGFR was 61 [44-81] ml/min per 1.73 m2. In order of importance, PENK, creatinine, and age were included, and sex or race did not improve performance. The PENK-based equation mean ± SD bias of the mGFR was 0.5 ± 15 ml/min per 1.73 m2, significantly less compared with MDRD (8 ± 17, P < 0.001) and 2009 CKD-EPI (5 ± 17, P < 0.001), not reaching statistical significance compared with 2021 CKD-EPI (1.3 ± 16, P = 0.06). The P30 accuracy of the PENK-based equation was 83%, significantly higher compared with MDRD (68%, P < 0.001) and 2009 CKD-EPI (76%, P < 0.001), similar to 2021 CKD-EPI (80%, P = 0.13). Conclusion: Overall, the PENK-based equation to assess eGFR performed better than most creatinine-based equations without using sex or race.

Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Mayo Clinic Consensus Report on Membranous Nephropathy: Proposal for a Novel Classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Estimating glomerular filtration rate with new equations: can one size ever fit all?

Glomerular filtration rate (GFR) is thought to be the best overall indicator of kidney health. On an individual patient basis, a working knowledge of GFR is important to understand the future risk for chronic kidney disease (CKD) progression, enhanced risk for cardiovascular disease and death, and for optimal medical management including the dosing of certain drugs. Although GFR can be directly measured using exogenous compounds that are eliminated by the kidney, these methods are not scalable for repeated and routine use in clinical care. Thus, in most circumstances GFR is estimated, termed estimated GFR (eGFR), using serum biomarkers that are eliminated by the kidney. Of these, serum creatinine, and to a lesser extent cystatin C, are most widely employed. However, the resulting number is simply a population average for an individual of that age and sex with a given serum creatinine and/or cystatin C, while the range of potential GFR values is actually quite large. Thus, it is important to consider characteristics of a given patient that might make this estimate better or worse in a particular case. In some circumstances, cystatin C or creatinine might be the better choice. Ultimately it is difficult, if not impossible, to have an eGFR equation that performs equally well in all populations. Thus, in certain cases it might be appropriate to directly measure GFR for high consequence medical decision-making, such as approval for kidney donation or prior to certain chemotherapeutic regimens. In all cases, the eGFR thresholds of CKD stage should not be viewed as absolute numbers. Thus, clinical care should not be determined solely by CKD stage as determined by eGFR alone, but rather by the combination of an individual patient's likely kidney function together with their current clinical situation.

The Site and Type of CLCN5 Genetic Variation Impact the Resulting Dent Disease-1 Phenotype.

Introduction: Dent disease is an X-linked recessive disorder associated with low molecular weight proteinuria (LMWP), nephrocalcinosis, kidney stones, and kidney failure in the third to fifth decade of life. It consists of Dent disease 1 (DD1) (60% of patients) because of pathogenic variants in the CLCN5 gene and Dent disease 2 (DD2) with changes in OCRL. Methods: Retrospective review of 162 patients from 121 different families with genetically confirmed DD1 (82 different pathogenic variants validated using American College of Medical Genetics [ACMG] guidelines). Clinical and genetic factors were compared using observational statistics. Results: A total of 110 patients had 51 different truncating (nonsense, frameshifting, large deletions, and canonical splicing) variants, whereas 52 patients had 31 different nontruncating (missense, in-frame, noncanonical splicing, and stop-loss) changes. Sixteen newly described pathogenic variants were found in our cohort. Among patients with truncating variants, lifetime stone events positively correlated with chronic kidney disease (CKD) evolution. Patients with truncating changes also experienced stone events earlier in life and manifested a higher albumin excretion rate than the nontruncating group. Nevertheless, neither age of nephrocalcinosis nor CKD progression varied between the truncating versus nontruncating patients. A large majority of nontruncating changes (26/31; 84%) were clustered in the middle exons that encode the voltage ClC domain whereas truncating changes were spread across the protein. Variants associated with kidney failure were restricted to truncating (11/13 cases), plus a single missense variant previously shown to markedly reduce ClC-5 functional activity that was found in the other 2 individuals. Conclusion: DD1 manifestations, including the risk of kidney stones and progression to kidney failure, may relate to the degree of residual ClC-5 function.

Performance of Nuclear Magnetic Resonance-Based Estimated Glomerular Filtration Rate in a Real-World Setting.

An accurate estimate of glomerular filtration rate (eGFR) is essential for proper clinical management, especially in patients with kidney dysfunction. This prospective observational study evaluated the real-world performance of the nuclear magnetic resonance (NMR)-based GFRNMR equation, which combines creatinine, cystatin C, valine, and myo-inositol with age and sex. We compared GFRNMR performance to that of the 2021 CKD-EPI creatinine and creatinine-cystatin C equations (CKD-EPI2021Cr and CKD-EPI2021CrCys), using 115 fresh routine samples of patients scheduled for urinary iothalamate clearance measurement (mGFR). Median bias to mGFR of the three eGFR equations was comparably low, ranging from 0.4 to 2.0 mL/min/1.73 m2. GFRNMR outperformed the 2021 CKD-EPI equations in terms of precision (interquartile range to mGFR of 10.5 vs. 17.9 mL/min/1.73 m2 for GFRNMR vs. CKD-EPI2021CrCys; p = 0.01) and accuracy (P15, P20, and P30 of 66.1% vs. 48.7% [p = 0.007], 80.0% vs. 60.0% [p < 0.001] and 95.7% vs. 86.1% [p = 0.006], respectively, for GFRNMR vs. CKD-EPI2021CrCys). Clinical parameters such as etiology, comorbidities, or medications did not significantly alter the performance of the three eGFR equations. Altogether, this study confirmed the utility of GFRNMR for accurate GFR estimation, and its potential value in routine clinical practice for improved medical care.

End Point Considerations for Clinical Trials in Enteric Hyperoxaluria.

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.

Outpatient Antibiotic Use is Not Associated with an Increased Risk of First-Time Symptomatic Kidney Stones.

SIGNIFICANCE STATEMENT: Antibiotics modify human microbiomes and may contribute to kidney stone risk. In a population-based case-control study using 1247 chart-validated first-time symptomatic kidney stone formers and 4024 age- and sex-matched controls, the risk of kidney stones was transiently higher during the first year after antibiotic use. However, this risk was no longer evident after adjustment for comorbidities and excluding participants with prior urinary symptoms. Findings were consistent across antibiotic classes and the number of antibiotic courses received. This suggests that antibiotics are not important risk factors of kidney stones. Rather, kidney stones when they initially cause urinary symptoms are under-recognized, resulting in antibiotic use before a formal diagnosis of kidney stones ( i.e. , reverse causality). BACKGROUND: Antibiotics modify gastrointestinal and urinary microbiomes, which may contribute to kidney stone formation. This study examined whether an increased risk of a first-time symptomatic kidney stone episode follows antibiotic use. METHODS: A population-based case-control study surveyed 1247 chart-validated first-time symptomatic kidney stone formers with a documented obstructing or passed stone (cases) in Olmsted County, Minnesota, from 2008 to 2013 and 4024 age- and sex-matched controls. All prescriptions for outpatient oral antibiotic use within 5 years before the onset of symptomatic stone for the cases and their matched controls were identified. Conditional logistic regression estimated the odds ratio (OR) of a first-time symptomatic kidney stone across time after antibiotic use. Analyses were also performed after excluding cases and controls with prior urinary tract infection or hematuria because urinary symptoms resulting in antibiotic prescription could have been warranted because of undiagnosed kidney stones. RESULTS: The risk of a symptomatic kidney stone was only increased during the 1-year period after antibiotic use (unadjusted OR, 1.31; P = 0.001), and this risk was attenuated after adjustment for comorbidities (OR, 1.16; P = 0.08). After excluding cases and controls with prior urinary symptoms, there was no increased risk of a symptomatic kidney stone during the 1-year period after antibiotic use (unadjusted OR, 1.04; P = 0.70). Findings were consistent across antibiotic classes and the number of antibiotic courses received. CONCLUSIONS: The increased risk of a first-time symptomatic kidney stone with antibiotic use seems largely due to both comorbidities and prescription of antibiotics for urinary symptoms. Under-recognition of kidney stones that initially cause urinary symptoms resulting in antibiotic use may explain much of the perceived stone risk with antibiotics ( i.e. , reverse causality).

Nedosiran in primary hyperoxaluria subtype 3: results from a phase I, single-dose study (PHYOX4).

Nedosiran is an N-acetyl-D-galactosamine (GalNAc)-conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate  ≥ 30 mL/min/1.73 m2. Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concerns. Although the PD response was not met, 24-h Uox excretion declined 24.5% in the nedosiran group and increased 10.5% in the placebo group at Day 85. Three of four nedosiran recipients had a > 30% reduction in 24-h Uox excretion during at least one visit, and one attained near-normal (i.e., ≥ 0.46 to < 0.60 mmol/24 h; ≥ 1.0 to < 1.3 × upper limit of the normal reference range) 24-h Uox excretion from Day 29 to Day 85. Nedosiran displayed predictable plasma PK. The acceptable safety and trend toward Uox-lowering after single-dose nedosiran treatment enables further clinical development of nedosiran in patients with PH3 who currently have no viable therapeutic options. A plain language summary is available in the supplementary information.

Impact of race-independent equations on estimating glomerular filtration rate for the assessment of kidney dysfunction in liver disease.

BACKGROUND: Altered hemodynamics in liver disease often results in overestimation of glomerular filtration rate (GFR) by creatinine-based GFR estimating (eGFR) equations. Recently, we have validated a novel eGFR equation based on serum myo-inositol, valine, and creatinine quantified by nuclear magnetic resonance spectroscopy in combination with cystatin C, age and sex (GFRNMR). We hypothesized that GFRNMR could improve chronic kidney disease (CKD) classification in the setting of liver disease. RESULTS: We conducted a retrospective multicenter study in 205 patients with chronic liver disease (CLD), comparing the performance of GFRNMR to that of validated CKD-EPI eGFR equations, including eGFRcr (based on creatinine) and eGFRcr-cys (based on both creatinine and cystatin C), using measured GFR as reference standard. GFRNMR outperformed all other equations with a low overall median bias (-1 vs. -6 to 4 ml/min/1.73 m2 for the other equations; p < 0.05) and the lowest difference in bias between reduced and preserved liver function (-3 vs. -16 to -8 ml/min/1.73 m2 for other equations). Concordant classification by CKD stage was highest for GFRNMR (59% vs. 48% to 53%) and less biased in estimating CKD severity compared to the other equations. GFRNMR P30 accuracy (83%) was higher than that of eGFRcr (75%; p = 0.019) and comparable to that of eGFRcr-cys (86%; p = 0.578). CONCLUSIONS: Addition of myo-inositol and valine to creatinine and cystatin C in GFRNMR further improved GFR estimation in CLD patients and accurately stratified liver disease patients into CKD stages.