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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.

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Abstract 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

OBJECTIVES/GOALS: Using a natural canine model of kidney stone disease, we previously identified a pathogenic variant in the uromodulin gene (UMOD) that imparts a dramatic risk for calcium oxalate (CaOx) stones. This study was designed to characterize the effects of the pathogenic variant on uromodulin processing, specifically polymerization and peptide excretion. METHODS/STUDY POPULATION: Uromodulin polymerization status and peptides were measured in random urine samples from CaOx stone-forming dogs with the pathogenic UMOD variant and breed-, sex-, and age-matched healthy control dogs. Polymerization status was determined using an ultracentrifugation protocol and Western blotting in 6 CaOx cases and 3 controls; relative abundance of the polymerizing and nonpolymerizing forms was evaluated. Uromodulin peptide abundances were measured by LC-MS/MS with 4 dogs per group; results were summed to determine total uromodulin peptide excretion for each dog, and individual peptide abundances were calculated as a percentage of the total. Polymerization status and peptides were compared between groups. RESULTS/ANTICIPATED RESULTS: Dogs with the pathogenic UMOD variant had abnormalities in both uromodulin polymerization and peptide processing. The polymerization data showed that the polymerizing form of uromodulin was abundant in all healthy controls but absent or severely reduced in most dogs with the variant. In contrast, nonpolymerizing uromodulin was detected in all dogs with no observed difference between those with and without the variant. The peptidomics data showed that stone-forming dogs with the pathogenic UMOD variant lacked a peptide cleavage site, resulting in the loss of two common peptides that terminate at that site and the presence of longer peptides that span the site. DISCUSSION/SIGNIFICANCE: These findings implicate uromodulin polymerization and peptide processing defects in kidney stone risk. Future studies will define the mechanisms through which these defects affect stone formation, ultimately informing development of novel preventative therapies.

Abstract Shock wave lithotripsy (SWL) is an effective and commonly applied clinical treatment for human kidney stones. Yet the success of SWL is counterbalanced by the risk of retained fragments causing recurrent stone formation, which may require retreatment. This study has applied GeoBioMed experimental and analytical approaches to determine the size frequency distribution, fracture patterns, and reactive surface area of SWL-derived particles within the context of their original crystal growth structure (crystalline architecture) as revealed by confocal autofluorescence (CAF) and super-resolution autofluorescence (SRAF) microscopy. Multiple calcium oxalate (CaOx) stones were removed from a Mayo Clinic patient using standard percutaneous nephrolithotomy (PCNL) and shock pulse lithotripsy (SPL). This produced approximately 4–12 mm-diameter PCNL-derived fragments that were experimentally treated ex vivo with SWL to form hundreds of smaller particles. Fractures propagated through the crystalline architecture of PCNL-derived fragments in a variety of geometric orientations to form rectangular, pointed, concentrically spalled, and irregular SWL-derived particles. Size frequency distributions ranged from fine silt (4–8 μm) to very fine pebbles (2–4 mm), according to the Wentworth grain size scale, with a mean size of fine sand (125–250 μm). Importantly, these SWL-derived particles are smaller than the 3–4 mm-diameter detection limit of clinical computed tomography (CT) techniques and can be retained on internal kidney membrane surfaces. This creates clinically undetectable crystallization seed points with extremely high reactive surface areas, which dramatically enhance the multiple events of crystallization and dissolution (diagenetic phase transitions) that may lead to the high rates of CaOx kidney stone recurrence after SWL treatment.

Introduction: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. In the 6-month double-blind period (DBP) of ILLUMINATE-A, a phase 3, randomized, placebo-controlled trial in patients with PH1 ≥6 years old, treatment with lumasiran, an RNA interference therapeutic, led to substantial reductions in urinary oxalate (UOx) levels. Methods: We report data to month 12 in the extension period (EP) of ILLUMINATE-A, including patients who continued lumasiran (lumasiran/lumasiran) or crossed over from placebo to lumasiran (placebo/lumasiran). Results: In the lumasiran/lumasiran group (n = 24), the reduction in 24-hour UOx level was sustained to month 12 (mean reduction from baseline, 66.9% at month 6; 64.1% at month 12). The placebo/lumasiran group (n = 13) had a similar time course and magnitude of 24-hour UOx reduction (mean reduction, 57.3%) after 6 months of lumasiran. Kidney stone event rates seemed to be lower after 6 months of lumasiran in both groups compared with the 12 months before consent, and this reduction was maintained at month 12 in the lumasiran/lumasiran group. At study start, 71% of patients in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group had nephrocalcinosis. Nephrocalcinosis grade improved after 6 months of lumasiran in the lumasiran/lumasiran and placebo/lumasiran groups (13% and 8% of patients, respectively). After an additional 6 months of lumasiran, 46% of patients had improvement in nephrocalcinosis grade within the lumasiran/lumasiran group. Estimated glomerular filtration rate (eGFR) remained stable during the course of lumasiran treatment. The most common adverse events (AEs) related to lumasiran were mild, transient injection-site reactions (ISRs). Conclusion: Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes.

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.

Rationale & Objective: The etiology of kidney disease remains unknown in many individuals with chronic kidney disease (CKD). We created the Mayo Clinic Nephrology Genomics Clinic to improve our ability to integrate genomic and clinical data to identify the etiology of unexplained CKD. Study Design: Retrospective study. Setting & Participants: An essential component of our program is the Nephrology Genomics Board which consists of nephrologists, geneticists, pathologists, translational omics scientists, and trainees who interpret the patient’s clinical and genetic data. Since September 2016, the Board has reviewed 163 cases (15 cystic, 100 glomerular, 6 congenital anomalies of kidney and urinary tract (CAKUT), 20 stones, 15 tubulointerstitial, and 13 other). Analytical Approach: Testing was performed with targeted panels, single gene analysis, or analysis of kidney-related genes from exome sequencing. Variant classification was obtained based on the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. Results: A definitive genetic diagnosis was achieved for 50 families (30.7%). The highest diagnostic yield was obtained in individuals with tubulointerstitial diseases (53.3%), followed by congenital anomalies of the kidney and urological tract (33.3%), glomerular (31%), cysts (26.7%), stones (25%), and others (15.4%). A further 20 (12.3%) patients had variants of interest, and variant segregation, and research activities (exome, genome, or transcriptome sequencing) are ongoing for 44 (40%) unresolved families. Limitations: Possible overestimation of diagnostic rate due to inclusion of individuals with variants with evidence of pathogenicity but classified as of uncertain significance by the clinical laboratory. Conclusions: Integration of genomic and research testing and multidisciplinary evaluation in a nephrology cohort with CKD of unknown etiology or suspected monogenic disease provided a diagnosis in a third of families. These diagnoses had prognostic implications, and often changes in management were implemented.

BackgroundClose monitoring of glomerular filtration rate (GFR) is essential for the management of patients post kidney transplantation. Measured GFR (mGFR), the gold standard, is not readily accessible in most centers. Furthermore, the performance of new estimated GFR (eGFR) equations based upon creatinine and/or cystatin C have not been validated in kidney transplant patients. Here we evaluate a recently published eGFR equation using cystatin C, creatinine, myo-inositol and valine as measured by nuclear magnetic resonance (eGFRNMR).MethodsResidual sera was obtained from a cohort of patients with clinically ordered iothalamate renal clearance mGFR (n = 602). Kidney transplant recipients accounted for 220 (37%) of participants.ResultsCompared to mGFR, there was no significant bias for eGFRcr or eGFRNMR, while eGFRcr-cys significantly underestimated mGFR. P30 values were similar for all eGFR. P15 was significantly higher for eGFRNMR compared to eGFRcr, while the P15 for eGFRcr-cys only improved among patients without a kidney transplant. Agreement with mGFR CKD stages of

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.

Abstract Backgrounds: Previous studies have demonstrated that excretion of urinary extracellular vesicles (EVs) from different nephron segments differs between kidney stone formers and non-stone formers (NSFs), and could reflect pathogenic mechanisms of urinary stone disease. In this study we quantified selected populations of specific urinary EVs carrying protein markers of immune cells and calcium/phosphorus physiology in calcium oxalate stone formers (CSFs) compared to non-stone formers (NSFs). Methods Biobanked urine samples from CSFs (n = 24) undergoing stone removal surgery and age- and sex- matched NSFs (n = 21) were studied. Urinary EVs carrying proteins related to renal calcium/phosphorus physiology (phosphorus transporters (PiT1 and PiT2), Klotho, and fibroblast growth factor 23 (FGF23); markers associated with EV generation (anoctamin-4 (ANO4) and Huntington interacting protein 1 (HIP1)), and markers shed from activated immune cells were quantified by standardized and published method of digital flow cytometry. Results Urine excretion of calcium, oxalate, phosphorus, and calcium oxalate supersaturation (SS) were significantly higher in CSFs compared to NSFs (P

Abstract A 24-h urine protein collection (24hUP), the gold standard for measuring albuminuria in systemic AL amyloidosis, is cumbersome and inaccurate. We retrospectively reviewed 575 patients with systemic AL amyloidosis to assess the correlation between a urine albumin to creatinine ratio (uACR) and the 24hUP. The uACR correlated strongly with 24hUP at diagnosis (Pearson’s r = 0.87, 95% CI 0.83–0.90) and during the disease course (Pearson’s r = 0.88, 95% CI 0.86–0.90). A uACR ≥300 mg/g estimated a 24hUP ≥ 500 mg with a sensitivity of 92% and specificity of 97% (area under the receiver operating curve = 0.938, 95% CI 0.919–0.957). A uACR cutoff of 3600 mg/g best predicted a 24hUP > 5000 g (sensitivity 93%, specificity 94%), and renal stage at diagnosis was strongly concordant using either 24hUP or uACR as the proteinuria measure (k = 0.823, 95% CI 0.728–0.919). In patients with serial urine collections, a > 30% decrease in uACR predicted a > 30% decrease in 24hUP with a sensitivity of 94%. In conclusion, the uACR is a reliable and convenient method for ruling out proteinuria >500 mg per day, prognosticating renal outcomes, and assessing renal response to therapy. Further studies are needed to validate the uACR cutoffs proposed in this study.

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.

Abstract 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

Abstract Background Patients with primary hyperoxaluria (PH) often develop kidney stones and chronic kidney disease. Noninvasive urine markers reflective of active kidney injury could be useful to gauge the effectiveness of ongoing treatments. Methods A panel of biomarkers that reflect different nephron sites and potential mechanisms of injury (clusterin, neutrophil gelatinase-associated lipocalin (NGAL), 8-isoprostane (8IP), monocyte-chemoattractant protein 1(MCP-1), liver-type fatty acid binding protein (L-FABP), heart-type fatty acid binding protein (H-FABP), and osteopontin (OPN)) were measured in 114 urine specimens from 30 PH patients over multiple visits. Generalized estimating equations were used to assess associations between biomarkers and 24 h urine excretions, calculated proximal tubular oxalate concentration (PTOx), and eGFR. Results Mean (±SD) age at first visit was 19.5 ± 16.6 years with an estimated glomerular filtration rate (eGFR) of 68.4 ± 21.0 ml/min/1.73m2. After adjustment for age, sex, and eGFR, a higher urine MCP-1 concentration and MCP-1/creatinine ratio was positively associated with CaOx supersaturation (SS). Higher urine NGAL and NGAL/creatinine as well as OPN and OPN/creatinine were associated with higher eGFR. 8IP was negatively associated with PTOx and urinary Ox, but positively associated with CaOx SS. Conclusion In PH patients greater urine MCP-1 and 8IP excretion might reflect ongoing collecting tubule crystallization, while greater NGAL and OPN excretion may reflect preservation of kidney mass and function. CaOx crystals, rather than oxalate ion may mediate oxidative stress in hyperoxaluric conditions. Further studies are warranted to determine whether urine MCP-1 excretion predicts long term outcome or is altered in response to treatment.

Abstract Background Prior papers have been inconsistent regarding how much creatinine clearance (CrCl) overestimates glomerular filtration rate (GFR). A recent cross-sectional study suggested that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio is larger when GFR is lower among patients with chronic kidney disease (CKD); but there have been no validation of this in other cohorts. Methods To fill these gaps in knowledge regarding the relation between CrCl and GFR, we conducted cross-sectional and longitudinal analysis of the Modification of Diet in Renal Disease study (MDRD) and African American Study of Kidney Disease and Hypertension (AASK); and cross-sectional analysis of a clinical dataset from the Mayo Clinic of four different patient populations (CKD patients, kidney transplant recipients, post kidney donation subgroup and potential kidney donors). In the cross-sectional analyses (MDRD, AASK and Mayo Clinic cohort), we examined the relation between the CrCl/iothalamate GFR (iGFR) ratio at different categories of iGFR or different levels of CrCl. In the MDRD and AASK longitudinal analyses, we studied how the CrCl/iGFR ratio changed with those who had improvement in iGFR (CrCl) over time versus those who had worsening of iGFR (CrCl) over time. Results Observed CrCl/iGFR ratios were generally on the lower end of the range reported in the literature for CKD (median 1.24 in MDRD, 1.13 in AASK and 1.25 in Mayo Clinic cohort). Among CKD patients in whom CrCl and iGFR were measured using different timed urine collections, CrCl/iGFR ratio were higher with lower iGFR categories but lower with lower CrCl categories. However, among CKD patients in whom CrCl and iGFR were measured using the same timed urine collections (which reduces dis-concordant measurement error), CrCl/iGFR ratio were higher with both lower iGFR categories and lower CrCl categories. Conclusions These data refute the recent suggestion that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio increases as GFR decreases in CKD patients. They also highlight the lack of certainty in our knowledge with regard to how much CrCl actually overestimates GFR.

Patients infected with HIV (human immunodeficiency virus) are at an increased risk of developing acute kidney injury (AKI) compared with patients without HIV infection. We report a rare case of disseminated Microsporidium infection–associated AKI affecting the native kidneys in a 30-year-old Asian woman with HIV infection. She initially presented to an outside institution with AKI after completing treatment with trimethoprim-sulfamethoxazole (Bactrim [Hoffmann-La Roche]) and prednisone for Pneumocystis pneumonia. She was empirically treated with prednisone for presumed acute interstitial nephritis due to Bactrim, and her serum creatinine concentration improved from 3.0 mg/dL to 1.8 mg/dL. She was subsequently initiated on antiretroviral therapy and was also treated with ganciclovir for cytomegalovirus viremia. Because of persistent fever, she was transferred to our institution and was diagnosed with a disseminated Mycobacterium avium complex infection and a disseminated Microsporidium infection. Her serum creatinine concentration increased to 4.2 mg/dL. A kidney biopsy was performed because of her worsening kidney function, which revealed plasma cell–rich acute interstitial nephritis associated with disseminated Microsporidium infection. She was maintained on antiretroviral therapy and was treated with albendazole. This case highlights the fact that there are various etiologies and kidney manifestations of AKI in patients infected with HIV with equally various implications for management; thus, performing a kidney biopsy is often crucial to help elucidate the underlying pathology and guide management.

Objectives: The urinary excretion of organic and inorganic substances and their concentrations have attracted extensive attention for their role in the pathogenesis of urinary stone disease. The urinary excretion of specific factors associates with sex and age and seems to have a hereditary component, but the precise genomic determinants remain ill-defined. Methods: Genome-wide association studies previously conducted in 3 cohorts (Genetic Epidemiology Network of Arteriopathy study, January 1, 2006, through December 31, 2012; the combined Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study, January 1, 1994, through December 31, 2003; and the Prevention of Renal and Vascular End-stage Disease study, January 1, 1997, through December 31, 1998) were combined into meta-analyses to evaluate genetic associations with available urinary phenotypes relevant to stone pathogenesis (calcium, magnesium, and uric acid excretion; total urine volume). Results: One region on chromosome 9q21.13 showed strong evidence of an association with urinary magnesium excretion. The strongest signal in this region was near TRPM6, whose protein product mediates magnesium transport in the colon and kidney, and C9orf40, C9orf41, NMRK1, and OSTF1 (rs1176815; P=1.70×10–14, with each copy of the A allele corresponding to a daily 5.29-mg decrease in magnesium excretion). The single nucleotide polymorphism (SNP) that achieved genome-wide significance for calcium excretion (rs17216707 on chromosome 20; P=1.12×10–8) was previously associated with fibroblast growth factor 23 levels, which regulate phosphorus and vitamin D metabolism. Urine volume and uric acid excretion did not have any genome-wide significant SNPs. Conclusion: Common variants near genes important for magnesium metabolism and bone health associate with urinary magnesium and calcium excretion.

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

Background: Low urine pH and volume are established risk factors for uric acid (UA) stone disease (UASD). Renal tubular epithelial cells exposed to an acidic pH and/or UA crystals can shed extracellular vesicles (EVs) into the tubular fluid, and these EVs may be a pathogenic biomarker of UASD. Methods: Urinary EVs bearing UA transporters (SLC2A9, SLC17A3, SLC22A12, SLC5A8, ABCG2, and ZNF365) were quantified in urine from UA stone formers (UASFs), calcium stone formers (CSFs), and age-/sex-matched non-stone formers (NSFs) using a standardized and published method of digital flow cytometry. Results: Urinary pH was lower (p < 0.05) and serum and urinary UA were greater (p < 0.05) in UASFs compared with NSFs. Urinary EVs carrying SLC17A3 and SLC5A8 were lower (p < 0.05) in UASFs compared with NSFs. Urinary EVs bearing SLC2A9, SLC22A12, SLC5A8, ABCG2, and ZNF365 were lower (p < 0.05) in CSFs than UASFs, while excretion of SLC17A3-bearing EVs did not differ between groups. Conclusion: EVs bearing specific UA transporters might contribute to the pathogenesis of UASD and represent non-invasive pathogenic biomarkers for calcium and UA stone risk.

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.

Serum cystatin C increases earlier than creatinine during acute kidney injury. However, whether cystatin C decreases earlier during recovery is unknown. This retrospective study aimed to determine the temporal trend between creatinine and cystatin C in acute kidney injury. Methods: We identified hospitalized patients with nonoliguric acute kidney injury who had serial creatinine and cystatin C values measured between May 2015 and May 2016. Demographic and laboratory data, causes of acute kidney injury, and relevant comorbidity data were collected through chart review. Results: For the 63 identified patients, mean (SD) age was 58.7 (13.9) years; male sex, 62%; white race/ethnicity, 95%. Baseline median (range) creatinine was 1.1 (0.5–3.0) mg/dl; 13% were kidney transplant recipients and 37% received corticosteroids. Comorbidities included malignancy (38%), diabetes mellitus (33%), heart failure (19%), and thyroid disorder (16%). The cause of kidney injury was acute tubular necrosis in 71%, 61% had acute kidney injury stage III, and 33% required dialysis. Cystatin C began to decrease before creatinine in 68% of patients: 1 day earlier, 46%; 2 days earlier, 16%; and 3 days earlier, 6%. In 24% of cases, both began decreasing on the same day; in only 8%, cystatin C decreased after creatinine. Overall, cystatin C mean (95% confidence interval) decrease was 0.92 (0.65–1.18) days before creatinine (P < 0.001). Conclusion: In summary, cystatin C decreases before creatinine in most hospitalized patients with acute kidney injury. If confirmed in large prospective studies, these findings may have important management implications, possibly shortening hospital stay and reducing costs.

Fibrillary glomerulonephritis (FGN) is a rare disease with unknown pathogenesis and a poor prognosis. Until now, the diagnosis of this disease has required demonstration of glomerular deposition of randomly oriented fibrils by electron microscopy that are Congo red negative and stain with antisera to Igs. We recently discovered a novel proteomic tissue biomarker for FGN, namely, DNAJB9. Methods: In this work, we developed DNAJB9 immunohistochemistry and tested its sensitivity and specificity for the diagnosis of FGN. This testing was performed on renal biopsy samples from patients with FGN (n = 84), amyloidosis (n = 21), a wide variety of non-FGN glomerular diseases (n = 98), and healthy subjects (n = 11). We also performed immunoelectron microscopy to determine whether DNAJB9 is localized to FGN fibrils. Results: Strong, homogeneous, smudgy DNAJB9 staining of glomerular deposits was seen in all but 2 cases of FGN. The 2 cases that did not stain for DNAJB9 were unique, as they had glomerular staining for IgG only (without κ or λ) on immunofluorescence. DNAJB9 staining was not observed in cases of amyloidosis, in healthy subjects, or in non-FGN glomerular diseases (with the exception of very focal staining in 1 case of smoking-related glomerulopathy), indicating 98% sensitivity and > 99% specificity. Immunoelectron microscopy showed localization of DNAJB9 to FGN fibrils but not to amyloid fibrils or immunotactoid glomerulopathy microtubules. Conclusion: DNAJB9 immunohistochemistry is sensitive and specific for FGN. Incorporation of this novel immunohistochemical biomarker into clinical practice will now allow more rapid and accurate diagnosis of this disease.

Assessment of renal function relies on the estimation of the glomerular filtration rate (eGFR). Existing eGFR equations, usually based on serum levels of creatinine and/or cystatin C, are not uniformly accurate across patient populations. In the present study, we expanded a recent proof-of-concept approach to optimize an eGFR equation targeting the adult population with and without chronic kidney disease (CKD), based on a nuclear magnetic resonance spectroscopy (NMR) derived ‘metabolite constellation’ (GFRNMR). A total of 1855 serum samples were partitioned into development, internal validation and external validation datasets. The new GFRNMR equation used serum myo-inositol, valine, creatinine and cystatin C plus age and sex. GFRNMR had a lower bias to tracer measured GFR (mGFR) than existing eGFR equations, with a median bias (95% confidence interval [CI]) of 0.0 (−1.0; 1.0) mL/min/1.73 m2 for GFRNMR vs. −6.0 (−7.0; −5.0) mL/min/1.73 m2 for the Chronic Kidney Disease Epidemiology Collaboration equation that combines creatinine and cystatin C (CKD-EPI2012) (p < 0.0001). Accuracy (95% CI) within 15% of mGFR (1-P15) was 38.8% (34.3; 42.5) for GFRNMR vs. 47.3% (43.2; 51.5) for CKD-EPI2012 (p < 0.010). Thus, GFRNMR holds promise as an alternative way to assess eGFR with superior accuracy in adult patients with and without CKD.

Urine pH is critical for net acid and solute excretion, but the genetic factors that contribute to its regulation are incompletely understood. Methods: We tested the association of single nucleotide polymorphisms (SNPs) from 16 genes related to ammonia (NH3) metabolism (15 biological candidates selected a priori, 1 selected from a previous genome-wide association study analysis) to that of 24-hour urine pH in 2493 individuals of European descent across 2 different cohorts using linear regression, adjusting for age, sex, and body mass index. Results: Of 2871 total SNPs in these genes, 13 SNPs in ATP6V0A4 (a4 subunit of hydrogen− adenosine triphosphatase), SLC9A3 (sodium/hydrogen exchanger, isoform 3), and RHCG (Rhesus C glycoprotein), and 12 SNPs from insulin-like growth factor binding protein 7 (IGFBP7) had a meta-analysis P value

Abstract Background Dent disease-1 is a rare X-linked recessive renal tubular disorder caused by pathogenic variants in the chloride voltage-gated channel 5 (CLCN5) gene. It is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal failure. This is the first report of a CLCN5 pathogenic variant in a Dent disease-1 family of Sri Lankan origin, and it highlights the value of genetic evaluation in children with refractory proteinuria. Case presentation A 2-year-old boy with non-nephrotic range proteinuria was referred for evaluation. His maternally related 24-year-old uncle had been investigated for similar features at the age of 14 years and his renal histology had shown few sclerosed glomeruli. He remained asymptomatic apart from proteinuria. Biochemical investigation of the child showed β-2 microglobulinuria and hypercalciuria. After providing pre-test counseling and obtaining written informed consent, the child, his mother and maternal uncle underwent genetic testing for confirmation of the clinically suspected diagnosis of Dent disease-1. Both the child and his maternal uncle were found to be hemizygous for a nonsense pathogenic variant in exon 9 of the CLCN5 gene [NM_000084.4; c.1399C>T; rs797044811] which results in a stop codon at residue 467, leading to a truncated non-functional protein [NP_000075.1; p.R467X]. His mother was confirmed to be an unaffected heterozygous carrier for the same variant. Following confirmation of the diagnosis our patient was started on thiazide diuretics and potassium citrate. Conclusions Even though the typical phenotype of Dent disease-1 often enables a clinical diagnosis to be made, less severe sub-clinical cases may go undiagnosed. The underlying diagnosis may be missed especially in children who are treated for non-minimal change nephrotic syndrome with steroids. This case highlights the need for tubular proteinuria to be considered in the differential diagnosis of children with refractory proteinuria and for appropriate genetic evaluation to be done to confirm the precise underlying diagnosis in such cases.

Abstract Background Kidney congestion is a common pathophysiologic pathway of acute kidney injury (AKI) in sepsis and heart failure. There is no noninvasive tool to measure kidney intracapsular pressure (KIP) directly. Methods We evaluated the correlation of KIP with kidney elasticity measured by ultrasound surface wave elastography (USWE). We directly measured transcatheter KIP in three pigs at baseline and after bolus infusion of normal saline, norepinephrine, vasopressin, dopamine, and fenoldopam; infiltration of 2-L peritoneal dialysis solution in the intra-abdominal space; and venous, arterial, and ureteral clamping. KIP was compared with USWE wave speed. Results Only intra-abdominal installation of peritoneal dialysis fluid was associated with significant change in KIP (mean (95% CI) increase, 3.7 (3.2–4.2)] mmHg; P

Non-invasive tests to identify age and early disease-associated pathology within the kidney are needed. Specific populations of urinary extracellular vesicles (EVs) could potentially be used for such a diagnostic test. Random urine samples were obtained from age- and sex-stratified living kidney donors before kidney donation. A biopsy of the donor kidney was obtained at the time of transplantation to identify nephron hypertrophy (larger glomerular volume, cortex per glomerulus and mean profile tubular area) and nephrosclerosis (% fibrosis, % glomerulosclerosis and arteriosclerosis). Renal parenchymal-derived EVs in cell-free urine were quantified by digital flow cytometry. The relationship between these EV populations and structural pathology on the kidney biopsy was assessed. Clinical characteristics of the kidney donors (n=138, age range: 20–70 years, 50% women) were within the normative range. Overall, urine from women contained more EVs than that from men. The number of exosomes, juxtaglomerular cells and podocyte marker–positive EVs decreased (p

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 1.8–115), 3a (HR 13.7, 95% CI 3.0–62), and 3b stages (HR 5.2, 95% CI 1.1–25), p < 0.05 for all. Within each POx quartile, the ESKD rate was higher in Q4 compared to Q1–Q3. In conclusion, among patients with PH, higher POx concentration was a risk factor for ESKD, particularly in advanced CKD stages.

ANTECEDENTES: A excreção urinária de albumina indica lesão nos rins e é reconhecida como fator de risco para a progressão das doenças renal e cardiovascular. A dosagem da albumina urinária chama a atenção sobre a necessidade clínica de relatos de resultados precisos e claramente descritos. O National Kidney Disease Education Program e a Federação Internacional de Química Clínica e Medicina Laboratorial (IFCC) reuniram-se para avaliar o estado atual das questões pré-analíticas, analíticas e pós-analíticas que afetam as dosagens da albumina na urina e para identificar as áreas que necessitam de melhorias. CONTEÚDO: A química da albumina na urina não é completamente compreendida. Diretrizes atuais recomendam a utilização da relação albumina/creatinina (RAC) como substituta para a coleta de amostras cronometradas de urina, frequentemente inadequadas. Os resultados da RAC são afetados pela preparação do paciente, pela hora do dia da coleta das amostras e não é padronizada. Foram relatadas consideráveis diferenças intermétodos para a dosagem tanto de albumina quanto de creatinina, mas a verdade é desconhecida, porque não existem procedimentos de referência para a dosagem de albumina e não há materiais de referência para qualquer um desses analitos na urina. Os intervalos de referência recomendados para a RAC não consideram as grandes diferenças intergrupos na excreção da creatinina (por exemplo, relacionadas com diferenças em idade, sexo e etnia), nem o aumento contínuo no risco relacionado com a excreção de albumina. DISCUSSÃO: Necessidades clínicas foram identificadas para a padronização de (a) métodos de coleta da urina, (b) dosagens de albumina e de creatinina na urina com base em um sistema de referência completo, (c) relatórios dos resultados dos testes e (d) intervalos de referência para a RAC.BACKGROUND: Urinary excretion of albumin indicates kidney damage and is recognized as a risk factor for progression of kidney disease and cardiovascular disease. The role of urinary albumin measurements has focused attention on the clinical need for accurate and clearly reported results. The National Kidney Disease Education Program and the IFCC convened a conference to assess the current state of preanalytical, analytical, and postanalytical issues affecting urine albumin measurements and to identify areas needing improvement. CONTENT: The chemistry of albumin in urine is incompletely understood. Current guidelines recommend the use of the albumin/creatinine ratio (ACR) as a surrogate for the error-prone collection of timed urine samples. Although ACR results are affected by patient preparation and time of day of sample collection, neither is standardized. Considerable intermethod differences have been reported for both albumin and creatinine measurement, but trueness is unknown because there are no reference measurement procedures for albumin and no reference materials for either analyte in urine. The recommended reference intervals for the ACR do not take into account the large intergroup differences in creatinine excretion (e.g., related to differences in age, sex, and ethnicity) nor the continuous increase in risk related to albumin excretion. DISCUSSION: Clinical needs have been identified for standardization of (a) urine collection methods, (b) urine albumin and creatinine measurements based on a complete reference system, (c) reporting of test results, and (d) reference intervals for the ACR.