Glomerular Filtration Rate Slope Research Articles

Estimated GFR Slope Across CKD Stages in Primary Hyperoxaluria Type 1

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. Retrospective observational study. 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. CKD GFR category, baseline patient and laboratory characteristics. Annualized rate of eGFR decline. 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. 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 m2 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. Data at regular time points were not available for all patients due to reliance on voluntary reporting in a retrospective rare disease registry. 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.

This Month's Highlights.

There has been substantial effort toward identifying robust alternative endpoints for kidney failure in clinical research, particularly for early stages of chronic kidney disease and for early phase trials. The glomerular filtration rate (GFR) slope has been proposed as a surrogate endpoint for

Increased Body Fat and Organic Acid Anions Production Are Associated with Larger Kidney Size in ADPKD.

Background and Objectives: A high body mass index (BMI) is associated with the progression of autosomal dominant polycystic kidney disease (ADPKD). However, body fat (BF), which is another adiposity marker, has not yet been studied. Excessive weight may promote elevation in the endogenous synthesis of organic acid (OA) anions. Accordingly, we aimed to investigate the possible association of the aforementioned markers with kidney volume and renal function in patients with ADPKD. Materials and Methods: We conducted a retrospective cohort study of adult ADPKD outpatients involving clinical, serum, and urinary laboratorial data and body composition assessments retrieved from their medical records. BF was estimated by skinfold thickness (mm) on the non-dominant arm and was considered as normal or high for each sex. Total kidney volume (TKV) and height-adjusted volume (htTKV) were measured by magnetic resonance imaging. The annual estimated glomerular filtration rate (eGFR) slope was analyzed during a median follow-up time of 6 (5.0–7.0) years to calculate rapid progression (decline in renal function ≥2.5 mL/min/year over 5 years). Results: A total of 104 patients were included (41.9 ± 11.9 years old, 38.5% men), with 62.5% of the patients classified as high BF. The High BF group presented higher levels of OA, glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), 24 h urinary sodium (UNa), and htTKV, and lower eGFR than those with a normal BF. In the multivariate linear regression, the associated variables with TKV were high BF, OA and BMI (std. β 0.47, p < 0.05; std. β 0.36, p = 0.001; std. β 0.25, p = 0.01, respectively). In the binary logistic regression, when adjusted for potential confounders, UNa was the only parameter associated with an increased risk of eGFR decline ≥2.5 mL/min/year (OR 1.02, 95% CI 1.01–1.03, p = 0.02). Conclusions: Increased body fat and endogenous production of organic acid anions are associated with larger kidney size in ADPKD but not with a decline in renal function.

Potential Role and Limitations of Estimated Glomerular Filtration Rate Slope Assessment in Cardiovascular Trials

Cardiovascular trials have traditionally been underpowered to assess advanced chronic kidney disease (CKD) outcomes, and when included as a secondary end point, trials have used progression of CKD as incidence of some variation of a composite of end-stage kidney disease (ESKD) outcomes. Such outcomes are infrequent or occur late in cardiovascular outcome trials, which highlights the need for alternate markers for assessing the impact of interventions on kidney function at an earlier stage of the disease and, from the prevention perspective, more relevant stage of the disease. Estimated glomerular filtration rate (eGFR) slope has demonstrated strong association with subsequent progression to ESKD. With adequate sample size, treatment effects in the range of 0.5 to 1.00 mL/min/1.73 m2/y had 96% probability of predicting CKD progression, defined as doubling of serum creatinine, eGFR less than 15 mL/min/1.73 m2, or ESKD. eGFR slope can be used in patients with higher baseline values and may provide CKD progression insights when few hard kidney events are observed, especially in trials with limited follow-up. However, among trials that have determined eGFR slope, significant variations exist regarding inclusion of baseline values, calculation of eGFR values, and the follow-up period, which make it difficult to compare and gauge the incremental benefit of the interventions. There are multiple challenges in computing eGFR slope in cardiovascular trials, such as accounting for initial eGFR dip, nonlinearity, and heteroscedasticity. eGFR slope may serve as a valuable marker to determine progression of CKD in cardiovascular trials. Further work is required to standardize data collection, follow-up duration, time points for kidney function assessment, and analytic methods to compute eGFR slope in cardiovascular trials.

Outcomes of Empagliflozin in Patients With Heart Failure With a Preserved Ejection Fraction and Atrial Fibrillation or Atrial Flutter: Insights From EMPEROR-Preserved

We investigated empagliflozin treatment effects on the composite of hospitalisation for heart failure (HHF) or CV death, total (first and recurrent) HHF, and estimated glomerular filtration rate (eGFR) slope in EMPEROR-Preserved participants with versus without ECG-documented or history of atrial fibrillation or atrial flutter (AF).

Urine tricarboxylic acid cycle signatures of early-stage diabetic kidney disease.

Urine tricarboxylic acid (TCA) cycle organic anions (OAs) are elevated in diabetes and may be biomarkers for diabetic kidney disease (DKD) progression. We assessed associations of 10 urine TCA cycle OAs with estimated glomerular filtration rate (eGFR) and eGFR slope. This study is ancillary to the Simultaneous Risk Factor Control Using Telehealth to SlOw Progression of Diabetic Kidney Disease (STOP-DKD) Trial-a randomized trial of pharmacist-led medication and behavior management in 281 patients with early to moderate DKD at Duke from 2014 to 2015. We used linear mixed models to assess associations of urine TCA cycle OAs with outcomes and modelled TCA cycle OAs as: (1) the average of z-scores for each OA; and (2) principal component (PC) scores derived by principal component analysis (PCA). Untargeted urine metabolomics were added for additional discovery. Among 132 participants with 24h urine samples (50% men; 58% Black; mean age 64years [SD 9]; mean eGFR 74ml/min/1.73m2 [SD 21] and medianurine albumin-to-creatinine [UACR] 20mg/g [IQR 8-95]), PCA identified 3 OA metabolite PCs. Malate, fumarate, pyruvate, α-ketoglutarate, lactate, succinate and citrate/isocitrate loaded positively on PC1; methylsuccinate, ethylmalonate and succinate loaded positively on PC2; and methylmalonate, ethylmalonate and citrate/isocitrate loaded negatively on PC3. Over a median follow-up of 1.8years (IQR, 1.2 to 2.2), higher average OA z-score was strongly associated with higher eGFR after covariate adjustment (p = 0.01), but not with eGFR slope (p = 0.9). Higher PC3, but not other PCs, was associated with lower eGFR (p < 0.001). Conditional random forests and smooth clipped absolute deviation models confirmed methylmalonate, citrate/isocitrate, and ethylmalonate, and added lactate as top ranked metabolites in models of baseline eGFR (R-squared 0.32 and 0.33, respectively). Untargeted urine metabolites confirmed association of urine TCA cycle OAs with kidney function. Thus, lower urine TCA cycle OAs, most notably lower methylmalonate, ethylmalonate and citrate/isocitrate, are potential indicators of kidney impairment in early stage DKD.

Long-term outcomes of transplant kidneys donated after circulatory death.

Donation after circulatory death (DCD) represents up to 40% of used kidney grafts. While studies have shown similar outcomes compared with donation after brain death (DBD) in the short term and mid-term, no data on long-term outcomes exist. We retrospectively analysed patients transplanted at our institution between January 1985 and March 2000. All DCD recipients were matched one-to-one with patients transplanted with DBD grafts during this period according to sex, age and year of transplantation and followed up until December 2020. During this period, 1133 kidney transplantations were performed, of which 122 were with a DCD graft. The median graft survival after 35 years of follow-up was 23 years [277 months {95% confidence interval (CI) 182-372}] in DBD recipients and 24.5 years [289 months (95% CI 245-333)] in DCD recipients (P = 0.65; hazard ratio 0.91). Delayed graft function occurred in 47 patients in the DCD group compared with 23 in the DBD group (P < 0.001), albeit without a significant long-term outcome difference in graft or patient survival. We could not show any difference in graft function in terms of creatinine levels (133 versus 119 µmol/L), proteinuria (370 versus 240 mg/24 h) and glomerular filtration rate slope (-0.6 versus -0.3 mL/min/year) between the two groups for graft survival >20 years. This is the first study to show similar graft survival and function in DCD kidneys compared with DBD kidneys after 35 years of follow-up. DCD grafts are a valuable resource and can be utilized in the same way as DBD grafts.

Effect of switching from tenofovir disoproxil fumarate to tenofovir alafenamide on estimated glomerular filtration rate slope in patients with HIV: A retrospective observational study

IntroductionThere is limited data on the effects of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) on estimated glomerular filtration rates (eGFR) slope in patients with human immunodeficiency virus (HIV) infection. This study aimed to compare the eGFR slope when administering TDF and TAF and to investigate the predictors of improvement in eGFR slope after switching from TDF to TAF. MethodsWe conducted a single-center, retrospective, observational study in Japanese patients with HIV infection who switched the antiretroviral drug from TDF to TAF. eGFR was calculated using serum cystatin C. The eGFR slope was defined as the regression coefficient between eGFR and time. Differences between eGFR slope during TDF and TAF administration were compared using Wilcoxon signed rank test. A stepwise logistic regression model was used to examine the associations between improvement of eGFR slope after switching from TDF to TAF and various parameters. ResultsOverall, 63 patients (656 eGFR) were included in the analysis. The median analyzed durations of TDF and TAF exposures were 1.6 and 1.5 years, respectively. There were no significant differences between eGFR slope during TDF and TAF periods (median: 0.6 vs. 4.0 mL/min/1.73 m2/year, p = 0.165). The eGFR slopes during the TDF period and while switching from TDF to TAF were independent predictors of improvement in eGFR slope after switching from TDF to TAF. ConclusionsThe results suggest that patients with poor renal function and those with progressive worsening during TDF administration would benefit from switching to TAF.

Sex-Specific Differences in Mortality and Incident Dialysis in the Chronic Kidney Disease Outcomes and Practice Patterns Study

IntroductionMore men than women start kidney replacement therapy (KRT) although the prevalence of chronic kidney disease (CKD) is higher in women than men. We therefore aimed at analyzing sex-specific differences in clinical outcomes among 8237 individuals with CKD in stages 3 to 5 from Brazil, France, Germany, and the United States participating in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps).MethodsFine and Gray models, evaluating the effect of sex on time to events, were adjusted for age, Black race (model A); plus diabetes, cardiovascular disease, albuminuria (model B); plus estimated glomerular filtration rate (eGFR) slope during the first 12 months after enrollment and first eGFR after enrollment (model C).ResultsThere were more men than women at baseline (58% vs. 42%), men were younger than women, and men had higher eGFR (28.9 ± 11.5 vs. 27.0 ± 10.8 ml/min per 1.73 m2). Over a median follow-up of 2.7 and 2.5 years for men and women, respectively, the crude dialysis initiation and pre-emptive transplantation rates were higher in men whereas that of pre-KRT death was more similar. The adjusted subdistribution hazard ratios (SHRs) between men versus women for dialysis were 1.51 (1.27–1.80) (model A), 1.32 (1.10–1.59) (model B), and 1.50 (1.25–1.80) (model C); for pre-KRT death, were 1.25 (1.02–1.54) (model A), 1.14 (0.92–1.40) (model B), and 1.15 (0.93–1.42) (model C); for transplantation, were 1.31 (0.73–2.36) (model A), 1.44 (0.76–2.74) (model B), and 1.53 (0.79–2.94) (model C).ConclusionMen had a higher probability of commencing dialysis before death, unexplained by CKD progression alone. Although the causal mechanisms are uncertain, this finding helps interpret the preponderance of men in the dialysis population.

Comparison of multiparametric magnetic resonance imaging sequences with laboratory parameters for prognosticating renal function in chronic kidney disease

Magnetic resonance imaging (MRI) is playing an increasingly important role in evaluating chronic kidney disease (CKD). It has the potential to be used not only for evaluation of physiological and pathological states, but also for prediction of disease course. Although different MRI sequences have been employed in renal disease, there are few studies that have compared the different sequences. We compared several multiparametric MRI sequences, and compared their results with the estimated glomerular filtration rate. Principal component analysis showed a similarity between T1 values and tissue perfusion (arterial spin labelling), and between fractional anisotropy (diffusion tensor imaging) and apparent diffusion coefficient values (diffusion-weighted imaging). In multiple regression analysis, only T2* values, derived from the blood oxygenation level-dependent (BOLD) MRI sequence, were associated with estimated glomerular filtration rate slope after adjusting for degree of proteinuria, a classic prognostic factor for CKD. In receiver operating characteristic curve analysis, T2* values were a good predictor of rapid deterioration, regardless of the degree of proteinuria. This suggests further study of the use of BOLD-derived T2* values in the workup of CKD, especially to predict the disease course.

Aortic Root Dilatation Is Attenuated with Diabetes but Is Not Associated with Renal Progression in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) often have cardiac functional and structural abnormalities which can lead to adverse cardiovascular outcomes. In this study, we investigated associations between diabetes mellitus (DM) and cardiac functional and structural parameters in patients with CKD focusing on aortic root diameter (ARD). We also investigated associations of renal outcomes with DM and cardiac functional and structural characteristics. We enrolled 419 patients with CKD stage 3–5 were enrolled. ARD was normalized to body surface area (BSA) (ARD/BSA), and the rate of decline in renal function was assessed by the estimated glomerular filtration rate (eGFR) slope (mL/min/1.73 m2/year). ARD/BSA ≥2.1 cm/m2 in men or ≥2.2 cm/m2 in women was defined as indicating aortic root dilatation. The patients with DM had lower ARD/BSA, higher left atrial dimension (LAD), lower left ventricular ejection fraction, lower ratio of peak early transmitral filling wave velocity to peak late transmitral filling wave velocity, and higher left ventricular relative wall thickness, than those without DM. After multivariable analysis, DM (vs. non-DM; coefficient β, −0.060; p = 0.018) was significantly associated with low ARD/BSA. Significantly fewer patients with DM had aortic root dilatation compared to those without DM (14.3% vs. 23.1%, p = 0.022). In the patients with DM, there were significant associations between a high left ventricular mass index (LVMI) (per 1 g/m2, β, −0.016; p = 0.040) and high LAD (per 1 cm; β, −1.965; p < 0.001) with a low eGFR slope. However, other parameters, including ARD/BSA, were not associated with eGFR slope. Furthermore, there were no associations between eGFR slope and any of the echocardiographic parameters in the patients without DM. Aortic root dilatation was attenuated in the patients with DM, but it was not associated with a decline in renal function. However, high LAD and LVMI were associated with rapid renal function decline in the CKD patients with DM.

Serum matrix metalloproteinase 7 and accelerated glomerular filtration rate decline in a general non-diabetic population.

BackgroundAge-related reduction of glomerular filtration rate (GFR) is a major contributor to the global chronic kidney disease (CKD) epidemic. We investigated whether baseline serum levels of the pro-fibrotic matrix metalloproteinase 2 (MMP2), MMP7 and their inhibitor, tissue inhibitor of metalloproteinase 1 (TIMP1), which mediates fibrosis development in aging animals, were associated with GFR decline in a general non-diabetic population.MethodsIn the Renal Iohexol Clearance Survey, we measured GFR using iohexol clearance in 1627 subjects aged 50–64 years without self-reported diabetes, kidney or cardiovascular disease. After a median of 5.6 years, 1324 had follow-up GFR measurements. Using linear mixed models and logistic regression analyses, we evaluated the association of MMP7, MMP2 and TIMP1 with the mean GFR decline rate, risk of accelerated GFR decline (defined as subjects with the 10% steepest GFR slopes: ≥1.8 mL/min/1.73 m2/year) and incident CKD [GFR <60 mL/min/1.73 m2 and/or urinary albumin to creatinine ratio (ACR) ≥3.0 mg/mmol].ResultsHigher MMP7 levels (per standard deviation increase of MMP7) were associated with steeper GFR decline rates [−0.23 mL/min/1.73 m2/year (95% confidence interval −0.34 to −0.12)] and increased risk of accelerated GFR decline and incident CKD [odds ratios 1.58 (1.30–1.93) and 1.45 (1.05–2.01), respectively, in a model adjusted for age, sex, baseline GFR, ACR and cardiovascular risk factors]. MMP2 and TIMP1 showed no association with GFR decline or incident CKD.ConclusionsThe pro-fibrotic biomarker MMP7, but not MMP2 or TIMP1, is associated with increased risk of accelerated GFR decline and incident CKD in middle-aged persons from the general population.

Intravenous immunoglobulins do not prove beneficial to reduce alloimmunity among kidney transplant recipients with BKV-associated nephropathy.

Reduced immunosuppression during BKV-DNAemia has been associated with T-cell mediated rejection (TCMR), de novo donor-specific antibodies (DSA) and antibody-mediated rejection (ABMR). Intravenous immunoglobulins (IVIG) may reduce alloimmunity. We studied 860 kidney transplant recipients (KTRs) for the development of BKV-DNAuria and BKV-DNAemia (low-level <10000IE/ml, high-level >10000IE/ml). 52/131 KTRs with high-level BKV-DNAemia received IVIG. The HLA-related immunological risk was stratified by the Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) algorithm. BKV-DNAuria only was observed in 86 KTRs (10.0%), low-level BKV-DNAemia in 180 KTRs (20.9%) and high-level BKV-DNAemia in 131 KTRs (15.2%). KTRs with low-level BKV-DNAemia showed significantly less TCMR compared to KTRs with high-level BKV-DNAemia (5.2% vs. 25.5%; P<0.001) and no BKV-replication (13.2%; P=0.014), lowest rates of de novo DSA (21.3%), ABMR (9.2%) and flattest glomerular filtration rate (GFR) slope (-0.8ml/min). KTRs with low-level BKV-DNAemia showed significantly higher median (interquartile range) total PIRCHE if they developed TCMR [100.22 (72.6) vs. 69.52 (49.97); P=0.020] or ABMR [128.86 (52.99) vs. 69.52 (49.96); P=0.005]. Administration of IVIG did not shorten duration of BKV-DNAemia (P=0.798) or reduce TCMR, de novo DSA and ABMR (P>0.05). KTRs with low-level BKV-DNAemia showed best protection against alloimmunity, with a high number of PIRCHE co-determining the remaining risk. The administration of IVIG, however, was not beneficial in reducing alloimmunity.

Association of glomerular filtration rate slope with timely creation of vascular access in incident hemodialysis

The factors associated with the timely creation of distal vascular access for hemodialysis initiation are unclear. We aimed to explore the association between the slope of estimated glomerular filtration rate (eGFR) and the successful usage of vascular access upon hemodialysis initiation. This single center retrospective cohort study enrolled chronic kidney disease patients who undertook a multidisciplinary care program from 2003 to 2016. Using eGFR slope as predictor, we evaluated the vascular access created timely upon hemodialysis initiation. Among the 987 patients, vascular access was created at a median eGFR of 5.8 min/ml/1.73 m2, with a median duration of 3.1 months before hemodialysis. The proportions of vascular access created timely, created not timely (vascular access immature), and not created were 68.5%, 8.8%, and 22.7%, respectively. There was a significant negative association of eGFR upon vascular access creation with eGFR slope (r = − 0.182, P < 0.001). The fastest eGFR slope patients (the first quartile or < − 10 min/ml/1.73 m2/year) had the lowest percentage of vascular access created timely. In the multivariable logistic regression analysis, only higher eGFR upon vascular access creation (P = 0.001) and eGFR slope (P = 0.009) were significantly associated with vascular access created timely. The adjusted odds ratios of each quartile of eGFR slopes for vascular access created timely were 0.46 (95% confidence interval 0.27–0.86), 1.30 (0.62, 2.72), 1.00 (reference), and 0.95 (0.48–1.87), respectively. eGFR slope is associated with the timely creation of vascular access for the initiation of hemodialysis in a reverse-J-shaped pattern and may help determine the time of vascular access creation.

Effect of estimating equations for glomerular filtration rate on novel surrogate markers for renal outcome.

BackgroundsRecently, alternative surrogate endpoints such as a 30% or 40% decline in estimated glomerular filtration rate (eGFR) or eGFR slope over 2 to 3 years have been proposed for predicting renal outcomes. However, the impact of GFR estimation methods on the accuracy and effectiveness of surrogate markers is unknown.MethodsWe retrospectively enrolled participants in health screening programs at three hospitals from 1995 to 2009. We defined two different participant groups as YR1 and YR3, which had available 1-year or 3-year eGFR values along with their baseline eGFR levels. We compared the effectiveness of eGFR percentage change or slope to estimate end-stage renal disease (ESRD) risk according to two estimating equations (modified Modification of Diet in Renal Disease equation [eGFRm] and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation [eGFRc]) for GFR.ResultsIn the YR1 and YR3 groups, 9,971 and 10,171 candidates were enrolled and ESRD incidence during follow-up was 0.26% and 0.19%, respectively. The eGFR percentage change was more effective than eGFR slope in estimating ESRD risk, regardless of the method of estimation. A 40% of decline in eGFR was better than 30%, and a 3-year baseline period was better than a 1-year period for prediction accuracy. Although some diagnostic indices from the CKD-EPI equation were better, we found no significant differences in the discriminative ability and hazard ratios for incident ESRD between eGFRc and eGFRm in either eGFR percentage change or eGFR slope. Conclusion There were no significant differences in the prediction accuracy of GFR percentage change or eGFR slope between eGFRc and eGFRm in the general population.

Pitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure.

Pitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure.

MO034A SUBGROUP ANALYSIS OF FEMALE PATIENTS IN A PHASE 3 OPEN-LABEL STUDY TO ASSESS THE SAFETY AND EFFICACY OF PEGUNIGALSIDASE ALFA IN PATIENTS WITH FABRY DISEASE PREVIOUSLY TREATED WITH AGALSIDASE ALFA

Abstract Background and Aims Females with Fabry disease (FD) often develop symptoms and disease complications later in life than males. However, they can experience significant health declines, including renal function impairment. Pegunigalsidase alfa is a novel PEGylated alpha-galactosidase A enzyme in development for the treatment of patients with FD with potential pharmacokinetic benefits. We previously reported that males with FD showed improvements in several parameters including median (minimum, maximum) estimated glomerular filtration rate (eGFR) slope from -4.6 (-20.5, 4.8) to -1.1 (-18.6, 14.2) mL/min/1.73m2/year after treatment with pegunigalsidase alfa.(Tondel et al. ASN 2020. PO0562. www.asn.scientificposters.com) Here we report a subgroup analysis of the safety and efficacy of pegunigalsidase alfa treatment in females with FD. Method BRIDGE (PB-102-F30; NCT03018730) is a phase 3, open-label, switch-over study designed to assess the safety and efficacy of pegunigalsidase alfa in adults with FD previously treated with agalsidase alfa for at least 2 years. Patients received intravenous pegunigalsidase alfa at 1 mg/kg every other week for 12 months. Results Twenty-two patients were enrolled in the study; of the 20 patients who completed 12 months of study treatment, 7 were female. Females had a mean age of 46.7 years (range: 26–59 years), and had the following median (minimum, maximum) baseline measurements: residual enzymatic activity in leucocytes of 23.7% (16, 46) of the normal laboratory mean; plasma lyso-Gb3 of 12.9 (7.4, 23.2) nmol/L; eGFR of 87.7 (55.3, 109.2) mL/min/1.73m2; and an annualized eGFR slope of −3.7 (-11.2, 1.5) mL/min/1.73m2/year. After 12 months of pegunigalsidase alfa treatment, the annualized eGFR slope was 1.4 (-6.3, 4.1) mL/min/1.73m2/year, indicating an improvement from baseline of 5.9 mL/min/1.73m2/year. In addition, plasma lyso-Gb3 had a reduction of 23.3% (-45.7, -17.3). Although all females had baseline mean residual enzyme activity &amp;gt; 5% and were previously treated with agalsidase alfa, only 2 had stable kidney disease (eGFR slope ≥ -3 mL/min/1.73m2/year), while 2 had moderately progressing kidney disease (eGFR slope between ≥-5 and &amp;lt; -3 mL/min/1.73m2/year), and 3 had fast progressing kidney disease (eGFR slope &amp;lt; -5 mL/min/1.73 m²/year).( Wanner et al. 2018 Mol Genet Metab 124:189-203) After treatment all but 1 patient experienced categorical improvement or remained stable; this patient had a decline of &amp;lt; 3 mL/min/1.73m2/year and remained in the fast progressing disease category. Mean left ventricular mass index in females increased from 66.9 g/m2 at baseline to 74.1 g/m2 at month 12, but remained within normal ranges(47–77 g/m2).(Kawel-Boehm et al. 2015 J Cardiovasc Magn Reson 17:29) All females had at least 1 treatment-emergent adverse event (TEAE), and all TEAEs were mild or moderate. The most common TEAEs reported in female were nasopharyngitis (n=2), oropharyngeal pain (n=2), and headache (n=2). None of these TEAEs were considered related to treatment. However, 2 females had injection site reactions and 2 developed transient, non-neutralizing anti-drug antibodies to pegunigalsidase alfa treatment. Conclusion The current study included females with symptoms of Fabry disease comparable to the disease presentation of males enrolled in this study. At baseline most females had eGFR decline characterizing progressive or rapidly progressive kidney disease. Most females showed improvements in disease status following 12 months of pegunigalsidase alfa treatment, as previously reported for males enrolled in this study. This long-term, controlled study suggests a potential benefit and a favorable safety profile for pegunigalsidase alfa on renal function in females with FD previously treated with agalsidase alfa. While this subgroup analysis should be interpreted with caution due to the small number of patients, these findings may provide valuable insight for future studies.

Recurrent FAN1 p.W707X Pathogenic Variant Originating Before ad 1800 Underlies High Frequency of Karyomegalic Interstitial Nephritis in South Pacific Islands

Recurrent FAN1 p.W707X Pathogenic Variant Originating Before ad 1800 Underlies High Frequency of Karyomegalic Interstitial Nephritis in South Pacific Islands

Pre-treatment hematuria and crescents predict estimated glomerular filtration rate trajectory after methylprednisolone pulse therapy with tonsillectomy for IgA nephropathy.

Glomerular hematuria and proteinuria are typical manifestations of IgA nephropathy (IgAN). However, hematuria severity is not considered a useful marker of the potential benefits of corticosteroid administration as proteinuria severityonly is includedin the current guidelines. In this retrospective cohort study, we enrolled 133 patients diagnosed with IgAN through biopsy. We calculated the 2-year estimated glomerular filtration rate (eGFR) slope (mL/min/1.73m2/year) and eGFR trajectory after methylprednisolone pulse therapy using mixed effects models stratified by the Oxford classification and three categories of pre-treatment hematuria: mild [urinary red blood cells (URBCs) < 10/high-power field (HPF)], moderate (URBCs 10-30/HPF), and severe (URBCs ≥ 30/HPF). The severe pre-treatment hematuria group showed a significantly higher likelihood of having crescents (odds ratio (OR), 4.3; 95% confidence interval (CI), 1.7-10.9). In the longitudinal analysis of 103 patients, most of whom underwent tonsillectomy, the severe pre-treatment hematuria group had a significantly higher 2-year eGFR slope after methylprednisolone pulse therapy than the mild and moderate hematuria groups (mild, -0.52 ± 1.97; moderate, -0.32 ± 1.99; severe, 1.44 ± 3.20 mL/min/1.73m2/year). Patients with C2 scores showed a significantly higher 2-year eGFR slope after methylprednisolone pulse therapy than those with C0 and C1 scores (C0, -0.38 ± 1.74; C1, 0.81 ± 3.02; C2, 3.29 ± 3.68 mL/min/1.73m2/year). Analyses of eGFR trajectory after methylprednisolone pulse therapy revealed that the eGFR improved only in patients with severe pre-treatment hematuria or C2 score (Pinteraction with time < 0.001). The eGFR is likely to improve after methylprednisolone pulse therapy with tonsillectomy in IgAN patients with severe pre-treatment hematuria or a high percentage of crescents.

Effect of serum potassium level on renal function progression in stage Ⅲ-Ⅴ chronic kidney disease patients without dialysis

Objective: To investigate the effect of serum potassium level and hyperkalemia on the renal function decline in chronic kidney disease (CKD) patients. Methods: The clinical data at baseline and follow-up in stage Ⅲ-Ⅴ CKD patients without dialysis who were followed up for more than one year in Tianjin First Central Hospital from May 2015 to June 2019 and Teikyo University School of Medicine from January 2008 to July 2013 were retrospectively collected. All patients were divided into stable group (337 cases), slow progression group (337 cases) and rapid progression group (338 cases) according to the tertile of estimated glomerular filtration rate (eGFR) slope (the annual average percentage of eGFR decline). Multivariate logistic regression analysis models were used to evaluate the correlations of baseline serum potassium or time-averaged serum potassium level with CKD rapid progression. Results: Three hundred and forty-three cases from Tianjin First Central Hospital and 669 cases from Teikyo University School of Medicine were included in the study, and 635 cases (62.7%) were male. The average age was (61±14) years old and the average eGFR decline slope was 4.0%/year. The levels of baseline serum potassium and time-averaged serum potassium of patients in the slow progression group [(4.47±0.52) and (4.51±0.43) mmo/L] and rapid progression group [(4.62±0.62) and (4.76±0.48) mmo/L] were higher than those in the stable group [(4.37±0.49) and (4.38±0.37) mmo/L] (both P<0.05). Meanwhile, 24.6% (83/338) of the patients in the rapid progression group had hyperkalemia at baseline (serum potassium ≥5.0 mmol/L) and 34.9% (118/338) of the patients had time-averaged serum potassium ≥5.0 mmol/L, which were higher than those in the stable group [10.7% (36/337) and 6.5% (22/337)] (both P<0.001). Multivariate logistic regression analysis showed that compared with the stable group, baseline serum potassium (OR=1.843, 95%CI: 1.051-3.234) and time-averaged serum potassium (OR=2.495, 95%CI: 1.040-5.987) were correlated with the rapid progression of CKD. Time-averaged serum potassium ≥5.0 mmol/L was the independent influencing factor for rapid progression of CKD. Conclusions: During the follow-up period, the average level of serum potassium in stage Ⅲ-Ⅴ CKD patients should be controlled under 5.0 mmol/L, which may reduce the risk of rapid decline of renal function.