Significance Statement To optimize the diagnosis of genetic kidney disorders in a cost-effective manner, we developed a workflow based on referral criteria for in-person evaluation at a tertiary center, whole-exome sequencing, reverse phenotyping, and multidisciplinary board analysis. This workflow reached a diagnostic rate of 67%, with 48% confirming and 19% modifying the suspected clinical diagnosis. We obtained a genetic diagnosis in 64% of children and 70% of adults. A modeled cost analysis demonstrated that early genetic testing saves 20% of costs per patient. Real cost analysis on a representative sample of 66 patients demonstrated an actual cost reduction of 41%. This workflow demonstrates feasibility, performance, and economic effect for the diagnosis of genetic kidney diseases in a real-world setting. Background Whole-exome sequencing (WES) increases the diagnostic rate of genetic kidney disorders, but accessibility, interpretation of results, and costs limit use in daily practice. Methods Univariable analysis of a historical cohort of 392 patients who underwent WES for kidney diseases showed that resistance to treatments, familial history of kidney disease, extrarenal involvement, congenital abnormalities of the kidney and urinary tract and CKD stage ≥G2, two or more cysts per kidney on ultrasound, persistent hyperechoic kidneys or nephrocalcinosis on ultrasound, and persistent metabolic abnormalities were most predictive for genetic diagnosis. We prospectively applied these criteria to select patients in a network of nephrology centers, followed by centralized genetic diagnosis by WES, reverse phenotyping, and multidisciplinary board discussion. Results We applied this multistep workflow to 476 patients with eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorders), obtaining genetic diagnosis for 319 of 476 patients (67.0%) (95% in 21 patients with disease onset during the fetal period or at birth, 64% in 298 pediatric patients, and 70% in 156 adult patients). The suspected clinical diagnosis was confirmed in 48% of the 476 patients and modified in 19%. A modeled cost analysis showed that application of this workflow saved 20% of costs per patient when performed at the beginning of the diagnostic process. Real cost analysis of 66 patients randomly selected from all categories showed actual cost reduction of 41%. Conclusions A diagnostic workflow for genetic kidney diseases that includes WES is cost-saving, especially if implemented early, and is feasible in a real-world setting. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_04_03_JASN2022060725.mp3

Background Autoantibodies against-phospholipase A2 receptor (PLA2R) are specific markers of idiopathic membranous nephropathy (iMN). Enzyme-linked immunosorbent assay (ELISA) is becoming the preferred method in many laboratories for the determination of anti-PLA2R antibodies, because it provides quantitative results, and is not prone to subjective interpretation, as is the case with indirect immunofluorescence assay. Methods The purpose of our study was to determine the diagnostic performance of serum PLA2R antibodies detected by commercially available ELISA in a large Italian multicenter cohort of patients with biopsy-proven iMN and in patients with other renal diseases, with special focus on evaluating the optimal cut-off value to discriminate positive and negative results. A total of 495 consecutive patients were recruited. Renal biopsies were performed in all patients, and blood samples were taken before the initiation of immunosuppressive treatment. Results According to the clinical diagnosis and to kidney biopsy, 126 patients were diagnosed with iMN and 369 had other non-membranous nephropathies. Anti-PLA2R autoantibodies were detected using a commercial anti-PLA2R ELISA. At a cut-off value of 20 relative units (RU)/ml indicated by the manufacturer for positive classification, sensitivity was 61.1% and specificity 99.7%. At a cut-off value of 14 RU/ml indicated by the manufacturer for borderline results, sensitivity was 63.5% and specificity remained the same (99.7%). At a cut-off of 2.7 RU/ml, selected as the optimal cut-off on the basis of ROC curve analysis, sensitivity was 83.3% and specificity 95.1%. The best overall efficiency of the test was observed at 2.7 RU/ml; however, the highest positive likelihood ratio and diagnostic odds ratio were achieved at 14 RU/ml. A cut-off threshold higher than 14 RU/ml or lower than 2.7 RU/ml entailed worse test performance. Conclusion Depending on the clinical use (early diagnosis or as a support to confirm clinical diagnosis), nephrologists may take advantage of this evidence by choosing the most convenient cut-off. However, renal biopsy remains mandatory for the definitive diagnosis of iMN and for the assessment of disease severity.

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The predictable benefit from renal stenting may be most likely in patients presenting with a rapid decline of GFR associated with renal artery stenosis affecting the whole renal mass that is both kidneys or single functioning kidney.

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BACKGROUND AND AIMS A complex interplay lies between COVID-19 infection and kidney disease. Patients with COVID-19 are at an increased risk of acute kidney injury (AKI), while CKD patients represent a population at a high risk of mortality from COVID-19 [1]. For 3 years, our hospital has been running an intradyalitic vaccination project (HBV, Haemophylus, Pneumococcus, Influenza) for haemodialysis patients. No data regarding the anti-COVID-19 vaccination administered during the dialysis session are available yet. This is a safety study aimed at defining the feasibility of this vaccination protocol. METHOD A total of 186 haemodialysis patients from 3 centres were vaccinated with the Spikevax-Moderna vaccine (Fig. 1). According to Italian law, patients with a COVID-19 infection in the previous 12 months received only one dose. The administration was performed between 1 and 2 h after the start of the dialysis session. Data regarding mild adverse events were collected. In 117 patients, a titration of the anti-RBD S1 antibodies of the virus spike antigen was performed 1 month after the completion of the vaccination [2]. Therefore, a new titration was obtained after 3 months in 50 patients. RESULTS Of the 117 patients, 65 (55.5%) were male, with a mean age of 69.2 ± 13.1 years. Of these, 25 patients (21.3%) showed mild adverse events without compromising dialysis administration. No serious adverse events took place. Seroconversion was noticed in 111 patients (94.9%) after 1 month, with a mean anti-RBD S1 antibody titer of 751.1 ± 610.5 BAU/mL. When a new titration was performed after 3 months, the titer decreased to 203.1 ± 134.3 BAU/mL (t-test; P = 0.005). CONCLUSION Intradialytic vaccination is a procedure with an excellent safety profile that may be implemented in dialysis settings. Further studies should be permormed to confirm these results.

BACKGROUND AND AIMS SGLT2 inhibitors (SGLT2i) are able to decrease proteinuria and slow down eGFR decline in DKD patients. The effect is mainly obtained by increase of natriuresis and glucose-induced osmotic diuresis, resulting in a reduction in intraglomerular pressure. These hemodynamic changes are beneficial in long-term period, but up to 28% of patients treated with SGLT2i experience an acute, usually transient, eGFR reduction of more than 10% [1]. Moreover, in some case, the decrease of eGFR can be more pronounced and compromise the maintenance of therapy. High sodium and protein intake can lead to intraglomerular pressure increase and predispose to a deeper fall of eGFR. We aimed at investigating whether measured creatinine clearance (CrCl) is a more sensitive method to detect the initial dip of GFR in patients with T2D treated with SGLT2i, and if dietary sodium and protein intake can influence the extent of the early change in GFR. METHOD Subjects with type 2 diabetes (T2D) were consecutively recruited among those referring to the inpatients of combined Nephrology and Diabetology clinic in years 2020–2021. Those eligible for treatment with SGLT2i were asked to collect 24-h urinary samples for sodium and urea determination, to estimate sodium and protein intake, respectively, before and 1, 3 and 6 months after treatment initiation. RESULTS At baseline, 27 patients (M 23/F 4; age 69 ± 7 years; BMI 28.2 ± 3.6 kg/m2; HbA1c 56 ± 16 mmol/mol) had a CrCl of 83.23 ± 25.52 mL/min/1.73 m2 (eGFR 67.32 ± 16.07), which dropped by 19% at month 1 (eGFR by 6%, although not significantly) and then increased to comparable baseline values at month 6. Exploring the potential correlation between changes in renal function and salt intake, ΔCrCl and baseline urinary sodium were inversely related at month 1 (r = −0.61; P <0.01), at month 3 (r = −0.51; P = 0.01) and month 6 (r= −0,48; P < 0.05) (Fig. 1). Likewise, an inverse correlation between ΔCrCl and baseline urinary urea (Fig. 2) was demonstrated at month 1 and 3 (r = −0.46; P <0.05 for both), at month 6 a similar, not significant, trend was observed (r = −0.47; P = 0.054). Proteinuria showed a significant reduction from baseline (P < 0.05); no significant relationship between change in proteinuria and urinary sodium or urea was observed. CONCLUSION The present study suggests that a higher dietary sodium and protein intake may amplify the extent of early dip in glomerular filtration rate, detected with measured CrCl, in diabetic patients undergoing SGLT2i treatment. We believe that measured creatinine clearance is a very sensitive method to detect it. Further studies are needed to confirm the results of our pilot study.

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