Primary membranous nephropathy in the Italian region of Emilia Romagna: results of a multicenter study with extended follow-up.

BACKGROUND: Since primary membranous nephropathy is a heterogeneous disease with variable outcomes and multiple possible therapeutic approaches, all 13 Nephrology Units of the Italian region Emilia Romagna decided to analyze their experience in the management of this challenging glomerular disease. METHODS: We retrospectively studied 205 consecutive adult patients affected by biopsy-proven primary membranous nephropathy, recruited from January 2010 through December 2017. The primary outcome was patient and renal survival. The secondary outcome was the rate of complete remission and partial remission of proteinuria. Relapse incidence, treatment patterns and adverse events were also assessed. RESULTS: Median (IQR) follow-up was 36 (24-60) months. Overall patient and renal survival were 87.4% after 5 years. At the end of follow-up, 83 patients (40%) had complete remission and 72 patients (35%) had partial remission. Among responders, less than a quarter (23%) relapsed. Most patients (83%) underwent immunosuppressive therapy within 6 months of biopsy. A cyclic regimen of corticosteroid and cytotoxic agents was the most commonly used treatment schedule (63%), followed by rituximab (28%). Multivariable analysis showed that the cyclic regimen significantly correlates with complete remission (odds ratio 0.26; 95% CI 0.08-0.79) when compared to rituximab (p < 0.05). CONCLUSIONS: In our large study, both short- and long-term outcomes were positive and consistent with those published in the literature. Our data suggest that the use of immunosuppressive therapy within the first 6 months after biopsy appears to be a winning strategy, and that the cyclic regimen also warrants a prominent role in primary membranous nephropathy treatment, since definitive proof of rituximab superiority is lacking.

Overcoming challenges in patient selection and monitoring in combined heart and kidney transplantation.

Combined heart-kidney transplantation (HKT) is a growing therapeutic strategy in patients with advanced heart failure (HF) and concomitant chronic kidney disease (CKD). Although patients with advanced HF and need for chronic haemodialysis have a clear indication for combined HKT, challenges to current practice lie in identifying those patients with severely depressed kidney function, which will not recover kidney function after restoration of appropriate haemodynamic conditions following heart transplantation (HT) alone. Because of the paucity of available organs, maximisation of kidney graft utility whilst minimising the operative risks associated with combined transplantation is mandatory. The benefits of HKT go beyond the mere restoration of kidney function. Data from registry analysis show that HKT improves overall survival in patients with CKD, as compared to heart transplant only, and it is associated with reduced incidence of heart allograft rejection, likely through the promotion of host immune tolerance mechanisms. In patients not requiring chronic dialysis, kidney-after-heart strategy may be explored, instead of combined HKT, in particular when the aetiology of CKD is unclear. This indeed allows for monitoring and gaging of indications for combined transplantation in the postoperative period. This approach however should be matched with priority listing for kidney transplantation given the high waitlist mortality in heart transplant recipients with associated CKD. The use of kidney machine perfusion may represent an additional tool to optimise the outcome of HKT, allowing more time to stabilise the patient after HT surgery.

Automated Prediction of Kidney Failure in IgA Nephropathy with Deep Learning from Biopsy Images.

BACKGROUND AND OBJECTIVES: Digital pathology and artificial intelligence offer new opportunities for automatic histologic scoring. We applied a deep learning approach to IgA nephropathy biopsy images to develop an automatic histologic prognostic score, assessed against ground truth (kidney failure) among patients with IgA nephropathy who were treated over 39 years. We assessed noninferiority in comparison with the histologic component of currently validated predictive tools. We correlated additional histologic features with our deep learning predictive score to identify potential additional predictive features. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Training for deep learning was performed with randomly selected, digitalized, cortical Periodic acid-Schiff-stained sections images (363 kidney biopsy specimens) to develop our deep learning predictive score. We estimated noninferiority using the area under the receiver operating characteristic curve (AUC) in a randomly selected group (95 biopsy specimens) against the gold standard Oxford classification (MEST-C) scores used by the International IgA Nephropathy Prediction Tool and the clinical decision supporting system for estimating the risk of kidney failure in IgA nephropathy. We assessed additional potential predictive histologic features against a subset (20 kidney biopsy specimens) with the strongest and weakest deep learning predictive scores. RESULTS: We enrolled 442 patients; the 10-year kidney survival was 78%, and the study median follow-up was 6.7 years. Manual MEST-C showed no prognostic relationship for the endocapillary parameter only. The deep learning predictive score was not inferior to MEST-C applied using the International IgA Nephropathy Prediction Tool and the clinical decision supporting system (AUC of 0.84 versus 0.77 and 0.74, respectively) and confirmed a good correlation with the tubolointerstitial score (r=0.41, P<0.01). We observed no correlations between the deep learning prognostic score and the mesangial, endocapillary, segmental sclerosis, and crescent parameters. Additional potential predictive histopathologic features incorporated by the deep learning predictive score included (1) inflammation within areas of interstitial fibrosis and tubular atrophy and (2) hyaline casts. CONCLUSIONS: The deep learning approach was noninferior to manual histopathologic reporting and considered prognostic features not currently included in MEST-C assessment. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_07_26_CJN01760222.mp3.

[Monoclonal gammopathies and kidney: a diagnostic challenge without any clues].

Diagnosis of monoclonal gammopathy of renal significance (MGRS) with histopathologic features of proliferative GN with monoclonal immunoglobulin deposits (PGNMID) is a challenge for clinicians because of the absence of laboratory findings suggestive of glomerular involvement in paraproteinemia. Renal biopsy remains the gold standard for diagnosis of PGNMID because it is a monoclonal gammopathy with kidney damage often "without a detectable serum/urine clone". Through this case report, we want to focus on the complexity both in the diagnostic process and in monitoring the renal-hematological response to therapy.

The Nephrologist's Role in the Collaborative Multi-Specialist Network Taking Care of Patients with Diabetes on Maintenance Hemodialysis: An Overview.

Diabetes mellitus is the leading cause of renal failure in incident dialysis patients in several countries around the world. The quality of life for patients with diabetes in maintenance hemodialysis (HD) treatment is in general poor due to disease complications. Nephrologists have to cope with all these problems because of the "total care model" and strive to improve their patients' outcome. In this review, an updated overview of the aspects the nephrologist must face in the management of these patients is reported. The conventional marker of glycemic control, hemoglobin A1c (HbA1c), is unreliable. HD itself may be responsible for dangerous hypoglycemic events. New methods of glucose control could be used even during dialysis, such as a continuous glucose monitoring (CGM) device. The pharmacological control of diabetes is another complex topic. Because of the risk of hypoglycemia, insulin and other medications used to treat diabetes may need dose adjustment. The new class of antidiabetic drugs dipeptidyl peptidase 4 (DPP-4) inhibitors can safely be used in non-insulin-dependent end-stage renal disease (ESRD) patients. Nephrologists should take care to improve the hemodynamic tolerance to HD treatment, frequently compromised by the high level of ultrafiltration needed to counter high interdialytic weight gain. Kidney and pancreas transplantation, in selected patients with diabetes, is the best therapy and is the only approach able to free patients from both dialysis and insulin therapy.

COVID-19 Infection: Viral Clearance and Antibody Response in Dialysis Patients and Renal Transplant Recipients.

BACKGROUND/AIMS: The coronavirus disease 2019 (CO-VID-19) pandemic is the major current health emergency worldwide, adding a significant burden also to the community of nephrologists for the management of their patients. Here, we analyzed the impact of COVID-19 infection in renal patients to assess the time to viral clearance, together with the production and persistence of IgG and IgM antibody response, in consideration of the altered immune capacity of this fragile population. METHODS: Viral clearance and antibody kinetics were investigated in 49 renal patients recovered from COVID-19 infection: 7 of them with chronic decompensated renal failure, 31 under dialysis treatment, and 11 kidney transplant recipients. RESULTS: The time span between the diagnosis of infection and recovery based on laboratory testing (2 negative nasopharyngeal swabs in consecutive days) was 31.7 ± 13.3 days. Three new positive cases were detected from 8 to 13 days following recovery. At the first serological determination after swab negativization, all the patients developed IgG and IgM antibodies. The semiquantitative analysis showed a progressive increase in IgG and a slow reduction in IgM. DISCUSSION/CONCLUSION: In subjects with decompensated chronic kidney disease, under dialysis and in transplant recipients, viral clearance is lengthened compared to the general population. However, in spite of their common status of immunodepression, all of them were able to produce specific antibodies. These data might provide useful insights for monitoring and planning health-care activities in the weak category of patients with compromised renal function recovered from COVID-19.

[Renal function performance in CKD stage 5: a sealed fate?]

Introduction and aims: Stages 4 and 5 of chronic kidney disease (CKD) have always been considered hard to modify in their speed and evolution. We retrospectively evaluated our CKD stage 5 patients (from 01/1/2016 to 12/31/2018), with a view to analyzing their kidney function evolution. Material and Methods: We included only patients with longer than 6 months follow-up and at least 4 clinical-laboratory controls that included measured Creatinine Clearance (ClCr) and estimated GFR with CKD-EPI (eGFR). We evaluated: the agreement between ClCr and eGFR through Bland-Altman analysis; progression rate, classified as fast (eGFR loss >5ml/min/year), slow (eGFR loss 1-5 ml/min/year) and non-progressive (eGFR loss <1 ml/min/year or eGFR increase). We also evaluated which clinical-laboratory parameters (diabetes, blood pressure control, use of ACEi/ARBs, ischemic myocardiopathy, peripheral obliterant arteriopathy (POA), proteinuria, hemoglobin, uric acid, PTH, phosphorus) were associated to the different eGFR progression classes by means of bivariate regression and multinomial multiple regression model. Results: Measured CrCl and eGFR where often in agreement, especially for GFR values <12ml/min. The average slope of eGFR was -3.05 ±3.68 ml/min/1.73 m2/year. The progression of kidney function was fast in 17% of the patients, slow in 57.6%, non-progressive in 25.4%. At the bivariate analysis, a fast progression was associated with poor blood pressure control (p=0.038) and ACEi/ARBs use (p=0.043). In the multivariable model, only peripheral obliterative arteriopathy proved associated to an increased risk of fast progression of eGFR (relative risk ratio=5.97). Discussion: Less than one fifth of our patients presented a fast GFR loss (>5 ml/min/year). The vast majority showed a slow progression, stabilisation or even an improvement. Despite the limits due to the small sample size, the data has encouraged us not to consider CKD stage 5 as an inexorable and short journey towards artificial replacement therapy.

Diffusion tensor imaging in renal artery stenosis: a preliminary report.

OBJECTIVE: To investigate the diffusion properties in the kidneys affected by renal artery stenosis (RAS) using diffusion tensor imaging (DTI). METHODS: In this prospective study, 35 patients with RAS and 15 patients without renal abnormalities were enrolled and examined using DTI. Cortical and medullary regions of interest (ROIs) were located to obtain the corresponding values of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA). The cortical and medullary ADC and FA were compared in the kidney affected by variable degrees of stenosis (RAS 50-75% and >75%) vs controls, using the one-way ANOVA and Student's t-test. The Spearman correlation test was used to correlate the mean ADC and FA values in the cortex and medulla with the estimate glomerular filtration rate (eGFR). RESULTS: For the controls, the ADC value was significantly (p = 0.03) higher in the cortex than in the medulla; the FA value was significantly (p = 0.001) higher in the medulla than in the cortex. Compared with the controls, a significant reduction in the cortical ADC was present with a RAS of 50-75% and >75% (p = 0.001 and 0.041, respectively); a significant reduction in the medullary FA was verified only for RAS >75% (p = 0.023). The Spearman correlation test did not show a statistically significant correlation between the cortical and medullary ADC and FA, and the eGFR. CONCLUSION: The alterations of the diffusional parameters caused by RAS can be detected by DTI and could be useful in the diagnostic evaluation of these patients. ADVANCES IN KNOWLEDGE: 1. Magnetic resonance DTI could provide useful information about renal involvement in RAS.2. Magnetic resonance DTI allows non-invasive repeatable evaluation of the renal parenchyma, without contrast media.

Developing and validating an algorithm to identify incident chronic dialysis patients using administrative data.

BACKGROUND: Administrative healthcare databases are widespread and are often standardized with regard to their content and data coding, thus they can be used also as data sources for surveillance and epidemiological research. Chronic dialysis requires patients to frequently access hospital and clinic services, causing a heavy burden to healthcare providers. This also means that these patients are routinely tracked on administrative databases, yet very few case definitions for their identification are currently available. The aim of this study was to develop two algorithms derived from administrative data for identifying incident chronic dialysis patients and test their validity compared to the reference standard of the regional dialysis registry. METHODS: The algorithms are based on data retrieved from hospital discharge records (HDR) and ambulatory specialty visits (ASV) to identify incident chronic dialysis patients in an Italian region. Subjects are included if they have at least one event in the HDR or ASV databases based on the ICD9-CM dialysis-related diagnosis or procedure codes in the study period. Exclusion criteria comprise non-residents, prevalent cases, or patients undergoing temporary dialysis, and are evaluated only on ASV data by the first algorithm, on both ASV and HDR data by the second algorithm. We validated the algorithms against the Emilia-Romagna regional dialysis registry by searching for incident patients in 2014 and performed sensitivity analyses by modifying the criteria to define temporary dialysis. RESULTS: Algorithm 1 identified 680 patients and algorithm 2 identified 676 initiating dialysis in 2014, compared to 625 patients included in the regional dialysis registry. Sensitivity for the two algorithms was respectively 90.8 and 88.4%, positive predictive value 84.0 and 82.0%, and percentage agreement was 77.4 and 74.1%. CONCLUSIONS: Algorithms relying on retrieval of administrative records have high sensitivity and positive predictive value for the identification of incident chronic dialysis patients. Algorithm 1, which showed the higher accuracy and has a simpler case definition, can be used in place of regional dialysis registries when they are not present or sufficiently developed in a region, or to improve the accuracy and timeliness of existing registries.

Gene Panel Analysis in a Large Cohort of Patients With Autosomal Dominant Polycystic Kidney Disease Allows the Identification of 80 Potentially Causative Novel Variants and the Characterization of a Complex Genetic Architecture in a Subset of Families.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans and the majority of patients carry a variant in either PKD1 or PKD2. Genetic testing is increasingly required for diagnosis, prognosis, and treatment decision, but it is challenging due to segmental duplications of PKD1, genetic and allelic heterogeneity, and the presence of many variants hypomorphic or of uncertain significance. We propose an NGS-based testing strategy for molecular analysis of ADPKD and its phenocopies, validated in a diagnostic setting. Materials and Methods: Our protocol is based on high-throughput simultaneous sequencing of PKD1 and PKD2 after long range PCR of coding regions, followed by a masked reference genome alignment, and MLPA analysis. A further screening of additional 14 cystogenes was performed in negative cases. We applied this strategy to analyze 212 patients with a clinical suspicion of ADPKD. Results and Discussion: We detected causative variants (interpreted as pathogenic/likely pathogenic) in 61.3% of our index patients, and variants of uncertain clinical significance in 12.5%. The majority (88%) of genetic variants was identified in PKD1, 12% in PKD2. Among 158 distinct variants, 80 (50.6%) were previously unreported, confirming broad allelic heterogeneity. Eleven patients showed more than one variant. Segregation analysis indicated biallelic disease in five patients, digenic in one, de novo variant with unknown phase in two. Furthermore, our NGS protocol allowed the identification of two patients with somatic mosaicism, which was undetectable with Sanger sequencing. Among patients without PKD1/PKD2 variants, we identified three with possible alternative diagnosis: a patient with biallelic mutations in PKHD1, confirming the overlap between recessive and dominant PKD, and two patients with variants in ALG8 and PRKCSH, respectively. Genotype-phenotype correlations showed that patients with PKD1 variants predicted to truncate (T) the protein experienced end-stage renal disease 9 years earlier than patients with PKD1 non-truncating (NT) mutations and >13 years earlier than patients with PKD2 mutations. ADPKD-PKD1 T cases showed a disease onset significantly earlier than ADPKD-PKD1 NT and ADPK-PKD2, as well as a significant earlier diagnosis. These data emphasize the need to combine clinical information with genetic data to achieve useful prognostic predictions.