ADPKD current management and ongoing trials

Among the diseases that require renal replacement therapy (RRT), ADPKD is the fourth for incidence and prevalence. In Italy, there are at least 32,000 patients affected by ADPKD, of which about 2900 in dialysis. The pure costs of dialysis treatment for the Italian National Health Service can be conservatively estimated at 87 million euros per year. Even a modest slowdown in the evolution of the disease would obtain an important result in terms of reduction of health expenditure. In recent years, many new or repurposed drugs have been evaluated in clinical trials for ADPKD. In this review we will mainly focus on advanced stage clinical trials (phase 2 and 3). We have grouped these studies according to the molecular pathway addressed by the experimental drug or the therapeutic strategy. More than 10 years after the start of the first Phase III clinical trials in ADPKD, the first drug active in slowing disease progression is finally available. It cannot be considered a goal but only the beginning of a journey because of the significant side effects and the high cost of Tolvaptan. An exuberant basic research activity in the field, together with the large number of ongoing protocols, keep the nephrologists and their patients positive with regard to the discovery of new and better therapies in a not-too-distant future. © 2019, Italian Society of Nephrology

Rene policistico autosomico dominante: nuovi aspetti terapeutici

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The frail world of haemodialysis patients in the COVID-19 pandemic era: a systematic scoping review

Background: Patients undergoing in-centre haemodialysis (HD) are particularly exposed to the dire consequences of COVID-19. The present systematic scoping review aims to identify the extent, range, and nature of articles related to COVID-19 and maintenance HD: it reports specifically the prevalence of the COVID-19 pandemic in the HD population, implementation of strategies for the prevention, mitigation and containment of the COVID-19 pandemic in HD centres, demographic and clinical characteristics, and outcomes of the pediatric and adult HD patients. Methods: A multi-step systematic search of the literature in Pubmed, Scopus, Ovid Medline, Embase and Web of Science, published between December 1, 2019, and January 30, 2021 was performed. Two authors separately screened the titles and abstracts of the documents and ruled out irrelevant articles. A report of the papers that met inclusion criteria was performed; then, a descriptive analysis of the characteristics of the included articles and a narrative synthesis of the results were performed. Results: The review process ended with the inclusion of 145 articles. Most of them were based on single-centre experiences, which spontaneously developed best practices. Most studies were conducted in high-income countries (69.7%) and a part of them (9.6%) were not in English. Prevalence of COVID-19 among dialysis patients accounted for 0%-37.6%. Preventive measures were reported in 54% of the included articles, with particular emphasis on education, triage, hygiene, and containment measures. Patients experienced a heterogeneous spectrum of symptoms that led 35%-88.2% of them to hospital admission. Median and mean hospital length of stay ranged from 8 to 28.5 and 16.2 to 22 days, respectively. Admission to intensive care units varied widely across studies (from 2.6% to 70.5%) and was associated with high mortality (42.8%–100%). Overall, prognosis was poor in 0%–47% of the hospitalized patients. Conclusions: This systematic scoping review provides an overview of the current knowledge on the impact of COVID-19 on the frail world of HD patients. Furthermore, it may help to implement the existing strategies of COVID-19 prevention and provide a list of unmet needs (safe transport, testing, shelter). Finally, it may be a stimulus for performing systematic reviews and meta-analyses which will form the basis for evidence-based guidelines. Graphic abstract: [Figure not available: see fulltext.

Clinical Predictors of Nondiabetic Kidney Disease in Patients with Diabetes: A Single-Center Study

Background. Although diabetic kidney disease (DKD) could affect up to one-third of patients with diabetes mellitus (DM), these patients can develop kidney diseases different from DKD, or these conditions can superimpose on DKD. Several potential predictors of nondiabetic kidney disease (NDKD) have been proposed, but there are no definitive indications available for kidney biopsy in diabetic patients. Methods. We designed a single-center, cross-sectional, and retrospective cohort study to identify clinical and laboratory factors associated with a diagnosis of NDKD after native kidney biopsy in diabetic patients and to investigate differences in time to end-stage kidney disease (ESKD) in patients with a diagnosis of DKD and NDKD. Results. Of 142 patients included in our analysis, 89 (62.68%) had a histopathological diagnosis of NDKD or mixed NDKD + DKD. Patients in the NDKD group had significantly lower HbA1C, lower prevalence of diabetic retinopathy (DR), and less severe proteinuria, and there was a lower proportion of patients with nephrotic syndrome; the DKD group had significantly lower proportion of patients with hematological conditions. In the multivariate binary logistic regression, only absence of DR and presence of a hematological condition significantly predicted NDKD after adjustment for age and sex. Time to ESKD was significantly higher in patients with NDKD or mixed forms than in those with DKD. Conclusions. After a careful selection, more than half of kidney biopsies performed in diabetic patients can identify NDKD (alone or with concomitant DKD). Absence of DR and coexistence of a hematological condition (especially MGUS) were strong predictors of NDKD in our cohort

Which criteria should we use to end isolation in hemodialysis patients with COVID-19?

Safe and timely discontinuation of quarantine of in-center hemodialysis (HD) patients with a previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a challenging issue for the nephrological community because current guidelines for ending isolation do not mention dialysis patients. To prevent potentially fatal outbreaks of coronavirus disease 2019 (COVID-19), a cautionary approach has been adopted by most dialysis units. The criteria for ending the isolation in the HD population generally coincide with those recommended for immunocompromised people. Thus, a test-based strategy relying on two consecutive negative reverse transcriptase-polymerase chain reaction (RT-PCR) nasopharyngeal swabs has been adopted to terminate quarantine. This strategy has the disadvantage of prolonging isolation as RT-PCR positivity does not equate to SARS-CoV-2 infectivity. Consequentially, prolonged positivity of SARS-CoV-2 results in excessive workload for the HD staff who must face an increasing number of COVID-19 patients requiring isolation. This condition leads also to serious implications for the patients and their households including work productivity loss, postponement of health-care appointments and an increased risk of COVID-19 reinfection. To counteract this problem, other diagnostic tests should be used to provide the best care to HD patients. Recent results seem to encourage the use of RT-PCR cycle threshold (Ct) values and rapid antigen tests given their better correlation with cell culture for SARS-CoV-2 than RT-PCR testing. Here, we provide an overview of the current scientific evidence on the tests used to verify the infectiousness of the virus in order to stimulate the nephrological community to adopt a streamlined and pragmatic procedure to end isolation in COVID-19 patients on HD

Prolonged RT-PCR test positivity in hemodialysis patients with COVID-19

Background: The weakened immune system of patients on hemodialysis (HD) may prolong SARS-CoV-2 infection compared to the general population. Current international guidelines recommend ending isolation in conjunction with serial testing in moderately and severely immunocompromised subjects. This study aimed to estimate SARS-CoV-2 infectivity by measuring RT-PCR test positivity in HD patients. A comparison between RT-PCR test and cycle threshold (Ct) value has been performed as a secondary endpoint. Methods: A single-center retrospective study was conducted at the University of Modena (Italy) from March 2020 to October 2022. Only patients on chronic HD therapy with COVID-19 were enrolled in the study. In our HD Center, two negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) results were used to end quarantine in this population. SARS-CoV-2 RT-PCR test positivity duration measured the time elapsed from a positive RT-PCR to a second negative test. Ct cut-off of 35 cycles was used to definite “high Ct value,” a condition characterized by a large number of cycles of PCR amplification to register a positive RT-PCR test. Results: During the observational period, 159 cases of SARS-CoV-2 infections were diagnosed in 151 patients. Median age was 70.1 (54.3–81.6) years and males accounted for 59.6% of the COVID-19 population. Median duration of SARS-CoV-2 RT-PCR test positivity on the nasal mucosa accounted for 30 (IQR, 21–40.5) days. Unvaccinated patients experienced significantly longer RT-PCR test positivity compared to vaccinated patients (42 [IQR,31–56] vs. 28 [IQR,20–35.7] days; p = < 0.001). The use of high Ct value, a laboratory surrogate of SARS-CoV-2 replication, anticipated a negative RT-PCR test of 9 (IQR, 6–12) days. Multivariate linear regression analysis showed that increased age (β coefficient 0.31; confidence interval [CI] 95%, 0.14—0.43; p = < 0.001) and the lack of anti-SARS-CoV-2 vaccination (β 0.49 CI95%, 11.9–22.5; p = < 0.001) were predictors of a prolonged RT-PCR positivity. Conclusions: Patients with COVID-19 on HD had prolonged RT-PCR test positivity. The adoption of “high Ct value” criteria led to a significant reduction in the duration of RT-PCR test positivity compared to the use of the classical nucleic acid amplification test. In our study, the lack of SARS-CoV-2 vaccination and older age were independently associated with a longer RT-PCR positivity

Urine Proteome Analysis May Allow Noninvasive Differential Diagnosis of Diabetic Nephropathy

AbstractObjective: Chronic renal insufficiency and/or proteinuria in type 2 diabetes may stem from chronic renal diseases (CKD) other than classic diabetic nephropathy (DN) in over one third of cases. We interrogated urine proteomic profiles generated by SELDI-TOF/MS with the aim to isolate a set of biomarkers able to reliably identify biopsy-proven DN and to establish a stringent correlation with the different patterns of renal injury. Research design and methods: Ten mug urine proteins from 190 subjects [20 healthy subjects (HS), 20 normoalbuminuric (NAD) and 18 microalbuminuric (MICRO) diabetic patients, and 132 patients with biopsy-proven nephropathy (65 DN, 10 diabetics with non-diabetic CKD (nd-CKD) and 57 non-diabetic patients with CKD)] were run by CM10 ProteinChip array and analysed by supervised learning methods (CART analysis). Results: The classification model correctly identified 75% NAD, 87.5% MICRO and 87.5% DN when applied to a blinded testing set. Most importantly, it was able to reliably differentiate DN from nd-CKD in both diabetic and non-diabetic patients. Among the best predictors of the classification model, we identified and validated 2 proteins, ubiquitin and ss2-microglobulin. Conclusions: Our data suggest the presence of a specific urine proteomic signature able to reliably identify type 2 diabetic patients with diabetic glomerulosclerosis

Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele

ERG Deregulation Induces PIM1 Over-Expression and Aneuploidy in Prostate Epithelial Cells

The ERG gene belongs to the ETS family of transcription factors and has been found to be involved in atypical chromosomal rearrangements in several cancers. To gain insight into the oncogenic activity of ERG, we compared the gene expression profile of NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG. We found that all three ERG fusions significantly up-regulate PIM1 expression in the NIH-3T3 cell line. PIM1 is a serine/threonine kinase frequently over-expressed in cancers of haematological and epithelial origin. We show here that tERG expression induces PIM1 in the non-malignant prostate cell line RWPE-1, strengthening the relation between tERG and PIM1 up-regulation in the initial stages of prostate carcinogenesis. Silencing of tERG reversed PIM1 induction. A significant association between ERG and PIM1 expression in clinical prostate carcinoma specimens was found, suggesting that such a mechanism may be relevant in vivo. Chromatin Immunoprecipitation experiments showed that tERG directly binds to PIM1 promoter in the RWPE-1 prostate cell line, suggesting that tERG could be a direct regulator of PIM1 expression. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability