Clinical Significance of the Cystic Phenotype in Alport Syndrome.

RATIONALE & OBJECTIVE: Alport syndrome (AS) is the most common genetic glomerular disease caused by mutations that affect type IV collagen. However, the clinical characteristics and significance of AS with kidney cysts are not well defined. This study investigated the prevalence and clinical significance of cystic kidney phenotype in AS. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: One hundred-eight patients with AS and a comparison cohort of 79 patients with IgA nephropathy (IgAN). Clinical, genetic, and imaging data were collected from medical records. EXPOSURE: Cystic kidney phenotype evaluated by ultrasonography and defined as the presence of≥3 cysts in each kidney; demographic characteristics and estimated glomerular filtration rate (eGFR) at disease onset. OUTCOME: Cystic kidney phenotype in the AS and IgAN cohorts; time to chronic kidney disease (CKD) stage 3b and longitudinal changes in eGFR in the AS cohort. ANALYTICAL APPROACH: Logistic regression analysis to test independent strengths of associations of clinical/demographic features with the binary outcome of cystic phenotype. Survival analysis for the outcome of reaching CKD stage 3b and linear mixed models for changes in eGFR over time in the AS cohort. RESULTS: We studied 108 patients with AS; 76 (70%) had a genetic diagnosis. Autosomal dominant AS was prevalent, accounting for 68% of patients with a genetic diagnosis. Cystic kidney phenotype was observed in 38% of patients with AS and was associated with normal-sized kidneys in all but 3 patients, who showed increased total kidney volume, mimicking autosomal dominant polycystic kidney disease. The prevalence of cystic kidney phenotype was significantly higher in patients with AS when compared with the group of patients with IgAN (42% vs 19%; P=0.002). Patients with the cystic kidney phenotype were older and had more marked reduction in eGFR than patients without cystic changes. Among patients with AS, the cystic phenotype was associated with older age and a faster decline eGFR. LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: Cystic kidney phenotype is a common finding in AS. The cystic kidney phenotype is a common finding in AS, suggesting a possible role in cystogenesis for the genetic variants that cause this disease. PLAIN-LANGUAGE SUMMARY: Hematuria is the classic renal presentation of Alport syndrome (AS), a hereditary glomerulopathy caused by pathogenic variants of the COL4A3-5 genes. An atypical kidney cystic phenotype has been rarely reported in individuals with these variants. To determine the prevalence of kidney cysts, we performed abdominal ultrasonography in a large group of patients with AS and a comparison group of patients with another glomerular kidney disease, IgA nephropathy (IgAN). Multiple kidney cysts, usually with normal kidney volume, were found in 38% of patients with AS. A few patients' kidney volumes were large enough to mimic a different hereditary cystic kidney disease, autosomal dominant polycystic kidney disease. The overall prevalence of kidney cysts in AS was more than double that observed in the well-matched comparison group with IgAN. These findings emphasize the high prevalence of cystic kidney phenotype in AS, suggesting a likely association between the genetic variants that cause this disease and the development of kidney cysts.

Monoallelic pathogenic IFT140 variants are a common cause of autosomal dominant polycystic kidney disease-spectrum phenotype.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, characterized by development and enlargement of kidney cysts, eventually leading to end-stage kidney disease (ESKD). Pathogenic variants in the PKD1 and PKD2 genes are the major cause of ADPKD; additional rare variants in the GANAB, DNAJB11, ALG5 and ALG9 genes have been found in a minority of ADPKD patients. More recently, a significant number of ADPKD families have been linked to monoallelic variants in the IFT140 gene. Methods: In this retrospective study, we tested the prevalence of the known causative genes of ADPKD-spectrum phenotype, including the PKD1, PKD2, GANAB, DNAJB11, ALG5, ALG and IFT140 genes, in a cohort of 129 ADPKD patients who consecutively underwent genetic testing in a single centre in Italy. Genetic testing utilized a combination of targeted next-generation sequencing, long-range polymerase chain reaction, Sanger sequencing and multiplex ligation-dependent probe amplification. Clinical evaluation was conducted through renal function testing and imaging features, including ultrasonography, computer tomography and magnetic resonance imaging. Results: Of the 129 enrolled patients, 86 (66.7%) had pathogenic variants in PKD1 and 28 (21.7%) in PKD2, loss of function pathogenic variants in the IFT140 gene were found in 3 unrelated patients (2.3%), no pathogenic variants were found in other ADPKD genes and 12 patients (9.3%) remained genetically unresolved (ADPKD-GUR). Familial clinical and genetic screening of the index patients with ADPKD due to an IFT140 pathogenic variant (ADPKD-IFT140) allowed identification of eight additional affected relatives. In the 11 ADPKD-IFT140 patients, the renal phenotype was characterized by mild and late-onset PKD, with large renal cysts and limited kidney insufficiency. Extrarenal manifestations, including liver cysts, were rarely seen. Conclusion: Our data suggest the monoallelic pathogenic IFT140 variants are the third most common cause of the ADPKD-spectrum phenotype in Italy, usually associated with a mild and atypical renal cystic disease.

Ten-year experience of an outpatient clinic for CKD-5 patients with multidisciplinary team and educational support.

PURPOSE: To analyze the results of an outpatient clinic with a multidisciplinary team and educational support for patients with late-stage CKD (lsCKD), to check its possible effect on their outcomes. METHODS: Longitudinal cohort study on patients followed up in the MaReA (Malattia Renale Avanzata = CKD5) outpatient clinic at ASST Spedali Civili of Brescia from 2005 to 2015 for at least six months. Trajectory of renal function over time has been evaluated only in those patients with at least four estimations of eGFR before referring to MaReA. RESULTS: Seven hundred and six patients were enrolled, their mean age was 72 ± 14 years, 59% were males. At the end of the study, 147 (21%) were still on MaReA, 240 (34%) on dialysis, 92 (13%) on very low-protein diet (VLPDs), 13 (2%) on pre-hemodialysis clinic, 23 (3%) improved renal function, 10 (1%) transplanted, 62 (9%) transferred/lost to follow-up, and 119 (17%) died. Optimal dialysis start (defined as start with definitive dialysis access, as an out-patient and without lsCKD complications) occurred in 180/240 (75%) patients. The results showed a slower eGFR decrease during MaReA follow-up compared to previous renal follow-up: - 2.0 vs. - 4.0 mL/min/1.73 m2 BSA/year (p < 0.05), corresponding to a median delay of 17.7 months in dialysis start in reference to our policy in starting dialysis. The patient cumulative survival was 75% after 24 months and 25% after 70. LIMITATIONS: (1) lack of a control group, (2) one-center-study, (3) about all patients were Caucasians. CONCLUSION: The follow-up of lsCKD patients on MaReA is associated with an optimal and delayed initiation of dialysis.

[ADPKD and intracranial aneurysms: indications for screening, follow-up and clinical management].

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary nephropathy and is the fourth most common cause for end-stage renal disease in Europe. ADPKD is a systemic disease; besides the typical renal involvement, characterized by progressive cyst expansion leading to massive enlargement and distortion of the kidney architecture and, ultimately, to end-stage renal disease, multiple extrarenal manifestations can be observed included cysts in other organs, diverticulosis, cardiac valvulopathies, abdominal and inguinal hernias, vascular anomalies. The rupture of an intracranial aneurysm is one of the most serious complications in ADPKD patients. Aim of this review is to provide useful indications for the clinician to define the risk of intracranial aneurysms in ADPKD population, to identify screening criteria (which patients to screen, how often and with which diagnostic methods), to estimate the risk of rupture of intracranial aneurysms, which may require intervention.

Changes in clinical scenarios, management, and perspectives of patients with chronic hepatitis C after viral clearance by direct-acting antivirals.

INTRODUCTION: Hepatitis C virus (HCV) causes a systemic infection inducing hepatic and extrahepatic diseases. These latter involve cardiovascular system, kidney, brain, endocrine, glucose, and lipid metabolism, and the immune system. HCV infection is associated with an increased risk of morbidity and mortality for both hepatic and extrahepatic events. Direct-acting antivirals (DAA), introduced in the most recent years for HCV treatment, are effective in up to 99% of cases and have changed the clinical scenarios and management of these patients. AREAS COVERED: The literature on the impact of HCV clearance by DAA on both hepatic and extrahepatic disease outcomes has been analyzed and discussed in this review in order to summarize the full therapeutic potential and its weaknesses. EXPERT OPINION: Patients achieving HCV clearance have improved hepatic and extrahepatic diseases, quality of life and survival. They have lower incidence of cardiovascular disease, type 2 diabetes, kidney damage, and immuno-mediated manifestations. However, the improvements are related to the degree of pre-treatment organ damage. Therefore, a significant percentage of patients with advanced disease remains at risk of morbidity and mortality and must be monitored in the post-treatment. In addition, data emphasize the importance of starting treatment during the early stages of HCV infection.

Acute Kidney Injury due to Anticoagulant-Related Nephropathy : A Suggestion for Therapy.

The relationship between kidneys and anticoagulation is complex, especially after introduction of the direct oral anticoagulants (DOAC). It is recently growing evidence of an anticoagulant-related nephropathy (ARN), a form of acute kidney injury caused by excessive anticoagulation. The pathogenesis of kidney damage in this setting is multifactorial, and nowadays, there is no established treatment. We describe a case of ARN, admitted to our Nephrology Unit with a strong suspicion of ANCA-associated vasculitis due to gross haematuria and haemoptysis; the patient was being given dabigatran. Renal biopsy excluded ANCA-associated vasculitis and diagnosed a red blood cell cast nephropathy superimposed to an underlying IgA nephropathy. Several mechanisms are possibly responsible for kidney injury in ARN: tubular obstruction, cytotoxicity of heme-containing molecules and free iron, and activation of proinflammatory/profibrotic cytokines. Therefore, the patient was given a multilevel strategy of treatment. A combination of reversal of coagulopathy (i.e., withdrawal of dabigatran and infusion of its specific antidote) along with administration of fluids, sodium bicarbonate, steroids, and mannitol resulted in conservative management of AKI and fast recovery of renal function. This observation could suggest a prospective study aiming to find the best therapy of ARN.

A more tubulocentric view of diabetic kidney disease.

Diabetic nephropathy (DN) is a common complication of Diabetes Mellitus (DM) Types 1 and 2, and prevention of end stage renal disease (ESRD) remains a major challenge. Despite its high prevalence, the pathogenesis of DN is still controversial. Initial glomerular disease manifested by hyperfiltration and loss of glomerular size and charge permselectivity may initiate a cascade of injuries, including tubulo-interstitial disease. Clinically, 'microalbuminuria' is still accepted as an early biomarker of glomerular damage, despite mounting evidence that its predictive value for DN is questionable, and findings that suggest the proximal tubule is an important link in the development of DN. The concept of 'diabetic tubulopathy' has emerged from recent studies, and its causative role in DN is supported by clinical and experimental evidence, as well as plausible pathogenetic mechanisms. This review explores the 'tubulocentric' view of DN. The recent finding that inhibition of proximal tubule (PT) glucose transport (via SGLT2) is nephro-protective in diabetic patients is discussed in relation to the tubule's potential role in DN. Studies with a tubulocentric view of DN have stimulated alternative clinical approaches to the early detection of diabetic kidney disease. There are tubular biomarkers considered as direct indicators of injury of the proximal tubule (PT), such as N-acetyl-ß-D-glucosaminidase, Neutrophil Gelatinase-Associated Lipocalin and Kidney Injury Molecule-1, and other functional PT biomarkers, such as Urine free Retinol-Binding Protein 4 and Cystatin C, which reflect impaired reabsorption of filtered proteins. The clinical application of these measurements to diabetic patients will be reviewed in the context of the need for better biomarkers for early DN.