Background: The pathophysiology of renal disease progression in autosomal-dominant polycystic kidney disease (ADPKD) involves not only cystogenesis but also endothelial dysfunction, leading to the activation of inflammatory and fibrotic pathways. This study evaluated the levels of biomarkers related to osmoregulation, immune system activation, and tubular injury in ADPKD patients with impaired or preserved renal function. Methods: This study included 26 ADPKD patients with modestly impaired renal function (estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m2; Group A), 26 age- and sex-matched ADPKD patients with relatively preserved renal function (eGFR >70 mL/min/1.73 m2; Group B), and 26 age- and sex-matched controls (Group C). Serum levels of copeptin, the inflammasome nucleotide-binding and oligomerization domain-like receptors pyrin domain-containing protein 3 (NLRP3), and soluble urokinase-type plasminogen activator receptor (suPAR) were measured with ELISA techniques. Results: Patients in Group A had higher levels of copeptin (median [interquartile range]: 50.44 [334.85] pg/mL), NLRP3 (5.86 [3.89] ng/mL), and suPAR (390.05 [476.53] pg/mL) compared to patients in Group B (32.38 [58.33], p = 0.042; 2.42 [1.96], p < 0.001; and 313.78 [178.85], p = 0.035, respectively) and Group C (6.75 [6.43]; 1.09 [0.56]; and 198.30 [28.53], respectively; p < 0.001 for all comparisons). Levels of all studied markers were also significantly higher in Group B patients compared to controls (p < 0.001), despite having similar eGFR. In patients with ADPKD, all studied biomarkers were correlated positively with asymmetric-dimethylarginine (ADMA) and endocan levels, and negatively with eGFR. ADMA and endocan levels were the only parameters independently associated with increased copeptin levels. Conclusions: This study showed that ADPKD patients with impaired and preserved renal function had higher copeptin, NLRP3, and suPAR levels than controls. Such findings support that cystogenesis and inflammation are associated with endothelial dysfunction, even in the early stages of ADKPD.

Management of the Primary Membranous Nephropathy (PMN) usually involves administration of immunosuppressives. Cyclophosphamide (Cyclo) and Calcineurin Inhibitors (CNIs) are both widely used but only limited data exist to compare their efficacy in long term follow-up. Aim of the present study was to estimate and compare long term effects of Cyclo and CNIs in patients with PMN. Patients-Methods Clinical data, histologic findings and long term outcome were retrospectively studied. The response to treatment and rate of relapse was compared between patients treated with CNIs or Cyclo based immunosuppressive regimens. Results Twenty three centers participated in the study, with 752 PMN patients (Mean age 53.4(14-87)yrs, M/F 467/285), followed for 10.1±5.7 years. All patients were initially treated with Renin Angiotensin Aldosterone System inhibitors (RAASi) for at least 6 months. Based on their response and tolerance to initial treatment, patients were divided into 3 groups, group I with spontaneous remission, who had no further treatment, group II, continued on RAASi only, and group III on RAASi+immunosuppression. Immunosuppressive regimes were mainly based on CNIs or Cyclo. Frequent relapses and failure to treatment were more common between patients who had started on CNIs (n=381) compared to those initially treated with Cyclo (n=110), relapse rate: 25.2% vs. 6.4%, p<0.0001, and no response rate: 22.5% vs. 13.6%, p=0.04, respectively. Conclusions Long term follow up showed that administration of Cyclo in PMN is followed by better preservation of renal function, increased response rate and less frequent relapses, compared to CNIs.

Immune-checkpoint-inhibitors (ICPIs) represent a novel class of immunotherapy against several malignancies. These agents are associated with several "immune-mediated" adverse effects, but the reported renal toxicity of ICPIs is less well defined. We present the case of a 60-year-old man with a history of non-small cell lung cancer, who developed acute kidney injury (AKI) approximately 3.5 months after initiation of immunotherapy with nivolumab. Urinalysis revealed sterile pyuria, without microscopic hematuria or proteinuria. Immunological examination was negative. A renal biopsy showed severe interstitial inflammatory infiltration of T-cells, monocytes, and eosinophils without interstitial granulomas and normal appearance of glomeruli, indicating acute interstitial nephritis (AIN) as the cause of AKI. After a short-term course of corticosteroids and permanent nivolumab discontinuation, partial recovery of renal function was noted. AIN is a rare adverse effect of ICPIs that mandates the close monitoring of renal function in patients under immunotherapy with these agents.

Aims Diagnosis of primary membranous nephropathy (PMN) is mainly based on immunofluorescence/immunohistochemistry findings. However, assessment of specific features on optical microscopy can help to estimate the severity of the disease, guide treatment and predict the response. The aim of this study was to identify, classify and grade the precise histological findings in PMN to predict renal function outcome and guide treatment. Methods and results Histological parameters, including focal segmental sclerosis (FSGS), tubular atrophy (TA), interstitial fibrosis (IF) and vascular hyalinosis (VH), were re-evaluated in 752 patients with PMN. Their predictive value was estimated separately, and also in a combination score (FSTIV) graded from 0 to 4. Finally, the impact of histology was assessed in the response to immunosuppressive treatment. Mean age of patients was 53.3 (15-85) years and most presented with nephrotic syndrome. FSGS was present in 32% and VH in 51% of the patients, while TA and IF were graded as stage >= 1 in 52% and 51.4%, respectively. The follow-up period was 122.3 (112-376) months. FSGS, TA and IF and VH were associated with impaired renal function at diagnosis (P = 0.02, P < 0.0001, P = 0.001 and P = 0.02, respectively) and at the end of follow-up (P = 0.004, P < 0.0001, P P = 0.04, respectively). In multiple regression and binary logistic analysis, the presence of FSGS and degree of TA were the most significant parameters predicting renal function outcome, defined either by eGFR (end), FSGS (r = 0.6, P < 0.0001) and TA (r = 0.6, P < 0.0001), or by the endpoint of >50% eGFR reduction, FSGS (P = 0.001) and TA (P = 0.02). Also, patients presented with FSGS, IF, VH and/or with FSTIV > 1 could benefit from immunosuppression, regardless of clinical presentation. Conclusions The presence and degree of four histological indices, FSGS, VH, TA and IF, assessed separately or in combination, and FSTIV score not only predict renal function outcome after long-term follow-up, but can also help in the choice of appropriate treatment. Decisions concerning immunosuppressive treatment can be guided by pathology regardless of clinical findings.

Background: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. Methods: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m2), 26 ADPKD patients with preserved renal function (Group B; eGFR >70 mL/min/1.73 m2), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. Results: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/mL, p = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan r = 0.908, p < 0.001, angiopoietin-2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. Conclusions: This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.

Background/Aims: The pathophysiology of renal disease progression in autosomal dominant polycystic disease (ADPKD) is largely unknown. Recent evidence suggests microvascular dysfunction leading to renal ischemia, as an additional pathway for renal function decline. This study examined the levels of serum Fas ligand (FasL), serum myostatin and urine transforming growth factor-beta 1 (TGF-β1) and their association with markers of endothelial dysfunction, in ADPKD patients with preserved or impaired renal function. Methods: Seventy-eight participants were enrolled in the study, divided in three groups: Group A consisted of 26 ADPKD patients with impaired renal function (eGFR 45-70 ml/min/1.73m2), Group B of 26 ADPKD patients with preserved renal function (eGFR > 70 ml/min/1.73m2), and Group C of 26 age- and sex- matched controls with no history of renal disease. Serum FasL, myostatin and urine levels of TGF-β1 were measured as biomarkers of vascular dysfunction, apoptosis and fibrosis with ELISA techniques. Results: Group A patients had significantly higher levels of FasL (13.12±1.69 ng/mL), myostatin (4.62±0.59 ng/mL) and urine logTGF-β1 (3.56±0.49 ng/24h) compared to Group B (9.6±1.28 ng/mL, 3.06±0.35, and 2.09±0.37, respectively, p< 0.001 for all comparisons) or controls (6.59±1.17 ng/mL, 2.18±0.45 ng/ml, and 1.58±0.21, respectively, p< 0.001 for all comparisons). Patients in Group B had also higher levels of all markers compared to controls (p< 0.001), despite having similar renal function. In ADKPD patients negative associations of eGFR with FasL (r=-0.799, p< 0.001), myostatin (r=-0.856, p< 0.001) and TGF-β1 (r=-0.476, p< 0.001) but positive correlations of these markers with asymmetric dimethylarginine (ADMA) (r=0.825; r=0.749; and r=0.599, respectively p< 0.001) were noted. Multivariate analysis demonstrated that FasL was independently associated with high urine TGF-β1 (OR 3.774, 95%CI 1.180-12.072, p=0.025). Conclusions: ADPKD patients with moderately preserved renal function have higher levels of FasL, myostatin and urine TGF-β1 than controls. These results indicate that an interplay between endothelial dysfunction and renal ischemia with mechanisms linked to apoptosis and fibrosis may be present even in early stages of ADPKD.

Objective: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an additional pathway of renal damage in autosomal-dominant-polycystic-kidney-disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. Design and method: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A) (eGFR 45–70 ml/min/1.73m2), 26 ADPKD patients with preserved renal function (Group B) (eGFR>70 ml/min/1.73m2), and 26 age- and sex- matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-induced-factor-1a (HIF-1a) were determined by ELISA techniques. Results: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/ml), angiopoietin-2 (5,595.43 ± 3,390) and HIF-1a (163.68 ± 37.84 pg/ml) compared to patients in Group B (6.86 ± 0.59 ng/ml, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/ml, p = 0.019, respectively) or controls (4.83 ± 0.69 ng/ml, 1,069 ± 427.88 pg/ml, 70.20 ± 17.49 pg/ml, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001), despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with ADMA (endocan r = 0.908, p < 0.001, angiopoietin2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. Conclusions: In conclusion, this study suggests that not only patients with low eGFR, but also those at early stages of the ADPKD had higher expression of markers indicative for endothelial dysfunction, angiogenesis and hypoxia in comparison to controls. These results could lead to the hypothesis that local microcirculatory changes may come early in the course of ADPKD and could be a cause rather than a result of disease progression and eGFR decline.

endpoint and 23 patients for the secondary endpoints. We excluded from analysis 11 patients because of loss to follow-up or Metformin withdrawal. Mean age at baseline was 47.2 69.6 years, 60.9% of participants were women and 47.6% had inherited the disease from the paternal line. Patients were characterized by overweight (BMI:27.463.5 kg/m2), 60.9% of them were dyslipidaemic, 78.3% hypertensive and 28.6% active smokers. At baseline, the majority of patients were in CKD stage G2. Regarding adverse events, we found 7 cases of nausea (20.5%), 2 of hunger (5.8%), 1 of abdominal pain (2.9%) and 1 of rash (2.9%). Among these, 2 patients (5.8%) stopped Metformin because of rash and abdominal pain. We report no event of hypoglicemia or lactic acidosis. After 4 months of treatment with Metformin, there was a slight, non-significant improvement in renal function, estimated with both CKD-EPI formula: eGFRþ2.10ml/min (95% CI -6.23 toþ10.44, p1⁄40.60) and CysC formula: eGFRþ11.60ml/min (95% CI -3.01 toþ26.21, p1⁄40.11). Also, we pointed out a significant decrease in weight by -0.52 kg/m2 (95% CI -0.80 to 0.25, p1⁄40.001). We found a significant, moderate negative correlation between kidney function estimated by CKD-EPI and BMI at 16 weeks of treatment ( r1⁄4 -0.48; p< 0.05).

Sodium polystyrene sulfonate (SPS) is a cation-exchanging resin that has been widely used for several decades as first-line therapy of mild chronic hyperkalemia in patients with chronic kidney disease (CKD). However, evidence to prove the long-term tolerability and efficacy of SPS for the treatment of this condition is still missing.

Background/Aims: In experimental models of polycystic kidney disease impaired bioavailability of nitric oxide (NO) and elevated mRNA expression of oxidative stress markers at the kidney level was noted. However, clinical studies investigating the potential role of endothelial dysfunction and oxidative stress in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) are limited. We evaluated asymmetric dimethylarginine (ADMA) as marker of NO synthase inhibitor as well as 15-F2t-Isoprostane and oxidized-low density lipoprotein (oxidized-LDL) as measures of oxidative stress in patients with early stages ADPKD. Methods: We recruited 26 ADPKD patients (Group A) with modestly impaired renal function (eGFR 45-70 ml/min/1.73m2), 26 age- and sex-matched ADPKD patients (Group B) with relatively preserved renal function (eGFR)>70 ml/min/1.73m2), and 26 age- and sex-matched controls (Group C). Determination of circulating levels of ADMA, 15-F2t-Isoprostane, oxidized-LDL and routine biochemistry was performed. Results: Group A and B had significantly higher ADMA levels as compared to controls (1.68±0.7 vs 0.51±0.2 μmol/l, P<0.001 and 1.26±0.7 vs 0.51±0.2 μmol/l, P<0.001, respectively). 15-F2t-IsoP and oxidized-LDL levels were also significantly higher in Group B relative to controls (788.8±185.0 vs 383.1±86.0 pgr/ml, P<0.001 and 11.4±6.6 vs 6.4±2.6 EU/ml, P<0.05 respectively) and were further elevated in Group A. In correlation analysis, ADMA levels exhibited strong associations with levels of 15-F2t-Isoprostane (r=0.811, P<0.001) and oxidized-LDL (r=0.788, P<0.001), whereas an inverse correlation was evident between ADMA and eGFR (r=-0.460, P<0.001). Conclusion: This study shows elevation in circulating levels of ADMA along with aggravation of oxidative stress from the early stages of ADPKD.

BACKGROUND The aim of this study was to correlate the psychological and health-related quality-of-life status of hemodialysis (HD) patients with recovery indices following maximal and submaximal exercise tests. METHODS Twenty patients on HD (aged 53.5 ± 12.9 years) and 18 healthy individuals (aged 54.1 ± 10.2 years) underwent a maximal and a submaximal cardiopulmonary test (CPETmax and CPETsubmax). Heart rate recovery (HRrec) 1 minute after exercise and time for VO2 to decrease by half (T1/2VO2) were determined. All subjects also completed 3 questionnaires: (a) the Beck Depression Inventory (BDI), (b) Quality of Life Index (QLI)-Spitzer Index and (c) SF-36 physical and mental component summary scales. RESULTS HRrec after maximal (p=0.029) and submaximal test (p=0.041) was found to be lower in patients compared with healthy individuals. T1/2VO2 was raised by 29% (p=0.003) in patients compared with controls. Moreover, a significantly higher BDI (by 133.7%), lower SF-36 physical (by 47.8%) and mental (by 42.9%) component summary score and lower QLI (by 32.1%) results were found in HD patients compared with controls. BDI (p=0.045), QLI (P=0.011), SF-36 physical (p=0.017) and mental component scales (p=0.021) were independently associated with HRrec in maximal tests in patients. Similar correlations remained for submaximal tests among HRrec and BDI (p=0.004), QLI (p=0.006), SF-36 physical (p=0.048) but not mental scales (p=0.369) in the patients' group. T1/2VO2 also correlated to BDI (p=0.019), QLI (p=0.005) and SF-36 mental scale (p=0.017) in maximal tests in these patients. In contrast, there was a correlation between HRrec and BDI (p=0.004) in the control group for maximal tests only. CONCLUSIONS In conclusion, in HD patients, recovery indices following maximal and submaximal exercise tests were shown to provide useful indications of the patients' psychological and quality-of-life profiles.

Background: Increased arterial stiffness characterizes the vasculature of end-stage renal disease (ESRD) [1] and is a strong predictor of their cardiovascular morbidity and mortality [2]. Apart from the increase burden of traditional cardiovascular risk factors, a number of functional alterations associated with chronic kidney disease have been proposed as additional mechanisms for the accelerated arteriosclerosis in such patients [3]. However, the question whether renal replacement treatment per se affects large artery elasticity and reflecting properties of peripheral sites in ESRD patients on maintenance hemodialysis remains largely unanswered, as previous studies that evaluating the acute effect of hemodialysis on large artery elasticity gave contradictory results [4, 5].