Histological grading in primary membranous nephropathy is essential for clinical management and predicts outcome of patients.

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 < 0.0001 and 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.

Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function.

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.

Serum Fas Ligand, Serum Myostatin and Urine TGF-ß1 Are Elevated in Autosomal Dominant Polycystic Kidney Disease Patients with Impaired and Preserved Renal Function.

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-ß1) 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-ß1 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-ß1 (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-ß1 (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-ß1 (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-ß1 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.

Hemodiafiltration does not have additional benefits over hemodialysis on arterial stiffness, wave reflections and central aortic pressures.

BACKGROUND/AIMS: The hypothesis that dialytic modality affects arterial stiffness was never investigated. This study includes comparative evaluation of hemodiafiltration versus hemodialysis on arterial function during first and second weekly dialysis sessions. METHODS: 24 patients receiving hemodiafiltration and another 24 age- and sex-matched controls receiving hemodialysis were included. Patients were evaluated before and after first and second weekly dialysis sessions. Applanation tonometry of peripheral arteries was applied to determine aortic and brachial pulse wave velocity and heart rate-adjusted augmentation index (AIx(75)). RESULTS: Hemodiafiltration and hemodialysis reduced AIx(75), but not aortic and brachial pulse wave velocity. Intradialytic reductions in AIx(75) did not differ between hemodiafiltration and hemodialysis in first and mid-week dialysis. In multivariate linear regression, predictors of intradialytic reduction in AIx(75) were changes in body weight and central aortic systolic blood pressure, but not dialytic modality. CONCLUSION: This study showed that hemodiafiltration has similar effects with hemodialysis on wave reflections and stiffness.

Elevated asymmetric dimethylarginine is associated with oxidant stress aggravation in patients with early stage autosomal dominant polycystic kidney disease.

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/1.73 m(2)), 26 age- and sex-matched ADPKD patients (Group B) with relatively preserved renal function (eGFR)>70 ml/min/1.73 m(2)), 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. © 2014 S. Karger AG, Basel.

Serum Copeptin, NLPR3, and suPAR Levels among Patients with Autosomal-Dominant Polycystic Kidney Disease with and without Impaired Renal Function.

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.

Acute Interstitial Nephritis in a Patient with Non-Small Cell Lung Cancer under Immunotherapy with Nivolumab.

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.

Immunosuppressive regimens based on Cyclophospamide or Calcineurin inhibitors: Comparison of their effect in the long term outcome of Primary Membranous Nephropathy.

INTRODUCTION: 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: The 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.

Increase in oxidative stress but not in antioxidant capacity with advancing stages of chronic kidney disease.

BACKGROUND/AIMS: Increased oxidative stress in chronic kidney disease (CKD) was suggested to be both a cause and an effect of renal injury. However, the evolution of oxidant stress from early stages of renal function decline is not fully clear. This study aimed to determine the oxidant-antioxidant balance across the whole range of renal function. METHODS: A total of 116 patients with CKD (85 predialysis patients divided into groups according to CKD stage, and 31 patients with end-stage renal disease (ESRD) on hemodialysis treatment), as well as 29 healthy subjects were evaluated. Plasma levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP), a valid marker of oxidant stress, as well as total antioxidant capacity (TAC) and serum levels of vitamin E were measured in all participants. RESULTS: Plasma 15-F(2t)-IsoP levels were higher in predialysis and ESRD patients compared to healthy subjects and were progressively increasing with advancing CKD stages (p < 0.001). In contrast, plasma TAC was similar between healthy subjects and predialysis patients, and presented a small reduction in ESRD patients (p < 0.001). Vitamin E levels were higher in healthy subjects compared to any other group (p < 0.001) and slightly higher in ESRD patients compared to predialysis patients (p < 0.01), but did not differ significantly between the groups of predialysis patients. Plasma 15-F(2t)-IsoP levels were inversely correlated with estimated glomerular filtration rate in predialysis patients (r = -0.65, p < 0.001). CONCLUSIONS: This study shows that 15-F(2t)-IsoP levels increase progressively with advancing CKD stages, whereas TAC and vitamin E levels remain rather stable with the loss of renal function and change only in patients with ESRD.

Evaluation of the tolerability and efficacy of sodium polystyrene sulfonate for long-term management of hyperkalemia in patients with chronic kidney disease.

PURPOSE: 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. METHODS: In this retrospective, observational study, we enrolled 26 outpatients with stages 3-4 CKD who received oral therapy with low-dose SPS for mild chronic hyperkalemia in the Outpatient Nephrology clinic of our Department during 2010-2016. We obtained medical records on side effects potentially attributable to SPS use, and we analyzed the changes in serum electrolytes before and after the initiation of SPS therapy. RESULTS: Serum potassium levels fell from 5.9 ± 0.4 to 4.8 ± 0.5 mmol/l (P < 0.001) over a median follow-up of 15.4 months (range 3-27 months). SPS use was associated with a slight, but significant elevation in serum sodium levels (139.5 ± 2.9 vs 141.2 ± 2.4, P = 0.006), whereas serum calcium and phosphate remained unchanged before and after the initiation of SPS. We recorded ten episodes of recurrent serum potassium elevation ≥ 5.5 mmol/l, none of which required hospitalization or acute dialysis. No episode of colonic necrosis or any other serious drug-related adverse event was observed. SPS therapy was well-tolerated, since only 1 out of 26 patients discontinued SPS at 3 months due to gastrointestinal intolerance. CONCLUSION: This study suggests that low-dose SPS is well-tolerated and can effectively normalize elevated serum potassium over several weeks in CKD outpatients with mild chronic hyperkalemia.

Relationship between exercise test recovery indices and psychological and quality-of-life status in hemodialysis patients: a pilot study.

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.

Effects of intradialytic exercise training on health-related quality of life indices in haemodialysis patients.

OBJECTIVE: To assess the effects of intradialytic exercise training on health-related quality of life indices in haemodialysis patients. SUBJECTS/PATIENTS: Thirty-five patients on haemodialysis, with a mean (SD) age of 48.8 (13.9) years, volunteered to participate in the study. They were randomized either to rehabilitation group (group A: 19 patients), following a 10-month intradialytic exercise training programme or to control group (group B: 14 patients). After the randomization, two of the patients, one of each group, withdrew from the study for reasons unrelated to exercise training. METHOD: All patients at the beginning and the end of the study underwent clinical examination, laboratory tests and a treadmill exercise testing with spiroergometric study for the evaluation of their aerobic capacity (Vo(2peak)). A formal psychosocial assessment, which included affective (Beck Depression Inventory), health-related quality of life (Quality of Life Index, Living Questionnaire of Minnesota, Life Satisfaction Index and Short Form-36 questionnaire) and personality (Eysenck Personality Questionnaire) parameters, was evaluated at beginning and end of the study. The dose of erythropoietin was changed as needed, according to the level of the haemoglobin, aiming to keep it at 11 (2) g/dL during the study. RESULTS: Baseline values were similar between the two groups. After training in group A, Vo(2peak) was increased by 21.1% (P<0.05) and exercise time by 23.6% (P<0.05). Moreover, group A showed a decrease in self-reported depression (Beck Depression Index) of 39.4% (P<0.001). In addition, trained patients demonstrated a significant improvement in Quality of Life Index (from 6.5 (1.8) to 9.0 (1.3), P<0.001) and Life Satisfaction Index (from 44.8 (8.6) to 53.0 (5.6), P<0.001), and an increase in the Physical Component Scale of the SF-36 (from 40.5 (5.6) to 44.5 (5.5), P<0.05), while the Mental Component Scale remained unchanged. Multiple regression analysis indicated that the improvement in quality of life depended on the participation in exercise programmes, the effects of training and the reduction in the level of depression. No changes were observed in Eysenck Personality Questionnaire by the end of the study, while all the above parameters remained almost unchanged in the controls. CONCLUSION: The results demonstrated that intradialytic exercise training improves both physical functioning and psychological status in haemodialysis patients, leading to an improvement of patients' quality of life.