Cardiovascular Risk and Quality of Life in Autosomal Dominant Polycystic Kidney Disease Patients on Therapy With Tolvaptan: A Pilot Study.

INTRODUCTION: Cardiovascular (CV) complications are the most frequent cause of morbidity and mortality in autosomal dominant polycystic kidney disease (ADPKD) patients. In 2017, the Italian Medicines Agency authorised tolvaptan, a vasopressin V2 receptor antagonist, for the treatment of ADPKD, based on the Tolvaptan Phase 3 Efficacy and Safety Study in ADPKD (TEMPO 3: 4), TEMPO 4: 4 and Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) studies. AIM OF THE STUDY: The aim of the study was to assess the impact of tolvaptan on CV risk and quality of life, evaluated by nutritional, inflammatory, metabolic, instrumental parameters and psychocognitive tests on ADPKD patients. METHODS AND MATERIALS: We evaluated 36 patients with ADPKD; 10 patients (7 males, mean age 42.5±7.0 years) treated with tolvaptan and 26 controls (11 males, mean age 36.7±9.1 years). They underwent, at T0, monthly, and at T1 (1 year) clinical, laboratory and instrumental evaluation, in addition to psychocognitive tests. RESULTS: In ADPKD patients treated with tolvaptan, we found at T1, a decrease in carotid intima-- media thickness (p=0.048), epicardial adipose tissue thickness (p=0.002), C-reactive protein (p=0.026), sympathovagal balance during night (p=0.045) and increased flow-mediated dilation (p=0.023) with a reduction in depression (Hamilton and Beck tests, p=0.008 and p=0.002, respectively) compared with controls. CONCLUSION: These preliminary results suggest that treatment with tolvaptan could improve early atherosclerosis and endothelial dysfunction markers and improve mood in ADPKD patients (probably by acting on endothelial cell and adipocyte V2 receptors).

Effect of Low-Protein Diet and Inulin on Microbiota and Clinical Parameters in Patients with Chronic Kidney Disease.

INTRODUCTION: The gut microbiota has coevolved with humans for a mutually beneficial coexistence and plays an important role in health and disease. A dysbiotic gut microbiome may contribute to progression to chronic kidney disease (CKD) and CKD-related complications such as cardiovascular disease. Microbiota modulation through the administration of prebiotics may represent an important therapeutic target. AIM: We sought to evaluate the effects of a low-protein diet (LPD) (0.6 g/kg/day) with or without the intake of the prebiotic inulin (19 g/day) on microbiota and clinical parameters in CKD patients. MATERIALS AND METHODS: We performed a longitudinal, prospective, controlled, and interventional study on 16 patients: 9 patients treated with LPD (0.6 g/kg/day) and inulin (19 g/day) and 7 patients (control group) treated only with LPD (0.6 g/kg/day). Clinical evaluations were performed and fecal samples were collected for a subsequent evaluation of the intestinal microbiota in all patients. These tests were carried out before the initiation of LPD, with or without inulin, at baseline (T0) and at 6 months (T2). The microbiota of 16 healthy control (HC) subjects was also analyzed in order to identify potential dysbiosis between patients and healthy subjects. RESULTS: Gut microbiota of CKD patients was different from that of healthy controls. The LPD was able to significantly increase the frequencies of Akkermansiaceae and Bacteroidaceae and decrease the frequencies of Christensenellaceae, Clostridiaceae, Lactobacillaceae, and Pasteurellaceae. Only Bifidobacteriaceae were increased when the LPD was accompanied by oral inulin intake. We showed a significant reduction of serum uric acid (SUA) and C-reactive protein (CRP) in patients treated with LPD and inulin (p = 0.018 and p = 0.003, respectively), an improvement in SF-36 (physical role functioning and general health perceptions; p = 0.03 and p = 0.01, respectively), and a significant increase of serum bicarbonate both in patients treated with LPD (p = 0.026) or with LPD and inulin (p = 0.01). Moreover, in patients treated with LPD and inulin, we observed a significant reduction in circulating tumor necrosis factor alpha (TNF-α) (p = 0.041) and plasma nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) (p = 0.027) levels. We did not find a significant difference in the circulating levels of Interleukin (IL)-1ß (p = 0.529) and IL-6 (p = 0.828) in the two groups. CONCLUSIONS: LPD, associated or not with inulin, modified gut microbiota and modulated inflammatory and metabolic parameters in patients with CKD. Our results suggest that interventions attempting to modulate the gut microbiome may represent novel strategies to improve clinical outcomes in CKD patients and may provide useful therapeutic effects.

Reduction in Heart Rate Variability in Autosomal Dominant Polycystic Kidney Disease.

INTRODUCTION: Cardiovascular disease is one of the main causes of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Autonomic dysfunction is associated with an increased risk for all cardiovascular events in the general population and can be evaluated with heart rate variability (HRV). OBJECTIVE: To evaluate HRV in ADPKD patients with mild hypertension versus hypertensive patients with organ damage and healthy controls (HC). MATERIALS AND METHODS: We have enrolled 65 patients: 21 ADPKD patients (10 males), 20 patients with hypertension (14 males), and 24 HC (10 males). Biochemical analysis, clinical evaluation, anthropometric data, intima-media thickness, 24-h ECG Holter recording, and echocardiography were investigated at the time of enrollment. RESULTS: No significant differences in HRV parameters were found between ADPKD with mild hypertension and hypertensive patients with organ damage. The median of HRV variables in time domain as SDNN (global autonomic activity) was significantly lower in ADPKD and hypertensive patients than HC (p < 0.05). In the frequency domain analysis, low frequency (LF), which mainly reflects the sympathetic component, showed higher values in ADPKD and hypertensive patients than HC during the night (p < 0.01). During the night, the sympathovagal balance, LF/high frequency (HF), showed higher values in ADPKD and hypertensive patients than HC (p < 0.0001). Conversely, LF day was lower in ADPKD and hypertensive patients than HC (p < 0.01). HF, which mainly reflects the parasympathetic component, was lower in ADPKD and hypertensive patients during the night than HC (p < 0.0001). CONCLUSIONS: HRV reduction is present in ADPKD patients with mild hypertension in the absence of organ damage. The evaluation of sympathovagal balance can provide novel information on the cardiovascular risk in ADPKD patients in addition to classical risk factors.

Magnetic resonance imaging 3T and total fibrotic volume in autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal hereditary disorder. Several authors have attempted to identify a kidney damage marker for predicting the prognosis and the effectiveness of therapy in ADPKD. AIM: To identify and quantify ADPKD, through a novel magnetic resonance imaging protocol with 3 Tesla (MRI 3Tesla), the presence of parenchymal fibrotic tissue at early stage of disease, able to correlate the glomerular filtrate and to predict the loss of the renal function. METHODS: A total of 15 ADPKD patients had undergone renal testing on MRI 3Tesla at T0 and were revaluated after follow up (T1) of 5 years. We have evaluated renal function, plasma aldosterone concentration (PAC), insulin resistance and surrogate markers of atherosclerosis (carotid intima-media thickness, ankle/brachial index (ABI) and left ventricular mass index (LVMI). RESULTS: Our study showed a significant negative correlation between total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) during observation (P < 0.02). We showed a negative correlation between eGFR with total fibrotic volume (TFV) (P < 0.04) and total perfusion volume/TKV (P < 0.02). Moreover TFV was correlated positively with PAC (P < 0.05), insulin values (P < 0.05), ABI (P < 0.05) and LVMI (P < 0.01). CONCLUSION: The MRI 3Tesla, despite the high costs, could be considered as a useful and non-invasive method in the evaluation of fibrotic tissue and progression of the disease in ADPKD patients. Further clinical trials on larger groups are due to confirm the results of this pilot study, suggesting that MRI 3Tesla can be useful to evaluate the effectiveness of new therapeutic strategies.