Citations

Background: This study aimed to evaluate the hospitalization rates for subarachnoid hemorrhage (SAH) among renal transplant patients with adult polycystic kidney disease (ADPKD) and its outcomes, when compared to non-ADPKD renal transplant patients. Methods: The 2005–2014 National Inpatient Sample databases were used to identify all hospitalized renal transplant patients. The inpatient prevalence of SAH as a discharge diagnosis between ADPKD and non-ADPKD renal transplant patients was compared. Among SAH patients, the in-hospital mortality, use of aneurysm clipping, hospital length of stay, total hospitalization cost and charges between ADPKD and non-ADPKD patients were compared, adjusting for potential confounders. Results: The inpatient prevalence of SAH in ADPKD was 3.8/1000 admissions, compared to 0.9/1000 admissions in non-ADPKD patients (p < 0.01). Of 833 renal transplant patients with a diagnosis of SAH, 30 had ADPKD. Five (17%) ADPKD renal patients with SAH died in hospitals compared to 188 (23.4%) non-ADPKD renal patients (p = 0.70). In adjusted analysis, there was no statistically significant difference in mortality, use of aneurysm clipping, hospital length of stay, or total hospitalization costs and charges between ADPKD and non-ADPKD patients with SAH. Conclusion: Renal transplant patients with ADPKD had a 4-fold higher inpatient prevalence of SAH than those without ADPKD. Further studies are needed to compare the incidence of overall admissions in ADPKD and non-ADPKD patients. When renal transplant patients developed SAH, inpatient mortality rates were high regardless of ADPKD status. The outcomes, as well as resource utilization, were comparable between the two groups.

Background: Fifty percent of patients with autosomal dominant polycystic kidney disease (ADPKD) present hypertension (HTN) early on, which increases to nearly 100% at end-stage, and is associated with faster renal functional decline. Endothelial dysfunction (ED) accompanied by oxidative stress (OS) precedes the development of HTN, but the mechanisms responsible remain unknown. The aim of this study was to determine whether NADPH oxidase (NOX4) and mitochondrial dysfunction contribute to OS and ED preceding HTN in early ADPKD. Methods: We prospectively measured plasma levels of homocysteine (Hcy), 8-isoprostane, NOX4 and the mtDNA genes COX3 and ND1 in young normotensive (without BP medication) ADPKD patients, and age-matched healthy volunteers (HV) (n=10, each). Total kidney volume (TKV) and Renal Blood Flow (RBF) were evaluated by MRI. Results: BP levels were higher in ADPKD, and HtTKV was twofold higher in ADPKD vs. controls. eGFR and RBF were similar between the groups (Table). Plasma Hcy, 8-isoprostanes and NOX4 were higher in ADPKD, and correlated directly with HtTKV (p<0.05, Figure), but the correlation with RBF was not significant. Plasma mtDNA copy number were lower in ADPKD compared to controls, and correlated inversely with HtTKV(R 2 0.397 and 0.392 respectively). Conclusion: Early ADPKD is associated with elevation in Hcy, 8-isoprostane, and NOX4 levels, and decreased mtDNA copy numbers, which precede the reduction in RBF and the development of HTN, and are associated with disease severity. NOX4 and mitochondrial abnormalities may contribute to oxidative stress, endothelial dysfunction, and possibly the development of HTN and disease progression in ADPKD.

In the past, the treatment of autosomal dominant polycystic kidney disease (ADPKD) has been limited to the management of its symptoms and complications. Recently, the US Food and Drug Administration (FDA) approved tolvaptan as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing ADPKD. Full prescribing information approved by the FDA provides helpful guidelines but does not address practical questions that are being raised by nephrologists, internists, and general practitioners taking care of patients with ADPKD, and by the patients themselves. In this review, we provide practical guidance and discuss steps that require consideration before and after prescribing tolvaptan to patients with ADPKD to ensure that this treatment is implemented safely and effectively. These steps include confirmation of diagnosis; identification of rapidly progressive disease; implementation of basic renal protective measures; counseling of patients on potential benefits and harms; exclusions to use; education of patients on aquaresis and its expected consequences; initiation, titration, and optimization of tolvaptan treatment; prevention of aquaresis-related complications; evaluation and management of liver enzyme elevations; and monitoring of treatment efficacy. Our recommendations are made on the basis of published evidence and our collective experiences during the randomized, clinical trials and open-label extension studies of tolvaptan in ADPKD.

Background and objectives In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy. Design, setting, participants, & measurements One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for ≥1 year (mean±SD, 4.6±2.8; range, 1.1–11.2) were analyzed for efficacy using three approaches: ( 1 ) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; ( 2 ) Stability of eGFR slopes with duration of follow-up; and ( 3 ) comparison of observed and predicted eGFRs at last follow-up. Results Patients treated with tolvaptan had lower eGFR slopes from baseline (mean±SD, −2.20±2.18 ml/min per 1.73 m 2 per year) and from month 1 (mean±SD, −1.97±2.44 ml/min per 1.73 m 2 per year) compared with controls (mean±SD, −3.50±2.09 ml/min per 1.73 m 2 per year; P <0.001), and lower risk of a 33% reduction in eGFR (risk ratio, 0.63; 95% confidence interval, 0.38 to 0.98 from baseline; risk ratio, 0.53; 95% confidence interval, 0.31 to 0.85 from month 1). Annualized eGFR slopes of patients treated with tolvaptan did not change during follow-up and differences between observed and predicted eGFRs at last follow-up increased with duration of treatment. Conclusions Follow-up for up to 11.2 years (average 4.6 years) showed a sustained reduction in the annual rate of eGFR decline in patients treated with tolvaptan compared with controls and an increasing separation of eGFR values over time between the two groups.

ABSTRACTBackgroundComplications related to peritoneal dialysis (PD) in patients with autosomal‐dominant polycystic kidney disease (ADPKD), including intraperitoneal rupture of renal cyst, hernia, membrane failure and peritonitis, have been reported. However, long‐term clinical outcomes of ADPKD patients on PD remain unclear. We performed this meta‐analysis to assess the risks of death, technique failure and peritonitis in ADPKD patients on PD.MethodsA systematic review was conducted using MEDLINE, EMBASE and Cochrane databases from inception to October 2017 to identify studies that evaluated the outcomes of ADPKD patients on PD, including the risks of death, technique failure and peritonitis. Non‐ADPKD patients on PD were used as controls. Effect estimates from the individual study were extracted and combined using the random‐effect, generic inverse variance method of DerSimonian and Laird.ResultsTwelve cohort studies with a total of 14 673 patients on PD (931 ADPKD and 13 742 non‐ADPKD patients) were enrolled. Compared with non‐ADPKD status, ADPKD was associated with significantly decreased mortality risk with pooled odds ratio (OR) of 0.68 (95% confidence interval (CI), 0.53–0.86; I2 = 0). There were no associations of ADPKD with the risks of technique failure of PD and peritonitis with pooled OR of 0.93 (95% CI, 0.79–1.10; I2 = 0) and 0.88 (95% CI, 0.75–1.05; I2 = 0), respectively. We found no publication bias as assessed by Egger's regression asymmetry test, with P = 0.90, 0.28 and 0.60 for the risks of mortality, technique failure and peritonitis in ADPKD patients on PD, respectively.ConclusionCompared with non‐ADPKD patients on PD, our study demonstrates that ADPKD patients on PD have 0.68‐fold decreased mortality risk. There are no associations of ADPKD status with the risks of technique failure or peritonitis.

The failure of the polycystins (PCs) to function in primary cilia is thought to be responsible for autosomal dominant polycystic kidney disease (ADPKD). Primary cilia integrate multiple cellular signaling pathways, including calcium, cAMP, Wnt, and Hedgehog, which control cell proliferation and differentiation. It has been proposed that mutated PCs result in reduced intracellular calcium, which in turn upregulates cAMP, protein kinase A (PKA) signaling, and subsequently other proliferative signaling pathways. However, the role of PKA in ADPKD has not been directly ascertained in vivo, although the expression of the main regulatory subunit of PKA in cilia and other compartments (PKA-RIα, encoded by PRKAR1A) is increased in a mouse model orthologous to ADPKD. Therefore, we generated a kidney-specific knockout of Prkar1a to examine the consequences of constitutive upregulation of PKA on wild-type and Pkd1 hypomorphic ( Pkd1 RC ) backgrounds. Kidney-specific loss of Prkar1a induced renal cystic disease and markedly aggravated cystogenesis in the Pkd1 RC models. In both settings, it was accompanied by upregulation of Src, Ras, MAPK/ERK, mTOR, CREB, STAT3, Pax2 and Wnt signaling. On the other hand, Gli3 repressor activity was enhanced, possibly contributing to hydronephrosis and impaired glomerulogenesis in some animals. To assess the relevance of these observations in humans we looked for and found evidence for kidney and liver cystic phenotypes in the Carney complex, a tumoral syndrome caused by mutations in PRKAR1A. These observations expand our understanding of the pathogenesis of ADPKD and demonstrate the importance of PRKAR1A highlighting PKA as a therapeutic target in ADPKD.