RESUMO
Polycystic kidney disease (PKD) is a chronic, progressive hereditary condition characterized by abnormal development and growth of cysts in the kidneys and other organs. There is increasing interest in exploring whether dietary modifications may prevent or slow the disease course in people with PKD. Although vasopressin-receptor agonists have emerged as a novel drug treatment in advancing care for people with PKD, several recent landmark trials and clinical discoveries also have provided new insights into potential dietary-related therapeutic strategies. In this review, we summarize the current evidence pertaining to nutrients, foods, dietary patterns, cyst growth, and progression of PKD. We also describe existing evidence-based dietary care for people with PKD and outline the potential implications for advancing evidence-based dietary interventions. Semin Nephrol 43:x-xx © 2023 Elsevier Inc. All rights reserved.
Assuntos
Doenças Renais Policísticas , Humanos , Rim , Dieta , NutrientesRESUMO
To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of ß cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery.
RESUMO
Mutations in PKD1 (encoding for polycystin-1 [PC1]) are found in 80%-85% of patients with autosomal dominant polycystic kidney disease (ADPKD). We tested the hypothesis that changes in actin dynamics result from PKD1 mutations through dysregulation of compartmentalized centrosomal RhoA signaling mediated by specific RhoGAP (ARHGAP) proteins resulting in the complex cellular cystic phenotype. Initial studies revealed that the actin cytoskeleton was highly disorganized in cystic cells derived from patients with PKD1 and was associated with an increase in total and centrosomal active RhoA and ROCK signaling. Using cilia length as a phenotypic readout for centrosomal RhoA activity, we identified ARHGAP5, -29, and -35 as essential regulators of ciliation in normal human renal tubular cells. Importantly, a specific decrease in centrosomal ARHGAP35 was observed in PKD1-null cells using a centrosome-targeted proximity ligation assay and by dual immunofluorescence labeling. Finally, the ROCK inhibitor hydroxyfasudil reduced cyst expansion in both human PKD1 3D cyst assays and an inducible Pkd1 mouse model. In summary, we report a potentially novel interaction between PC1 and ARHGAP35 in the regulation of centrosomal RhoA activation and ROCK signaling. Targeting the RhoA/ROCK pathway inhibited cyst formation in vitro and in vivo, indicating its relevance to ADPKD pathogenesis and for developing new therapies to inhibit cyst initiation.
Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Rim Policístico Autossômico Dominante/patologia , Proteínas Repressoras/metabolismo , Canais de Cátion TRPP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Actinas/metabolismo , Animais , Linhagem Celular , Centrossomo/metabolismo , Cílios/metabolismo , Modelos Animais de Doenças , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Camundongos Transgênicos , Mutação , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/metabolismo , Proteína Quinase C/genética , Proteínas Repressoras/genética , Transdução de Sinais , Canais de Cátion TRPP/genética , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismoRESUMO
OBJECTIVES: A number of randomised control trials (RCTs) investigating the effects of long-acting somatostatin analogues in autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD) have been recently reported. We sought to evaluate all available RCTs investigating the efficacy of somatostatin analogues treatment in ADPKD and PLD. DATA SOURCES: Electronic databases; Pubmed, Clincaltrials.gov and Cochrane Central Register of Controlled Trials ELIGIBILITY CRITERIA FOR SELECTING STUDIES: RCTs and randomised cross-over trials comparing the effects of somatostatin analogue treatment with controls in patients with ADPKD or PLD. DATA EXTRACTION AND SYNTHESIS: Data extraction and bias assessments were performed by two independent reviewers between January and May 2019. Outcomes assessed included estimated glomerular filtration rate (eGFR), total kidney volume (TKV), total liver volume (TLV), progression to end stage renal failure (ESRF) and adverse effects. Data were pooled using a random-effects model and reported as relative risk or mean difference with 95% CIs. RESULTS: Meta-analysis was performed of six RCTs or randomised cross-over trials and three secondary analyses. A total of 592 patients were included. Compared with controls, somatostatin analogue treatment significantly reduced TLV (mean difference -0.15 L, 95% CI -0.26 to -0.03, p=0.01). There was no significant effect on TKV (mean difference -0.19 L, 95% CI -0.50 to 0.12, p=0.23) or eGFR (mean difference 0.27 mL/min/1.73 m2, 95% CI -2.03 to 2.57, p=0.82). There was no effect on progression to ESRF. Somatostatin analogues were associated with known adverse effects such as gastrointestinal symptoms. CONCLUSIONS: The available RCT data show improvement in TLV with somatostatin analogue treatment. There was no benefit to TKV or eGFR in patients with ADPKD, while being associated with various side effects. Further studies are needed to assess potential benefit in reducing cyst burden in patients with PLD.