Coexistence of autosomal dominant polycystic kidney disease type 1 and hereditary renal hypouricemia type 2: A model of early-onset and fast cyst progression.

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluid-filled cyst development leading to end-stage renal disease. The rate of disease progression in ADPKD exhibits high inter- and intrafamilial variability suggesting involvement of modifier genes and/or environmental factors. Renal hypouricemia (RHUC) is an inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and chronic kidney disease (CKD). However, the two disorders have distinct and well-delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and RHUC (type 1) in a single individual have been reported. We report a family with two members: an ADPKD 24-year-old female which presented bilateral renal cysts in utero and hypouricemia since age 5, and her mother with isolated hypouricemia. Next-generation sequencing identified two mutations in two genes PKD1 and SLC2A9 in this patient and one isolated SLC2A9 mutation in her mother, showing RHUC type 2, associated to CKD. The coexistence of these two disorders provides evidence of SLC2A9 variant could act as a modifier change, with synergistic actions, that could promote cystogenesis and rapid ADPKD progression. This is the first case of coexistence of PKD1 and SLC2A9 mutations treated with tolvaptan.

Dysmetabolic markers predict outcomes in autosomal dominant polycystic kidney disease.

BACKGROUND: Overweight and obesity were recently associated with a poor prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD). Whether the metabolic consequences of obesity as defined by the metabolic syndrome (MS) are also linked with disease progression remains untested. METHODS: Eligible ADPKD patients with different stages of CKD (n = 105) and 105 non-diabetic controls matched for CKD stage were enrolled in the study. Groups were evaluated at baseline for presence of MS, blood markers of metabolism, homeostasis model assessment of insulin resistance (HOMA-IR) score, and biochemical markers of inflammation (hs-CRP, IL-1ß, IL-6, TNF-α and PON-1). MS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). Patients were followed for 12 months and progression defined as a decrease in baseline eGFR > 10%. RESULTS: MS and hypertension were more prevalent amongst ADPKD patients than in the control group. Meanwhile, markers of inflammation such as hs-CRP (3.63 [3.45-5.17] vs. 4.2 [3.45-8.99] mg/dL; p = 0.014), IL-6 (21.65 [14.1-27.49] vs. 24.9 [16.23-39.4] pg/mL; p = 0.004) and IL-1ß (21.33 [15.8-26.4] vs. 26.78 [18.22-35] pg/mL; p < 0.001) levels were all more elevated in ADPKD patients than in non-diabetic CKD subjects. In multivariate analysis having a truncating PKD1 mutation predicted (OR 1.25 [1.09-1.43]; p = 0.002) fulfilling the MS criteria. Finally, ADPKD patients fulfilling MS criteria had a significantly more rapid progression during 12 months of follow-up than did those that did not (OR 3.28 [1.09-9.87]; p = 0.035). CONCLUSIONS: Our data supports the notion that dysmetabolisms part of the ADPKD phenotype and associated with a poor outcome, especially in patients with a truncating PKD1 mutation.

A potentially crucial role of the PKD1 C-terminal tail in renal prognosis.

BACKGROUND: Autosomal dominant polycystic disease (ADPKD) often results in renal failure. Recently, allelic influences of PKD1 mutation types on renal survival were extensively investigated. Here, we analyzed integrated influences of PKD1 mutation types and positions on renal survival. METHODS: We included 338 (82 pedigrees) and 72 (12 pedigrees) patients with PKD1 and PKD2 mutations, respectively, identified through comprehensive gene analysis of 101 probands with ADPKD. Genetic testing was performed using next-generation sequencing, long-range PCR, and multiplex ligation-dependent probe amplification. Pathogenic mutations were identified by a software package-integrated seven databases and provided access to five cloud-based computing systems. RESULTS: Mean renal survivals of carriers with PKD1 non-truncating-type mutations at positions upstream of G-protein-coupled receptor proteolytic site (GPS-upstream domain), transmembrane domain, or cytoplasmic C-terminal tail (CTT) domain were 70.2, 67.0, and 50.1 years, respectively (P < 0.0001); renal survival was shorter for mutation positions closer to CTT domain, suggesting its crucial role in renal prognosis. Furthermore, in truncating-type mutations, strong inactivation is anticipated on nucleotides downstream from the mutation site, implying CTT domain inactivation irrespective of mutation site. Shorter mean renal survival was found for PKD1 truncating-type than non-truncating-type mutation carriers (P = 0.0348); mean renal survival was not different between PKD1 3'- and 5'-region truncating-type mutation carriers (P = 0.4375), but was shorter in PKD1 3'-region than in 5'-region non-truncating-type mutation carriers (P = 0.0014). Variable strength of CTT domain inactivation might account for these results. CONCLUSIONS: Aforementioned findings indicate that CTT domain's crucial role in renal prognosis needs further investigation by larger studies (ClinicalTrials.gov; NCT02322385).

PKD1 Mutation Is a Biomarker for Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) occurs in 1 in 500-4000 people worldwide. Genetic mutation is a biomarker for predicting renal dysfunction in patients with ADPKD. In this study, we performed a genetic analysis of Japanese patients with ADPKD to investigate the prognostic utility of genetic mutations in predicting renal function outcomes. METHODS: Patients clinically diagnosed with ADPKD underwent a panel genetic test for germline mutations in PKD1 and PKD2. This study was conducted with the approval of the Ethics Committee of Juntendo University (no. 2019107). RESULTS: Of 436 patients, 366 (83.9%) had genetic mutations. Notably, patients with PKD1 mutation had a significantly decreased ΔeGFR/year compared to patients with PKD2 mutation, indicating a progression of renal dysfunction (-3.50 vs. -2.04 mL/min/1.73 m2/year, p = 0.066). Furthermore, PKD1 truncated mutations had a significantly decreased ΔeGFR/year compared to PKD1 non-truncated mutations in the population aged over 65 years (-6.56 vs. -2.16 mL/min/1.73 m2/year, p = 0.049). Multivariate analysis showed that PKD1 mutation was a more significant risk factor than PKD2 mutation (odds ratio, 1.81; 95% confidence interval, 1.11-3.16; p = 0.020). CONCLUSIONS: The analysis of germline mutations can predict renal prognosis in Japanese patients with ADPKD, and PKD1 mutation is a biomarker of ADPKD.

Single-Cell and CellChat Resolution Identifies Collecting Duct Cell Subsets and Their Communications with Adjacent Cells in PKD Kidneys.

ADPKD is a genetic disorder with a molecular complexity that remains poorly understood. In this study, we sampled renal cells to construct a comprehensive and spatiotemporally resolved gene expression atlas in whole Pkd1 mutant polycystic mouse kidneys at single-cell resolution. We characterized cell diversity and identified novel collecting duct (CD) cell subtypes in cystic kidneys. We further found that CD cells appear to take different cell fate trajectories, and the first and the most important step might take place around day 14 in Pkd1 homozygous kidneys. After that day, increased numbers of CD cells showed highly proliferative and fibrotic characteristics, as detected in later-stage Pkd1 homozygous kidneys, both of which should contribute to cyst growth and renal fibrosis. With a newly developed modeling algorithm, called CellChat Explorer, we identify cell-to-cell communication networks mediated by the ligand receptor, such as MIF-CD44/CD74, in cystic kidneys, and confirm them via the expression patterns of ligands and receptors in four major cell types, which addresses the key question as to whether and how Pkd1 mutant renal epithelial cells affect their neighboring cells. The allele-specific gene expression profiles show that the secretion of cytokines by Pkd1 mutant epithelial cells may affect the gene expression profiles in recipient cells via epigenetic mechanisms, and vice versa. This study can be used to drive precision therapeutic targeting of ADPKD.

Turner syndrome and autosomal dominant polycystic kidney disease.

Turner syndrome is a chromosomal disorder that involves multiple organ systems and is typically associated with short stature. A multidisciplinary approach with regular screening and surveillance is key to managing this condition's multiple comorbidities. We present a case of a young girl with Turner syndrome and associated short stature on growth hormone treatment who presented with cystic renal disease found to be autosomal dominant kidney disease. We propose reevaluation of renal screening guidelines in this population due to the potential association of growth hormone and cyst proliferation.

Epidemiological evaluation of cats associated with feline polycystic kidney disease caused by the feline PKD1 genetic mutation in Japan.

Feline polycystic kidney disease (PKD), an inherited autosomal dominant disease, has been reported to occur mostly in Persian or Persian related cats, and to be associated with a mutation from C to A at position 10063 in exon 29 of the feline PKD1 gene (PKD1 mutation). Many clinical cases have been recognized in Japan, but the mutation rate in cats has not been reported. The objective of this study was to determine epidemiological characteristics and clinical features in cats with the PKD1 mutation. Referring veterinarians sent blood samples of 377 cats for the PKD1 gene evaluation. The blood samples were from 159 cats with renal cysts confirmed by ultrasonography, 60 cats without renal cysts, and 158 cats that did not undergo ultrasonography. In total, 150 cats carried the PKD1 mutation and the signalment, site and number of renal cysts, and results of blood test were evaluated in cats with the PKD1 mutation. The breeds with the highest rate of the PKD1 mutation were Persian (46%), Scottish Fold (54%) and American Shorthair cats (47%). However, mixed breed cats also showed high rates of the PKD1 mutation. Of cats with the mutation, the incidence of high plasma creatinine (≥1.6 mg/dl) was greater in cats ≥3 years old, although a few cats ≥9 years of age had low plasma creatinine (<1.6 mg/dl). The coincidence of renal and hepatic cysts was 12.6%, with the high prevalence in Persian cats (31%).