bims-bicyki 2021-01-03 papers

Nephrol Dial Transplant. 2020 Dec 30. pii: gfaa283. [Epub ahead of print]

Serum bicarbonate is associated with kidney outcomes in autosomal dominant polycystic kidney disease.

DIPAK Consortium

BACKGROUND: Metabolic acidosis accelerates progression of chronic kidney disease, but whether this is also true for autosomal dominant polycystic kidney disease (ADPKD) is unknown.
METHODS: Patients with ADPKD from the DIPAK (Developing Interventions to halt Progression of ADPKD) trial were included [n = 296, estimated glomerular filtration rate (eGFR) 50 ± 11 mL/min/1.73 m2, 2.5 years follow-up]. Outcomes were worsening kidney function (30% decrease in eGFR or kidney failure), annual eGFR change and height-adjusted total kidney and liver volumes (htTKV and htTLV). Cox and linear regressions were adjusted for prognostic markers for ADPKD [Mayo image class and predicting renal outcomes in ADPKD (PROPKD) scores] and acid-base parameters (urinary ammonium excretion).
RESULTS: Patients in the lowest tertile of baseline serum bicarbonate (23.1 ± 1.6 mmol/L) had a significantly greater risk of worsening kidney function [hazard ratio = 2.95, 95% confidence interval (CI) 1.21-7.19] compared with patients in the highest tertile (serum bicarbonate 29.0 ± 1.3 mmol/L). Each mmol/L decrease in serum bicarbonate increased the risk of worsening kidney function by 21% in the fully adjusted model (hazard ratio = 1.21, 95% CI 1.06-1.37). Each mmol/L decrease of serum bicarbonate was also associated with further eGFR decline (-0.12 mL/min/1.73 m2/year, 95% CI -0.20 to -0.03). Serum bicarbonate was not associated with changes in htTKV or htTLV growth.
CONCLUSIONS: In patients with ADPKD, a lower serum bicarbonate within the normal range predicts worse kidney outcomes independent of established prognostic factors for ADPKD and independent of urine ammonium excretion. Serum bicarbonate may add to prognostic models and should be explored as a treatment target in ADPKD.

Keywords: ammonium; end-stage kidney disease; glomerular filtration rate; total kidney volume

DOI: https://doi.org/10.1093/ndt/gfaa283

Cell Stem Cell. 2020 Dec 21. pii: S1934-5909(20)30585-3. [Epub ahead of print]

Plasticity of distal nephron epithelia from human kidney organoids enables the induction of ureteric tip and stalk.

Sara E Howden, Sean B Wilson, Ella Groenewegen, Lakshi Starks, Thomas A Forbes, Ker Sin Tan, Jessica M Vanslambrouck, Emily M Holloway, Yi-Hsien Chen, Sanjay Jain, Jason R Spence, Melissa H Little.

During development, distinct progenitors contribute to the nephrons versus the ureteric epithelium of the kidney. Indeed, previous human pluripotent stem-cell-derived models of kidney tissue either contain nephrons or pattern specifically to the ureteric epithelium. By re-analyzing the transcriptional distinction between distal nephron and ureteric epithelium in human fetal kidney, we show here that, while existing nephron-containing kidney organoids contain distal nephron epithelium and no ureteric epithelium, this distal nephron segment alone displays significant in vitro plasticity and can adopt a ureteric epithelial tip identity when isolated and cultured in defined conditions. "Induced" ureteric epithelium cultures can be cryopreserved, serially passaged without loss of identity, and transitioned toward a collecting duct fate. Cultures harboring loss-of-function mutations in PKHD1 also recapitulate the cystic phenotype associated with autosomal recessive polycystic kidney disease.

Keywords: directed differentiation; disease modelling; distal tubule; kidney development; kidney organoid; pluripotent stem cell; polycystic kidney disease; transcriptome profiling; ureteric epithelium; ureteric tip

DOI: https://doi.org/10.1016/j.stem.2020.12.001

Clin J Am Soc Nephrol. 2020 Dec 29. pii: CJN.17981120. [Epub ahead of print]

Long-Term Safety of Tolvaptan in ADPKD: Where Do We Stand?

Dipal M Patel, Neera K Dahl.

Keywords: ADPKD; Tolvaptan; autosomal dominant polycystic kidney disease; clinical trial; safety

DOI: https://doi.org/10.2215/CJN.17981120

Clin J Am Soc Nephrol. 2020 Dec 29. pii: CJN.10250620. [Epub ahead of print]

Multicenter Study of Long-Term Safety of Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.

Vicente E Torres, Arlene B Chapman, Olivier Devuyst, Ron T Gansevoort, Ronald D Perrone, Jennifer Lee, Molly E Hoke, Alvin Estilo, Olga Sergeyeva.

BACKGROUND AND OBJECTIVES: Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4, 2-year extension to TEMPO 3:4 (TEMPO 4:4), and 1-year Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, aquaretic adverse events were common. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in all three studies. Three patients met Hy Law criteria (ALT or AST more than three times and total bilirubin more than two times the upper limit of normal) for severe drug-induced liver injury (two in TEMPO 3:4 and one in TEMPO 4:4). In REPRISE, liver enzyme monitoring frequency was increased to monthly, with no Hy Law cases. A long-term, phase 3 safety study has further characterized tolvaptan safety.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Subjects who completed TEMPO 4:4, REPRISE, or other tolvaptan trials could enroll in this prospective, multinational, open-label safety study. Assessments included monthly liver enzyme testing during the first 18 months of tolvaptan exposure and every 3 months thereafter.
RESULTS: Among 1803 subjects, median tolvaptan exposure during the extension was 651 days (interquartile range, 538-924), and cumulative exposure (extension and previous trials) was ≤11 years. Subjects entering from REPRISE placebo experienced more aquaretic adverse events compared with subjects from TEMPO 4:4 or REPRISE tolvaptan (i.e., patients with prior long-term tolvaptan exposure). Liver enzyme elevations also occurred more frequently in subjects from REPRISE placebo. Percentages experiencing ALT ≥3/≥5/ ≥10/≥20 times the upper limit of normal were 3.2%/2.1%/0.9%/0.7%, respectively, in subjects from REPRISE placebo and 0.6%-1.1%/0.0%-0.1%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. Percentages experiencing AST ≥3/ ≥5/≥10/≥20 times the upper limit of normal were 6.9%/3.8%/2.3%/0.8%, respectively, in subjects from REPRISE placebo and 0.9%-2.0%/0.0%-1.0%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. No Hy Law cases occurred.
CONCLUSIONS: No new safety signals emerged during this long-term extension. Monthly liver function testing for the first 18 months of treatment appeared to enable effective detection and management of transaminase elevations.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Open Label Extension of TEMPO 3:4, NCT02251275.

Keywords: ADPKD; cystic kidney; tolvaptan

DOI: https://doi.org/10.2215/CJN.10250620

Front Physiol. 2020 ;11 606996

Physiological and Pathological Roles of Mammalian NEK7.

Zhenzhen Sun, Wei Gong, Yue Zhang, Zhanjun Jia.

NEK7 is the smallest NIMA-related kinase (NEK) in mammals. The pathological and physiological roles of NEK7 have been widely reported in many studies. To date, the major function of NEK7 has been well documented in mitosis and NLRP3 inflammasome activation, but the detailed mechanisms of its regulation remain unclear. This review summarizes current advances in NEK7 research involving mitotic regulation, NLRP3 inflammasome activation, related diseases and potential inhibitors, which may provide new insights into the understanding and therapy of the diseases associated with NEK7, as well as the subsequent studies in the future.

Keywords: NEK7; NLRP3 inflammasome; cellular homeostasis; inhibitors; mitosis

DOI: https://doi.org/10.3389/fphys.2020.606996

J Pathol. 2020 Dec 29.

LCC18, a benzamide-linked small molecule, ameliorates IgA nephropathy in mice.

Shin-Ruen Yang, Kuo-Feng Hua, Akiko Takahata, Chung-Yao Wu, Chih-Yu Hsieh, Hsiao-Wen Chiu, Cheng-Hsu Chen, Debabrata Mukhopadhyay, Yusuke Suzuki, Shuk-Man Ka, Hsu-Shan Huang, Ann Chen.

IgA nephropathy (IgAN), an immune complex-mediated process and the most common primary glomerulonephritis, can progress to end-stage renal disease in up to 40% of patients. Accordingly, a therapeutic strategy targeting a specific molecular pathway is urgently warranted. Aided by structure characterization and target identification, we predicted that a novel ring-fused 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione, LCC18, targets the NLRP3 inflammasome, which participate in IgAN pathogenesis. We further developed biomarkers for the disease. We used two complementary IgAN models in C57BL/6 mice, involving TEPC-15 hybridoma-derived IgA, and in gddY mice. Moreover, we created specific cell models to validate therapeutic effects of LCC18 on IgAN and to explain its underlying mechanisms. IgAN mice benefited significantly from treatment with LCC18, showing dramatically improved renal function, including greatly reduced proteinuria and renal pathology. Mechanistic studies show that the mode of action specifically involved: (1) blocking of the MAPKs/COX-2 axis-mediated priming of NLRP3 inflammasome; (2) inhibition of ASC oligomerization and NLRP3 inflammasome assembly by inhibiting NLRP3 binding to PKR, NEK7 and ASC; and (3) activation of autophagy. LCC18 exerts therapeutic effects on murine IgAN by differentially regulating NLRP3 inflammasome activation and autophagy induction, suggesting this new compound as a promising drug candidate to treat IgAN. This article is protected by copyright. All rights reserved.

Keywords: Autophagy; IgA nephropathy; NEK7; NLRP3 inflammasome; PKR; TEPC-15 hybridoma, gddY mice

DOI: https://doi.org/10.1002/path.5609

J Pharmacol Sci. 2021 Jan;pii: S1347-8613(20)30111-0. [Epub ahead of print]145(1): 88-96

The ginsenoside metabolite compound K stimulates glucagon-like peptide-1 secretion in NCI-H716 cells by regulating the RhoA/ROCKs/YAP signaling pathway and cytoskeleton formation.

Fengyuan Tian, Xi Wang, Haixiang Ni, Xiaohong Feng, Xiao Yuan, Qi Huang.

Ginsenoside Rb1 has been shown to have antidiabetic and anti-inflammatory effects. Its major metabolite, compound K (CK), can stimulate the secretion of glucagon-like peptide-1 (GLP1), a gastrointestinal hormone that plays a vital role in regulating glucose metabolism. However, the mechanism underlying the regulation of GLP1 secretion by compound K has not been fully explored. This study was designed to investigate whether CK ameliorates incretin impairment by regulating the RhoA/ROCKs/YAP signaling pathway and cytoskeleton formation in NCI-H716 cells. Using NCI-H716 cells as a model cell line for GLP1 secretion, we analyzed the effect of CK on the expression of RhoA/ROCK/YAP pathway components. Our results suggest that the effect of CK on GLP1 secretion depends on the anti-inflammatory effect of CK. We also demonstrated that CK can affect the RhoA/ROCK/YAP pathway, which is downstream of transforming growth factor β1 (TGFβ1), by maintaining the capacity of intestinal differentiation. In addition, this effect was mediated by regulating F/G-actin dynamics. These results provide not only the mechanistic insight for the effect of CK on intestinal L cells but also the molecular basis for the further development of CK as a potential therapeutic agent to treat type 2 diabetes mellitus (T2D).

Keywords: Compound K; Cytoskeleton; Diabetes; Glucagon-like peptide-1 (GLP1); NCI–H716 cell line

DOI: https://doi.org/10.1016/j.jphs.2020.11.005