scholarly journals Ultrabright Plasmonic-Fluor Nanolabel-Enabled Detection of a Urinary ER Stress Biomarker in Autosomal Dominant Tubulointerstitial Kidney Disease

2021 ◽  
Author(s):  
Yeawon Kim ◽  
Zheyu Wang ◽  
Chuang Li ◽  
Kendrah Kidd ◽  
Yixuan Wang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Autosomal Dominant ◽  
Early Stage ◽  
Clinical Feature ◽  
Thick Ascending Limb ◽  
Enhanced Fluorescence ◽  
Er Chaperone ◽  
Genetic Kidney Disease ◽  
Detection Of Biomarkers ◽  
Progression Prediction

Autosomal dominant tubulointerstitial kidney disease (ADTKD)-uromodulin (UMOD) is the most common non-polycystic genetic kidney disease, but it remains unrecognized due to its clinical heterogeneity and lack of screening test. Moreover, clinical feature being a poor predictor of the disease outcome further highlights the need for development of mechanistic biomarkers in ADTKD. However, low abundant urinary proteins secreted by thick ascending limb (TAL) cells, where UMOD is synthesized, have posed a challenge on detection of biomarkers in ADTKD-UMOD. In the CRISPR/Cas9-generated murine model and patients with ADTKD-UMOD, we find that immunoglobulin heavy chain-binding protein (BiP), an ER chaperone, was exclusively upregulated by mutant UMOD in TAL and easily detected by Western blot in the urine at an early stage of disease. However, even the most sensitive ELISA failed to detect urinary BiP in affected individuals. We therefore developed an ultrasensitive, plasmon-enhanced fluorescence-linked immunosorbent assay (p-FLISA) to quantify urinary BiP concentration by harnessing the newly invented ultrabright fluorescent nanoconstruct, termed "plasmonic fluor" (Nat Biomed Eng 2020). p-FLISA demonstrated that urinary BiP excretion was significantly elevated in ADTKD-UMOD patients compared with unaffected controls, which may have potential utility in risk stratification, disease activity monitoring, disease progression prediction, and guidance of ER-targeted therapies in ADTKD.

scholarly journals Overweight and Obesity Are Predictors of Progression in Early Autosomal Dominant Polycystic Kidney Disease

2017 ◽  
Vol 29 (2) ◽  
pp. 571-578 ◽  
Author(s):  
Kristen L. Nowak ◽  
Zhiying You ◽  
Berenice Gitomer ◽  
Godela Brosnahan ◽  
Vicente E. Torres ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Early Stage ◽  
Normal Weight ◽  
Overweight And Obesity ◽  
Polycystic Kidney ◽  
Annual Percent Change ◽  
Percent Change ◽  
Autosomal Dominant Polycystic Kidney

The association of overweight/obesity with disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) remains untested. We hypothesized that overweight/obesity associates with faster progression in early-stage ADPKD. Overall, 441 nondiabetic participants with ADPKD and an eGFR>60 ml/min per 1.73 m2 who participated in the Halt Progression of Polycystic Kidney Disease Study A were categorized on the basis of body mass index (BMI; calculated using nonkidney and nonliver weight) as normal weight (18.5–24.9 kg/m2; reference; n=192), overweight (25.0–29.9 kg/m2; n=168), or obese (≥30 kg/m2; n=81). We evaluated the longitudinal (5-year) association of overweight/obesity with change in total kidney volume (TKV) by magnetic resonance imaging using linear regression and multinomial logistic regression models. Among participants, mean±SD age was 37±8 years, annual percent change in TKV was 7.4%±5.1%, and BMI was 26.3±4.9 kg/m2. The annual percent change in TKV increased with increasing BMI category (normal weight: 6.1%±4.7%, overweight: 7.9%±4.8%, obese: 9.4%±6.2%; P<0.001). In the fully adjusted model, higher BMI associated with greater annual percent change in TKV (β=0.79; 95% confidence interval [95% CI], 0.18 to 1.39, per 5-unit increase in BMI). Overweight and obesity associated with increased odds of annual percent change in TKV ≥7% compared with <5% (overweight: odds ratio, 2.02; 95% CI, 1.15 to 3.56; obese: odds ratio, 3.76; 95% CI, 1.81 to 7.80). Obesity also independently associated with greater eGFR decline (slope) versus normal weight (fully adjusted β =−0.08; 95% CI, −0.15 to −0.02). In conclusion, overweight and, particularly, obesity are strongly and independently associated with rate of progression in early-stage ADPKD.

Expression of aquaporins-1 and -2 during nephrogenesis and in autosomal dominant polycystic kidney disease

1996 ◽  
Vol 271 (1) ◽  
pp. F169-F183 ◽  
Author(s):  
O. Devuyst ◽  
C. R. Burrow ◽  
B. L. Smith ◽  
P. Agre ◽  
M. A. Knepper ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cell Membranes ◽  
Autosomal Dominant ◽  
Early Stage ◽  
Basolateral Membrane ◽  
Apical Cell ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
End Stage

Aquaporin-1 (AQP1), located in proximal tubules (PT) and descending thin limbs of Henle (DTL), and aquaporin-2 (AQP2), located in collecting ducts (CD), are channels involved in water transport across renal tubule epithelia. Using antibodies against AQP1 and AQP2, we here show expression of AQP1 and AQP2 in normal human developing and adult kidneys and in autosomal dominant polycystic kidney disease (ADPKD). Unlike in rats, AQP1 and AQP2 are expressed early during human nephrogenesis (12-wk gestation). AQP1 was first seen in developing PT epithelia, predominantly in apical cell membranes, and, at 15 wk, was also detected in DTL. AQP2 was seen in apical cell membranes of the branching ureteric bud and CD system from 12 wk and throughout development. In adult normal kidneys, AQP1 was localized to apical and basolateral membrane domains of PT and DTL, whereas AQP2 was restricted to principal cells of CD. This distribution of AQP1 and AQP2 was also seen in early stage ADPKD, except that AQP1 was mostly located in the apical membrane region of expanded PT. In end-stage ADPKD, two-thirds of the cysts expressed either AQP1 or AQP2, but these two water channels were never colocalized in the same cyst. Western blot analysis showed maximal expression of AQP1 and AQP2 in normal adult kidneys, lower levels in fetal kidneys, and decreases associated with degree of cystic progression in ADPKD. These data 1) demonstrate specific, mutually exclusive localization of AQP1 and AQP2 in human fetal and adult kidneys; 2) show that both channels are expressed early during nephrogenesis; and 3) show that the mutual exclusivity of localization is maintained even into end-stage ADPKD.

scholarly journals Autosomal dominant tubulointerstitial kidney disease-UMOD is the most frequent non polycystic genetic kidney disease

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Christine Gast ◽  
Anthony Marinaki ◽  
Monica Arenas-Hernandez ◽  
Sara Campbell ◽  
Eleanor G. Seaby ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Autosomal Dominant ◽  
Genetic Kidney Disease

scholarly journals Detection of Autosomal Dominant Polycystic Kidney Disease by Medical Checkup at an Early Stage

Cureus ◽  
2021 ◽  
Author(s):  
Shohei Fukunaga ◽  
Fumika Kamei ◽  
Hirotaka Sonoda ◽  
Masafumi Oba ◽  
Miharu Kawanishi ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Early Stage ◽  
Polycystic Kidney ◽  
Medical Checkup ◽  
Autosomal Dominant Polycystic Kidney

scholarly journals Rationale and Design of a Clinical Trial Investigating Tolvaptan Safety and Efficacy in Autosomal Dominant Polycystic Kidney Disease

2017 ◽  
Vol 45 (3) ◽  
pp. 257-266 ◽  
Author(s):  
Vicente E. Torres ◽  
Olivier Devuyst ◽  
Arlene B. Chapman ◽  
Ron T. Gansevoort ◽  
Ronald D. Perrone ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Late Stage ◽  
Autosomal Dominant ◽  
Early Stage ◽  
Polycystic Kidney ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Stage 4 ◽  
Autosomal Dominant Polycystic Kidney

Background: In TEMPO 3:4, the vasopressin V2-receptor antagonist tolvaptan slowed kidney growth and function decline in autosomal dominant polycystic kidney disease (ADPKD) patients with relatively preserved kidney function. Methods: Prospective, phase 3b, multi-center, randomized-withdrawal, placebo-controlled, double-blind trial of tolvaptan in ADPKD patients with late stage 2 to early stage 4 chronic kidney disease (CKD). The primary endpoint was estimated glomerular filtration rate (eGFR) change from pre-treatment baseline to post-treatment follow-up. Secondary endpoints included annualized eGFR slope, incidence of ADPKD complications, and overall and hepatic safety profiles. Participants were 18-55 year-old ADPKD patients with baseline eGFR ≥25 and ≤65 mL/min/1.73 m2 or 56-65 year-old with eGFR ≥25 and ≤44 mL/min/1.73 m2 and evidence of eGFR decline >2.0 mL/min/1.73 m2 per year. Daily split doses of tolvaptan were titrated to tolerance (30/15, 45/15, 60/30, or 90/30 mg) and maintained for 12 months, after an 8-week pre-randomization period to screen out subjects unable to tolerate at least 60/30 mg for 3 weeks. Results: Of 1,495 subjects who entered the tolvaptan titration period, 125 (8.4%) discontinued the study before randomization. One thousand three hundred seventy subjects (684 tolvaptan, 686 placebo) from 213 centers across 21 countries were randomized. Baseline demographics were well balanced across treatment arms. Information collected during the study included eGFR, survey scores (PKD history and outcome), adverse events, vital signs, hematology, urinalysis, and serum chemistry tests. Conclusion: Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) determines whether tolvaptan administered over 1 year exhibits disease-modifying properties in ADPKD patients with late stage 2 to early stage 4 CKD, which provides an important therapeutic advancement for this difficult-to-treat disease.

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