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Aim: Chronic high salt intake exaggerates renal injury and inflammation, especially with the loss of functional ET B receptors. Tauroursodeoxycholic acid (TUDCA) is a chemical chaperone and bile salt that is approved for the treatment of hepatic diseases. Our aim was to determine whether TUDCA is reno-protective in a model of ET B receptor deficiency with chronic high salt-induced renal injury and inflammation., Methods: ET B -deficient and transgenic control rats were placed on normal (0.8% NaCl) or high salt (8% NaCl) diet for 3 weeks, receiving TUDCA (400 mg/kg/d; ip) or vehicle. Histological and biochemical markers of kidney injury, renal cell death and renal inflammation were assessed., Results: In ET B -deficient rats, high salt diet significantly increased glomerular and proximal tubular histological injury, proteinuria, albuminuria, excretion of tubular injury markers KIM-1 and NGAL, renal cortical cell death and renal CD4 + T cell numbers. TUDCA treatment increased proximal tubule megalin expression as well as prevented high salt diet-induced glomerular and tubular damage in ET B -deficient rats, as indicated by reduced kidney injury markers, decreased glomerular permeability and proximal tubule brush border restoration, as well as reduced renal inflammation. However, TUDCA had no significant effect on blood pressure., Conclusions: TUDCA protects against the development of glomerular and proximal tubular damage, decreases renal cell death and inflammation in the renal cortex in rats with ET B receptor dysfunction on a chronic high salt diet. These results highlight the potential use of TUDCA as a preventive tool against chronic high salt induced renal damage., (© 2018 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: In patients with diabetes mellitus, hyperfiltration precedes the development of albuminuria. Pediatric sickle cell anemia (SCA) patients have a high prevalence of hyperfiltration and albuminuria during early childhood and adolescence. We tested the hypothesis that hyperfiltration precedes the development of albuminuria in a longitudinal pediatric SCA cohort., Methods: We identified 91 participants with HbSS or SB0 thalassemia 5-21 years of age enrolled in a longitudinal sickle cell nephropathy cohort study who had a cystatin C measured during early childhood (4-10 years of age). Early hyperfiltration was defined as a mean eGFR >180 mL/min/1.73m 2 using cystatin C obtained from 4 to 10 years of age. Persistent albuminuria was defined as an albumin to creatinine ratio > 30 mg/g on two of three untimed urine specimens. Time to event analysis estimated survival curves for participants with and without hyperfiltration using Kaplan-Meier curves and used logrank test for categorical variables to assess the association with time to development of the first episode persistent albuminuria., Results: Persistent albuminuria occurred more often and at an earlier age in participants with early hyperfiltration compared to those without early hyperfiltration (log-rank, P = .004). Participants who developed albuminuria have a significant increase in their eGFR during childhood (P = .003) as compared to participants who have not yet progressed to albuminuria (P = .26). For every 1 g/dL increase in hemoglobin, the hazard ratio for developing persistent proteinuria decreased by 0.56 (95% CI: 0.3, 1.06, P = .07)., Conclusion: Hyperfiltration precedes the development of persistent proteinuria in pediatric SCA patients. Intervention strategies should target lowering eGFR during early childhood., (© 2018 Wiley Periodicals, Inc.)

Aim: The objective of this study is to determine if ambrisentan (ET A selective antagonist) and hydroxyurea (HU) treatment has a synergistic effect on renal injury in sickle cell nephropathy when compared to HU treatment alone. The premise of the study is based on recent studies showing that endothelin-1 (ET-1) contributes to the pathophysiology of nephropathy in sickle cell disease (SCD) and that ET A receptor blockade improves renal function and protects against renal injury. Hydroxyurea (HU) is commonly prescribed for the treatment of SCD and has been shown to reduce renal injury in patients with SCD., Methods: Male 12-week-old humanized sickle mice (HbSS) and their genetic controls (HbAA) were treated with vehicle, HU, ambrisentan, or HU with ambrisentan for 2 weeks and renal structure and function were assessed., Results: Vehicle treated HbSS mice exhibited significant proteinuria compared to vehicle treated HbAA mice. HbSS mice also displayed significantly elevated plasma ET-1 concentrations and decreased urine osmolality compared to HbAA controls. Proteinuria was significantly lower in both HU and ambrisentan treated animals compared to vehicle treated HbSS mice; however, there was no additional improvement in HbSS mice treated with combined ambrisentan and HU. The combination of HU and ambrisentan resulted in significantly lower KIM-1 excretion, glomerular injury, and interstitial inflammation than HU alone., Conclusion: These findings indicate that HU and ET A receptor blockade produce similar reductions in renal injury in the humanized sickle mouse suggesting that both treatments may converge on the same mechanistic pathway., (© 2018 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)