Validation of Robotic-assisted Ureteroplasty with Buccal Mucosa Graft for Stricture at the Proximal and Middle Ureters: The First Comparative Study

Although ureteroplasty with buccal mucosa graft for long-segmental ureteral stenosis has been developed long ago, evidence was still restricted to case series in published literature. This study aims to validate ureteroplasty with buccal mucosa graft (BMG) in long-segment stricture at the proximal and middle ureters under designed comparative methods. From April 2015 to January 2019, we performed robotic-assisted ureteroplasty with BMG with a two-phase design and compared ureteroplasty and BMG (phase 2 surgery) with endoscopic stenting (phase 1 surgery). Paired data of effective renal plasma flow (ERPF), glomerular filtration rate (GFR), hydronephrosis grade, and physical and psychological domains of the World Health Organization Quality of Life (WHOQOL)-BREF were compared. A total of 29 patients were enrolled, and only three (10%) patients had hydronephrosis resolution after treatment with endoscopic stenting (p = 0.250 to baseline). Compared to endoscopic ureteral stent, Hedges’ g of ureteroplasty with BMG was 0.56 (95% CI: 0.43-0.69), 0.63 (95% CI: 0.46-0.80), 0.80 (95% CI: 0.56-1.04), and 1.06 (95% CI: 0.69-1.43) in EGFR, GFR, physical domain of WHOQOL-BREF, and psychological domain of WHOQOL-BREF, respectively (All significance; p<0.001). After 12-month follow-ups, no recurrence of stricture was reported. In conclusion, Robotic-assisted ureteroplasty with BMG onlay is efficient in reconstruction of long-segment stricture of the proximal and middle ureters.

Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine

Background Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail. Methods Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model. Results Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups. Conclusions In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects. Trial registration: The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016

GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans

Epoxyeicosatrienoic acids (EETs) reduce blood pressure by acting in the vasculature and kidney, and interventions to increase circulating EETs improve insulin sensitivity and prevent diabetes in animal models. Inhibition of EET hydrolysis with a sEH (soluble epoxide hydrolase) inhibitor is an attractive approach for hypertension and diabetes. We tested the hypothesis that sEH inhibition increases circulating EETs, reduces blood pressure, and improves insulin sensitivity, blood flow, and inflammation in a randomized, double-blind, placebo-controlled crossover study. Sixteen participants with obesity and prediabetes were randomized to GSK2256294 10 mg QD or placebo for 7 days, insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and adipose and muscle tissues biopsies were performed to assess insulin-stimulated Akt phosphorylation. We assessed tissue and plasma EETs and their respective diol concentrations and sEH activity within plasma, muscle, and adipose tissues. GSK2256294 reduced circulating and adipose tissue sEH activity, but blood pressure, circulating EET, and tissue EETs were unchanged. Plasma sEH activity correlated with muscle and adipose tissue sEH activity. Insulin sensitivity assessed during hyperinsulinemic clamps, as well as adipose and muscle phosphorylated-Akt/Akt expression were similar during GSK2256294 and placebo. sEH inhibition with GSK2256294 reduced plasma F2-isoprostanes (50.7±15.8 versus 37.2±17.3 pg/mL; P =0.03) but not IL (interleukin)-6. Resting blood pressure, forearm blood flow, and renal plasma flow were similar during GSK2256294 and placebo. We demonstrate that GSK2256294 administration for 7 days effectively inhibits sEH activity in plasma, muscle, and adipose tissue and reduces F2-isoprostanes—a marker of oxidative stress—but does not improve insulin sensitivity or blood pressure.

Diclofenac toxicity in susceptible bird species results from a combination of reduced glomerular filtration and plasma flow with subsequent renal tubular necrosis

Diclofenac caused the death of millions of vultures on the Asian subcontinent. Other non-steroidal anti-inflammatory drugs (NSAIDs) have since also been shown to be toxic to vultures with the exception of meloxicam. For this study, we evaluated the effect of diclofenac on renal uric acid transport and glomerulus filtration in an acute toxicity model. In a two-phase study with the same birds, healthy chickens (a validated model species) were treated intravenously with para-amino hippuric acid (PAH) and iohexol (IOH) in combination in phase 1. In phase 2, the same PAH and IOH combination was then combined with diclofenac (10 mg/kg). In both phases, blood and faeces were sequentially collected. In phase 1, the birds showed no signs of ill health. Moreover, PAH, IOH and uric acid clearance was rapid. In phase 2, two chickens showed early signs of hyperuricemia 8 hours after exposure and died approximately 24h later. Necropsy showed classic signs of renal damage and gout. Diclofenac had a rapid plasma half-life of elimination of less than 2 hours indicating that toxicity was likely due to an irreversible destruction of a physiological process. All the birds in phase 2 had decreased uric acid, PAH and IOH clearance in comparison to phase 1. The decrease in PAH clearance was variable between the birds (average of 71%) but was near 98% reduced in the two birds that died. It is concluded that diclofenac alters both renal perfusion and renal plasma flow, with death associated with tubular secretion being reduced to negligible functionality for a prolonged period. This would support previous in vitro findings of early cell death from ROS accumulation. However, further evaluation is needed to elucidate this final step.

Renal Negative Pressure Treatment as a Novel Therapy for Heart Failure Induced Renal Dysfunction

Congestion is the primary pathophysiologic lesion in most heart failure (HF) hospitalizations. Renal congestion increases renal tubular pressure, reducing glomerular filtration rate (GFR) and diuresis. Because each nephron is a fluid filled column, renal negative pressure therapy (rNPT) applied to the urinary collecting system should reduce tubular pressure, potentially improving kidney function. We evaluated the renal response to rNPT in congestive HF. Ten anesthetized ∼80 kg pigs underwent instrumentation with bilateral renal pelvic JuxtaFlow® catheters. GFR was determined by iothalamate clearance (mGFR) and renal plasma flow (RPF) by para-aminohippurate clearance. Each animal served as its own control with randomization of L vs. R kidney to -30mmHg rNPT or no rNPT mGFR and RPF were measured simultaneously from the rNPT and no rNPT kidney. Congestive HF was induced via cardiac tamponade maintaining central venous pressure at 20-22.5mmHg throughout the experiment. Prior to HF induction, rNPT increased natriuresis, diuresis, and mGFR compared with the control kidney (p<0.001 for all). Natriuresis, diuresis, and mGFR, decreased following HF (p<0.001 for all) but were higher in rNPT kidney vs. control (p<0.001 for all). RPF decreased during HF (p<0.001) without significant differences between rNPT treatments. During HF the rNPT kidney had similar diuresis and natriuresis (p>0.5 for both), and higher fractional excretion of sodium (p=0.001) compared with the non-rNPT kidney in the no-HF period. In conclusion, rNPT resulted in significantly increased diuresis, natriuresis, and mGFR, with or without experimental HF. rNPT improved key renal parameters of the congested cardio-renal phenotype.

Intraglomerular Dysfunction Predicts Kidney Failure in Type 2 Diabetes

No longitudinal data link intraglomerular hemodynamic dysfunction with end-stage kidney disease (ESKD) in people with type 2 diabetes (T2D). Afferent (R_A) and efferent (R_E) arteriolar tone and intraglomerular pressure (P_GLO) are not directly measurable in humans but are estimable from glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure, hematocrit, and plasma oncotic pressure. We examined the association of the R_A/R_E ratio and P_GLO with ESKD incidence in 237 Pima Indian persons with T2D who underwent serial measures of GFR (iothalamate) and RPF (<i>p</i>-aminohippurate). Their association with kidney structural lesions was also examined in a subset of 111 participants.<b> </b>Of the 237 participants (mean age 42 years, diabetes duration 11 years, GFR 153 ml/min, median ACR 36 mg/g), 69 progressed to ESKD during median follow-up of 17.5 years. In latent class analysis, distinct trajectories characterized by increasing R_A/R_E ratio (HR: 4.60, 95% CI 2.55-8.31) or elevated P_GLO followed by a rapid decline (HR: 2.96, 95% CI 1.45-6.02) strongly predicted incident ESKD. P_GLO(R²=21%, <i>p</i><0.0001) and R_A/R_E (R²=15%, <i>p</i><0.0001) also correlated with mesangial fractional volume, a structural predictor of DKD progression.<b> </b>In conclusion, intraglomerular hemodynamic parameters associated strongly with incident ESKD and correlated with structural lesions of DKD.

Intraglomerular Dysfunction Predicts Kidney Failure in Type 2 Diabetes

No longitudinal data link intraglomerular hemodynamic dysfunction with end-stage kidney disease (ESKD) in people with type 2 diabetes (T2D). Afferent (R_A) and efferent (R_E) arteriolar tone and intraglomerular pressure (P_GLO) are not directly measurable in humans but are estimable from glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure, hematocrit, and plasma oncotic pressure. We examined the association of the R_A/R_E ratio and P_GLO with ESKD incidence in 237 Pima Indian persons with T2D who underwent serial measures of GFR (iothalamate) and RPF (<i>p</i>-aminohippurate). Their association with kidney structural lesions was also examined in a subset of 111 participants.<b> </b>Of the 237 participants (mean age 42 years, diabetes duration 11 years, GFR 153 ml/min, median ACR 36 mg/g), 69 progressed to ESKD during median follow-up of 17.5 years. In latent class analysis, distinct trajectories characterized by increasing R_A/R_E ratio (HR: 4.60, 95% CI 2.55-8.31) or elevated P_GLO followed by a rapid decline (HR: 2.96, 95% CI 1.45-6.02) strongly predicted incident ESKD. P_GLO(R²=21%, <i>p</i><0.0001) and R_A/R_E (R²=15%, <i>p</i><0.0001) also correlated with mesangial fractional volume, a structural predictor of DKD progression.<b> </b>In conclusion, intraglomerular hemodynamic parameters associated strongly with incident ESKD and correlated with structural lesions of DKD.

Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species

The objective of this study was to systematically assess literature datasets and quantitatively analyze metformin PK in plasma and some tissues of nine species. The pharmacokinetic (PK) parameters and profiles of metformin in nine species were collected from the literature. Based on a simple allometric scaling, the systemic clearances (CL) of metformin in these species highly correlate with body weight (BW) (R2 = 0.85) and are comparable to renal plasma flow in most species except for rabbit and cat. Reported volumes of distribution (VSS) varied appreciably (0.32 to 10.1 L/kg) among species. Using the physiological and anatomical variables for each species, a minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue compartments (Tissues 1 and 2) was used for modeling metformin PK in the nine species. Permeability-limited distribution (low fd1 and fd2) and a single tissue-to-plasma partition coefficient (Kp) value for Tissues 1 and 2 were applied in the joint mPBPK fitting. Nonlinear regression analysis for common tissue distribution parameters along with species-specific CL values reasonably captured the plasma PK profiles of metformin across most species, except for rat and horse with later time deviations. In separate fittings of the mPBPK model to each species, Tissue 2 was considered as slowly-equilibrating compartment consisting of muscle and skin based on in silico calculations of the mean transit times through tissues. The well-fitted mPBPK model parameters for absorption and disposition PK of metformin for each species were compared with in vitro/in vivo results found in the literature with regard to the physiological details and physicochemical properties of metformin. Bioavailability and absorption rates decreased with the increased BW among the species. Tissues such as muscle dominate metformin distribution with low permeability and partitioning while actual tissue concentrations found in rats and mice show likely transporter-mediated uptake in liver, kidney, and gastrointestinal tissues. Metformin has diverse pharmacologic actions, and this assessment revealed allometric relationships in its absorption and renal clearance but considerable variability in actual and modeled tissue distribution probably caused by transporter differences.

Hemodynamic and biological correlates of glomerular hyperfiltration in sickle cell patients before and under renin–angiotensin system blocker

Glomerular hyperfiltration alone or associated with albuminuria is a well-known feature of sickle cell associated nephropathy. Though, glomerular hyperfiltration is currently considered to be related to a high renal plasma flow and chronic hemolysis, cardiac output influence on measured glomerular filtration rate (mGFR) have not been investigated so far. Thirty seven homozygous sickle cell patients (SCA) from the RAND study investigated before and under angiotensin converting enzyme inhibitor (ACEI) were included. Both mGFR and cardiac index (CI) were high (> 110 ml/min/1.73 m2 and > 3.5 l/m2 in 81% and 97% of cases) with low systemic vascular resistance (SVR) (< 700 dynes/s/cm−5) in 38% of cases. mGFR association with CI and SVR were significant at baseline (respectively ρ: 0.44, p = 0.008 and ρ: − 0.37, p = 0.02) and under ACEI (p = 0.007 and 0.01 respectively), in accordance with previous data showing that hyperfiltration was linked to an increased glomerular perfusion and a glomerulomegaly rather than increased capillary hydrostatic pressure. Of notice, after adjustment on CI, mGFR remained associated with reticulocyte count and albuminuria under ACEI (p = 0.006 and 0.02 respectively). Our results suggest that hyperfiltration is tightly linked to an increased cardiac output which may account for an increased renal blood flow. Chronic hemolysis could be a relevant factor accounting for hyperfiltration potentially acting on glomerular enlargement which appears as a key factor. Our data suggest that cardiac output assessment is a relevant tool in the routine management and monitoring of SCA nephropathy.

The role of thyroid in renovascular function: Independent association of serum TSH with renal plasma flow

Context There are well-established interactions between the thyroid and the kidney. Thyroid hypofunction is associated with reduced renal plasma flow and hypothyroidism is highly prevalent in chronic kidney disease; however, less is known about the thyroid-kidney axis in the euthyroid state. Objective To study the association of thyroid function with renovascular parameters in a well phenotyped cohort of euthyroid normotensive and hypertensive individuals. Design Cross sectional study, the HyperPATH Consortium Setting Multi-center study in five US and European academic institutions Participants 789 individuals aged 18-65 years with serum TSH 0.4-5.5 mIU/L. Subjects with uncontrolled or secondary hypertension or on medication affecting the hypothalamus-pituitary-thyroid axis were excluded. Interventions Hemodynamic parameters including renal plasma flow, thyroid function testing and the Thr92Ala deiodinase 2 polymorphism were assessed in the setting of liberal and restricted salt diet. Main outcome measures We searched for associations between thyroid function and renovascular parameters and accounted for confounding factors, such as older age, hypertension and diabetes. Results Serum TSH was inversely associated with renal plasma flow assessed in the setting of both liberal and restricted salt diets. This association remained significant and independent when accounting for confounding factors, whereas free thyroxine index (fTI) and the Thr92Ala polymorphism, associated with lower deiodinase 2 catalytic activity and disrupted thyroid hormone tissue availability, were not independently associated with renal plasma flow. Serum TSH remained an independent predictor of renal plasma flow on a liberal salt diet when the analysis was restricted to healthy young individuals. Conclusions Serum TSH levels, but not fTI nor the Thr92Ala deiodinase 2 polymorphism, were independently inversely associated with renal plasma flow in individuals of the HyperPATH Consortium. These findings suggest a direct interconnection of TSH and renovascular dynamics even with TSH within reference range, warranting further investigation.