Para-aminohippuric Acid Clearance Research Articles

#444 Novel MRI filtration fraction method to assess glomerular hemodynamics in diabetic kidney disease

Abstract Background and Aims Filtration fraction (FF) is the ratio of the glomerular filtration rate (GFR) to renal plasma flow (RPF) and is therefore an important measure of glomerular hemodynamics. The gold standard method to assess effective RPF is renal clearance of para-aminohippuric acid (PAH) but technical and labour-intensive difficulties limit its application [1]. Quicker and simpler assays of FF are needed, particularly to assess the renal hemodynamic dysfunction (hyper- or hypofiltration) and effects/mode of action of therapeutic interventions in chronic kidney disease (CKD). We assessed a novel magnetic resonance imaging (MRI) technique to measure FF in patients with diabetic kidney disease (DKD) and healthy controls (HC) [2]. Method This cross-sectional sub-study included 32 DKD subjects with measured GFR (mGFR) ≤ 60 ml/ min/1.73 m2 and stratified into the following GFR stages as per the Kidney Disease Improving Global Outcomes (KDIGO) classification: stage G3a (mGFR 45-59 ml/ min/1.73 m2, n = 3), G3b (mGFR 30-44 ml/ min/1.73 m2, n = 8), G4 (mGFR 15-29 ml/ min/1.73 m2, n = 15), G5 (<15 ml/ min/1.73 m2, n = 6), and 18 age-, gender-matched HC with mGFR ≥ 60 ml/min/1.73 m2. All subjects were 18-79 years old. mGFR was assessed using iohexol clearance. Renal blood flow (RBF) (ml/min) was measured by a 5-minute add-on phase contrast MRI of the renal artery of each kidney and then summed together. RBF was corrected for Body Surface Area. RPF and FF were calculated as below: ${\rm{RPF }} = {\rm{ RBF}} \times \ ( {1\ -{\rm{ Hematocrit}}} )$ ${\rm{FF}} = {\rm{mGFR}}/{\rm{RPF}}$ Results RBF and mGFR were highly correlated (R2 = 0.70, Fig. 1). FF was 17.1% for HC and decreased with increasing degrees of renal impairment (Fig. 2). While the difference between HC and G3a DKD group was not significant, there was highly significant difference between HC and all other DKD groups (p < 0.001). The standard deviation in the G3a group was relatively large with only 3 subjects in this group. Conclusion The phase contrast MRI scan can provide a quick and simple measurement of glomerular hemodynamics and therewith further insights into the pathophysiology of DKD and its progression. Given the limitations of the existing method for assessing renal plasma flow, this MRI method can facilitate the inclusion of filtration fraction in DKD clinical trials. Further, the described method could be used to identify hyperfiltration, a compensatory mechanism that can influence results in clinical trials of DKD.

Relationship of Thyroid Function with Renal Hemodynamics and Cholesterol Metabolism in Proteinuric Kidney Disease: A Pilot Study.

Nephrotic syndrome and hypothyroidism are respectively reported to influence renal hemodynamics and hypercholesterolemia. However, the relationship of proteinuria-associated thyroid function with renal hemodynamics and cholesterol metabolism has yet to be determined in a simultaneous analysis of thyroid, renal, and cholesterol variables. We investigated the hypothesis that the changes in thyroid hormones by proteinuria may contribute to changes in cholesterol metabolism and renal hemodynamics by proteinuria. Twenty-nine patients (17 men and 12 women) with proteinuric kidney disease (mean age 46 years) were enrolled in a pilot study. Data for serum free triiodothyronine (FT3), free thyroxine (FT4), total cholesterol, and filtration fraction (FF; assessed by para-aminohippuric acid clearance) were used in variable-adjusted correlation analyses. The patients had the following data (mean ± standard deviation): urinary protein 5.18 ± 3.28 g/day, FT3 2.18 ± 0.44 pg/mL, FT4 1.03 ± 0.26 ng/dL, FF 0.27 ± 0.07, and total cholesterol 327 ± 127 mg/dL. There was a significant positive correlation of FT3 with FF (β = 0.58, p = 0.01) and a significant inverse correlation of FT4 with total cholesterol (β = -0.40, p = 0.01). A positive correlation of FT3 with FF and an inverse correlation of FT4 with total cholesterol were demonstrated in patients with proteinuric kidney disease. The proteinuria-associated reduction in serum thyroid hormone levels was correlated with hypercholesterolemia and the reduced glomerular FF. Further studies of these relationships are required.

Rationale and study design of a randomized controlled trial to investigate the renoprotective effect of canagliflozin assessed by test of renal hemodynamics in diabetic kidney disease (the FAGOTTO study)

BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2i) are considered to have the potential to maintain renal function by correcting glomerular hypertension in patients with diabetic kidney disease (DKD). The aim of this study is to demonstrate the renoprotective effect of SGLT2i by measuring renal hemodynamics, including glomerular filtration fraction (FF), in type 2 diabetic patients with moderate renal dysfunction.MethodsRenoprotective effect of canagliflozin derived from test of renal hemodynamics in diabetic kidney disease (FAGOTTO) study is a 12-week multicenter, open-label, randomized (1:1), parallel-group trial of type 2 diabetic patients with diabetic kidney disease (30 ≤ estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m2). A total of 110 patients are to be randomly allocated to receive once-daily canagliflozin 100 mg or control (standard therapy). FF will be calculated by dividing the measured GFR (mGFR) by the effective renal plasma flow (eRPF). mGFR and eRPF will be measured by the clearance of inulin and para-aminohippuric acid (PAH), respectively. The primary endpoint of this trial is the percentage change in FF after 4 weeks of treatment in the canagliflozin and control groups.DiscussionThe FAGOTTO study will elucidate the mechanism of the renoprotective action of SGLT2i. The background, rationale, and study design of this trial are presented. To date, > 80 patients have been enrolled in this trial. The study will end in 2025.Trial registrationjRCT (Japan Registry Of Clinical Trials) jRCTs041200069. Date of registration: November 27, 2020.

Functional and Morphological Changes Associated with Burst Wave Lithotripsy-Treated Pig Kidneys.

Purpose: Burst wave lithotripsy (BWL) is a new technique for comminution of urinary stones. This technology is noninvasive, has a low positive pressure magnitude, and is thought to produce minor amounts of renal injury. However, little is known about the functional changes related to BWL treatment. In this study, we sought to determine if clinical BWL exposure produces a functional or morphological change in the kidney. Materials and Methods: Twelve female pigs were prepared for renal clearance assessment and served as either sham time controls (6) or were treated with BWL (6). In the treated group, 1 kidney in each pig was exposed to 18,000 pulses at 10 pulses/s with 20 cycles/pulse. Pressure levels related to each pulse were 12 and -7 MPa. Inulin (glomerular filtration rate, GFR) and para-aminohippuric acid (effective renal plasma flow, eRPF) clearance was measured before and 1 hour after treatment. Lesion size analysis was performed to assess the volume of hemorrhagic tissue injury created by each treatment (% FRV). Results: No visible gross hematuria was observed in any of the collected urine samples of the treated kidneys. BWL exposure also did not lead to a change in GFR or eRPF after treatment, nor did it cause a measurable amount of hemorrhage in the tissue. Conclusion: Using the clinical treatment parameters employed in this study, BWL did not cause an acute change in renal function or a hemorrhagic lesion.

Whole-body insulin clearance in people with type 2 diabetes and normal kidney function: Relationship with glomerular filtration rate, renal plasma flow, and insulin sensitivity

ObjectiveKidney insulin clearance, proposed to be the main route of extra-hepatic insulin clearance, occurs in tubular cells following glomerular filtration and peritubular uptake, a process that may be impaired in people with type 2 diabetes (T2D) and/or impaired kidney function. Human studies that investigated kidney insulin clearance are limited by the invasive nature of the measurement. Instead, we evaluated relationships between whole-body insulin clearance, and gold-standard measured kidney function and insulin sensitivity in adults with T2D and normal kidney function. Research design and methodsWe determined insulin, inulin/iohexol and para-aminohippuric acid (PAH) clearances during a hyperinsulinemic-euglycemic clamp to measure whole-body insulin clearance and kidney function. Insulin sensitivity was expressed by glucose infusion rate (M value). Associations between whole-body insulin clearance, kidney function and insulin sensitivity were examined using univariable and multivariable linear regressions models. ResultsWe investigated 44 predominantly male (77%) T2D adults aged 63 ± 7, with fat mass 34.5 ± 9 kg, lean body mass 63.0 ± 11.8 kg, and HbA1c 7.4 ± 0.6%. Average whole-body insulin clearance was 1188 ± 358 mL/min. Mean GFR was 110 ± 22 mL/min, mean ERPF 565 ± 141 mL/min, and M value averaged 3.9 ± 2.3 mg/min. Whole-body insulin clearance was positively correlated with lean body mass, ERPF and insulin sensitivity, but not with GFR. ERPF explained 6% of the variance when entered in a nested multivariable linear regression model op top of lean body mass (25%) and insulin sensitivity (15%). ConclusionsIn adults with T2D and normal kidney function, whole-body insulin clearance was predicted best by lean body mass and insulin sensitivity, and to a lesser extent by ERPF. GFR was not associated with whole-body insulin clearance. In contrast to prior understanding, this suggests that in this population kidney insulin clearance may not play such a dominant role in whole-body insulin clearance.

Effects of levosimendan on renal blood flow and glomerular filtration in patients with acute kidney injury after cardiac surgery: a double blind, randomized placebo-controlled study

BackgroundAcute kidney injury (AKI) is a common and serious complication after cardiac surgery, and current strategies aimed at treating AKI have proven ineffective. Levosimendan, an inodilatating agent, has been shown to increase renal blood flow and glomerular filtration rate in uncomplicated postoperative patients and in patients with the cardiorenal syndrome. We hypothesized that levosimendan through its specific effects on renal vasculature, a preferential vasodilating effect on preglomerular resistance vessels, could improve renal function in AKI-patients with who did not have clinical indication for inotropic support.MethodsIn this single-center, double-blind, randomized controlled study, adult patients with postoperative AKI within 2 days after cardiac surgery, who were hemodynamically stable with a central venous oxygen saturation (ScvO2) ≥ 60% without inotropic support were eligible for inclusion. After randomization, study drug infusions, levosimendan (n = 16) or placebo (n = 13) were given for 5 h. A bolus infusion of levosimendan (12 µg/kg), were given for 30 min followed by 0.1 µg/kg/min for 5 h. Renal blood flow and glomerular filtration rate were measured using infusion clearance of para-aminohippuric acid and a filtration marker, respectively. As a safety issue, norepinephrine was administered to maintain mean arterial pressure between 70–80 mmHg. Intra-group differences were tested by Mann–Whitney U-tests, and a linear mixed model was used to test time and group interaction.ResultsTwenty-nine patients completed the study. At inclusion, the mean serum creatinine was higher in the patients randomized to levosimendan (148 ± 29 vs 127 ± 22 µmol/L, p = 0.030), and the estimated GFR was lower (46 ± 12 vs 57 ± 11 ml/min/1.73 m2, p = 0.025). Levosimendan induced a significantly (p = 0.011) more pronounced increase in renal blood flow (15%) compared placebo (3%) and a more pronounced decrease in renal vascular resistance (− 18% vs. − 4%, respectively, p = 0.043). There was a trend for a minor increase in glomerular filtration rate with levosimendan (4.5%, p = 0.079), which did differ significantly from the placebo group (p = 0.440). The mean norepinephrine dose was increased by 82% in the levosimedan group and decreased by 29% in the placebo group (p = 0.012).ConclusionsIn hemodynamically stable patients with AKI after cardiac surgery, levosimendan increases renal blood flow through renal vasodilatation.Trial registrationNCT02531724, prospectly registered on 08/20/2015. https://clinicaltrials.gov/ct2/show/NCT02531724?cond=AKI&cntry=SE&age=1&draw=2&rank=1

P0002A NEW INSIGHT INTO THE MECHANISM OF HYPERCHLOREMIC METABOLIC ACIDOSIS IN KIDNEY TRANSPLANT RECIPIENTS: INCREASED POSTGLOMERULAR PERITUBULAR BLOOD FLOW IS A KEY CONDITION FOR THE DEVELOPEMENT OF CALCINEURIN INHIBITOR-INDUCED RENAL TUBULAR ACIDOSIS

Abstract Background and Aims Hyperchloremic metabolic acidosis (HCMA) due to renal tubular acidosis is a common complication in kidney transplant recipients(KTR). Potential renal dysfunction, rejection, ischemia, persistent hyperparathyroidism, calcineurin inhibitors (CNIs), etc. have been identified as causes but have not been fully proven, and whether HCMA is a determinant of poor graft prognosis in KTR is still controversial. The purpose of this study is to elucidate the actual mechanism of HCMA in KTR. Method HCMA was defined as follows: i) simple strong ion difference (SID) Na-CL, which is the most dominant metabolic factor in physicochemical approach for acid-base balance, is 34 or less, or â…±) the alkalizing drugs have been started after the KT to correct HCMA. And all the cases of having diarrhea from mycophenolate mofetil(MMF), and gastroenterocolitis from cytomegalovirus infection were excluded. The study group consisted of 47 KTRs who underwent living-kidney transplantation(KT) at our hospital as well as a control group of 43 of the matched donors. Among them, a total of 26 KTRs received the renal hemodynamic studies which were based on urinary clearance of inulin and para-aminohippuric acid 1year after KT. 1) The incidence of HCMA in KTR at 3 months(3m) and 1 year(1y) after KT were examined. 2) To elucidate factors related to HCMA in KTR at 1y, we comprehensively examined factors and compared HCMA groups with non-HCMA groups; donor and recipient background (gender, age, body size), immunological factors, information on transplant surgery, salt and protein intake, effective buffering factors for extracellular body fluids such as albumin and hemoglobin, serum calcium and phosphate concentrations and their ratios, administration of renin-angiotensin system inhibitors and diuretics,Tac trough level and Banff score of each histopathological lesion in 1y biopsy. As for the 26 KTRs who received the renal hemodynamic studies, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction(FF) (GFR/RPF) and pre-/post-glomerular vascular resistance (pre-/postVR) calculated from the Gomez' equations were also analyzed. Results 1) The incidence of HCMA in the KTR at 3m was 51% (24/47), which was much higher than the 6.9% (3/43) in those donors (p<0.001), and the range of odds ratios (vs donor) adjusted by the background factors (age,gender, estimated GFR, albumin and hemoglobin) was 6.7-15.7 (p=0.0001-0.001). The incidence of HCMA in KTR at 1y decreased to 34%. 2)The univariate analysis of HCMA in KTR at 1y compared with non-HCMA showed an increase in RPF (p= 0.016), a decrease in post-VR (p= 0.003), and a decrease in FF (p= 0.0001), suggesting an increase in post-glomerular peritubular blood flow. In addition, the aah lesion score, an indicator of CNI vasculopathy, was also significantly higher in the HCMA (p = 0.015). There was no difference in Tac trough levels between HCMA and nonHCMA, and no independent factors were found by multivariate analysis. All cases with HCMA were classified into low post-VR (Fig.1). Furthermore, in low post-VR alone (n= 15), the Tac trough level at 1y was significantly higher in the HCMA (p= 0.002) (Fig.2). Conclusion In kidney transplant recipients, increased post-glomerular peritubular blood flow is a key condition for the development of CNI-induced renal tubular acidosis. The presence of HCMA suggests that it is probably not a serious condition, but rather a desirable hemodynamic state, however, more attention should be paid not to elevate CNI concentration levels in such conditions.

Increased Glomerular Hydrostatic Pressure is Associated with Tubular Creatinine Reabsorption in Healthy Subjects

Background: Cr is secreted by the proximal tubules and thus Cr clearance (C_cr) can overestimate inulin clearance (C_in). However, in some cases, C_cr can even underestimate C_in. This suggests that Cr could be reabsorbed in the tubuli. We examined the clinical parameters that are associated with tubular Cr reabsorption. Methods: In 80 kidney donor candidates (53.9 ± 13.2 years, 29 males), C_in and para-aminohippuric acid clearance were measured simultaneously. Intrarenal hemodynamic parameters were calculated by Gomez’s formulae. To quantify the secretory component of C_cr (SF_cr), it was calculated as follows: SF_cr = (C_cr − C_in)/C_cr. Results: Twenty-five subjects (31.3%) showed SF_cr values <0. SF_cr that correlated significantly and negatively with efferent arteriolar resistance (R_e) and glomerular hydrostatic pressure (P_glo) (R_e: r = −0.30, p = 0.008; P_glo: r = −0.28, p = 0.025). In multiple regression analyses, R_e and P_glo were significantly and negatively associated with SF_cr after adjustment for other confounders. Conclusions: These findings suggest that tubular reabsorption of Cr can occur in some cases. Intrarenal glomerular hemodynamic burden may be related to tubular creatinine reabsorption, which possibly leads to lower C_cr values.

Comparison of pancreatic and renal blood flow in a canine tachycardia-induced cardiomyopathy model.

The pancreas is believed to be vulnerable to hypoperfusion. In dogs with acute pancreatitis, pancreatic ischemia due to heart failure can worsen the condition. However, changes in pancreatic blood flow associated with decreased cardiac function have not been previously studied in dogs. Therefore, we aimed to identify and compare changes in pancreatic versus renal blood flow as a result of cardiac dysfunction. Seven dogs were subjected to rapid ventricular pacing to create heart failure models. Noninvasive blood pressure measurement, ultrasonic cardiography, contrast-enhanced ultrasonography for pancreatic blood flow measurement, and para-aminohippuric acid clearance for renal blood flow measurement were performed before starting and at 2 and 4 weeks after starting the pacing. Left ventricular cardiac output and mean blood pressure decreased at 2 and 4 weeks after starting the pacing, and pancreatic blood flow decreased at 2 and 4 weeks after starting the pacing. However, renal blood flow did not change at 2 weeks but decreased 4 weeks after starting the pacing. Overall, this study demonstrated that reduced pancreatic blood flow due to cardiac dysfunction occurs, similar to renal blood flow. This suggests that decreased pancreatic blood flow is not unusual and may frequently occur in dogs with heart failure. The results of this study support the speculation that heart failure can exacerbate acute pancreatitis. Additionally, this study provides useful basic information for designing further studies to study this association.

Association of Albuminuria With Intraglomerular Hydrostatic Pressure and Insulin Resistance in Subjects With Impaired Fasting Glucose and/or Impaired Glucose Tolerance.

Little is known about the relationships between insulin resistance, intrarenal hemodynamics, and urinary albumin excretion (UAE) in humans with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). The aim of the current study was to examine intrarenal hemodynamic abnormalities, insulin resistance, and UAE in subjects with IFG or IGT. We hypothesized that intrarenal hemodynamic abnormalities would be associated with insulin resistance. Fifty-four kidney donors underwent 75-g oral glucose tolerance and inulin and para-aminohippuric acid clearance testing. Insulin sensitivity index (ISI) was evaluated by the Matsuda index. Intrarenal hemodynamic parameters were calculated by the Gomez formulae. Of the 54 subjects, 33 exhibited IFG or IGT and 31 exhibited normal glucose tolerance (NGT). Glomerular hydrostatic pressure (Pglo) and UAE were significantly higher in the IFG or IGT subjects with obesity (P = 0.015 and 0.0001, respectively). Log ISI correlated significantly and negatively with Pglo (r = -0.351, P = 0.009) in all subjects. In multiple regression analyses among all subjects, log ISI was associated significantly and independently with Pglo (β = -0.316, P = 0.015), after adjustment for age, sex, and systolic blood pressure. Further, BMI (β = 0.517, P = 0.0004), Pglo (β = 0.420, P = 0.004), and log ISI (β = -0.366, P = 0.008) were each associated significantly and independently with UAE after adjustment. We demonstrated that increased insulin resistance is associated with increased Pglo and UAE in IFG or IGT subjects. These hemodynamic burdens and insulin resistance may cause injury to the glomeruli even in subjects with IFG or IGT.

Renal Blood Flow, Glomerular Filtration Rate, and Renal Oxygenation in Early Clinical Septic Shock.

Data on renal hemodynamics, function, and oxygenation in early clinical septic shock are lacking. We therefore measured renal blood flow, glomerular filtration rate, renal oxygen consumption, and oxygenation in patients with early septic shock. Prospective comparative study. General and cardiothoracic ICUs. Patients with norepinephrine-dependent early septic shock (n = 8) were studied within 24 hours after arrival in the ICU and compared with postcardiac surgery patients without acute kidney injury (comparator group, n = 58). None. Data on systemic hemodynamics and renal variables were obtained during two 30-minute periods. Renal blood flow was measured by the infusion clearance of para-aminohippuric acid, corrected for renal extraction of para-aminohippuric acid. Renal filtration fraction was measured by renal extraction of chromium-51 labeled EDTA. Renal oxygenation was estimated from renal oxygen extraction. Renal oxygen delivery (-24%; p = 0.037) and the renal blood flow-to-cardiac index ratio (-21%; p = 0.018) were lower, renal vascular resistance was higher (26%; p = 0.027), whereas renal blood flow tended to be lower (-19%; p = 0.068) in the septic group. Glomerular filtration rate (-32%; p = 0.006) and renal sodium reabsorption (-29%; p = 0.014) were both lower in the septic group. Neither renal filtration fraction nor renal oxygen consumption differed significantly between groups. Renal oxygen extraction was significantly higher in the septic group (28%; p = 0.022). In the septic group, markers of tubular injury were elevated. In early clinical septic shock, renal function was lower, which was accompanied by renal vasoconstriction, a lower renal oxygen delivery, impaired renal oxygenation, and tubular sodium reabsorption at a high oxygen cost compared with controls.

Well Preserved Renal Function in Children With Untreated Chronic Liver Disease.

On the basis of studies with hepatorenal syndrome, it is widely regarded that renal function is impacted in chronic liver disease (CLD). Therefore, we investigated renal function in children with CLD. In a retrospective study of 277 children with CLD, renal function was investigated as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), measured as clearance of inulin and para-amino hippuric acid or clearance of iohexol. The data were analyzed with regard to different subgroups of liver disease and to the grade of damage. Hyperfiltration (>+2 SD of controls) was found in the subgroups of progressive familial intrahepatic cholestasis (44%), glycogenosis (75%), and acute fulminant liver failure (60%). Patients with biliary atresia, most other patients with metabolic disease and intrahepatic cholestasis, and those with vascular anomalies and cryptogenic cirrhosis had normal renal function. Decreased renal function was found in patients with Alagille's syndrome (64% < -2 SD). Increased GFR and ERPF was found in patients with elevated transaminases, low prothrombin level, high bile acid concentration, and high aspartate-aminotransferase-to-platelet ratio. Most children with CLD had surprisingly well preserved renal function and certain groups had even hyperfiltration. The finding that children with decompensated liver disease and ongoing liver failure had stable kidney function suggests that no prognostic markers of threatening hepatorenal syndrome were at hand. Moreover, estimation of GFR based on serum creatinine fails to reveal hyperfiltration.

Abstract P139: Dual Angiotensin Receptor and Neprilysin Inhibition Improves Renal Hemodynamics and Reduces Kidney Damage in Diabetic Rats

Dual blockade with an Angiotensin Receptor/Neprilysin Inhibitor (ARNI) reduces proteinuria and glomerulosclerosis in diabetic TGR(mREN2)27 rats (i.e., rats displaying angiotensin II-dependent hypertension) more strongly than single AR blockade (ARB), despite a similar effect on blood pressure. Here we investigated whether this is due to improved renal hemodynamics and/or suppression of renal inflammation. TGR(mREN2)27 rats were made diabetic with streptozotocin for 12 weeks, and treated with placebo (n=10), valsartan (ARB; n=8) or valsartan/sacubitril (ARNI; n=8) from week 9-12. Blood pressure was measured by telemetry. Effective renal plasma flow (eRPF) and glomerular filtration rate (GFR) were assessed by quantifying para-aminohippuric acid and inulin clearances. Renal inflammation was quantified by qPCR (CD68 and CD3ε expression, representative for macrophages and T cells, respectively) and fluorescent activated cell sorting (FACS) analysis. ARNI and ARB lowered blood pressure identically, while only ARNI reduced albuminuria. Severe, chronic ischemia and globally sclerotic glomeruli occurred less frequently in kidneys of ARNI-treated animals vs. ARB-treated animals and controls. ARNI, but not ARB, increased eRPF, and a similar trend was observed for GFR. No treatment affected filtration fraction. ARNI decreased CD68 mRNA expression in both renal cortex and medulla, while ARB increased CD68 as well as CD3ε expression in renal medulla. FACS analysis revealed no differences between the treatment groups in the immune-cell fractions that had infiltrated the kidney. In conclusion, improved renal hemodynamics, combined with reduced macrophage infiltration, may underlie the stronger beneficial effects of ARNI on albuminuria and renal histology in diabetic TGR(mREN2)27 rats versus ARB.

OP.5A.07] IMPROVED RENAL HEMODYNAMICS REDUCE ALBUMINURIA AND RENAL MACROPHAGE INFILTRATION IN DIABETIC RATS TREATED WITH DUAL ANGIOTENSIN RECEPTOR AND NEPRILYSIN INHIBITION

Objective: Dual blockade with an Angiotensin Receptor/Neprilysin Inhibitor (ARNI) reduces proteinuria and glomerulosclerosis in diabetic TGR(mREN2)27 rats (i.e., rats displaying angiotensin II-dependent hypertension) more strongly than single AR blockade (ARB), despite a similar effect on blood pressure. Here we investigated whether this is due to improved renal hemodynamics and/or suppression of renal inflammation. Design and method: TGR(mREN2)27 rats were made diabetic with streptozotocin for 12 weeks, and treated with placebo (n = 10), valsartan (ARB; n = 8) or valsartan/sacubitril (ARNI; n = 8) from week 9–12. Blood pressure was measured by telemetry. Effective renal plasma flow (eRPF) and glomerular filtration rate (GFR) were assessed by quantifying para-aminohippuric acid and inulin clearances. Renal inflammation was quantified by qPCR (CD68 and CD3ε expression, representative for macrophages and T cells, respectively) and fluorescent activated cell sorting (FACS) analysis. Results: ARNI and ARB lowered blood pressure identically, while only ARNI reduced albuminuria. Severe, chronic ischemia and globally sclerotic glomeruli occurred less frequently in kidneys of ARNI-treated animals vs. ARB-treated animals and controls. ARNI, but not ARB, increased eRPF, and a similar trend was observed for GFR. No treatment affected filtration fraction. ARNI decreased CD68 mRNA expression in both renal cortex and medulla, while ARB increased CD68 as well as CD3ε expression in renal medulla. FACS analysis revealed no differences between the treatment groups in the immune-cell fractions that had infiltrated the kidney. Conclusions: Improved renal hemodynamics, combined with reduced macrophage infiltration, may underlie the stronger beneficial effects of ARNI on albuminuria and renal histology in diabetic TGR(mREN2)27 rats versus ARB.

Significant association between glycemic status and increased estimated postglomerular resistance in nondiabetic subjects - study of inulin and para-aminohippuric acid clearance in humans.

We investigated whether glomerular hemodynamic parameters in nondiabetic subjects, including healthy subjects, are associated with glycemic status indices, by simultaneous measurement of inulin (Cin) and para-aminohippuric acid (CPHA) clearance. Twenty-six subjects (age 49.5 ± 13.3 years; 13 men and 13 women; 14 healthy subjects and 12 subjects with mild proteinuria) were enrolled. Cin and CPAH were measured simultaneously. All 26 subjects were nondiabetics. Estimated preglomerular resistance, estimated postglomerular resistance, and estimated glomerular hydrostatic pressure (Pglo) were calculated according to Gomez’ formula. Pglo correlated significantly and positively with hemoglobin A1c (HbA1c) in both healthy subjects (r = 0.532, P = 0.0498) and subjects with mild proteinuria (r = 0.681, P = 0.015). While there was no significant correlation between estimated preglomerular resistance and HbA1c, estimated postglomerular resistance correlated significantly and positively with HbA1c both in healthy subjects (r = 0.643, P = 0.013) and subjects with mild proteinuria (r = 0.589, P = 0.044). Glomerular filtration fraction, estimated Pglo and estimated postglomerular resistance in total subjects were associated significantly with HbA1c after adjustment for age, gender, and body mass index. These results demonstrate that, even in nondiabetic subjects, glycemic status is associated with estimated postglomerular resistance, but not estimated preglomerular resistance. It is suggested that increased estimated postglomerular resistance associated with higher HbA1c levels, even within the normal range, causes increased estimated Pglo, leading to increased FF. Thus, hemodynamic abnormalities associated with higher HbA1c levels may be related to glomerular hypertension, even in nondiabetic subjects.

Renal hemodynamic effects of serelaxin in patients with chronic heart failure: a randomized, placebo-controlled study.

Serelaxin is a promising therapy for acute heart failure. The renal hemodynamic effects of serelaxin in patients with chronic heart failure are unknown. In this double-blind, randomized, placebo-controlled, multicenter study, patients with New York Heart Association Class II to III chronic heart failure, left ventricular ejection fraction ≤45%, and estimated glomerular filtration rate (GFR) 30 to 89 mL/min per 1.73 m(2) received intravenous serelaxin 30 μg/kg per day or placebo for 24 hours. Primarily, we assessed the difference between serelaxin and placebo on renal plasma flow (para-aminohippuric acid clearance) and GFR (iothalamate clearance) over 8 to 24 hours. All 22 patients from 1 clinical site were excluded from primary analyses before unblinding because of implausible measurements. The primary analysis comprised 65 patients, mean age was 68 (±10) years, 89% were male, mean estimated GFR was 64 (±19) mL/min per 1.73 m(2), and 34% had New York Heart Association Class III symptoms. Renal plasma flow increased by 29% with serelaxin and 14% with placebo (13% relative increase with serelaxin; P=0.0386), whereas GFR changes did not differ significantly during 8 to 24 hours. Filtration fraction increased by 36% with serelaxin and 62% with placebo (16% relative decrease with serelaxin; P=0.0019) during 8 to 24 hours. Changes in systolic blood pressure were largely similar, and creatinine clearance did not differ between groups. Adverse event rates were similar with serelaxin (20.5%) and placebo (25.0%). In patients with chronic heart failure, serelaxin increased renal plasma flow and reduced the increase in filtration fraction compared with placebo, but did not affect GFR. These results suggest beneficial renal hemodynamic effects in patients with chronic heart failure. http://www.clinicaltrials.gov. Unique identifier: NCT01546532.

Systemic Arterial Hemodynamics and the “Renal Resistive Index:” What is in a Name?

Systemic Arterial Hemodynamics and the “Renal Resistive Index:” What is in a Name?

Significant association of poor glycemic control with increased resistance in efferent arterioles – Study of inulin and para-aminohippuric acid clearance in humans

AimsTo examine whether glomerular hemodynamic parameters in humans are associated with glycemic control indices, by simultaneously measuring clearance of inulin (Cin) and para-aminohippuric acid (CPHA). MethodsThirty-one subjects (age 55.4±14.7 years; 15 men and 16 women; 21 diabetics and 10 non-diabetics) were enrolled. Cin and CPAH were measured simultaneously. Afferent arteriolar resistance (Ra), efferent arteriolar resistance (Re), glomerular hydrostatic pressure (Pglo) and glomerular filtration fraction (FF) were calculated according to Gomez’ formula. ResultsFF correlated significantly and positively with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) and glycated albumin (GA) (r=0.396, p=0.0303; r=0.587, p=0.0007; r=0.525, p=0.0070, respectively). Pglo correlated significantly and positively with FPG, HbA1c and GA (r=0.572, p=0.0008; r=0.535, p=0.0019; r=0.540, p=0.0053, respectively). Although there was no significant correlation between Ra and glycemic control indices, Re correlated significantly and positively with HbA1c and GA (r=0.499, p=0.0043; r=0.592, p=0.0018, respectively). FF, Pglo and Re were associated significantly with HbA1c and GA after adjustment for age. ConclusionsThese results demonstrate, in humans, that poor glycemic control is associated with increased Re, but not Ra. It is suggested that increased Re causes increased Pglo, leading to increased FF. Thus, hemodynamic abnormalities with poor glycemic control may be related to glomerular hypertension in humans.

Acute Kidney Injury: Arterial Spin Labeling to Monitor Renal Perfusion Impairment in Mice—Comparison with Histopathologic Results and Renal Function

Purpose To determine if arterial spin-labeling (ASL) magnetic resonance (MR) imaging can show serial changes in renal perfusion in mice with ischemia-induced acute kidney injury (AKI) and to compare imaging results with those of renal histologic examination and inulin and para-aminohippuric acid (PAH) clearance. Materials and Methods In this animal care committee–approved study, AKI was induced in C57Bl/6 mice (n = 26) by clamping the right renal pedicle for 35 minutes for moderate (n = 16) or 45 minutes (n = 11) for severe AKI. Renal perfusion was measured in 10 animals with moderate and seven animals with severe AKI before and at five time points 1–28 days after surgery by using ASL with a 7-T MR imaging unit. Kidney volume loss and histologic evidence of acute tubular injury were assessed. Inulin and PAH clearance was determined in four animals with moderate and six animals with severe AKI to evaluate renal function and plasma flow for statistical analysis. Repeated measures analysis of variance, unpaired t tests, and correlation analysis were used. Results Renal perfusion values at day 7 were significantly reduced after moderate (56% ± 8; P < .01) and severe (33% ± 6; P < .001) AKI compared with presurgery values. Renal perfusion had returned to baseline levels at day 21 after moderate (96% ± 14) and remained compromised until day 28 after severe (46 % ± 9; P < .05) AKI. At day 28, for moderate versus severe AKI, kidney volume (84% ± 6 vs 60% ± 5; P < .05), degree of tubular injury (5.6% ± 1.8 vs 15.8% ± 2.4; P < .01), and inulin and para-aminohippuric acid clearance (47.5 µL/min ± 5.6 vs 7.3 µL/min ± 2.7; P < .001 and 100.8 µL/min ± 24.3 vs 4.8 µL/min ± 1.0; P < .001, respectively) were significantly different. Relative renal perfusion at days 7–28 significantly correlated with kidney volume loss (P < .01) and tubular injury (P < .05) 4 weeks after AKI. Conclusion ASL allows evaluation of renal perfusion impairment associated with kidney volume loss and histologic changes after AKI in mice and may serve as a noninvasive biomarker for AKI. © RSNA, 2013

Acute Kidney Injury: Arterial Spin Labeling to Monitor Renal Perfusion Impairment in Mice—Comparison with Histopathologic Results and Renal Function

To determine if arterial spin-labeling (ASL) magnetic resonance (MR) imaging can show serial changes in renal perfusion in mice with ischemia-induced acute kidney injury (AKI) and to compare imaging results with those of renal histologic examination and inulin and para-aminohippuric acid (PAH) clearance. In this animal care committee-approved study, AKI was induced in C57Bl/6 mice (n = 26) by clamping the right renal pedicle for 35 minutes for moderate (n = 16) or 45 minutes (n = 11) for severe AKI. Renal perfusion was measured in 10 animals with moderate and seven animals with severe AKI before and at five time points 1-28 days after surgery by using ASL with a 7-T MR imaging unit. Kidney volume loss and histologic evidence of acute tubular injury were assessed. Inulin and PAH clearance was determined in four animals with moderate and six animals with severe AKI to evaluate renal function and plasma flow for statistical analysis. Repeated measures analysis of variance, unpaired t tests, and correlation analysis were used. Renal perfusion values at day 7 were significantly reduced after moderate (56% ± 8; P < .01) and severe (33% ± 6; P < .001) AKI compared with presurgery values. Renal perfusion had returned to baseline levels at day 21 after moderate (96% ± 14) and remained compromised until day 28 after severe (46 % ± 9; P < .05) AKI. At day 28, for moderate versus severe AKI, kidney volume (84% ± 6 vs 60% ± 5; P < .05), degree of tubular injury (5.6% ± 1.8 vs 15.8% ± 2.4; P < .01), and inulin and para-aminohippuric acid clearance (47.5 µL/min ± 5.6 vs 7.3 µL/min ± 2.7; P < .001 and 100.8 µL/min ± 24.3 vs 4.8 µL/min ± 1.0; P < .001, respectively) were significantly different. Relative renal perfusion at days 7-28 significantly correlated with kidney volume loss (P < .01) and tubular injury (P < .05) 4 weeks after AKI. ASL allows evaluation of renal perfusion impairment associated with kidney volume loss and histologic changes after AKI in mice and may serve as a noninvasive biomarker for AKI.