Effective Renal Plasma Flow Research Articles

Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial.

Aims/hypothesisThis study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients.MethodsWe included overweight (BMI 25–40 kg/m2) men and postmenopausal women, aged 35–75 years with type 2 diabetes (HbA1c 48–75 mmol/mol; 6.5–9.0%) and estimated GFR ≥ 60 ml min−1 1.73 m−2. Exenatide or placebo (NaCl solution, 154 mmol/l) was administrated intravenously in an acute, randomised, double-blind, placebo-controlled trial conducted at the Diabetes Center VU University Medical Center (VUMC). GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance, respectively, based on timed urine sampling. Filtration fraction (FF) and effective renal vascular resistance (ERVR) were calculated, and glomerular hydrostatic pressure (PGLO) and vascular resistance of the afferent (RA) and efferent (RE) renal arteriole were estimated. Tubular function was assessed by absolute and fractional excretion of sodium (FENa), potassium (FEK) and urea (FEU), in addition to urine osmolality, pH and free water clearance. Renal damage markers, BP and plasma glucose were also determined.ResultsOf the 57 patients randomised by computer, 52 were included in the final analyses. Exenatide (n = 24) did not affect GFR (mean difference +2 ± 3 ml min−1 1.73 m−2, p = 0.489), ERPF, FF, ERVR or PGLO, compared with placebo (n = 28). Exenatide increased RA (p < 0.05), but did not change RE. Exenatide increased FENa, FEK, urine osmolality and pH, while FEU, urinary flow and free water clearance were decreased (all p < 0.05). Osmolar clearance and renal damage makers were not affected. Diastolic BP and mean arterial pressure increased by 3 ± 1 and 6 ± 2 mmHg, respectively, whereas plasma glucose decreased by 1.4 ± 0.1 mmol/l (all p < 0.05).Conclusions/interpretationExenatide infusion does not acutely affect renal haemodynamics in overweight type 2 diabetes patients at normal filtration levels. Furthermore, acute GLP-1RA administration increases proximal sodium excretion in these patients.Trial registrationClincialTrials.gov NCT01744236FundingThe research leading to these results has been funded from: (1) the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 282521 – the SAFEGUARD project; and (2) the Dutch Kidney Foundation, under grant agreement IP12.87.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3938-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

PD41-10 COMPARISON OF WARM AND COLD ISCHEMIA ON RENAL FUNCTION AFTER PARTIAL NEPHRECTOMY

You have accessJournal of UrologyKidney Cancer: Localized: Surgical Therapy IV1 Apr 2016PD41-10 COMPARISON OF WARM AND COLD ISCHEMIA ON RENAL FUNCTION AFTER PARTIAL NEPHRECTOMY Yushi Yamauchi, Yasuhito Funahashi, Naoto Sassa, Yasushi Yoshino, Tokunori Yamamoto, and Momokazu Gotoh Yushi YamauchiYushi Yamauchi More articles by this author , Yasuhito FunahashiYasuhito Funahashi More articles by this author , Naoto SassaNaoto Sassa More articles by this author , Yasushi YoshinoYasushi Yoshino More articles by this author , Tokunori YamamotoTokunori Yamamoto More articles by this author , and Momokazu GotohMomokazu Gotoh More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1556AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To assess renal functional deterioration after partial nephrectomy with warm and cold ischemia using 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) renal scintigraphy parameters. METHODS Open partial nephrectomy was performed in 59 patients with warm ischemia and 64 patients with cold ischemia. 99mTc-MAG3 renal scintigraphy was performed and effective renal plasma flow was calculated to evaluate split renal function. In addition, regional 99mTc-MAG3 uptake was analyzed in the surgically unaffected parts to evaluate ischemic damage. RESULTS The mean tumor size in the warm and cold ischemia groups was 2.9 and 3.2 cm, respectively, and the mean ischemic time was 24.2 minutes (range, 8-46 minutes) and 26.7 minutes (range, 8-58 minutes), respectively. One week after surgery, effective renal plasma flow in the operated kidney decreased to 66.2% (from 160.2 to 105.4 mL/min/1.73 m2) in the warm ischemia group and to 77.4% (from 152.3 to 116.6 mL/min/1.73 m2) in the cold ischemia group. Reginal 99mTc-MAG3 uptake changed to 89.2% of baseline in the warm ischemia group and 101.5% of baseline in the cold ischemia group. When the ischemic time was 25 minutes, regional 99mTc-MAG3 uptake in the warm ischemia group did not recover to the baseline level at 6 months. Multiple regression analyses demonstrated a significant correlation between ischemic time and the decrease in regional 99mTc-MAG3 uptake in the warm ischemia group, but not in the cold ischemia group. CONCLUSIONS Warm ischemia for 25 minutes caused long lasting diffuse damage throughout the operated kidney, whereas cold ischemia for up to 58 minutes prevented ischemic injury to the renal remnant. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e943-e944 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Yushi Yamauchi More articles by this author Yasuhito Funahashi More articles by this author Naoto Sassa More articles by this author Yasushi Yoshino More articles by this author Tokunori Yamamoto More articles by this author Momokazu Gotoh More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The correlation between effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) with renal scintigraphy 99mTc-DTPA study

The prevalence of chronic renal diseases in Indonesia has an increasing annual trend, because it is frequently unrecognized and often co-exists with other disease. GFR and ERPF are parameters currently utilized to estimate renal function at routine renal scintigraphy 99m-Tc DTPA study. This study used 99m-Tc DTPA to measure GFR and ERPF. The purpose of this study was to find the correlation between ERPF and GFR, for ERPF analysis with Schlegel's method, and GFR analysis with Gate's method, as well as to find correction factor between both variables. Analysis of renal scintigraphy has been performed at Department of Nuclear Medicine Pertamina Center Hospital to thirty patient images acquired from 2014 to 2015 which were analyzed retrospectively data, using gamma camera dual head with counting method from renal scintigraphy 99m-Tc DTPA study. The calculation was executed by means of both display and manual calculation. Pearson's statistical analysis resulted on Positive Correlation for all data, with ERPF and GFR (display) showing Strongly Positive Correlation (r = 0.82; p- value < 0.05). Standard deviation was found to be 27.58 and 107.64 for GFR and ERPF (display), respectively. Our result indicated that the use of 99mTc-DTPA measure ERPF was not recommended.

Effect of increased protein intake on renal acid load and renal hemodynamic responses

Increased protein intake versus maltodextrin intake for 4 weeks lowers blood pressure. Concerns exist that high‐protein diets reduce renal function. Effects of acute and 4‐week protein intake versus maltodextrin intake on renal acid load, glomerular filtration rate and related parameters were compared in this study. Seventy‐nine overweight individuals with untreated elevated blood pressure and normal kidney function were randomized to consume a mix of protein isolates (60 g/day) or maltodextrin (60 g/day) for 4 weeks in energy balance. Twenty‐four‐hour urinary potential renal acid load (uPRAL) was compared between groups. A subgroup (maltodextrin N = 27, protein mix N = 25) participated in extra test days investigating fasting levels and postprandial effects of meals supplemented with a moderate protein‐ or maltodextrin‐load on glomerular filtration rate, effective renal plasma flow, plasma renin, aldosterone, pH, and bicarbonate. uPRAL was significantly higher in the protein group after 4 weeks (P ≤ 0.001). Postprandial filtration fraction decreased further after the protein‐supplemented breakfast than after the maltodextrin‐supplemented breakfast after 4 weeks of supplementation (P ≤ 0.001). Fasting and postprandial levels of glomerular filtration rate, effective renal plasma flow, renin, aldosterone, angiotensin‐converting enzyme, pH and bicarbonate did not differ between groups. In conclusion, 4 weeks on an increased protein diet (25% of energy intake) increased renal acid load, but did not affect renal function. Postprandial changes, except for filtration fraction, also did not differ between groups. These data suggest that a moderate increase in protein intake by consumption of a protein mix for 4 weeks causes no (undesirable) effects on kidney function in overweight and obese individuals with normal kidney function.

177Lu-DOTATATE PRRT in Patients with Metastatic Neuroendocrine Tumor and a Single Functioning Kidney: Tolerability and Effect on Renal Function.

Our objective was to assess the renal toxicity profile of (177)Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with a metastatic neuroendocrine tumor (NET) and a single functioning kidney. This was a retrospective analysis of NET patients who had undergone (177)Lu-DOTATATE PRRT at a large tertiary-care center. All patients selected for the study had somatostatin receptor-positive NETs, had received at least 3 cycles of (177)Lu-DOTATATE PRRT, and had a documented single functioning kidney. The analyzed parameters included patient characteristics, metastatic burden, renal characteristics at diagnosis and during therapy, and nephrotoxic factors. For the renal assessment, the following characteristics were studied before each PRRT cycle: glomerular filtration rate (GFR) as estimated by (99m)Tc-diethylenetriamine pentaacetic acid renography, effective renal plasma flow (ERPF) as measured by (99m)Tc-ethylenedicysteine renography, and blood urea and serum creatinine levels. Renal toxicity was evaluated using version 4.0 of the Common Terminology Criteria for Adverse Events (NCI-CTCAE score). The percentage reduction in GFR and ERPF was also assessed. Filtration fraction was calculated to clarify whether there was a relatively greater reduction in one index of renal function than in the other. At the time of analysis, 6 patients met the inclusion criteria, having received between 3 and 5 cycles of therapy with a cumulative activity of 16.6-36.2 GBq. The duration of follow-up ranged from 12 to 56 mo. The overall toxicity profile (as per the NCI-CTCAE score) showed no acute renal toxicity in any patient. Regarding overall chronic renal toxicity, 3 patients had none, 1 patient had grade II, and 2 patients had grade I. All patients with overall chronic renal toxicity showed compromised renal function at the outset (baseline). The 2 patients with grade I chronic renal toxicity after PRRT had grade II at baseline and gradual improvement over the subsequent cycles. One patient with grade II at baseline showed transient worsening to grade III after the first cycle followed by gradual improvement and a return to baseline after the second cycle. Only 2 patients showed a reduction in GFR (5.3% in one and 13.84% in the other). Four patients showed a reduction in ERPF (31.4% in the patient with the greatest reduction), and all had a rise in filtration fraction signifying that tubular parameters were more affected than glomerular parameters. With proper renal protection and dose fractionation, it is feasible to use (177)Lu-DOTATATE PRRT in patients with NET and a single functioning kidney. Further studies are required to assess the long-term renal consequences of changes in ERPF and filtration fraction in these patients.

Plasma uric acid effects on glomerular haemodynamic profile of patients with uncomplicated Type 1 diabetes mellitus.

Increased plasma uric acid (PUA) levels are associated with impaired renal function in patients with Type 1 diabetes, but the mechanisms are not well understood. Our aim was to evaluate whether higher PUA levels are associated with increased afferent arteriolar resistance in patients with Type 1 diabetes vs. healthy controls, thereby influencing renal function. PUA, GFR (inulin) and effective renal plasma flow (ERPF; para-aminohippurate) were measured in 70 otherwise healthy patients with Type 1 diabetes and 60 healthy controls. Gomez's equations were used to estimate afferent (RA ) and efferent (RE ) arteriolar resistances, glomerular hydrostatic pressure (PGLO ) and filtration pressure (ΔPF ). The relationships between PUA and glomerular haemodynamic parameters were evaluated by univariable linear regression correlation coefficients. In patients with Type 1 diabetes, higher PUA correlated with lower PGLO (P = 0.002) and ΔPF (P = 0.0007), with higher RA (P = 0.001), but not with RE (P = 0.55). These associations were accompanied by correlations between higher PUA with lower GFR (P = 0.0007), ERPF (P = 0.008), RBF (P = 0.047) and higher RVR (P = 0.021). There were no significant correlations between PUA and renal haemodynamic parameters in the healthy controls. The association between higher PUA with lower GFR and lower ERPF in patients with Type 1 diabetes is driven by alterations in the estimated RA . PUA-mediated RA may be caused by increased tone or thickening of the afferent renal arteriole, which might potentiate renal injury by causing ischaemia to the renal microcirculation.

Recovery of native renal function in patients with hepatorenal syndrome following combined liver and kidney transplant with Mercaptoacetyltriglycine-3 renogram: Developing a methodology

Many patients with hepatorenal syndrome (HRS) end up receiving a combined liver and kidney transplant (CKLT) with preservation of native kidneys, specially type 1 HRS since is characterizes by a very rapid deterioration of renal function. Eventually, most of the patients regain renal function, but it is unknown if this is due to the transplanted kidney, the recovery of native renal function, or both. The aim of this study is to evaluate if there is recovery of native renal function in patients with HRS following CKLT. 22 patients (16 men; 6 women) with history of HRS and status post CKLT were studied. Mercapto-acetyltriglycine-3 renograms in the anterior and posterior views with the three kidneys in the field of view were simultaneously acquired. The renograms were analyzed by creating regions of interest around the transplanted and native kidneys. Relative contribution to the renal function, clearance, and effective renal plasma flow for the transplanted and native kidneys were obtained. 1/22 (4.5%) patients presented with a very poor functioning transplanted kidney, in 15/22 (68%) cases the combined native renal function was markedly poorer than the transplanted renal function and in 6/22 (27%) native kidneys showed a contribution to the renal function similar to the transplanted kidney. In conclusion, our series show that around 32% of the HRS patients recovered their native renal function after CKLT. Identification of common factors that affect recovery of native renal function may help to avoid unnecessary renal transplants, significantly reducing morbidity and cost, while facilitating a reallocation of scarce donor resources.

Determination of p-aminohippuric acid with β-cyclodextrin sensitized fluorescence spectrometry

Sensitive spectrofluorometric and HPLC with fluorescence detection methods have been developed for detection and determination of para-aminohippuric acid (a marker used for estimating effective renal plasma flow) in the presence of β-cyclodextrin.

Cardiovascular, renal and gastrointestinal effects of incretin-based therapies: an acute and 12-week randomised, double-blind, placebo-controlled, mechanistic intervention trial in type 2 diabetes

IntroductionIncretin-based therapies, that is, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, are relatively novel antihyperglycaemic drugs that are frequently used in type 2 diabetes management. Apart from...

Percutaneous Renal Access: Surgical Factors Involved in the Acute Reduction of Renal Function.

Studies in patients and experimental animals have shown that percutaneous nephrolithotomy (PCNL) can acutely impair glomerular filtration and renal perfusion, but the factors contributing to this decline in renal function are unknown. The present study assessed the contribution of needle puncture of the kidney vs dilation of the needle tract to the acute decline in renal hemodynamic and tubular transport function associated with PCNL surgery. Acute experiments were performed in three groups of anesthetized adult farm pigs: sham-percutaneous access (PERC), that is, no surgical procedure (n = 7); a single-needle stick to access the renal collecting system (n = 8); expansion of the single-needle access tract with a 30F NephroMax balloon dilator and insertion of a nephrostomy sheath (n = 10). The glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and renal extraction of para-amino hippurate (EPAH, estimates tubular organic anion transporter [OAT] activity) were assessed before and 1 to 4.5 hours after sham-PERC or PERC surgical procedures. Overall, GFR responses were similar in all three groups. Sham-treated PERC pigs showed no significant change in ERPF over the experimental observation period, whereas a single-needle stick to access the renal collecting system resulted in renal vasoconstriction (∼30% reduction in ERPF, p < 0.05). Dilation of the single-needle access tract to create the nephrostomy did not lead to a further decline in ERPF. PERC surgical procedure-mediated renal vasoconstriction was most evident at the 1-hour posttreatment time point. A reduction in EPAH was only observed in pig kidneys with a nephrostomy. Needle puncture of the kidney for percutaneous access to the renal collecting system is the major driving force for the renal vasoconstriction observed after PCNL surgery, whereas creation of the nephrostomy appears to be largely responsible for decreasing tubular OAT activity.

Anatomical and physiological basis for the allometric scaling of cisplatin clearance in dogs.

Cisplatin is a platinum-containing cytotoxic drug indicated for the treatment of solid tumors in veterinary and human patients. Several of the algorithms used to standardize the doses of cytotoxic drugs utilize allometry, or the nonproportional relationships between anatomical and physiological variables, but the underlying basis for these relationships is poorly understood. The objective of this proof of concept study was to determine whether allometric equations explain the relationships between body weight, kidney weight, renal physiology, and clearance of a model, renally cleared anticancer agent in dogs. Postmortem body, kidney, and heart weights were collected from 364 dogs (127 juveniles and 237 adults, including 51 dogs ≥ 8 years of age). Renal physiological and cisplatin pharmacokinetic studies were conducted in ten intact male dogs including two juvenile and eight adult dogs (4-55 kg). Glomerular filtration rate (GFR), effective renal plasma flow, effective renal blood flow, renal cisplatin clearance, and total cisplatin clearance were allometrically related to body weight with powers of 0.75, 0.59, 0.61, 0.71, and 0.70, respectively. The similar values of these diverse mass exponents suggest a common underlying basis for the allometry of kidney size, renal physiology, and renal drug handling.

تقييم وظائف الكلى لدى الحوامل السعوديات بمنطقة جازان

تظهر تغيرات ديناميكية الدم الكلوية الملحوظة بنهاية الثلث الأول من الحمل. كلا الكبيبي معدل الترشيح وتدفق البلازما الكلوي الفعال يزيد بنسبة 50٪ من النساء الحوامل. من المحتمل أن يكون تدفق البلازما الكلوي الفعال يزداد إلى حد كبير ، وبالتالي ، ينخفض ​​جزء الترشيح أثناء الحمل المبكر والمتوسط. الأهداف: للتقييم مستويات مصل وظائف الكلى بين النساء الحوامل السعوديات في منطقة جازان. المواد والطرق: دراسة مستقبلية تعتمد على الحالات والشواهد في المستشفى أجريت في منطقة جازان من مارس 2014 إلى يونيو 2015. 30 امرأة حامل تم اختياره في مستشفى جازان العام وتقييمه لاختبارات وظائف الكلى. تم اختيار 30 من الأشخاص الأصحاء كمجموعة تحكم كانوا العمر ، والاجتماعية والاقتصادية المتطابقة مع مجموعة الحمل. تم استخدام SPSS لتحليل البيانات باستخدام اختبار الطالب ‟t و Pearson الارتباط لتقييم الارتباط بين المتغيرات المختلفة. النتائج: كان هناك فرق معنوي في متوسط ​​مستويات اليوريا والكرياتينين في الدم في مجموعة الاختبار (p &lt;0.05) بالمقارنة مع مجموعة السيطرة مع وجود ارتباط إيجابي معتدل معنوي بين مستويات الكرياتينين في الدم مع فترة الحمل. الخلاصة: انخفاض مستويات اليوريا والكرياتينين في الدم بشكل ملحوظ عند النساء الحوامل في المملكة العربية السعودية. يشير الانخفاض التدريجي في مستويات اليوريا والكرياتينين خلال الأشهر الثلاثة الأخيرة من الحمل إلى زيادة في معدل الترشيح الكبيبي ، وربما يرجع ذلك إلى زيادة معدل ضربات القلب. الإخراج وتدفق الدم الكلوي والتغيرات في توزيع السوائل.

Kidney Dysfunction in Adult Offspring Exposed In Utero to Type 1 Diabetes Is Associated with Alterations in Genome-Wide DNA Methylation.

BackgroundFetal exposure to hyperglycemia impacts negatively kidney development and function.ObjectiveOur objective was to determine whether fetal exposure to moderate hyperglycemia is associated with epigenetic alterations in DNA methylation in peripheral blood cells and whether those alterations are related to impaired kidney function in adult offspring.DesignTwenty nine adult, non-diabetic offspring of mothers with type 1 diabetes (T1D) (case group) were matched with 28 offspring of T1D fathers (control group) for the study of their leukocyte genome-wide DNA methylation profile (27,578 CpG sites, Human Methylation 27 BeadChip, Illumina Infinium). In a subset of 19 cases and 18 controls, we assessed renal vascular development by measuring Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) at baseline and during vasodilatation produced by amino acid infusion.ResultsGlobally, DNA was under-methylated in cases vs. controls. Among the 87 CpG sites differently methylated, 74 sites were less methylated and 13 sites more methylated in cases vs. controls. None of these CpG sites were located on a gene known to be directly involved in kidney development and/or function. However, the gene encoding DNA methyltransferase 1 (DNMT1)—a key enzyme involved in gene expression during early development–was under-methylated in cases. The average methylation of the 74 under-methylated sites differently correlated with GFR in cases and controls.ConclusionAlterations in methylation profile imprinted by the hyperglycemic milieu of T1D mothers during fetal development may impact kidney function in adult offspring. The involved pathways seem to be a nonspecific imprinting process rather than specific to kidney development or function.

The role of pharmacological steroid therapy in preservation of renal function in severely injured patients requiring massive transfusion.

Glucocorticoids (GC) attenuate the post-insult inflammatory response and have been observed to confer end-organ protection following a variety of ischemic insults. We aim to assess this benefit on renal perfusion and function in injured patients requiring massive transfusion. The effect of pharmacologic methylprednisolone (MP) therapy was studied in 118 patients (pts), of whom 60, by random, received 1g MP intraoperatively and 15mg/kg for an additional 3days. Postoperative measurements were made of effective renal plasma flow (ERPF), glomerular filtration by inulin (CIn), creatinine clearance (CCr) and clearances of osmoles (CCosm), sodium (CNa), and free water ([Formula: see text]). Continuous variables were compared between the two groups using the student's t test. Enrolled pts on average received 13.5 units of PRBCs with no differences in the resuscitation regimen. There were no statistically significant differences in the postoperative renal function as measured by ERPF (p=0.57), CIn (p=0.84), CCr (p=0.99), CNa (p=0.07), COsm (p=0.95), and [Formula: see text] (p=0.33). The incidence of renal compromise, as determined by an inulin clearance of <25mL/min or serum creatinine greater than 3.0mg/dL, was also similar. Three patients in the MP treatment group had renal compromise compared to one in the control group. In the absence of larger studies, this study demonstrates that GC likely have no role in preserving renal function in severely injured patients.

Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats.

BackgroundAortocaval fistula (AV) in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral nephrectomized (UNX) rats.MethodsAdult male Sprague-Dawley (SD) rats were divided into Sham (n = 10), UNX (right kidney remove, n = 10), AV (AV established between the levels of renal arteries and iliac bifurcation, n = 18) and UNX+AV (AV at one week after UNX, n = 22), respectively. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, fractional excretion of sodium, albuminuria, plasma creatinine, and cystatin C. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function was measured by echocardiography and hemodynamic measurements.ResultsUNX alone induced compensatory left kidney enlargement, increased plasma creatinine and cystatin C levels, and slightly reduced glomerular filtration rate and increased FGS. AV induced significant cardiac enlargement and hypertrophy and reduced cardiac function and increased FGS, these changes were aggravated in UNX+AV rats.ConclusionsAlthough UNX only induces minor renal dysfunction, additional chronic volume overload placement during the adaptation phase of the remaining kidney is associated with aggravated cardiac dysfunction and remodeling in UNX rats, suggesting special medical care is required for UNX or congenital monokidney subjects in case of chronic volume overload as in the case of pregnancy and hyperthyroidism to prevent further adverse cardiorenal events in these individuals.

Gender differences in response to acute and chronic angiotensin II infusion: a translational approach.

Women with renal disease progress at a slower rate to end stage renal disease than men. As angiotensin II has both hemodynamic and direct renal effects, we hypothesized that the female protection may result from gender differences in responses to angiotensin II. Therefore, we studied gender differences in response to angiotensin II, during acute (human) and chronic (rats) angiotensin II administration. In young healthy men (n = 18) and women (n = 18) we studied the responses of renal hemodynamics (125I-iothalamate and 131I-Hippuran) and blood pressure to graded angiotensin II infusion (0.3, 1.0, and 3.0 ng/kg/min for 1 h). Men had increased responses of diastolic blood pressure (P = 0.01), mean arterial pressure (P = 0.05), and a more pronounced decrease in effective renal plasma flow (P = 0.009) than women. We measured the changes in proteinuria and blood pressure in response to chronic administration (200 ng/kg/min for 3 weeks) of angiotensin II in rats. Male rats had an increased response of proteinuria compared with females (GEE analysis, P = 0.001). Male, but not female, angiotensin II-treated rats had increased numbers of renal interstitial macrophages compared to sham-treated rats (P < 0.001). In conclusion, gender differences are present in the response to acute and chronic infusion of angiotensin II. Difference in angiotensin II sensitivity could play a role in gender differences in progression of renal disease.

Long-term changes in renal function and perfusion in heart failure patients with reduced ejection fraction.

IntroductionLittle is known about the natural course of renal function and renal hemodynamics in heart failure patients with reduced ejection fraction (HFREF).Methods and resultsWe prospectively studied effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in 73 HFREF patients with 125I-iothalamate/131I-hippuran clearances with a mean follow-up of 34.6 ± 4.4 months. Fifteen percent were female, with age 58 ± 12 years and left ventricular ejection fraction (LVEF) 29 ± 10 %. Baseline GFR was 81 ± 23 mL/min/1.73 m2 and declined 0.6 ± 4.7 mL/min/1.73 m2 per year. Baseline ERPF was 292 ± 83 mL/min/1.73 m2 and declined 4.3 ± 19 mL/min/1.73 m2 per year. Of the baseline variables, older age and high urinary kidney injury molecule-1 were the only variables associated with GFR decline (p < 0.05). Following stepwise backward analysis, only age (p < 0.001) remained significant. In addition, we found an association between change in GFR and changes in ERPF, N-terminal pro-brain natriuretic peptide and renovascular resistance. In the multivariable analysis, only the change in ERPF remained significantly associated with a change in GFR (p < 0.001).ConclusionIn this cohort of stable chronic HFREF patients, the average decline in GFR over time was small. The decline of GFR was associated with a higher age and a lower baseline GFR, and was strongly related to changes in renal perfusion.Electronic supplementary materialThe online version of this article (doi:10.1007/s00392-015-0881-9) contains supplementary material, which is available to authorized users.

TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping

Renal ischemia-reperfusion (I/R) is a common clinical complication in critically ill patients that is associated with considerable morbidity and mortality. Renal I/R is a major cause of acute kidney injury (AKI) resulting from I/R-induced oxidative stress, sterile inflammation, and microcirculatory perfusion defects, which can be ameliorated with the superoxide scavenger TEMPOL. The most common cause of AKI in the clinical setting is aortic surgery with suprarenal aortic clamping. The protective effect of TEMPOL in aortic clamping-induced renal I/R has not been studied before. To evaluate the protective effects of TEMPOL on oxidative stress, inflammation, tissue injury, and renal hemodynamics and oxygenation in a clinically representative rat model of I/R using aortic cross-clamping. Animals (N = 24) were either sham-operated or subjected to ischemia (30 min) and 90-min reperfusion, with or without TEMPOL treatment (15 min before ischemia and during entire reperfusion phase, 200 μmol/kg/h). Systemic and renal hemodynamics, renal oxygenation, and blood gas values were determined at 15 min and 90 min of reperfusion. At 90-min reperfusion, iNOS, inflammation (IL-6, MPO), oxidative stress (MDA), and tissue damage (NGAL, L-FABP) were determined in tissue biopsies. TEMPOL administration at a cumulative dose of 400 μmol/kg conferred a protective effect on AKI in terms of reducing renal damage, inflammation, and iNOS activation. With respect to renal hemodynamics and oxygenation, TEMPOL only reduced renal vascular resistance to near-baseline levels at both reperfusion time points and partially ameliorated the I/R-induced drop microvascular partial tension of oxygen at 90 min reperfusion. Also, TEMPOL alleviated the I/R-induced metabolic acidosis. However, TEMPOL exerted no restorative effect in terms of the severely reduced mean arterial pressure, renal blood flow, and renal oxygen delivery and consumption. The renal oxygen extraction ratio remained unchanged during the 90-min reperfusion phase. Kidneys in all groups were anuric throughout the experiment. This clinically representative renal I/R model, which entails both renal I/R and hind limb I/R as opposed to the standardly used renal I/R model that employs renal artery clamping, resulted in relatively moderate direct AKI. The damage was exacerbated by the perturbed systemic hemodynamics and metabolic acidosis as a result of the hind limb I/R. TEMPOL partially intervened in the factors that led to AKI as well as renal microvascular partial tension of oxygen and metabolic acidosis. However, more effective interventions should be devised for the mean arterial pressure drop (i.e., anuria) associated with aortic clamping and for restoring other critical renal hemodynamic and oxygenation parameters in order to improve post-I/R renal function. TEMPOL is a promising compound that has been shown to protect kidneys from I/R damage, which is relevant in kidney transplantation, pancreas transplantation, and aortic aneurysm repair in kidney transplant patients. This study suggests that intervening with TEMPOL is not sufficient to ensure optimal clinical outcome in patients that have undergone aortic clamping and that more effective interventions should be investigated.

The giraffe kidney tolerates high arterial blood pressure by high renal interstitial pressure and low glomerular filtration rate.

The tallest animal on earth, the giraffe (Giraffa camelopardalis) is endowed with a mean arterial blood pressure (MAP) twice that of other mammals. The kidneys reside at heart level and show no sign of hypertension-related damage. We hypothesized that a species-specific evolutionary adaption in the giraffe kidney allows normal for size renal haemodynamics and glomerular filtration rate (GFR) despite a MAP double that of other mammals. Fourteen anaesthetized giraffes were instrumented with vascular and bladder catheters to measure glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Renal interstitial hydrostatic pressure (RIHP) was assessed by inserting a needle into the medullary parenchyma. Doppler ultrasound measurements provided renal artery resistive index (RI). Hormone concentrations as well as biomechanical, structural and histological characteristics of vascular and renal tissues were determined. GFR averaged 342 ± 99 mL min(-1) and ERPF 1252 ± 305 mL min(-1) . RIHP varied between 45 and 140 mmHg. Renal pelvic pressure was 39 ± 2 mmHg and renal venous pressure 32 ± 4 mmHg. A valve-like structure at the junction of the renal and vena cava generated a pressure drop of 12 ± 2 mmHg. RI was 0.27. The renal capsule was durable with a calculated burst pressure of 600 mmHg. Plasma renin and AngII were 2.6 ± 0.5 mIU L(-1) and 9.1 ± 1.5 pg mL(-1) respectively. In giraffes, GFR, ERPF and RI appear much lower than expected based on body mass. A strong renal capsule supports a RIHP, which is >10-fold that of other mammals effectively reducing the net filtration pressure and protecting against the high MAP.

Metformin's Intrinsic Blood-to-Plasma Partition Ratio (B/P): Reconciling the Perceived High In Vivo B/P > 10 with the In Vitro Equilibrium Value of Unity.

Blood cells are considered an important distributional compartment for metformin based on the high blood-to-plasma partition ratio (B/P) in humans (>10 at Cmin). However, literature reports of metformin's intrinsic in vitro B/P values are lacking. At present, the extent and rate of metformin cellular partitioning was determined in incubations of fresh human and rat blood with [(14)C]metformin for up to 1 week at concentrations spanning steady-state plasma Cmin, Cmax, and a concentration associated with lactic acidosis. The results showed that metformin's intrinsic equilibrium B/P was ∼0.8-1.4 in blood, which is <10% of the reported clinical value. Kinetics of metformin partitioning into human blood cells and repartitioning back into plasma were slow (repartitioning half-life ∼32-39 hours). These data, along with in vivo rapid and efficient renal clearance of plasma metformin (plasma renal extraction ratio ∼90%-100%), explain why the clinical terminal half-life of metformin in plasma (6 hours) is 3- to 4-fold shorter than the half-life in whole blood (18 hours) and erythrocytes (23 hours). The rate constant for metformin repartitioning from blood cells to plasma (∼0.02 h(-1)) is far slower than the clinical renal elimination rate constant (0.3 h(-1)). Blood distributional rate constants were incorporated into a metformin physiologically-based pharmacokinetic model, which predicted the differential elimination half-life in plasma and blood. The present study demonstrates that the extent of cellular drug partitioning in blood observed in a dynamic in vivo system may be very different from the static in vitro values when repartitioning from blood cells is far slower than clearance of drug in plasma.