Search

Elevated copeptin, a stable surrogate of vasopressin, is recognized to be higher in T1D and predicts diabetic kidney disease and cardiovascular (CV) mortality. Vasopressin increases renal oxygen consumption through enhanced sodium reabsorption and may result in renal hypoxia. Given the natriuretic and cardiorenal protective effects of SGLT2 inhibition (SGLT2i) in clinical trials, our aim was to: 1) examine serum copeptin in adults with T1D after SGLT2i with empagliflozin (EMPA) for 8-weeks; and 2) determine the relationship between copeptin and metabolic, renal and system hemodynamic parameters. In this post hoc, exploratory analysis, serum copeptin concentration, glomerular filtration rate (GFR) by inulin clearance, effective renal plasma flow (ERPF) by PAH clearance, vascular stiffness parameters, plasma RAAS markers, HbA1c, 24-hour urine volume and sodium and glucose excretion were measured in 40 participants with T1D (24.1±5.0 years, HbA1c 8.0±0.9%) during eu- and hyperglycemia at baseline and after 25 mg of daily EMPA. Copeptin concentrations increased under both eu- and hyperglycemic conditions (4.0±2.1 to 5.1±6.0 pmol/L, p=0.005 and p SGLT2i increased serum copeptin concentrations, which positively correlated with HbA1c and inversely with urine output and natriuresis, but not with renal or system hemodynamic parameters. Further work is required to evaluate the clinical implications of elevated copeptin with SGLT2i; whether it is simply a marker of diuresis or may contribute to CV disease long-term. Disclosure Y. Lytvyn: None. P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. A. Katz: None. S.K. Singh: None. L.C. Godoy: None. L.T. Chung: None. C.L. Vinovskis: None. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi.

Although single-photon-emitting radiotracers have long been the standard for renal functional molecular imaging, recent years have seen the development of positron emission tomography (PET) agents for this application. We provide an overview of renal radionuclide PET radiotracers, in particular focusing on novel 18F-labelled and 68Ga-labelled agents. Several reported PET imaging probes allow assessment of glomerular filtration rate, such as [68Ga]ethylenediaminetetraacetic acid ([68Ga]EDTA), [68Ga]IRDye800-tilmanocept and 2-deoxy-2-[18F]fluorosorbitol ([18F]FDS)). The diagnostic performance of [68Ga]EDTA has already been demonstrated in a clinical trial. [68Ga]IRDye800-tilmanocept shows receptor-mediated binding to glomerular mesangial cells, which in turn may allow the monitoring of progression of diabetic nephropathy. [18F]FDS shows excellent kidney extraction and excretion in rats and, as has been shown in the first study in humans. Further, due to its simple one-step radiosynthesis via the most frequently used PET radiotracer 2-deoxy-2-[18F]fluoro-d-glucose, [18F]FDS could be available at nearly every PET centre. A new PET radiotracer has also been introduced for the effective assessment of plasma flow in the kidneys: Re(CO)3-N-([18F]fluoroethyl)iminodiacetic acid (Re(CO)3([18F]FEDA)). This compound demonstrates similar pharmacokinetic properties to its 99mTc-labelled analogue [99mTc](CO)3(FEDA). Thus, if there is a shortage of molybdenum-99, Re(CO)3([18F]FEDA would allow direct comparison with previous studies with 99mTc. The PET radiotracers for renal imaging reviewed here allow thorough evaluation of kidney function, with the tremendous advantage of precise anatomical coregistration with simultaneously acquired CT images and rapid three-dimensional imaging capability.

Objective: To determine the ability of renal contrast-enhanced ultrasonography (CEUS) to detect acute drug-induced changes in renal perfusion (using the glucagon-like peptide (GLP)-1 receptor agonist exenatide and nitric oxide [NO]-synthase inhibitor L-NG-monomethyl arginine [l-NMMA]), and assess its correlation with gold standard-measured effective renal plasma flow in humans. Methods: In this prespecified exploratory analysis of a placebo-controlled cross-over study, renal hemodynamics was assessed in 10 healthy overweight males (aged 20-27 years; BMI 26-31 kg/m2) over two separate testing days; during placebo (isotonic saline) and subsequent exenatide infusion (Day-A), and during l-NMMA, and subsequent exenatide plus l-NMMA infusion (Day-B). Renal cortical microvascular blood flow was estimated following microbubble infusion and CEUS destruction-refilling-sequences. Renal cortical microvascular blood flow was compared with simultaneously measured effective renal plasma flow in humans, derived from para-aminohippuric acid-clearance methodology. Results: On Day-A, effective renal plasma flow increased by 68 [26-197] mL/min/1.73 m2 during exenatide vs placebo infusion (+17%; P =.015). In parallel, exenatide increased renal cortical microvascular blood flow, from 2.42 × 10−4 [6.54 × 10−5-4.66 × 10−4] AU to 4.65 × 10−4 [2.96 × 10−4-7.74 × 10−4] AU (+92%; P =.027). On Day-B, effective renal plasma flow and renal cortical microvascular blood flow were reduced by l-NMMA, with no significant effect of concomitant exenatide on renal hemodynamic-indices assessed by either technique. Effective renal plasma flow correlated with renal cortical microvascular blood flow on Day-A (r =.533; P =.027); no correlation was found on Day-B. Conclusions: Contrast-enhanced ultrasonography can detect acute drug-induced changes human renal hemodynamics. CEUS-assessed renal cortical microvascular blood flow moderately associates with effective renal plasma flow, particularly when perfusion is in normal-to-high range. Renal CEUS cannot replace effective renal plasma flow measurements, but may be a complementary tool to characterize regional kidney perfusion.

Aim Increased plasma uric acid (PUA) concentrations are associated with chronic kidney disease in type 2 diabetes (T2D) patients. The mechanisms involved remain unclear. We investigated the relation between PUA and (intra)renal haemodynamics in T2D patients without overt kidney disease. Methods Eighty‐eight white men and women with T2D were included (age 64 (58–68) years; body mass index 30.9 (28.3–33.6) kg/m2; glycated haemoglobin 7.1 (6.8–7.6)%). Plasma UA and fractional excretion of UA were measured, while glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were assessed by inulin and PAH‐clearance techniques, respectively. Effective renal vascular resistance was calculated (ERVR). Renal afferent and efferent arteriolar resistances and glomerular hydrostatic pressure were estimated. Relationships between PUA and fractional excretion of UA and (intra)renal haemodynamic parameters were evaluated by multivariable linear regression analyses. Results Plasma UA concentrations were at the higher end of the normal range in most participants: 342 ± 68 μmol/L or 5.7 ± 1.1 mg/dL (mean ± SD). In multivariable analyses, PUA concentrations were negatively associated with GFR (r = −0.471; P = 0.001), ERPF (r = −0.436; P = 0.003) and glomerular hydrostatic pressure (r = −0.427; P = 0.003). In contrast, PUA concentrations had a positive correlation with ERVR (r = 0.474; P = 0.001), but not with efferent vascular resistance. Fractional excretion of UA was not related to renal haemodynamics. Conclusion Plasma UA was negatively associated to GFR, ERPF but positively related to ERVR in T2D patients without overt renal impairment. Plasma UA‐related increase in ERVR may be related to increased arterial afferent tone, which may put the kidney at risk for renal damage through ischaemia., SUMMARY AT A GLANCE This paper, which explored the relationship between plasma uric acid (UA) and renal haemodynamics in patients with type 2 diabetes without overt kidney disease showed that higher plasma UA is associated with lower glomerular filtration rate and effective renal plasma flow but higher effective renal vascular resistance, which may contribute to glomerular dysfunction due to impairment in kidney perfusion.

The preterm-born adult population is ever increasing following improved survival rates of premature births. We conducted a meta-analysis to investigate long-term effects of preterm birth on renal function in preterm-born survivors. We searched PubMed and EMBASE to identify studies that compared renal function in preterm-born survivors and full-term-born controls, published until 2 February 2019. A random effects model with standardized mean difference (SMD) was used for meta-analyses. Heterogeneity of the studies was evaluated using Higgin’s I2 statistics. Risk of bias was assessed using the Newcastle–Ottawa quality assessment scale. Of a total of 24,388 articles screened, 27 articles were finally included. Compared to full-term-born controls, glomerular filtration rate and effective renal plasma flow were significantly decreased in preterm survivors (SMD −0.54, 95% confidence interval (CI), −0.85 to −0.22, p = 0.0008, SMD −0.39, 95% CI, −0.74 to −0.04, p = 0.03, respectively). Length and volume of the kidneys were significantly decreased in the preterm group compared to the full-term controls (SMD −0.73, 95% CI, −1.04 to −0.41, p &lt, 0.001, SMD −0.82, 95% CI, −1.05 to −0.60, p &lt, 0.001, respectively). However, serum levels of blood urea nitrogen, creatinine, and cystatin C showed no significant difference. The urine microalbumin to creatinine ratio was significantly increased in the preterm group. Both systolic and diastolic blood pressures were also significantly elevated in the preterm group, although the plasma renin level did not differ. This meta-analysis demonstrates that preterm-born survivors may be subject to decreased glomerular filtration, increased albuminuria, decreased kidney size and volume, and hypertension even though their laboratory results may not yet deteriorate.

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease. A major challenge in preventing DKD is the difficulty in identifying high-risk patients at a preclinical stage. Existing methods that are used to assess renal function, including albuminuria and eGFR, do not give detailed insight into the location of the renal hemodynamic effects of pharmacological agents at the segmental level. To gain additional information about the intrarenal circulation in vivo in humans, equations were developed by Gomez et al. in the 1950s. These equations used measurements of glomerular filtration rate, renal blood flow, effective renal plasma flow, renal vascular resistance, hematocrit, and serum protein to calculate afferent and efferent arteriolar resistances, glomerular hydrostatic pressure, and filtration pressure. The Gomez equations are, however, indirect and based on physiological assumptions derived from animal models, which may not hold true in human pathophysiology, including the assumption of a normal gross filtration coefficient and not considering changes in intratubular pressure that may affect the pressure gradient across the glomerular capillaries. Nevertheless, the equations have the potential to improve researchers' ability to identify early preclinical changes in renal hemodynamic function in patients with a variety of conditions, including DKD, thereby offering potential in mechanistic human research studies. In this review, we focus on the application of Gomez' equations and summarize the potential and limitations of these techniques in DKD research. We also summarize illustrative data derived from Gomez' equations in patients with type 1 and type 2 diabetes and hypertension.

Purpose: Urinary biomarkers of renal injury urinary may identify loss of renal function following nephron-sparing surgery (NSS). This study was designed to evaluate whether urinary l-type fatty acid-binding protein (l-FABP) is an early biomarker of loss of renal function after NSS. Specifically, the kinetics of urinary l-FABP level after NSS and its correlation with factors related to ischemic renal injury were analyzed. Methods: This study prospectively evaluated 18 patients who underwent NSS between July and December 2014, including 12 who underwent laparoscopic and six who underwent robot-assisted partial nephrectomy. Urinary l-FABP concentrations were measured preoperatively and 1, 2, 3, 6, 12, 24, 48, and 72 h after renal artery declamping. Loss of renal function loss was calculated by comparing the effective renal plasma flow, as determined by 99mTc-mercaptoacetyltriglycine (MAG3) clearance, on the operated and normal sides. The decrease in estimated glomerular filtration rate from before surgery to six months after surgery was also measured. Results: Urinary l-FABP concentration peaked within 2 h of declamping, which may quantify nephron damage caused by ischemia. The decrease in MAG3 reduction ratio correlated with both the ischemia time and peak urinary l-FABP concentration. Peak urinary l-FABP concentration showed a significant correlation with MAG3 reduction ratio. Conclusions: l-FABP is a suitable urinary biomarker for predicting the extent of ischemic renal injury.

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.

Introduction Many studies have suggested that post-transplantation renal allograft function is associated with long-term allograft outcomes. However, accurate examination through non-invasive methods remains rare. The aim of the present study is to assess the association between 99mTc mercaptoacetyltriglycine (MAG3) effective renal plasma flow (ERPF) and first-year post-transplantation renal allograft function. Methods We conducted a retrospective cohort study at our center between January 2011 and December 2016. Kidney transplant recipients without an ERPF examination within 14 days post-transplantation, or those with less than 1 year of follow-up were excluded. Eligible cases were divided into 3 groups according to first-year eGFR 60. The Kruskal-Wallis test and χ2 were used for comparisons between continuous and categorical variables. Results A total of 123 patients were analyzed. Each group received 41 patients. The baseline characteristics were comparable in the 3 groups, except for repeated transplantation and delayed graft function. The results of the ERPF median (interquartile range) for the 3 groups were 193 (140.0–244.5) in the eGFR 60 group (P 276 exhibited the best sensitivity (65.85%) and specificity (75.61%) for predicting first-year eGFR > 60 mL/min/1.73 m2, with an area under the receiver operating characteristic curve of .712, P Conclusion Our findings suggest that an ERPF value of more than 276 is likely to be associated with a favorable first-year renal graft outcome after transplantation. The 99mTc MAG3 ERPF may be a non-invasive alternative to sequential protocol biopsies.

Background: Delayed graft function (DGF) could worsen early and long-term outcomes of kidney transplantation (KT). DGF is caused by several pre-transplantation and perioperative factors in both donors and recipients. At present, there are no biomarkers or tests during the immediate post-KT period that can accurately predict the development of DGF. Materials and methods: This prospective study was conducted in deceased donor KT (DDKT) at King Chulalongkorn Memorial Hospital, Thailand. All recipients underwent furosemide stress test (FST) by receiving a single dose of intravenous furosemide, 1.5 mg/kg at 3 h after allograft reperfusion. We determined the correlations between DGF (requiring dialysis within the first week after transplantation) and the values of urine volume recorded hourly after FST until 6 h, the parameters of postoperative dynamic tests, including resistive index (RI) of renal arteries and effective renal plasma flow (ERPF), and urine neutrophil gelatinase-associated lipocalin (NGAL). Results: Of the 59 total DDKT recipients enrolled, 24 developed DGF. The FST is a more accurate biomarker than urine NGAL, RI of renal arteries, and ERPF in the prediction of DGF. The 4-h urine volume less than 350 mL (FST non-responsive) was the best cut-off value in predicting DGF with 87.5% sensitivity, 82.9% specificity, and 82.5% accuracy. Multiple logistic regression analyses showed an odds ratio of 0.993 (0.986–0.999, p = 0.035) for the 4-h urine volume to predict DGF. Conclusions: The FST is a simple and accurate biomarker for predicting DGF in early post-KT period. Close monitoring and well prepared dialysis are suggested in patients with urine volume < 350 mL after 4 h of FST. The FST non-responsive patients could be the target for further DGF preventive intervention. ClinicalTrials.gov identifier: NCT03071536.

Objectives The tyrosine kinase inhibitor crizotinib may affect renal function. The mechanism of this effect is not understood. We aimed to get more insight by measuring renal hemodynamics in patients treated with crizotinib. Materials and methods Renal hemodynamics (i.e. glomerular filtration rate and effective renal plasma flow) were measured with radioactive tracers in three patients with stage IV non small-cell lung cancer during treatment with crizotinib. The results were compared with simultaneous creatinine based renal function measurements in the same patients. Results Patients had been treated with crizotinib between 155 and 320 days at the first measurement. In one patient the measurement was repeated after a total of one year and two months of treatment. All patients had been treated with chemotherapy containing cisplatin before. In these patients true glomerular filtration rate was 64–83% higher than estimated by creatinine based measurements. Filtration fraction, a measure of glomerular pressure, was increased in all three patients. The glomerular pressure was even further increased in a follow-up measurement. Conclusion Creatinine-based estimates of GFR on crizotinib may underestimate the true GFR. However, evidence of increased glomerular pressure may increase risk of long term true nephrotoxicity.

OBJECTIVE Central adiposity is considered to be an important cardiorenal risk factor in the general population and in type 1 diabetes. We sought to determine the relationship between central adiposity and intrarenal hemodynamic function in adults with long-standing type 1 diabetes with and without diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS Patients with type 1 diabetes (n = 66, duration ≥50 years) and age-/sex-matched control subjects (n = 73) were studied. The cohort was stratified into 44 DN Resistors (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2 and RESULTS Whereas measures of adiposity did not associate with GFRINULIN or ERPFPAH in healthy control subjects, trunk fat mass inversely correlated with GFRINULIN (r = −0.46, P < 0.0001) and ERPFPAH (r = −0.31, P = 0.01) and positively correlated with RVR (r = 0.53, P = 0.0003) in type 1 diabetes. In analyses stratified by DN status, greater central adiposity related to lower GFRINULIN values in DN and DN Resistors, but the relationships between central adiposity and ERPFPAH and RVR were attenuated and/or reversed in patients with DN compared with DN Resistors. CONCLUSIONS The adiposity-intrarenal hemodynamic function relationship may be modified by the presence of type 1 diabetes and DN, requiring further study of the mechanisms by which adiposity influences renal hemodynamic function.

Aldosterone blockade confers substantial cardiovascular and renal protection. The effects of aldosterone on mineralocorticoid receptors (MR) expressed in endothelial cells (EC) within the renal vasculature have not been delineated. We hypothesized that lack of MR in EC may be protective in renal vasculature and examined this by ablating the Nr3c2 gene in endothelial cells (EC-MR) in mice. Blood pressure, heart rate and PAH clearance were measured using indwelling catheters in conscious mice. The role of the MR in EC on contraction and relaxation was investigated in the renal artery and in perfused afferent arterioles. Urinary sodium excretion was determined by use of metabolic cages. EC-MR transgenics had markedly decreased MR expression in isolated aortic endothelial cells as compared to littermates (WT). Blood pressure and effective renal plasma flow at baseline and following AngII infusion was similar between groups. No differences in contraction and relaxation were observed between WT and EC-MR KO in isolated renal arteries during baseline or following 2 or 4 weeks of AngII infusion. The constriction or dilatations of afferent arterioles between genotypes were not different. No changes were found between the groups with respect to urinary excretion of sodium after 4 weeks of AngII infusion, or in urinary albumin excretion and kidney morphology. In conclusion, deletion of the EC-MR does not confer protection towards the development of hypertension, endothelial dysfunction of renal arteries or renal function following prolonged AngII-infusion.

BackgroundHyperglycaemia impairs tubulo-glomerular feedback. We tested whether variable tubulo-glomerular feedback during hyperglycaemia contributes to renal risk heterogeneity seen in Type 1 diabetes.MethodsDuring the period 1990–92, we studied the tubulo-glomerular feedback in Type 1 diabetic patients at high or low renal risk [21 of 54 with glomerular hyperfiltration and/or microalbuminuria against 11 of 55 with normal glomerular filtration rate (GFR) and urinary albumin despite uncontrolled diabetes]. The GFR, effective renal plasma flow, mean arterial pressure and fractional reabsorptions of glucose, osmols, sodium and lithium were measured sequentially during normo- and hyperglycaemia. All patients were followed up until 2016 for incident proteinuria, estimated GFR ResultsGlycaemia increased from 6.1 ± 1.3 to 15.1 ± 1.9 mmol/L in both high-risk and low-risk patients. Glycosuria was lower in the high- versus low-risk patients: 0.34 ± 0.25 versus 0.64 ± 0.44 mmol/min (P = 0.03). Both groups displayed similar kidney function during normoglycaemia. Hyperglycaemia increased more importantly GFR and fractional reabsorptions, and pre-glomerular vasodilatation in the high- than in the low-risk patients (all P ConclusionsReduced tubulo-glomerular feedback and glycosuria during hyperglycaemia indicate high renal risk for Type 1 diabetic patients. Inter-individual variability in tubulo-glomerular feedback activity determines renal risk in Type 1 diabetes.

Aim: To determine whether lixisenatide, a prandial short-acting glucagon-like peptide receptor agonist (GLP-1RA), ameliorates postprandial glomerular hyperfiltration in patients with type 2 diabetes mellitus (T2DM) compared with insulin-glulisine (iGlu). Methods: Postprandial renal haemodynamic effects of 8-week treatment with lixisenatide 20 µg vs once-daily titrated iGlu were measured in 35 overweight patients with T2DM inadequately controlled on insulin-glargine, with or without metformin [mean ± SD age 62 ± 7 years, HbA1c 8.0% ± 0.9%, estimated glomerular filtration rate (GFR) 85 ± 12 mL/min/1.73 m2, median (IQR) urinary albumin/creatinine ratio 1.5 (0.9-3.0) mg/mmol]. After a standardised breakfast, GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid renal clearance, respectively, based on timed urine sampling. Intrarenal haemodynamic functions were estimated using Gomez equations. Results: Compared with iGlu, lixisenatide did not affect GFR [+0.1 mL/min/1.73 m2 (95% CI −9 to 9)], ERPF [−17 mL/min/1.73 m2 (−61 to 26)], other (intra-)renal haemodynamics or renal damage markers, but increased fractional sodium excretion [+0.25% (0.09-0.41)] and urinary pH [+0.7 (0.3-1.2)]. Plasma renin, angiotensin-II and aldosterone were unchanged. Lixisenatide and iGlu reduced HbA1c similarly, by 0.8% ± 0.1% and 0.6% ± 0.1%, respectively, while postprandial glucose was lower with lixisenatide (P =.002). Compared with iGlu, lixisenatide reduced bodyweight [−1.4 kg (−2.5 to −0.2)] and increased postprandial mean arterial pressure [+9 mm Hg (4-14)]. Conclusion: Eight-week lixisenatide treatment does not affect postprandial (intra-)renal haemodynamics compared with iGlu when added to insulin-glargine in patients with T2DM without overt nephropathy. Prolonged lixisenatide treatment has a sustained natriuretic effect, which is in contrast to previous reports on long-acting GLP-1RA, reduces body weight and increases postprandial blood pressure compared with iGlu. Trial registration: ClinicalTrials.gov identifier NCT02276196.

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.

Obstructive sleep apnea (OSA) and nocturnal hypoxemia are associated with chronic kidney disease and up-regulation of the renin-angiotensin system (RAS), which is deleterious to renal function. The extent to which the magnitude of RAS activation is influenced by the severity of nocturnal hypoxemia and comorbid obesity has not been determined.To determine the association between the severity of nocturnal hypoxemia and RAS activity and whether this is independent of obesity in patients with OSA.Effective renal plasma flow (ERPF) response to angiotensin II (AngII) challenge, a marker of renal RAS activity, was measured by paraaminohippurate clearance technique in 31 OSA subjects (respiratory disturbance index, 51 ± 25 h(-1)), stratified according to nocturnal hypoxemia status (mean nocturnal SaO2, ≥90% [moderate hypoxemia] or90% [severe hypoxemia]) and 13 obese control subjects.Compared with control subjects, OSA subjects demonstrated decreased renovascular sensitivity (ERPF, -153 ± 79 vs. -283 ± 31 ml/min; P = 0.004) (filtration fraction, 5.4 ± 3.8 vs. 7.1 ± 2.6%; P = 0.0025) in response to 60 minutes of AngII challenge (mean ± SD; all P values OSA vs. control). The fall in ERPF in response to AngII was less in patients with severe hypoxemia compared with those with moderate hypoxemia (P = 0.001) and obese control subjects after 30 minutes (P 0.001) and 60 minutes (P 0.001) of AngII challenge, reflecting more augmented renal RAS activity. Severity of hypoxemia was not associated with the blood pressure or the systemic circulating RAS component response to AngII.The severity of nocturnal hypoxemia influences the magnitude of renal, but not the systemic, RAS activation independently of obesity in patients with OSA.

BACKGROUND: Animal studies suggest that progression of chronic kidney disease (CKD) is related to renal hypoxia. With renal blood supply determining oxygen delivery and sodium absorption being the main contributor to oxygen consumption, we describe the relationship between renal oxygenation, renal artery blood flow, and sodium absorption in patients with CKD and healthy controls.STUDY DESIGN: Cross-sectional study.SETTING & PARTICIPANTS: 62 stable patients with CKD stages 3 to 4 (mean age, 61±13 [SD] years) and 24 age- and sex-matched controls.PREDICTORS: CKD versus control status.OUTCOMES: Renal artery blood flow, tissue oxygenation (relative changes in deoxyhemoglobin concentration of the renal medulla [MR2*] and cortex [CR2*]), and sodium absorption.MEASUREMENTS: Renal artery blood flow was determined by phase-contrast magnetic resonance imaging (MRI); MR2* and CR2* were determined by blood oxygen level-dependent MRI. Ultrafiltered and reabsorbed sodium were determined from measured glomerular filtration rate (mGFR) and 24-hour urine collections.RESULTS: mGFR in patients was 37% that of controls (36±15 vs 97±23mL/min/1.73m(2); P < 0.001), and reabsorbed sodium was 37% that of controls (6.9 vs 19.1mol/24 h; P < 0.001). Single-kidney patient renal artery blood flow was 72% that of controls (319 vs 443mL/min; P < 0.001). Glomerular filtration fraction was 9% in patients and 18% in controls (P < 0.001). Patients and controls had similar CR2* (13.4 vs 13.3s(-1)) and medullary MR2* (26.4 vs 26.5s(-1)) values. Linear regression analysis demonstrated no associations between R2* and renal artery blood flow or sodium absorption. Increasing arterial blood oxygen tension by breathing 100% oxygen had very small effects on CR2*, but reduced MR2* in both groups.LIMITATIONS: Only renal artery blood flow was determined and thus regional perfusion could not be related to CR2* or MR2*.CONCLUSIONS: In CKD, reductions of mGFR and reabsorbed sodium are more than double that of renal artery blood flow, whereas cortical and medullary oxygenation are within the range of healthy persons. Reduction in glomerular filtration fraction may prevent renal hypoxia in CKD.

Background Both immunological and non-immunological etiologies affect graft function after kidney transplantation, including acute rejection, calcineurin inhibitor toxicity, and a recurrence of glomerulonephritis. Glomerular enlargement or glomerular sclerosis due to glomerular hyperfiltration related to increased renal blood flow is another cause. Although the glomerular volume in baseline biopsies predicts late allograft function, the relationship between allograft function and the annual changes in glomerular volume after kidney transplantation are unclear. Aim We investigated changes in glomerular volume after kidney transplantation and their clinicopathological relationship. Methods We enrolled 23 patients with stable kidney function without an episode of rejection or any complication resulting in a functional decrease in the graft. We measured glomerular volume (GV) using the Weibel–Gomez method and glomerular density (GD) using 0,1 h biopsy samples as baseline controls and 1 yr biopsy samples and investigated the association between the changes in them and clinical parameters, including graft function, proteinuria, and renal hemodynamic markers, including effective renal plasma flow (ERPF) and filtration fraction (FF). The ERPF was calculated from a 99mTc-mercaptoacetyltriglycine (MAG3) renogram. Results The GV and ERPF increased significantly 1 yr after kidney transplantation. In contrast, proteinuria decreased significantly and Δproteinuria (1 yr – 1 month after transplantation) was correlated with ΔGV (P

The human kidney provides essential regulatory and excretory functions. Body water content, plasma electrolyte composition and plasma pH are all under the regulatory control of the kidney. In addition, the kidney provides a path of excretion for blood-borne, water-soluble, low-molecular-weight compounds. These include the end-products of protein metabolism, such as urea and creatinine, as well as foreign compounds with similar physicochemical characteristics and their metabolites. Endocrine activity of the human kidney includes the secretion of the hormones erythropoietin and renin and the activation of vitamin D by hydroxylation to its 1,25-dihydroxycholecalciferol form. The renal blood flow is immense, constituting 20–25% of resting cardiac output. The glomeruli form 170–200 litres of ultrafiltrate per day and the selective reabsorption of water and solutes results in the final formation of approximately 1.5 litres of urine. Here, commonly used laboratory tests of renal function are discussed, including glomerular filtration rate (GFR), creatinine clearance, serum creatinine concentration estimation of GFR, serum urea concentration, novel measures of renal function, emerging biomarkers for acute kidney injury, urinalysis, free water clearance and endocrine changes in renal disease. It must be noted, however, that these tests require a clinical assessment of the patient to allow meaningful interpretation.

Endothelin-1 (ET-1) is potent vasoconstrictor peptide which is able to contribute to the functional and structural renal changes. The aim of this study was to investigate the relationship between plasma concentration of ET-1 and indices of renal function in patients with diabetic nephropathy.We measured plasma ET-1 levels in 99 patients with type 2 diabetes, divided into two groups according to the values of their glomerular filtration rate (GFR): group I (GFR ≥ 60 mL/min/1.73 m(2); n = 50), group II (GFR ≥ 60 mL/min/1.73 m(2), n = 49), and the control group (n = 30) with clinically healthy subjects who were matched by age and sex. GFR and effective renal plasma flow (ERPF) were measured by the radioisotopic clearance. Other renal function parameters, such as serum concentrations of cystatin C, urea, creatinine, uric acid, 24-h albuminuria and proteinuria were additionally measured.There were significant differences in plasma concentration of ET-1 among groups I, II and the control group (1.45 vs. 2.40 vs. 0.80 pg/mL, p 0.001). The correlation between ET-1 and mGFR (r = -0.52, p 0.001), ERPF (r = -0.42, p 0.001), albuminuria and proteinuria (r = 0.36, p 0.001; r = 0.48, p 0.001) and cystatin C (r = 0.42, p 0.001) was significant. In multiple regression analyses, only plasma concentration of ET-1 (p 0.001) and duration of hypertension (p 0.05) were independently and significantly associated with mGFR.A higher plasma concentration of ET-1 is independently associated with a decreased value of GFR in patients with diabetic nephropathy.

Renal plasma flow (RPF) (derived from renal blood flow, RBF) and glomerular filtration rate (GFR) allow the determination of the filtration fraction (FF), which may have a role as a non-invasive renal biomarker. This is a hypothesis-generating pilot study assessing the effect of nephrectomy on renal function in healthy kidney donors.Eight living kidney donors underwent arterial spin labelling (ASL) magnetic resonance imaging (MRI) and GFR measurement prior to and 1 year after nephrectomy. Chromium-51 labelled ethylenediamine tetraacetic acid ((51)Cr-EDTA) with multi-blood sampling was undertaken and GFR calculated. The RBF and GFR obtained were used to calculate FF.All donors showed an increase in single kidney GFR of 24 - 75 %, and all but two showed an increase in FF (-7 to +52 %) after nephrectomy. The increase in RBF, and hence RPF, post-nephrectomy was not as great as the increase in GFR in seven out of eight donors. As with any pilot study, the small number of donors and their relatively narrow age range are potential limiting factors.The ability to measure RBF, and hence RPF, non-invasively, coupled with GFR measurement, allows calculation of FF, a biomarker that might provide a sensitive indicator of loss of renal reserve in potential donors.• Non-invasive MRI measured renal blood flow and calculated renal plasma flow. • Effect of nephrectomy on blood flow and filtration in donors is presented. • Calculated filtration fraction may be a useful new kidney biomarker.

This study was planned to determine the efficacies of single plasma sample methods (SPSMs) in indicating glomerular filtration rate (GFR) by taking two plasma sample method (TPSM) as reference in the determination of the GFR in cases with clinically stable renal transplantation.Ninety-six renal transplantation cases (33 female, 63 male; age interval 18-67, mean age 37.46 ± 11.81 years) progressing stably clinically and as laboratory, with minimum 6 months after transplantation were included in the study. The GFR values of the cases were measured with SPSM and TPSM.It is observed that all SPSMs have a strong correlation with TPSM. Highest correlation was observed between GrothAasted SPSM and TPSM GFR (intraclass correlation coefficient: 0.965). In the analyses performed by using the Bland-Altman analysis, GFR values calculated by all SPSMs were concordant to the TPSM which is the gold standard method in 95 % confidence interval (average ± 1.96 standard deviation) and were within the clinically acceptable limits. The narrowest concordance interval was obtained between GrothAasted Tc-99 m DTPA SPSM and Tc-99 m DTPA TPSM..Besides, we have obtained the minimum bias and precision value by the GrothAasted method.As a result; we can see that all the SPSMs give reliable results in measuring GFR in cases with renal transplantation; besides, we suggest GrothAasted method as the first option.

Objective To assess renal functional deterioration after partial nephrectomy with warm and cold ischemia using 99m Tc-mercaptoacetyltriglycine ( 99m Tc-MAG3) renal scintigraphy parameters. Methods Open partial nephrectomy was performed in 59 patients with warm ischemia and 64 patients with cold ischemia. 99m Tc-MAG3 renal scintigraphy was performed and effective renal plasma flow was calculated to evaluate split renal function. In addition, regional 99m Tc-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 min (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 m 2 ) in the warm ischemia group and to 77.4% (from 152.3 to 116.6 mL/min/1.73 m 2 ) in the cold ischemia group. Regional 99m Tc-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 99m Tc-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 99m Tc-MAG3 uptake in the warm ischemia group, but not in the cold ischemia group. Conclusion 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.

Patients undergoing cardiac surgery with moderate hypothermic cardiopulmonary bypass (CPB) were allocated randomly to receive either saline (control group, n = 29) or a high-dose regimen of aprotinin (aprotinin group, n = 28). In both groups, CPB was associated with similar and transient increases in effective renal plasma flow (+54% in controls and +48% in aprotinin-treated patients) and in fractional excretion of sodium and potassium, but glomerular filtration rate remained unchanged. Plasma and urinary ratios of 6-keto-PGF1 alpha to thromboxane B2 (TxB2) increased significantly, indicating systemic and renal release of vasodilatory prostaglandins. Osmolar clearance correlated with urinary excretion of cyclic GMP (r = 0.79 and 0.86 in the control and aprotinin groups, respectively) and 6-keto-PGF1 alpha (r = 0.63 and 0.69 in the control and aprotinin groups, respectively). Compared with preoperative values, plasma atrial natriuretic peptide increased after weaning from CPB (+71% and +93% in the control and aprotinin groups, respectively). Aprotinin had no apparent adverse effect on renal function and it did not alter mechanisms involving prostanoids and atrial natriuretic peptide during cardiac surgery.

BACKGROUND. Glomerular hyperfiltration (GHF) is a well-recognized early renal alteration in diabetic patients. As the prevalence of GHF is largely unknown in populations in the African region with respect to normal fasting glucose (NFG), impaired fasting glucose (IFG) and type 2 diabetes [diabetes mellitus (DM)], we conducted a cross-sectional study in the Seychelles islands among families including at least one member with hypertension. METHODS. The glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and proximal tubular sodium reabsorption were measured using inulin, p-aminohippurate (PAH) and endogenous lithium clearance, respectively. Twenty-four-hour urine was collected on the preceding day. RESULTS. Of the 363 participants (mean age 44.7 years), 6.6% had IFG, 9.9% had DM and 63.3% had hypertension. The prevalence of GHF, defined as a GFR >140 ml/min, was 17.2%, 29.2% and 52.8% in NFG, IFG and DM, respectively (P trend

Higher plasma uric acid (PUA) levels are associated with lower glomerular filtration rate (GFR) and higher blood pressure (BP) in patients with type 1 diabetes (T1D). Our aim was to determine the impact of PUA lowering on renal and vascular function in patients with uncomplicated T1D. T1D patients (n = 49) were studied under euglycemic and hyperglycemic conditions at baseline and after PUA lowering with febuxostat (FBX) for 8 weeks. Healthy control subjects were studied under normoglycemic conditions (n = 24). PUA, GFR (inulin), effective renal plasma flow (para-aminohippurate), BP, and hemodynamic responses to an infusion of angiotensin II (assessment of intrarenal renin-angiotensin-aldosterone system [RAAS]) were measured before and after FBX treatment. Arterial stiffness, flow-mediated dilation (FMD), nitroglycerin-mediated dilation (GMD), urinary nitric oxide (NO), and inflammatory markers were measured before and after FBX treatment. Gomez equations were used to estimate arteriolar afferent resistance, efferent resistance (RE), and glomerular hydrostatic pressure (PGLO). FBX had a modest systolic BP–lowering effect in T1D patients (112 ± 10 to 109 ± 9 mmHg, P = 0.049) without impacting arterial stiffness, FMD, GMD, or NO. FBX enhanced the filtration fraction response to hyperglycemia in T1D patients through larger increases in RE, PGLO, and interleukin-18 but without impacting the RAAS. FBX lowered systolic BP and modulated the renal RE responses to hyperglycemia but without impacting the RAAS or NO levels, suggesting that PUA may augment other hemodynamic or inflammatory mechanisms that control the renal response to hyperglycemia at the efferent arteriole. Ongoing outcome trials will determine cardiorenal outcomes of PUA lowering in patients with T1D.

Aim The combination of weight excess and hypertension significantly contributes to cardiovascular risk and progressive kidney damage. An unfavorable renal hemodynamic profile is thought to contribute to this increased risk and may be ameliorated by direct renin inhibition (DRI). The aim of this trial was to assess the effect of DRI on renal and systemic hemodynamics and on RAAS activity, in men with weight excess and hypertension. Methods A randomized, double-blind, cross-over clinical trial to determine the effect of DRI (aliskiren 300 mg/day), with angiotensin converting enzyme inhibition (ACEi; ramipril 10 mg/day) as a positive control, on renal and systemic hemodynamics, and on RAAS activity (n = 15). Results Mean (SEM) Glomerular filtration rate (101 (5) mL/min/1.73m2) remained unaffected by DRI or ACEi. Effective renal plasma flow (ERPF; 301 (14) mL/min/1.73m2) was increased in response to DRI (320 (14) mL/min/1.73m2, P = 0.012) and ACEi (317 (15) mL/min/1.73m2, P = 0.045). Filtration fraction (FF; 34 (0.8)%) was reduced by DRI only (32 (0.7)%, P = 0.044). Mean arterial pressure (109 (2) mmHg) was reduced by DRI (101 (2) mmHg, P = 0.008) and ACEi (103 (3) mmHg, P = 0.037). RAAS activity was reduced by DRI and ACEi. Albuminuria (20 [9–42] mg/d) was reduced by DRI only (12 [5–28] mg/d, P = 0.030). Conclusions In men with weight excess and hypertension, DRI and ACEi improved renal and systemic hemodynamics. Both DRI and ACEi reduced RAAS activity. Thus, DRI provides effective treatment in weight excess and hypertension. Trial Registration Dutch trial register, registration number: 2532 www.trialregister.nl

Objectives To examine differences in postoperative renal functional outcomes when comparing clampless with conventional laparoscopic partial nephrectomy (LPN) by using renal scintigraphy, and to identify the predictors of poorer postoperative renal functional outcomes after clampless LPN. Patients and Methods Between September 2010 and September 2012, 87 patients with renal masses suitable for LPN were prospectively enrolled in the study. From September 2010 to September 2011, LPN with renal artery clamping was performed and from September 2011 to September 2012 clampless LPN (no clamping of renal artery) was performed. Patients who underwent clampless LPN were unselected and consecutive, and the procedure was performed at the end of surgeon's learning curve. Patients were divided into two groups according to warm ischaemia time (WIT): group A, conventional LPN and group B, clampless-LPN (WIT = 0 min). Demographic and peri-operative data were collected and analysed and functional outcomes were evaluated using biochemical markers and renal scintigraphy at baseline and at 3 months after surgery. The percentage loss of renal function, evaluated according to renal scintigraphy, was calculated. Chi-squared and Student's t-tests were carried out and regression analysis was performed. Results Group A was found to be similar to group B in all variables measured except for WIT and blood loss (P < 0.001). The percentage reduction in renal scintigraphy values was not significantly different between the groups (reductions of 5% in group A and 6% in group B for split renal function [SRF] and 12% in group A and 17% in group B for estimated renal plasmatic flow [ERPF]; P = 0.587 and P = 0.083, respectively). Multivariate analysis in group B showed that the lower the baseline values of SRF and ERPF, the poorer the postoperative functional outcome of the treated kidney. Conclusions In our experience, even clampless LPN was not found to be functionally harmless. The patients who benefitted most from a clampless approach were those with the poorest baseline renal function.

OBJECTIVE Renal hyperfiltration is a common abnormality associated with diabetic nephropathy in patients with type 1 diabetes (T1D). In animal models, increased proximal tubular sodium reabsorption results in decreased distal sodium delivery, tubuloglomerular feedback activation, afferent vasodilatation, and hyperfiltration. The role of tubular factors is less well understood in humans. The aim of the current study was therefore to compare the fractional sodium excretion (FENa) in hyperfiltering (T1D-H) versus normofiltering (T1D-N) patients and healthy control (HC) subjects, as well as the role of ambient hyperglycemia on FENa. RESEARCH DESIGN AND METHODS Blood pressure, renal function (inulin for glomerular filtration rate [GFR], and paraaminohippurate for effective renal plasma flow), FENa, and circulating neurohormones were measured in T1D-H (n = 28, GFR ≥135 mL/min/1.73 m2), T1D-N (n = 30), and HC (n = 35) subjects during clamped euglycemia. Studies were repeated in a subset of patients during clamped hyperglycemia. RESULTS During clamped euglycemia, T1D-H exhibited lower FENa than T1D-N and HC subjects (0.64 ± 0.06% vs. 0.91 ± 0.12% and 0.90 ± 0.10%, P < 0.05). During clamped hyperglycemia, FENa increased (Δ + 0.88 ± 0.22% vs. Δ + 0.02 ± 0.21%; between-group effect, P = 0.01) significantly in T1D-H, whereas FENa did not change in T1D-N. When treated as continuous variables, elevated GFR values were associated with hyperglycemia-induced increases in FENa (R2 = 0.20, P = 0.007). CONCLUSIONS Patients with uncomplicated T1D-H exhibit lower FENa under euglycemic conditions, which may help to identify patients with hyperfiltration outside of a controlled laboratory setting. Increased FENa in T1D-H but not T1D-N under clamped hyperglycemic conditions suggests that the mechanisms responsible for increased sodium reabsorption leading to hyperfiltration can be saturated.