Search

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

Para-aminohippuric acid (PAH)-derived effective renal plasma flow (ERPF) is increasingly being used in parallel with the revived interest in kidney hemodynamic function due to the development of sodium glucose co-transporter 2 (SGLT2) inhibitors. In our trial (Kidney Int 2020;97: 202-12) we measured ERPF by urinary PAH clearance and calculated fractional PAH extraction ratios, which initially were very low during both the hyperglycemic clamps at baseline, as well as the euglycemic conditions following treatment with SGLT2 inhibitor dapagliflozin. Previous literature showed that hyperglycemic i.e. glucosuric conditions reduce urinary PAH concentrations, due to a Schiff base that is formed between the para-amino group of PAH and the aldehyde group of glucose. By using hydrochloric acid (HCl) any PAH that has been glycosylated can be reconverted, independent of storage time. After treatment with HCL we indeed found higher PAH extraction ratios in the expected range. In addition, a negative correlation between storage time and PAH extraction ratio in people treated with SGLT2 inhibitor dapagliflozin during a euglycemic clamp before treatment with HCl. Besides these human data, comparable results were observed in male obese ZSF1 rats with hyperglycemia. Therefore, researchers should be aware that even under euglycemic conditions, SGLT2 inhibitors induce glucosuria that interferes with accurate ERPF measurement due to glycosylation of PAH in stored urine samples. Pre-treatment of urine with NaOH or adding HCl prior to measurement will overcome this problem.

To develop an equation for the evaluation of renal function in rats using three dilutions of plasma samples and to validate this method by comparison with a reference method. The investigation was conducted in Sprague-Dawley (SD) rats after delivery of three doses of iohexol, with blood samples collected before and after dosage using a quantitative blood collection method. Plasma iohexol concentrations were detected by high performance liquid chromatography (HPLC). The extraction recovery of iohexol from plasma was >97.30% and the calibration curve was linear (r2 = 0.9997) over iohexol concentrations ranging from 10 to 1000 µg/mL. The method had an RE of

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.

Organ clearance, which has been derived from the organ blood flow and extraction ratio (E), has been extensively used by clinical pharmacologists to explain the pharmacokinetics of many drugs in health and disease. For example, the extent of hepatic clearance or E (Eh) of drugs would determine their response to changes in the liver blood flow and/or activities of the metabolizing enzymes. Although Eh may be obtained directly by cannulating internal blood vessels, the method is invasive. Therefore, indirect methods have been used to estimate Eh from the peripheral blood concentration-time data after intravascular administration of drugs. Additionally, these indirect methods require an estimate of the liver blood flow in the patients or animals. However, some investigators use plasma concentrations and/or liver plasma flow for the estimation of Eh, which could potentially result in significant errors. It is shown here that when plasma concentrations are used along with liver blood flow, an overestimation or underestimation of the true value will result if the blood: plasma concentration (B:P) ratio is >1 or < 1, respectively, with the estimated Eh being different from the true value by a factor equal to the B:P ratio. On the other hand, the use of plasma concentrations and plasma liver flow will always result in an overestimation of the true Eh unless the drug does not penetrate the red blood cells. It is concluded that for the accurate estimation of Eh from the in vivo data, the blood concentration and blood flow should be used.

Acute normocapnic hypoxemia can cause functional renal insufficiency by increasing renal vascular resistance (RVR), leading to renal hypoperfusion and decreased glomerular filtration rate (GFR). Insulin-like growth factor 1 (IGF-1) activity is low in fetuses and newborns and further decreases during hypoxia. IGF-1 administration to humans and adult animals induces pre- and postglomerular vasodilation, thereby increasing GFR and renal blood flow (RBF). A potential protective effect of IGF-1 on renal function was evaluated in newborn rabbits with hypoxemia-induced renal insufficiency. Renal function and hemodynamic parameters were assessed in 17 anesthetized and mechanically ventilated newborn rabbits. After hypoxemia stabilization, saline solution (time control) or IGF-1 (1 mg/kg) was given as an intravenous (i.v.) bolus, and renal function was determined for six 30-min periods. Normocapnic hypoxemia significantly increased RVR (+16%), leading to decreased GFR (−14%), RBF (−19%) and diuresis (−12%), with an increased filtration fraction (FF). Saline solution resulted in a worsening of parameters affected by hypoxemia. Contrarily, although mean blood pressure decreased slightly but significantly, IGF-1 prevented a further increase in RVR, with subsequent improvement of GFR, RBF and diuresis. FF indicated relative postglomerular vasodilation. Although hypoxemia- induced acute renal failure was not completely prevented, IGF-1 elicited efferent vasodilation, thereby precluding a further decline in renal 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.

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.

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.

Expression of proximal tubular organic anion transporters Oat1 and Oat3 is reduced by PGE2after renal ischemia and reperfusion (I/R) injury. We hypothesized that impaired expression of Oat1/3 is decisively involved in the deterioration of renal function after I/R injury. Therefore, we administered probenecid, which blocks proximal tubular indomethacin uptake, to abolish the indomethacin-mediated restoration of Oat1/3 regulation and its effect on renal functional and morphological outcome. Ischemic acute kidney injury (iAKI) was induced in rats by bilateral clamping of renal arteries for 45 min with 24-h follow-up. Low-dose indomethacin (1 mg/kg) was given intraperitoneally (ip) at the end of ischemia. Probenecid (50 mg/kg) was administered ip 20 min later. Indomethacin restored the expression of Oat1/3, PAH net secretion, and PGE2clearance. Additionally, indomethacin improved kidney function as measured by glomerular filtration rate (GFR), renal perfusion as determined by corrected PAH clearance, and morphology, whereas it reduced renal cortical apoptosis and nitric oxide production. Notably, indomethacin did not affect inflammation parameters in the kidneys (e.g., monocyte chemoattractant protein-1, ED1+ cells). On the other hand, probenecid blocked the indomethacin-induced restoration of Oat1/3 and moreover abrogated all beneficial effects. Our study indicates that the beneficial effect of low-dose indomethacin in iAKI is not due to its anti-inflammatory potency, but in contrast to its restoration of Oat1/3 expression and/or general renal function. Inhibition of proximal tubular indomethacin uptake abrogates the beneficial effect of indomethacin by resetting the PGE2-mediated Oat1/3 impairment, thus reestablishing renal damage. This provides evidence for a mechanistic effect of Oat1/3 in a new model of the induction of renal damage after iAKI.

Objective Inhaled nitric oxide (iNO) is commonly used as a treatment of pulmonary hypertension. Its action is purported to be specific to the lung, but extrapulmonary effects have been reported. The objective of this study was to evaluate if iNO could compensate the renal impairment induced by ketoprofen, a conventional non-steroidal anti-inflammatory drug (NSAID), during general anaesthesia. Methods Under pseudo-normovolaemic condition, thirty piglets were randomly assigned into 5 equal groups and equipped for renal and systemic parameters measurements. A first experiment was carried out to validate methods and reproduce the renal effects of iNO (40 ppm) in comparison with a placebo (100% oxygen). In a second experiment, iNO was inhaled for 120 minutes right after NSAID treatment (ketoprofen 2 mg×kg-1 IV, and 40 ppm iNO; group KiNO) and its effects were compared to ketoprofen alone (2 mg×kg-1 IV; group K) and placebo (saline; group C). Results In this model, iNO increased significantly renal blood flow measured by ultrasonic (RBFUL: +53.2±17.2%; p = 0.008) and by PAH clearance (RBFPAH:+78.6±37.6%; p = 0.004) methods, glomerular filtration rate (GFR: +72.6±32.5%; p = 0.006) and urinary output (UO: +47.4±24.2%; p = 0.01). In the second experiment, no significant temporal variation was noted for renal parameters in groups KiNO and C, whereas a significant and constant decrease was observed in the group K for RBFUL (max -19.0±7.1%), GFR (max -26.6±10.4%) and UO (max -30.3±10.5%). Clinical significance Our experiments show that iNO, released from its transport forms after its inhalation, can improve renal safety of NSAIDs. This result is promising regarding the use of NSAIDs in critical conditions, but needs to receive clinical confirmation.

Practical relevance: Routinely used markers of renal function in clinical practice include urea and creatinine. However, these are insensitive markers, particularly in the early stages of kidney disease. Measurement of glomerular filtration rate (GFR) is regarded as the most sensitive index of functioning renal mass. It may be useful for feline patients in varying clinical scenarios; for example, where a more accurate measurement of renal function may aid diagnosis, to enable response to therapeutic interventions to be more closely monitored, or to evaluate renal function prior to the use of nephrotoxic or renally cleared drugs. Clinical challenges: Traditional methods of measuring GFR, such as renal clearance or multisample plasma clearance techniques, are generally impractical for clinical use. Limited sampling and single sample plasma clearance methods using the filtration marker iohexol have been validated in cats. These have the advantages of reduced stress to cats associated with repeated sampling and reduced costs of analysis, and therefore offer greater clinical utility. Attempts to develop an estimated GFR (eGFR) formula similar to that used in human patients have been made in cats, although currently an accurate and reliable formula is not available. Audience: This review presents the basis for the theoretical understanding and practical measurement of GFR for any veterinary practitioner wishing to obtain a more accurate and sensitive assessment of renal function than routinely used markers provide. Evidence base: The review draws evidence from peer-reviewed publications, the author’s PhD thesis and also clinical experience.

Testing the rate of creatinine clearance by measuring the level of creatinine in the blood and in a 24-h urine collection is a common method of evaluating renal function. The result is routinely normalized for body surface area (BSA). Alternatively, renal clearance can be measured by 99mTc-mercaptoacetyltriglycine (MAG3) renal imaging without the need for urine collection. Frequently, the 99mTc-MAG3 camera-based result is also normalized for BSA. Methods: I evaluated the need for BSA normalization of renal clearance measurements in 99mTc-MAG3 imaging studies from both a conceptual and a mathematic point of view. Both approaches involved analyzing the effect of patient size, that is, BSA, on the factors blood volume, renal blood flow, and amount of test substance present in the blood in the creatinine clearance method compared with the 99mTc-MAG3 camera-based method. Results: Both the conceptual and the mathematic analyses were consistent with a significant difference between the creatinine and 99mTc-MAG3 approaches to measuring renal clearance. Larger patients have larger kidneys, greater renal blood flow, higher renal clearances, larger blood volumes, more muscle mass, and higher BSAs than smaller patients. However, the concentration of creatinine in the blood of patients of any size with normal renal function is similar because the amount of creatinine released into the blood varies with patient muscle mass, which varies with blood volume. Because normalization for BSA is needed for creatinine clearance, a single reference range can be used for all patients. In the case of measurement of renal clearance with 99mTc-MAG3 imaging (assuming a constant dose), the concentration of tracer in the blood will vary inversely with patient size because blood volume varies with patient size. Thus, as patient size increases, the blood concentration of tracer will go down and compensate for the increase in renal blood flow and renal clearance, and conversely. Consequently, the 99mTc-MAG3 renal imaging study is self-correcting for BSA and no additional correction is needed. Conclusion: A conceptual and mathematic analysis suggests that, although normalization for BSA is necessary in the measurement of renal clearance by the standard creatinine clearance test, such normalization is inappropriate in the 99mTc-MAG3 camera-based imaging study because the 99mTc-MAG3 method is inherently self-normalizing for BSA.

Laboratory investigation in rats submitted to experimental spinal cord injury (SCI). To characterize changes in renal function during acute SCI. Sprague Dawley rats were subjected to severe spinal cord contusion at T8 level or to laminectomy as control. Twenty-four hours after spine surgery, clearance assessments of a single dose of iohexol (120 mg kg−1) or of p-aminohippuric acid (PAH, 100 mg kg−1) were used to evaluate glomerular filtration rate (GFR) and tubular secretion (TS), respectively. Blood sampling was used to determine concentrations of both compounds by high-performance liquid chromatography for pharmacokinetic measurements. Iohexol clearance decreased significantly after injury, which resulted in increased concentrations and half-life of iohexol in blood; PAH clearance remained unchanged. GFR but not TS is altered during spinal shock. These observations should be of interest to professionals caring for early cord-injured patients, in order to prevent toxicity and therapeutic failure when administering drugs eliminated by the kidney.

The measurement of glomerular filtration rate by the clearance of inulin or creatinine has evolved over the past 50 years into an estimated value based solely on plasma creatinine concentration. We have examined some of the misconceptions and misunderstandings of the classification of renal disease and its course, which have followed this evolution. Furthermore, renal plasma flow and tubular function, which in the past were estimated by the clearance of the exogenous aryl amine, para-aminohippurate, are no longer measured. Over the past decade, studies in experimental animals with reduced nephron mass and in patients with reduced renal function have identified small gut-derived, protein-bound uremic retention solutes (“uremic toxins”) that are poorly filtered but are secreted into the lumen by organic anion transporters (OATs) in the proximal renal tubule. These are not effectively removed by conventional hemodialysis or peritoneal dialysis. Residual renal function, urine produced in patients with advanced renal failure or undergoing dialysis treatment, may represent, at least in part, secretion of fluid and uremic toxins, such as indoxyl sulfate, mediated by proximal tubule OATs and might serve as a useful survival function. In light of this new evidence of the physiological role of proximal tubule OATs, we suggest that measurement of renal tubular function and renal plasma flow may be of considerable value in understanding and managing chronic kidney disease. Data obtained in normal subjects indicate that renal plasma flow and renal tubular function might be measured by the clearance of the endogenous aryl amine, hippurate.

The assessment of glomerular filtration rate (GFR) in patients with liver disease is necessary to make decisions about organ allocation. Creatinine is widely used as a marker of GFR; however, it is not reliable in patients with liver disease. The aims of this study were to (1) determine if iodine 125-labeled iothalamate ((125)I-iothalamate) clearance calculated using the plasma decay method is equal to renal clearance of (125)I-iothalamate and (2) estimate kidney function using the creatinine-based Cockcroft-Gault and the Modification of Diet in Renal Disease equations, a cystatin C-based equation, the urine collection method for creatinine clearance, and plasma clearance of vancomycin (V) and compare these estimates to renal clearance of (125)I-iothalamate in adult patients with liver disease. Adults with liver disease received (125)I-iothalamate and V and had a catheter placed for urine collection. Blood and urine samples were collected over 8 h for analysis of (125)I-iothalamate, creatinine, and V to determine kidney function. Estimates were compared to renal (125)I-iothalamate clearance. Eight patients classified as Child-Pugh class B were enrolled: age was 52 ± 6 years; body mass index was 36.5 ± 19 kg/m(2); and Model for End-Stage Liver Disease score was 13 ± 3. Mean estimates of kidney function did not differ significantly from mean renal (125)I-iothalamate clearance (74 ± 38 mL/min/1.73 m(2)). Other methods overestimated kidney function at lower levels of GFR (

Increased blood viscosity reduces blood flow and elevates vascular resistance in the cardiovascular system. The aim of this study was to elucidate how blood viscosity could affect renal function and eventually contribute to renal damage in essential hypertensives (EHT). In 164 untreated EHT without apparent renal damage (96 men, 56±12 years old, creatinine clearance 123±33 ml min(-1) per 1.73 m(2) and urinary albumin excretion 19±19 mg per day), blood and plasma viscosity was determined using a falling ball microviscometer. Blood viscosity correlated negatively with creatinine clearance (r=-0.185, P=0.018) and positively with urinary albumin excretion (r=0.253, P=0.001). This indicated that increased blood viscosity is associated with reduced renal function and worsening of albuminuria in EHT. Stepwise multiple regression analysis identified blood viscosity as an independent determinant of creatinine clearance (R(2)=0.058) and urinary albumin excretion (R(2)=0.216). In conclusion, increased blood viscosity may be a risk for development of renal disease in EHT.

Homeostatic and excretory functions of the kidney depend on blood flow (∼25% cardiac output) and glomerular ultrafiltration (∼20% renal plasma flow). Blood flow distribution is not uniform, with only 10% reaching the medulla. Selectivity of ultrafiltration is related to molecular size, shape and electrostatic charge of molecules, and structure of the glomerular capillary barrier with its negatively charged glycoproteins. Ultrafiltration, determined by the balance between hydrostatic and colloid osmotic pressures (Starling forces) in the glomerular capillary and Bowman's space, occurs along the length of the capillary: hydrostatic pressure is relatively unchanged and always exceeds plasma colloid osmotic pressure plus pressure in Bowman's space. Ultrafiltration is influenced by changes in renal plasma flow, altered surface area (mesangial cell activity) and changes in vascular resistance afforded by afferent and efferent arterioles (mediated by sympathetic nerve activity, vasoconstrictors and vasodilators). Autoregulation of renal plasma flow minimizes changes in ultrafiltration (hence, filtered load). Myogenic and tubuloglomerular feedback mechanisms are responsible for autoregulation, but their relative contribution is yet to be resolved. Clearance measurements are used to assess renal plasma flow (RPF), glomerular filtration rate (GFR) (creatinine, inulin), filtration fraction (GFR/RPF), net reabsorption or secretion, and proximal and distal nephron function (lithium, free-water) but all have their limitations.

During acute administration of native glucagon-like peptide-1 (GLP-1), we previously demonstrated central hemodynamic effects in healthy males, whereas renal hemodynamics, despite renal uptake of GLP-1 in excess of glomerular filtration, was unaffected. In the present study, we studied hemodynamic effects of GLP-1 in patients with type 2 diabetes under fixed sodium intake. During a 3-h infusion of GLP-1 (1.5 pmol·kg−1·min−1) or saline, intra-arterial blood pressure and heart rate were measured continuously, concomitantly with cardiac output estimated by pulse contour analysis. Renal plasma flow, glomerular filtration rate, and uptake/release of hormones and ions were measured using Fick's Principle after catheterization of a renal vein. Urine collection was conducted throughout the experiments at voluntary voiding, and patients remained supine during the experiments. During the GLP-1 infusion, systolic and diastolic blood pressure and cardiac output remained unchanged, whereas heart rate increased significantly. Arterio-venous gradients for GLP-1 exceeded glomerular filtrations significantly, but renal plasma flow and glomerular filtration rate as well as renal sodium and lithium excretion were not affected. In conclusion, acute administration of GLP-1 in patients with type 2 diabetes leads to a positive chronotropic effect, but in contrast to healthy individuals, cardiac output does not increase in patients with type 2 diabetes. Renal hemodynamics and sodium excretion are not affected.

In order to assess possible renal mechanisms causing the as yet unexplained side-effects of peripheral edema, weight gain and swollen limbs seen during the chronic administration of opioids in patients, a rat study was designed, mimicking a constant infusion (24 h) of morphine (CAS 57-27-2) using subcutaneous drug delivery device systems. Subcutaneous (s.c.) morphine infusions (0, 10, 30 mg/kg body weight/24 h) have been administered using implantable mini-osmotic pumps with a delivery rate of 10 µl/h. In addition, s.c. implantable inulin/PAH clearance depot systems were used in order to measure renal functions such as glomerular filtration rate (GFR = inulin clearance), renal plasma flow (RPF = PAH clearance), creatinine clearance and urea clearance in the conscious rat. Compared to controls, morphine caused an increase in PAH clearance, creatinine clearance (both dose dependent), urea clearance (higher dose), body weight, and urine potassium concentration (both groups). Urine minute volume was reduced in the 10 mg morphine group, a dose dependent highly significant decrease of urine sodium in the 30 mg morphine group compared to controls and a significant decrease compared to the 10 mg group could be found. Serum sodium was highly significant and food uptake was significantly increased in the 30 mg group compared to controls. The histological examination of kidneys revealed no differences among the various groups. These data indicate a role of the kidney in the induction of peripheral edema during permanent morphine administration.

The technique for assisting renal blood circulation may be a useful therapeutic method in acute cardiorenal syndrome (ACRS), because renal ischemic dysfunction due to the reduced renal blood circulation is a powerful negative prognostic factor in ACRS. We constructed a circuit assisting renal arterial pressure and flow, and performed renal-selective blood perfusion (RSP) to the left kidney in a goat model of ACRS induced by right ventricular rapid pacing (n = 8), with the right kidney left intact as an internal control. Upon induction of ACRS, renal arterial flow (RAF), creatinine clearance (CCr), and renal oxygen consumption (RVO(2)) of the left kidney decreased to 49, 48, and 63% of the respective baseline values accompanied by a significant increase in renal vascular resistance (RVR), and similar results were observed in the right kidney. Then, RSP improved RVR and increased left RAF, CCr, and RVO(2) up to 91, 86, and 93% of baseline values, respectively, without a significant change in systemic hemodynamics. The RSP-treated kidney showed significantly higher CCr and urinary excretion of water and sodium compared to the contralateral kidney. Additional infusion of prostaglandin E(1) with RSP decreased RVR further and enabled the left RAF to increase up to 129% of the baseline value, without a significant change in systemic hemodynamic parameters. The CCr and RVO(2) did not change significantly, and urinary excretion of water and sodium showed a tendency to increase. These findings suggest that the technique for assisting renal blood circulation for both kidneys may offer a new treatment strategy for patients with ACRS.

Because renal function in newborns is immature, the pharmacokinetics of drugs administered to neonates vary significantly from adult patients. The establishment of drug transport systems is a key process in the functional maturation of the nephron. However, a thorough examination of the expression of the main drug transporters in the kidney throughout all stages of development (embryonic, postnatal, and mature) has yet to be carried out, and the functional (physiological) impact is not well understood. Using time-series microarray data, we analyzed the temporal behavior of mRNA levels for a wide range of SLC and ABC transporters in the rodent kidney throughout a developmental time series. We find dynamic increases between the postnatal and mature stages of development for a number of transporters, including the proximal tubule-specific drug and organic anion transporters (OATs) OAT1 (SLC22a6) and OAT3 (SLC22a8). The OATs are the major multispecific basolateral drug, toxin, and metabolite transporters in the proximal tubule responsible for handling of many drugs, as well as the prototypical OAT substrate para-aminohippurate (PAH). We therefore performed specific in vivo pharmacokinetic analysis of the transport of PAH in postnatal and maturing rodent kidney. We show that there is a 4-fold increase in PAH clearance during this period. Clearance studies in Oat1 and Oat3 knockouts confirm that, as in the adult, Oat1 is the principle transporter of PAH in the postnatal kidney. The substantial differences observed supports the need for better understanding of pharmacokinetics in the newborn and juvenile kidney compared with the adult kidney at the basic and clinical level.

This paper compares three methods for estimating renal function, as tested in rats. Acute renal failure (ARF) was induced via a 60-min bilateral renal artery clamp in 8 Sprague-Dawley rats and renal function was monitored for 1 week post-surgery. A two-compartment model was developed for estimating glomerular filtration via a bolus injection of a radio-labelled inulin tracer, and was compared with an estimated creatinine clearance method, modified using the Cockcroft-Gault equation for rats. These two methods were compared with selected ion flow tube-mass spectrometry (SIFT-MS) monitoring of breath analytes. Determination of renal function via SIFT-MS is desirable since results are available non-invasively and in real time. Relative decreases in renal function show very good correlation between all 3 methods (R^2=0.84, 0.91 and 0.72 for breath-inulin, inulin-creatinine, and breath-creatinine correlations, respectively), and indicate good promise for fast, non-invasive determination of renal function via breath testing.

During acute kidney injury (AKI), lowered glomerular filtration rate (GFR) is believed to be consequent to reduced renal plasma flow (RPF). We aimed to systematically evaluate the evidence for such an association. Using specific search terms, we systematically interrogated the Pub Med electronic reference database for studies of human AKI where renal plasma or blood flow and GFR were measured; older articles were then identified by screening bibliographies of retrieved reports. We identified 22 articles describing 250 patients (203 native kidney, 47 in renal allograft). Of these studies, 8 articles (110 patients) estimated effective renal plasma flow (ERPF) by clearance techniques and 14 articles (140 patients) estimated true renal plasma flow (TRPF). Mean RPF was 272 mL/min (95% CI 213-331) and GFR 13.9 mL/min (9.9-17.9). Mean TRPF was significantly greater than mean ERPF (344 vs. 180, p=0.004) despite lower mean GFR (8.8 vs. 20.4, p=0.002). There was no significant association between RPF and GFR between studies. Eleven studies presented individual patient data (76 patients: 49 TRPF, 27 ERPF); here, individual patient ERPF was associated with GFR (r2=0.52), but TRPF was not. During AKI in man, there is only a limited association between ERPF and GFR, and no detectable association between TRPF and GFR.

Glomerular filtration rate (GFR) can be determined using Patlak plot analysis with single-slice dynamic computed tomography (CT). Acute autologous graft failure has several causes, all of which induce a measurable decrease in glomerular filtration rate. This study demonstrated in an experimental model of canine autologous renal transplant that CT-derived renal plasma clearance was significantly lower (p = 0.002) in dogs having undergone transplant (0.077 +/- 0.058 ml min(-1) ml renal tissue(-1)) compared with control dogs (0.396 +/- 0.139 ml min(-1) ml renal tissue(-1)). A significant negative curvilinear relationship was seen between serum creatinine and total renal plasma clearance (R(2) = 0.84, p = 0.0001). Alterations in renal time attenuation curve shape in dogs having undergone transplant may have been related to increased renal vascular resistance related to tubular necrosis. CT-GFR may be a useful experimental tool in the evaluation of renal dysfunction in transplant models.

Background: The beneficial effects of vasopressin on diuresis and creatinine clearance have been demonstrated when used as an additional/alternative therapy in catecholamine-dependent vasodilatory shock. A detailed analysis of the effects of vasopressin on renal perfusion, glomerular filtration, excretory function and oxygenation in man is, however, lacking. The objective of this pharmacodynamic study was to evaluate the effects of low to moderate doses of vasopressin on renal blood flow (RBF), glomerular filtration rate (GFR), renal oxygen consumption (RVO 2 ) and renal oxygen extraction (RO 2 Ex) in post-cardiac surgery patients. Methods: Twelve patients were studied during sedation and mechanical ventilation after cardiac surgery. Vasopressin was sequentially infused at 1.2, 2.4 and 4.8U/h. At each infusion rate, systemic haemodynamics were evaluated by a pulmonary artery catheter, and RBF and GFR were measured by the renal vein thermodilution technique and by renal extraction of 51 chromium-ethylenediaminetetraacetic acid, respectively. RVO 2 and RO 2 Ex were calculated by arterial and renal vein blood samples. Results: The mean arterial pressure was not affected by vasopressin while cardiac output and heart rate decreased. RBF decreased and GFR, filtration fraction, sodium reabsorption, RVO 2 , RO 2 Ex and renal vascular resistance increased dose-dependently with vasopressin. Vasopressin exerted direct antidiuretic and antinatriuretic effects. Conclusions: Short-term infusion of low to moderate, non-hypertensive doses of vasopressin induced a post-glomerular renal vasoconstriction with a decrease in RBF and an increase in GFR in post-cardiac surgery patients. This was accompanied by an increase in RVO 2 , as a consequence of the increases in the filtered tubular load of sodium. Finally, vasopressin impaired the renal oxygen demand/supply relationship.

Radioisotope renography with 13I-hippuran has been undertaken in 14 kidney donors with normal renal function 26–53 months after unilateral nephrectomy. Immediately after renography simultaneous creatinine, 125iothalamate and 131I-hippuran clearances were determined. Ratios calculated within the first 2.5 min of the renogram could not be correlated to clearance values or to the size of the remaining kidney. There was a statistically significant correlation between clearance values and renal size. The range of the ratios calculated was 5–10%, whereas the range of clearance values was 15–30%. 131I-hippuran reached the bladder after a minimum of 2.0 min. There was a correlation between transit time and time to the renogram's maximum.

Clearance studies in patients with markedly reduced renal function can be performed with satisfactory accuracy without catheterization of the bladder. A reliable infusion technique, careful instruction and supervision during the study, together with clearance periods of adequate length, are necessary. Endogenous creatinine clearance does not provide a reliable expression for glomerular filtration in patients with renal insufficiency and in patients with the nephrotic syndrome, because renal function is consistently overestimated. This overestimation is approximately 25 to 50% in patients with an inulin clearance less than 25 ml/min. 125iothalamate clearance in the same series of patients provided an exact measure of glomerular filtration rate, as the mean ratio cIo/cIn was 0.97.

Preservation of pig kidneys for 24 hours at 8°C has been studied using continuous perfusion with cryoprecipitated, microfiltered serum with a pH of 7.67, an oxygen tension of 520 mm Hg and a flow rate of 0.2 ml/g kidney tissue/min. Twenty consecutive experiments were performed. In all cases rapid onset of urine flow was seen after autotransplantation of the kidney, and histological examination one hour after recirculation showed only minor tubular damage in most cases. Nine animals died from complications unrelated to the perfusion. Two animals died from uraemia due to technically deficient perfusion (clamping of the renal vein and perfusion with lipaemic serum). With apparently optimal technique three animals died from cortical necrosis whereas six survived and were observed for three months. Measurements of inulin, endogenous creatinine, urea and PAH clearance 10, 31 and 94 days after transplantation in these six animals showed normal values as compared to a control group of autotransplanted, not long-term preserved pig kidneys. There was no difference in the results using pulsatile and non-pulsatile flow.

This paper compares three methods for estimating renal function, tested in rats. Acute Renal Failure (ARF) was induced via a 60-minute bilateral renal artery clamp in 8 Sprague-Dawley rats and renal function was monitored for 1 week post-surgery. A two-compartment model was developed for estimating renal function via a bolus injection of a radio-labelled inulin tracer, and was compared with the current gold standard plasma creatinine measurement, modified using the Cockcroft-Gault equation for rats. These two methods were compared with Selected Ion Flow Tube-Mass Spectrometry (SIFT-MS) monitoring of breath analytes. Determination of renal function via SIFT-MS is desirable since results are available non-invasively and in real time. Relative decreases in renal function show excellent correlation between methods, and indicate good promise for fast, non-invasive determination of renal function via breath testing.

SUMMARY Experimental studies of renal blood flow have been made with radio-Hippuran I125using isolated perfused canine kidneys. These studies were made in two groups. First, the renogram curve was analysed by applying theoretical equations and it was shown that quantitative values could be obtained for the effective renal blood flow. In the second group of experiments the analysis of the rate of disappearance of the isotope from the blood showed a definite relationship with directly measured renal blood flow, but this could not be resolved into a quantitative value. The authors' thanks are due to Professor Ralph Shackman for his encouragement and guidance in this work, to Mr E. Gains and his technical staff for their help, to the Department of Photography and Medical Illustration of the Post-graduate School for their assistance in drawing of the charts, and to Mr Ole Kalnaes, Radiofysisk laboratorium, Arhus Kommunehospital, for his help with mathematical equations. The expenses incurred in these experiments were defrayed by a grant to one of us (A. E. K.) from the Medical Research Council.

Renal solute clearances are reduced in ischemic acute kidney injury. However, the mechanisms explaining how solute clearance is impaired have not been clarified. Recently, we reported that cadaveric renal allografts exhibit maldistribution of organic anion transporter 1 (OAT1) in proximal tubule cells after ischemia and reperfusion, resulting in impairment of PAH clearance. In the present study, we characterized renal OAT1 in detail after ischemia-reperfusion using a rat model. We analyzed renal OAT1 using confocal microscopy with a three-dimensional reconstruction of serial optical images, Western blot, and quantitative real-time RT-PCR. OAT1 was distributed to basolateral membranes of proximal tubule cells in controls. With ischemia, OAT1 decreased in basolateral membrane, especially in the lateral membrane domain, and appeared diffusely in cytoplasm. After reperfusion following 60-min ischemia, OAT1 often formed cytoplasmic aggregates. The staining for OAT1 started reappearing in lateral membrane domain 1 h after reperfusion. The basolateral membrane staining was relatively well discernable at 240 h of reperfusion. Of note, a distinct increase in OAT1 expression was noted in vasculature early after ischemia and after reperfusion. The total amount of OAT1 protein expression in the kidney diminished after ischemia-reperfusion in a duration-dependent manner until 72 h, when they began to recover. However, even at 240 h, the amount of OAT1 did not reach control levels. The kidney tissues tended to show a remarkable but transient increase in mRNA expression for OAT1 at 5 min of ischemia. Our findings may provide insights of renal OAT1 in its cellular localization and response during ischemic acute kidney injury and recovery from it.

Vascular calcifications are common among patients with hypertension. The vitamin K-dependent protein matrix Gla-protein plays an important role in preventing arterial calcification. Since a decrease in renal clearance is a prevalent clinical problem in patients with hypertension, we aimed to study the renal clearance of matrix Gla-protein from the circulation in these patients having a wide range of creatinine clearances. Ninety moderate to severe hypertensive patients who were scheduled for renal angiography were enrolled in the study. In these patients, renal arterial and renal venous blood was sampled prior to the administration of contrast material in order to determine the total renal and single kidney clearance of matrix Gla-protein. The average renal fractional extraction of matrix Gla-protein was 12.8%. There was no significant correlation between creatinine clearance (range 26-154) and renal fractional extraction of matrix Gla-protein in this population. The extraction of matrix Gla-protein was not influenced by the presence of a renal artery stenosis. In conclusion, we demonstrate that the kidney is able to extract matrix Gla-protein from the plasma at a constant level of 12.8%, independent of renal function in hypertensive subjects.

p38 mitogen-activated protein kinase (p38) has been implicated in mediating vascular smooth muscle and mesangial cell contraction in response to several vasoactive factors, including angiotensin II. Early stages of diabetic nephropathy are associated with renal hemodynamic changes that are, at least in part, attributable to the dysbalance of vasoactive factors that control afferent and efferent arteriolar tone resulting in increased glomerular capillary pressure. Vascular and renal p38 have been found to be activated in diabetes. Therefore, p38 may be involved in the control of systemic and renal hemodynamics in diabetes. To address this issue, mean arterial blood pressure (MAP), glomerular filtration rate (GFR, inulin clearance), renal plasma flow (RPF, PAH clearance), metabolic parameters, and plasma renin concentrations (PRC) were determined in streptozotocin-diabetic rats (DM), and in age-matched non-diabetic controls (C), administered with the p38 inhibitor SB 239063 (SB, 50 mg/bwt, p.o.) or with vehicle. Furthermore, renal vascular responses to p38 inhibition (SB 202190, 25 microM) before and after stimulation with the endothelium-dependent vasodilator acetylcholine (ACh) were studied in vitro in tertiary branches of the renal artery from separate groups of DM and C rats, using a fixed support and a force transducer in a myograph system. SB treatment was associated with marked reductions in MAP and GFR in both C and DM rats, whereas RPF remained unchanged, as compared with vehicle-treated animals. Observed differences in MAP and renal hemodynamics were not associated with changes in urinary sodium excretion or PRC. Incubation of KCl-contracted renal arteries from both C and DM rats with the p38 inhibitor resulted in progressive and significant vasorelaxation. Also, vessels from control and diabetic rats treated with the p38 inhibitor exhibited enhancement of ACh-induced vasorelaxation. These data indicate the role of p38 in the control of systemic and renal hemodynamics both in normal and in diabetic rats. The observed effects of p38 inhibition could be mediated at least in part by enhancement of endothelium-dependent vasodilation.

Glomerular filtration rate (GFR), which measures the amount of plasma filtered through the kidney within a given time, is an essential and clinically important indicator of kidney function. Here, we report a new ratiometric measurement technique based on intravital fluorescence microscopy that allows rapid evaluations of renal function in rodent models. By using this technique, plasma clearance rates of a fluorescent GFR marker can be measured in less than 5 min following a bolus infusion of a fluorescent dye mixture into the bloodstream. The plasma clearance kinetics of the GFR marker showed consistent values when measured in healthy animals at locations both in the kidney and from the skin. In addition, by using this technique, we were able to rapidly determine renal function with acute renal failure animal models and with other animal models where kidney filtration functions were altered. The measured plasma clearance kinetics using this technique correlated with expected changes in kidney function. We found this ratiometric approach offers improved accuracy and speed for quantifying renal function compared with the approach using single fluorescent probes, and the measurement can be done noninvasively from the skin. This approach also offers a high sensitivity for determining plasma clearance rate of a fluorescent compound. This feature is important for rapidly quantifying small differences in plasma clearance when kidney function is changing.

Background To determine the effect of statins on renal hemodynamics in normal volunteers and those with autosomal dominant polycystic kidney disease either with mild or moderate renal dysfunction. Methods Thirty-two study subjects were enrolled in this study: 11 normal volunteers, 11 study subjects with autosomal dominant polycystic kidney disease (ADPKD) and mild kidney disease and 10 study subjects with ADPKD and moderate kidney disease. Subjects in each group received simvastatin 40 mg once daily for a period of 4 weeks. Renal blood flow was measured based on para-amino-hippurate (PAH) clearance and with the use of a magnetic resonance (MR) scanner at the beginning and following 4 weeks of therapy with statins. Results At the end of the study, except for the lipid profile, which was significantly lower in all groups, other laboratory results showed no change. Four weeks of therapy with simvastatin resulted in no change in serum creatinine, 24-h urinary protein, sodium, iothalamate clearance, PAH clearance or renal blood flow as measured by MRI or based on PAH clearance. Conclusions Four weeks of therapy with simvastatin did not change renal blood flow in the study subjects with ADPKD with mild-to-moderate renal dysfunction or in healthy volunteers. Clinical trial registration number NCT02511418.

Measurements of glomerular filtration rate (GFR), and the fractional excretion of sodium (Na) and potassium (K) are critical in assessing renal function in health and disease. GFR is measured as the steady state renal clearance of inulin which is filtered at the glomerulus, but not secreted or reabsorbed along the nephron. The fractional excretion of Na and K can be determined from the concentration of Na and K in plasma and urine. The renal clearance of inulin can be demonstrated in an anesthetized animal which has catheters in the femoral artery, femoral vein and bladder. The equipment and supplies used for this procedure are those commonly available in a research core facility, and thus makes this procedure a practical means for measuring renal function. The purpose of this video is to demonstrate the procedures required to perform a lab demonstration in which renal function is assessed before and after a diuretic drug. The presented technique can be utilized to assess renal function in rat models of renal disease.

BACKGROUND: 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 hemodynamics and glomerular filtration rate (GFR) despite a MAP double that of other mammals.METHODS: 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.RESULTS: 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 and 9.1±1.5 pg/ml, respectively.CONCLUSION: 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. This article is protected by copyright. All rights reserved.