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The CKD-EPI creatinine-based estimation equation for glomerular filtration rate (GFR) cannot be used in children, overestimates GFR in young adults, and its combination with the KDIGO recommended pediatric CKiD (Schwartz bedside) equation causes implausible increases in estimated GFR when switching from pediatric to adult care. By establishing sex-specific creatinine growth curves for children and young adults, creatinine levels of children and young adults below age 40 years were adjusted with 40 as assigned age and applied in the CKD-EPI equation. Validation was performed in 4005 children (2-17 years) and 3309 young adults (18-39 years) using metrics based on bias, precision, and accuracy including percentage of estimates within 30% (P30) of measured GFR (mGFR). Comparisons were made with the CKiD and Schwartz-Lyon equations in children. CKD-EPI with age-adjusted creatinine instead of actual age and creatinine led to extensive improvements in bias, precision, and accuracy at all ages, in both sexes and at all levels of mGFR. At mGFR below and above 75 mL/min/1.73m2, the P30 increased from 12% to 75% and 33% to 88% in children, respectively, and from 56% to 73% and 83% to 92% in young adults, respectively. In children adjusted CKD-EPI was more accurate than CKiD, especially above mGFR 75 mL/min/1.73m2 (P30 88% vs. 82%), while Schwartz-Lyon was more accurate than adjusted CKD-EPI at mGFR below 75 mL/min/1.73m2 (P30 81% vs. 75%). Thus, the proposed strategy based on age-adjusted creatinine in children and young adults makes the CKD-EPI equation applicable across the full spectrum of age and kidney function. ispartof: KIDNEY INTERNATIONAL vol:99 issue:4 pages:940-947 ispartof: location:United States status: published

Antecedents of the high rates of chronic kidney disease in Australian Indigenous peoples may originate early in life. Fourteen percent of Australian Indigenous infants are born preterm (under 37 weeks gestation) and, therefore, at risk. Here, our observational cohort study sought to determine the impact of preterm birth on renal function in Australian Indigenous and non-Indigenous infants. Renal function was assessed between 4-29 days postnatally in 60 Indigenous and 42 non-Indigenous infants born at 24-36 weeks gestation. Indigenous ethnicity was associated with impaired renal function, with significantly higher serum creatinine (geometric mean ratio (GMR) 1.15 [1.06, 1.25]), fractional excretion of sodium (GMR 1.21 [1.04, 1.39]), and urine albumin (GMR 1.57 [1.05, 2.34]), β-2 microglobulin (GMR 1.82 [1.11, 2.98]) and cystatin C (GMR 3.27 [1.54, 6.95]) when controlling for gestational/postnatal age, sex and birth weight Z-score. Renal injury, as indicated by high urine neutrophil gelatinase-associated lipocalin levels, was associated with maternal smoking and postnatal antibiotic exposure. Indigenous infants appeared to be most susceptible to the adverse impact of antibiotics. These findings show that preterm Australian Indigenous infants are highly vulnerable to renal dysfunction. Preterm birth may contribute to their increased risk of chronic kidney disease. Thus, we recommended that renal function should be closely monitored life-long in Indigenous children born preterm.

The hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, constitutes a serious complication of hepatic decompensation. Coexistence of liver/kidney damage, mentioned in the dropsy literature, was highlighted by Richard Bright in 1827 and confirmed in 1840 by his contemporary nephrology pioneer Pierre Rayer. Cholemic nephrosis was described in 1861 by Friedrich Frerichs, and the renal tubular lesions of HRS by Austin Flint in 1863. The term "acute hepato-nephritis" was introduced in 1916 by Paul Merklen, and its chronic form was designated HRS by Marcel Derot in 1930s. HRS then was applied to renal failure in biliary tract surgery and to cases of coexistent renal and hepatic failure of diverse etiology. The pathogenesis of HRS was elucidated during the 1950 studies of renal physiology. Notably, studies of salt retention in edema and its relation to regulating the circulating plasma volume by John Peters and subsequently Otto Gauer defined the concept of "effective blood volume" and the consequent elucidation of ascites formation in liver failure. Parallel studies of intrarenal hemodynamics demonstrated severe renal vasoconstriction and preferential cortical ischemia to account for the functional renal dysfunction of HRS. Dialysis and liver or combined liver-kidney transplantation transformed the fatal HRS of old into a treatable disorder by the 1970s. Elucidation of the pathogenetic mechanisms of renal injury and refinements in definition, classification, and diagnosis of HRS since then have allowed for earlier therapeutic intervention with combined i.v. albumin and vasoconstrictor therapy, enabling the continued improvement of patient outcomes.

All methods used to measure and estimate glomerular filtration rate (GFR) are associated with systematic or random error, which leads to differences in measured GFR (mGFR) and estimated GFR (eGFR) from "true GFR." In this issue of Kidney International, Rowe et al. evaluate time-to-time variability using repeated assessments of mGFR and eGFR within a short time frame. They show that biological variability is larger for mGFR than eGFR, and the magnitude of reference change values when interpreting changes in mGFR and eGFR.

To assess apolipoprotein L1 gene ( APOL1 ) renal-risk-variant effects on the brain, magnetic resonance imaging (MRI)-based cerebral volumes and cognitive function were assessed in 517 African American–Diabetes Heart Study (AA-DHS) Memory IN Diabetes (MIND) and 2568 hypertensive African American Systolic Blood Pressure Intervention Trial (SPRINT) participants without diabetes. Within these cohorts, 483 and 197 had cerebral MRI, respectively. AA-DHS participants were characterized as follows: 60.9% female, mean age of 58.6 years, diabetes duration 13.1 years, estimated glomerular filtration rate of 88.2 ml/min/1.73 m 2 , and a median spot urine albumin to creatinine ratio of 10.0 mg/g. In additive genetic models adjusting for age, sex, ancestry, scanner, intracranial volume, body mass index, hemoglobin A1c, statins, nephropathy, smoking, hypertension, and cardiovascular disease, APOL1 renal-risk-variants were positively associated with gray matter volume (β = 3.4 × 10 –3 ) and negatively associated with white matter lesion volume (β = –0.303) (an indicator of cerebral small vessel disease) and cerebrospinal fluid volume (β= –30707) (all significant), but not with white matter volume or cognitive function. Significant associations corresponding to adjusted effect sizes (β/SE) were observed with gray matter volume (0.16) and white matter lesion volume (–0.208), but not with cerebrospinal fluid volume (–0.251). Meta-analysis results with SPRINT Memory and Cognition in Decreased Hypertension (MIND) participants who had cerebral MRI were confirmatory. Thus, APOL1 renal-risk-variants are associated with larger gray matter volume and lower white matter lesion volume suggesting lower intracranial small vessel disease.

Progressively decreasing glomerular filtration rate (GFR), or renal decline, is seen in patients with type 1 diabetes (T1D) and normoalbuminuria or microalbuminuria. Here we examined the associations of kidney injury molecule-1 (KIM-1) in plasma and urine with the risk of renal decline and determine whether those associations are independent of markers of glomerular damage. The study group comprised patients with T1D from the 2nd Joslin Kidney Study of which 259 had normoalbuminuria and 203 had microalbuminuria. Serial measurements over 4 to 10 years of follow-up (median 8 years) of serum creatinine and cystatin C were used jointly to estimate eGFRcr-cys slopes and time of onset of CKD stage 3 or higher. Baseline urinary excretion of IgG2 and albumin were used as markers of glomerular damage, and urinary excretion of KIM-1 and its plasma concentration were used as markers of proximal tubular damage. All patients had normal renal function at baseline. During follow-up, renal decline (eGFRcr-cys loss 3.3% or more per year) developed in 96 patients and 62 progressed to CKD stage 3. For both outcomes, the risk rose with increasing baseline levels of plasma KIM-1. In multivariable models, elevated baseline plasma KIM-1 was strongly associated with risk of early progressive renal decline, regardless of baseline clinical characteristics, serum TNFR1 or markers of glomerular damage. Thus, damage to proximal tubules may play an independent role in the development of early progressive renal decline in non-proteinuric patients with T1D.

Removal of small molecular weight solutes shows a strong relationship to hemodialysis outcomes. In contrast, survival with high-flux dialysis or hemodiafiltration is only slightly better than with low-flux hemodialysis. Despite laboratory evidence regarding toxicity of protein-bound uremic solutes, few data exist showing that increased removal of this class of molecules impacts outcomes. In the FHN trials, there was no effect of frequent dialysis, including frequent and long dialysis, on nutrition or control of anemia, outcomes expected to be sensitive to uremic toxin removal; the main benefit appeared to be better volume control. Scaling of hemodialysis dose to total body water may not be optimal. Kt/V scaling to body surface area and use of a continuous measure such as standard Kt/V reduces the likelihood of underdialysis of small patients, including children, and women. Minimum hemodialysis time may best be considered in respect to ultrafiltration rate, and a maximum target ultrafiltration rate unscaled to body size may be optimal. Intensive, extended dialysis may cause adverse effects to residual kidney function, and more information needs to be collected to better understand how urine volume modifies dose requirements, and how to maximize the chances of preserving residual kidney function.

Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mortality. A standardized definition is important to facilitate clinical care and research. The definition of AKI has evolved rapidly since 2004, with the introduction of the Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) classifications. RIFLE was modified for pediatric use (pRIFLE). They were developed using both evidence and consensus. Small rises in serum creatinine are independently associated with increased mortality, and hence are incorporated into the current definition of AKI. The recent definition from the international KDIGO guideline merged RIFLE and AKIN. Systematic review has found that these definitions do not differ significantly in their performance. Health-care staff caring for children or adults should use standard criteria for AKI, such as the pRIFLE or KDIGO definitions, respectively. These efforts to standardize AKI definition are a substantial advance, although areas of uncertainty remain. The new definitions have enabled the use of electronic alerts to warn clinicians of possible AKI. Novel biomarkers may further refine the definition of AKI, but their use will need to produce tangible improvements in outcomes and cost effectiveness. Further developments in AKI definitions should be informed by research into their practical application across health-care providers. This review will discuss the definition of AKI and its use in practice for clinicians and laboratory scientists.

Genomewide association studies have identified numerous chronic kidney disease–associated genetic variants, but often do not pinpoint causal genes. This limitation was addressed by combining Mouse Genome Informatics with human genomewide association studies of kidney function. Genes for which mouse models showed abnormal renal physiology, morphology, glomerular filtration rate (GFR), or urinary albumin-to-creatinine ratio were identified from Mouse Genome Informatics. The corresponding human orthologs were then evaluated for GFR-associated single-nucleotide polymorphisms in 133,814 individuals and urinary albumin-to-creatinine ratio-associated SNPs in 54,451 individuals in genome-wide association studies meta-analysis of the CKDGen Consortium. After multiple testing corrections, significant associations with estimated GFR in humans were identified for single-nucleotide polymorphisms in 2, 7, and 17 genes causing abnormal GFR, abnormal physiology, and abnormal morphology in mice, respectively. Genes identified for abnormal kidney morphology showed significant enrichment for estimated GFR–associated single-nucleotide polymorphisms. In total, 19 genes contained variants associated with estimated GFR or the urinary albumin-to-creatinine ratio of which 16 mapped into previously reported genomewide significant loci. CYP26A1 and BMP4 emerged as novel signals subsequently validated in a large, independent study. An additional gene, CYP24A1 , was discovered after conditioning on a published nearby association signal. Thus, our novel approach to combine comprehensive mouse phenotype information with human genomewide association studies data resulted in the identification of candidate genes for kidney disease pathogenesis.

Renal blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) is a noninvasive fast technique to characterize renal function. Here we evaluated the impact of renal function on the relaxation rate (R2(*)) in the cortex and medulla to provide baseline data for further use of renal BOLD-MRI. This parameter was evaluated in 400 patients scheduled for abdominal imaging who underwent transversal blood oxygen level-dependent measurements with a multi-echo gradient-echo sequence with 12 echo times. The loss of phase coherence (T2(*)) maps were generated in which kidney regions of interest were selected to differentiate the medulla and cortex, and R2(*) was equated to 1/T2(*). Individual R2(*) values were, in turn, correlated to the eGFR (MDRD formula of 280 patients with available serum creatinine measurements), age, and gender each for 1.5 and 3.0 T field-strength scans of 342 patients. At both the field strengths, no significant differences in R2(*) of the cortex and medulla were found between patient gender, age, eGFR, or between different stages of chronic kidney disease determined using the KDOQI system. Thus, BOLD-MRI of a non-specific patient population failed to discriminate between the patients with various stages of chronic kidney disease.

The RIFLE criteria were developed to improve consistency in the assessment of acute kidney injury. The high face validity, collaborative development method, and validation against mortality have supported the widespread adoption of the RIFLE to evaluate adult patients; however, its inconsistent application in adult studies is associated with significant effects on the estimated incidence of acute kidney injury. As the RIFLE criteria are now being used to determine acute kidney injury in children, we conducted a systematic review to describe its application and assess associations between the RIFLE and measures of mortality and morbidity in pediatric patients. In 12 studies we found wide variation in the application of the RIFLE, including the range of assessed RIFLE categories, omission of urine output criteria, varying definitions of baseline renal function, and methods for handling missing baseline measurements. Limited and conflicting associations between the RIFLE and mortality, length of stay, illness severity, and measures of kidney function were found. Thus, although the RIFLE was developed to improve the consistency of defining acute kidney injury, there are still major discrepancies in its use in pediatric patients that may undermine its potential utility as a standardized measure of acute kidney injury in children.

Measurement of the glomerular filtration rate (GFR) is the gold standard for precise assessment of kidney function. A rapid, point-of-care determination of the GFR may provide advantages in the clinical setting over currently available assays. Here we demonstrate a proof of principle for such an approach in a pig and dogs, two species that approximate the vascular access and GFR results expected in humans. In both animal models, a sub-millimeter optical fiber that delivered excitation light and collected fluorescent emissions was inserted into a peripheral vein (dog) or central venous access (pig) by means of commercial intravenous catheters. A mixture of fluorescent chimeras of a small freely filterable reporter and large non-filterable plasma volume marker were infused as a bolus, excited by light-emitting diodes, and the in vivo signals detected and quantified by photomultiplier tubes in both species in less than 60 min. Concurrent standardized 6-h iohexol plasma kidney clearances validated the accuracy of our results for both physiologic and a chronic kidney disease setting. Thus, our ratiometric technique allows for both measurement of plasma vascular volume and highly accurate real-time GFR determinations, enabling clinical decision making in real time.

Exposure to nephrotoxic medication is among the most common causes of acute kidney injury (AKI) in hospitalized patients. Here we conducted a prospective quality improvement project implementing a systematic Electronic Health Record screening and decision support process (trigger) in our quaternary pediatric inpatient hospital. Eligible patients were noncritically ill hospitalized children receiving an intravenous aminoglycoside for more than 3 days or more than 3 nephrotoxins simultaneously (exposure) from September 2011 through March 2015. Pharmacists recommended daily serum creatinine monitoring in exposed patients after appearance on the trigger report and AKI was defined by the Kidney Disease Improving Global Outcomes AKI criteria. A total of 1749 patients accounted for 2358 separate hospital admissions during which a total of 3243 episodes of nephrotoxin exposure were identified with 170 patients (9.7%) experiencing 2 or more exposures. A total of 575 individual AKI episodes occurred over the 43-month study period. Overall, the exposure rate decreased by 38% (11.63–7.24 exposures/1000 patient days), and the AKI rate decreased by 64% (2.96–1.06 episodes/1000 patient days). Assuming initial baseline exposure rates would have persisted without our project implementation, we estimate 633 exposures and 398 AKI episodes were avoided. Thus, systematic surveillance for nephrotoxic medication exposure and near real-time AKI risk can lead to sustained reductions in avoidable harm. These interventions and outcomes are translatable to other pediatric and nonpediatric hospitalized settings.

In this study, we attempted to identify threshold values for kidney function measures that maximally discriminate short-term mortality, to identify major population segments in which these thresholds apply, and to classify the hierarchical rank of the thresholds when other classic risk factors are also considered. To do this we retrospectively identified estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (ACR) thresholds to maximize sensitivity and specificity predictions for death in non-institutionalized NHANES III participants, representative of the United States population from 1988 to 1994 and followed through 2000. In a classification tree excluding dichotomizing variables, age 57 years was initially selected; ACR appeared in the second round and eGFR in the third. The prognostic discrimination of optimum eGFR and ACR thresholds exceeded those of commonly advocated public health screening measures, such as LDL cholesterol and fasting blood glucose, with body mass index appearing in the third round, and smoking and LDL cholesterol in the fourth. In a tree permitting dichotomizing variables, the ACR, systolic blood pressure, and glucose first appeared in the third round, with eGFR, smoking, and LDL in the fourth. Thus, the albumin-creatinine ratio and eGFR may be at least as efficient for survival-based clinical triage as most other classic risk factors.

To examine the relationship between systolic blood pressure and progression of carotid intima-media thickness in patients with chronic kidney disease (CKD), we studied 3364 patients from a community-based cohort of elderly individuals of whom 724 had CKD defined as creatinine clearances of stage 3 or less. The contribution of systolic blood pressure was evaluated in four ranges (120, 120-129, 130-139, andor = 140 mm Hg). All multiple linear regression analyses were adjusted for traditional and nontraditional cardiovascular risk factors. The higher ranges of systolic blood pressure at baseline were associated with a greater carotid intima-media thickness at the initiation of the study in patients with or without CKD. Covariate-adjusted averages of carotid intima-media thickness at the initiation of the study in patients with CKD significantly increased across the four strata of systolic blood pressure. Higher systolic blood pressure at baseline was associated with a significantly greater yearly change in covariate-adjusted mean carotid intima-media thickness and vascular events in patients with CKD over a 4-year follow-up period.

Vancomycin is a key tool in the treatment of serious Gram-positive infections. A progressive increase in vancomycin resistance with consequent treatment failure has been observed in staphylococci. Therefore, new dosing guidelines advocating much higher vancomycin doses have been issued. Target trough levels of 15-20 microg/ml are proposed. Whether and how these targets can be achieved in patients with chronic kidney disease or those on dialysis are still under evaluation. The higher vancomycin doses to achieve these treatment targets carry a substantial risk for nephrotoxicity. This risk is incremental with higher trough levels and longer duration of vancomycin use. Critically ill patients, patients receiving concomitant nephrotoxic agents, and patients with already compromised renal function are particularly at risk for vancomycin-induced nephrotoxicity.

This study was performed to quantify the fraction of excreted creatinine not attributable to creatinine filtration for accurately determining the glomerular filtration rate in mice. To measure this we compared creatinine filtration with the simultaneous measurement of inulin clearance using both single-bolus fluorescein isothiocyanate (FITC)-inulin elimination kinetics and standard FITC-inulin infusion. During anesthesia, creatinine filtration was found to be systematically higher than inulin clearance in both male and female C57BL/6J mice. The secretion fraction was significantly less in female mice. Administration of either cimetidine or para-aminohippuric acid, competitors of organic cation and anion transport respectively, significantly reduced the secretion fraction in male and female mice and both significantly increased the plasma creatinine level. Creatinine secretion in both genders was not mediated by the organic cation transporters OCT1 or OCT 2 since secretion fraction levels were identical in FVB wild-type and OCT1/2 knockout mice. Thus, secretion accounts for about 50 and 35% of excreted creatinine in male and female mice, respectively. Increasing plasma creatinine threefold by infusion further increased the secretion fraction. Renal organic anion transporter 1 mRNA expression was higher in male than in female mice, reflecting the gender difference in creatinine secretion. Hence we show that there is a major secretory contribution to creatinine excretion mediated through the organic anion transport system. This feature adds to problems associated with measuring endogenous creatinine filtration in mice.

Reactive oxygen species (ROS) contribute to the development of interstitial fibrosis and tubular atrophy seen in chronic allograft nephropathy (CAN). As molecular hydrogen gas can act as a scavenger of ROS, we tested the effect of treatment with hydrogen water (HW) in a model of kidney transplantation, in which allografts from Lewis rats were orthotopically transplanted into Brown Norway recipients that had undergone bilateral nephrectomy. Molecular hydrogen was dissolved in water and recipients were given HW from day 0 until day 150. Rats that were treated with regular water (RW) gradually developed proteinuria and their creatinine clearance declined, ultimately leading to graft failure secondary to CAN. In contrast, treatment with HW improved allograft function, slowed the progression of CAN, reduced oxidant injury and inflammatory mediator production, and improved overall survival. Inflammatory signaling pathways, such as mitogen-activated protein kinases, were less activated in renal allografts from HW-treated rats as compared with RW-treated rats. Hence, oral HW is an effective antioxidant and antiinflammatory agent that prevented CAN, improved survival of rat renal allografts, and may be of therapeutic value in the setting of transplantation.

We sought to identify predictors of the decline in renal function, especially those that are modifiable, in the 5488 participants of the prospective, community-based cohort study PREVEND who completed three visits during a mean follow-up of 6.5 years. The change in renal function was used as the outcome and this was calculated as the linear regression of three estimated GFR measurements obtained during follow-up. Risk factors, known to influence renal outcome in patients with primary renal diseases, were used as potential predictors in multivariate regression analyses. High systolic blood pressure and plasma glucose were found to be independent predictors for an accelerated decline in function for both genders. In males, albuminuria was the strongest independent predictor for renal function decline, whereas in females albuminuria was univariately associated only after adjustment for age. The direction of the association between cholesterol/HDL ratio and decline of renal function differed by gender. Surprisingly, in males, waist circumference was an independent predictor and positively associated with renal function outcome. These studies show that there are gender differences in the standard predictors of the decline in renal function.

Contains fulltext : 71200.pdf (Publisher’s version ) (Open Access) Heparan sulfate in the glomerular basement membrane has been considered crucial for charge-selective filtration. In many proteinuric diseases, increased glomerular expression of heparanase is associated with decreased heparan sulfate. Here, we used mice overexpressing heparanase and evaluated the expression of different heparan sulfate domains in the kidney and other tissues measured with anti-heparan sulfate antibodies. Glycosaminoglycan-associated anionic sites were visualized by the cationic dye cupromeronic blue. Transgenic mice showed a differential loss of heparan sulfate domains in several tissues. An unmodified and a sulfated heparan sulfate domain resisted heparanase action in vivo and in vitro. Glycosaminoglycan-associated anionic sites were reduced about fivefold in the glomerular basement membrane of transgenic mice, whereas glomerular ultrastructure and renal function remained normal. Heparanase-resistant heparan sulfate domains may represent remnant chains or chains not susceptible to cleavage. Importantly, the strong reduction of glycosaminoglycan-associated anionic sites in the glomerular basement membrane without development of a clear renal phenotype questions the primary role of heparan sulfate in charge-selective filtration. We cannot, however, exclude that overexpression of heparanase and heparan sulfate loss in the basement membrane in glomerular diseases contributes to proteinuria.

Beta-blockers are known to improve postoperative outcome after major vascular surgery. We studied the effects of beta-blockers in 2126 vascular surgery patients with and without kidney disease followed for 14 years. Creatinine clearance was calculated using the Cockcroft-Gault equation, and kidney function was categorized as Stage 1 for a reference group of 550 patients, Stage 2 with 808 patients, Stage 3 with 627 patients, and combined Stages 4 and 5 with 141 patients. Outcome measures were 30-day and long-term all-cause mortality with a mean follow-up of 6 years. Cox proportional hazards models were used to control cardiovascular risk factors, including propensity for beta-blocker use. In all, 129 (6%) and 1190 (56%) patients died respectively. Mortality rates were three- and two-fold higher, respectively, for patients at Stages 3-5 compared to the reference group for the two outcomes. beta-Blocker use was significantly associated with a lower risk of mortality after surgery. The overall adjusted hazard ratio was 0.35 and 0.62, respectively, for individuals at Stages 3-5 compared to the reference group for 30-day and long-term mortality. This study shows that kidney function is a predictor of all-cause mortality and beta-blocker use is associated with a lower risk of death in kidney disease patients undergoing elective vascular surgery.

The use of novel biomarkers of acute kidney injury (AKI) in clinical trials may help evaluate treatments for AKI. Here we explore potential applications of biomarkers in simulated clinical trials of AKI using data from the TRIBE-AKI multicenter, prospective cohort study of patients undergoing cardiac surgery. First, in a hypothetical trial of an effective therapy at the time of acute tubular necrosis to prevent kidney injury progression, use of an indirect kidney injury marker such as creatinine compared to a new direct biomarker of kidney injury reduces the proportion of true acute tubular necrosis cases enrolled. The result is a lower observed relative risk reduction with the therapy, and lower statistical power to detect a therapy effect at a given sample size. Second, the addition of AKI biomarkers (interleukin-18 and NGAL) to clinical risk factors as eligibility criteria for trial enrollment in early AKI has the potential to increase the proportion of patients who will experience AKI progression and reduce trial cost. Third, we examine AKI biomarkers as outcome measures for the purposes of identifying therapies that warrant further testing in larger, multicenter, multi-country trials. In the hypothetical trial of lower cardiopulmonary bypass time to reduce the risk of postoperative AKI, the sample size required to detect a reduction in AKI is lower if new biomarkers are used to define AKI rather than serum creatinine. Thus, incorporation of new biomarkers of AKI has the potential to increase statistical power, decrease the sample size, and lower the cost of AKI trials.

Severe obesity is associated with increased risk of kidney disease. Whether bariatric surgery reduces the risk of adverse kidney outcomes is uncertain. To resolve this we compared the risk of estimated glomerular filtration rate (eGFR) decline of ≥30% and doubling of serum creatinine or end-stage renal disease (ESRD) in 985 patients who underwent bariatric surgery with 985 patients who did not undergo such surgery. Patients were matched on demographics, baseline body mass index, eGFR, comorbidities, and previous nutrition clinic use. Mean age was 45 years, 97% were white, 80% were female, and 33% had baseline eGFR 90 ml/min per 1.73 m(2). Mean 1-year weight loss was 40.4 kg in the surgery group compared with 1.4 kg in the matched cohort. Over a median follow-up of 4.4 years, 85 surgery patients had an eGFR decline of ≥30% (22 had doubling of serum creatinine/ESRD). Over a median follow-up of 3.8 years, 177 patients in the matched cohort had an eGFR decline of ≥30% (50 had doubling of serum creatinine/ESRD). In adjusted analysis, bariatric surgery patients had a significant 58% lower risk for an eGFR decline of ≥30% (hazard ratio 0.42, 95% confidence interval 0.32-0.55) and 57% lower risk of doubling of serum creatinine or ESRD (hazard ratio 0.43, 95% confidence interval: 0.26-0.71) compared with the matched cohort. Results were generally consistent among subgroups of patients with and without eGFR 90 ml/min per 1.73 m(2), hypertension, and diabetes. Thus, bariatric surgery may be an option to prevent kidney function decline in severely obese individuals.

In dialyzed patients, preservation of residual renal function is associated with better survival, lower morbidity, and greater quality of life. To analyze the evolution of residual diuresis over time, we prospectively monitored urine output in 401 pediatric patients in the global IPPN registry who commenced peritoneal dialysis (PD) with significant residual renal function. Associations of patient characteristics and time-variant covariates with daily urine output and the risk of developing oligoanuria (under 100 ml/m(2)/day) were analyzed by mixed linear modeling and Cox regression analysis including time-varying covariates. With an average loss of daily urine volume of 130 ml/m(2) per year, median time to oligoanuria was 48 months. Residual diuresis significantly subsided more rapidly in children with glomerulopathies, lower diuresis at start of PD, high ultrafiltration volume, and icodextrin use. Administration of diuretics significantly reduced oligoanuria risk, whereas the prescription of renin-angiotensin system antagonists significantly increased the risk oligoanuria. Urine output on PD was significantly associated in a negative manner with glomerulopathies (-584 ml/m(2)) and marginally with the use of icodextrin (-179 ml/m(2)) but positively associated with the use of biocompatible PD fluid (+111 ml/m(2)). Children in both Asia and North America had consistently lower urine output compared with those in Europe perhaps due to regional variances in therapy. Thus, in children undergoing PD, residual renal function depends strongly on the cause of underlying kidney disease and may be modifiable by diuretic therapy, peritoneal ultrafiltration, and choice of PD fluid.

Nephropathia epidemica (NE) is a hemorrhagic fever with renal syndrome caused by Puumala hantavirus. Its long-term prognosis is considered favorable. There are, however, some reports about subsequent hypertension, glomerular hyperfiltration, and proteinuria after previous hantavirus infection. Therefore, we studied 36 patients 5 and 10 years after acute NE, with 29 seronegative controls. Office blood pressure, ambulatory 24-h blood pressure (ABP), glomerular filtration rate (GFR), and proteinuria were examined. Hypertensive subjects were defined as those patients having increased ambulatory or office blood pressure, or receiving antihypertensive therapy. Office blood pressure was used to define hypertension only if ABP was not determined. At 5 years, the prevalence of hypertension was higher among NE patients than in controls (50 vs 21%, P=0.020). At 10 years, the difference between the groups was no more significant (39 vs 17%, P=0.098). Five years after NE, patients showed higher GFR (121+/-19 vs 109+/-16 ml/min/1.73 m(2), P=0.012) and urinary protein excretion (0.19 g/day, range 0.12-0.38 vs 0.14 g/day, range 0.09-0.24, P=0.001) than controls. At 10 years, there were no more differences in GFR or protein excretion between the groups (GFR: 113+/-20 vs 108+/-17 ml/min/1.73 m(2), P=0.370; proteinuria: 0.14 g/day, range 0.07-0.24 vs 0.13 g/day, range 0.06-0.31, P=0.610). In conclusion, the 10-year prognosis of NE is favorable, as glomerular hyperfiltration and slight proteinuria detected at 5 years disappeared during the longer follow-up. However, the possibility exists that NE may predispose some patients to the development of hypertension.

Low calorie commercial sugar is a sensitive marker of glomerular filtration rate. Background Glomerular filtration rate (GFR) in humans and animals might be determined with precision by measuring the clearance of an ideal marker, such as inulin. However, the use of inutest, an inulin analog, is limited by its cost and accessibility. The present study tested whether low calorie commercial sugar (LC sugar) can be used to measure GFR during normal and renal dysfunction. Methods Two groups of 6 male Wistar rats weighing 300 to 350 g were included. One group was treated with a daily dose of cyclosporine (CsA) 30 mg/kg subcutaneously for 7 days and the other group was formed by nontreated control rats. In one half of each group, GFR was evaluated by using inutest and in the other half by using LC sugar. GFR was also evaluated by using a wide LC sugar plasma concentration range in an additional group. Results In nontreated rats, the mean GFR evaluated with LC sugar was 2.2 ± 0.1 mL/min. This value is equal to that obtained with inutest: 2.3 ± 0.1 mL/min. CsA administration produced a significant reduction of renal blood flow and renal function. The GFR reduction induced by CsA was similarly determined by both LC sugar and inutest to be at 1.0 ± 0.2 and 1.1 ± 0.2 mL/min ( P = NS), respectively. In addition, GFR did not change when LC sugar plasma concentration gradually increased. Conclusion Our results show that in both normal and pathophysiologic conditions, LC sugar is a good marker of GFR similar to the gold standard inutest.

Epidemic glomerulonephritis due to Streptococcus zooepidemicus in Nova Serrana, Brazil. Background In 1998, there was a large outbreak of acute glomerulonephritis in Nova Serrana, Brazil, caused by group C Streptococcus zooepidemicus . This article reviews the characteristics of the outbreak and some aspects of the patients' follow-up. Methods We describe clinical characteristics of patients with acute nephritis. Using case-control studies, we identified the source of infection. Cultures of oropharyngeal swabs from patients were performed. Of 135 patients identified in 1998, available patients were reexamined in a prospective study after 2 and 5 years. Results Lancefield group C S. zooepidemicus was identified as the causative organism and linked to the consumption of cheese produced from unpasteurized milk. Of the original group of 134 patients, 4 died in the acute phase and 5 (3.7%) required chronic dialysis. After 2 years, of the 69 cases reevaluated, 94% were adults (mean ± standard error age: 39 ± 2 years); we found arterial hypertension in 42% ( N = 27/64) of the patients, reduced creatinine clearance ( 2 ) in 30% ( N = 20/67), and increased microalbuminuria (>20 μg/min) in 34% ( N = 22/65). Preliminary data at 5-year follow-up suggest that the percentage of patients with creatinine clearance lower than 60mL/min increased from 9% to 15%. Conclusion This article highlights the dangers of consuming unpasteurized dairy products. Follow-up of patients with epidemic poststreptococcal glomerulonephritis due to S. zooepidemicus show that a considerable proportion present hypertension, reduced renal function, and increased microalbuminuria.

Biomarkers of inflammation and progression of chronic kidney disease. Background Chronic kidney disease is associated with higher levels of inflammatory biomarkers. Statins have anti-inflammatory properties and may attenuate loss of kidney function. Although inflammation may mediate progressive renal injury, the relation between statin use, markers of inflammation, and the rate of kidney function loss has not been elucidated. We examined the association between pravastatin use, levels of C-reactive protein (CRP), soluble tumor necrosis factor receptor II (sTNFrii), and the rate of kidney function loss. Methods We performed a post hoc analysis of data from a randomized placebo controlled trial of pravastatin 40mg daily in people with previous myocardial infarction. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease Study (MDRD) GFR equation. We studied 687 subjects with chronic kidney disease (GFR 2 ) who did not experience a cardiovascular event during follow-up. Multivariate linear regression was used to study the relation between baseline CRP and sTNFrii and the rate of kidney function loss in mL/min/1.73m 2 /year. Cross-product interaction terms were used to determine if these relations varied with pravastatin use. Results Median baseline GFR was 54.5 mL/min/1.73m 2 (interquartile range 49.7, 57.8) and median duration of follow-up was 58 months. Higher baseline CRP level was independently associated with more rapid kidney function loss (highest tertile 0.6 mL/min/1.73m 2 per year faster than lowest tertile) ( P = 0.001). A similar independent relation was observed between tertile of sTNFrii and rate of kidney function loss (highest tertile 0.5 mL/min/1.73m 2 per year faster than lowest tertile) ( P = 0.006). Subjects with both CRP and sTNFrii in the highest tertile ("inflamed" status) appeared to derive more renal benefit from pravastatin than those without ( P for interaction 0.047). In these 108 subjects, renal function loss in pravastatin recipients was 0.8 mL/min/1.73m 2 /year slower than placebo (95% CI 0 to 1.5 mL/min/1.73m 2 /year slower) ( P = 0.039). Conclusion Higher CRP and sTNFrii are independently associated with faster rates of kidney function loss in chronic kidney disease. Pravastatin appears to prevent loss of kidney function to a greater extent in individuals with greater evidence of inflammation, although this was of borderline significance. These data suggest that inflammation may mediate the loss of kidney function among subjects with chronic kidney disease and concomitant coronary disease.

Blockade of NFκB activation and renal inflammation by ultrasound-mediated gene transfer of Smad7 in rat remnant kidney.BackgroundTransforming growth factor-β (TGF-β) in renal fibrosis has been well studied, but little attention has been paid to the potential role of TGF-β in the resolution of renal inflammation. We hypothesize that TGF-β exerts its anti-inflammation properties by stimulating its negative signaling pathway involving Smad7.MethodsA rat remnant kidney model was treated with a doxycycline-regulated Smad7 gene or control empty vector using an ultrasound-microbubble (Optison)–mediated system. Smad7 transgene expression within the kidney was tightly controlled by the addition of doxycycline in the daily drinking water. All animals were euthanized at week 4 for examination of inflammatory responses.ResultsReal-time polymerase chain reaction (PCR) and immunohistochemistry revealed that gene transfer of Smad7 resulted in a substantial inhibition of interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) expression (all P < 0.01 vs. control). This was associated with the attenuation of histology damage, proteinuria, serum creatinine, and an increase in creatinine clearance (all P < 0.05). In addition, overexpression of Smad7 significantly inhibited renal inflammation, including ICAM-1, iNOS, and accumulation of macrophages and T cells in both glomeruli and tubulointerstitium. Furthermore, gene transfer of Smad7 also substantially blocked nuclear factor kappa B (NFκB) activation in the rat remnant kidney (P < 0.01).ConclusionTGF-β/Smad7 signaling plays a critical role in the resolution of renal inflammation in rat remnant kidney model. Inhibition of NFκB activation is a key mechanism by which Smad7 suppresses renal inflammation, which suggests a crosstalk pathway between NFκB and Smad7. The ability of Smad7 to inhibit renal inflammation indicates that ultrasound-microbubble–mediated Smad7 gene therapy may represents a new therapeutic strategy for glomerulonephritis.

The diagnostic value of serum concentrations of 2-(α-mannopyranosyl)-l-tryptophan for normal renal function.BackgroundWe have previously reported that the serum concentration of 2-(α-mannopyranosyl)-l-tryptophan (MPT), tryptophan glycoconjugate, is a more accurate measure of renal function than that of serum creatinine concentration. The aim of the present study was to compare the diagnostic value of serum concentrations of MPT and creatinine as a measure of normal renal function.MethodsA total of 156 subjects with serum creatinine concentration ≤1.60mg/dL aged 0 to 88years were recruited. Serum concentrations of MPT and creatinine, and creatinine clearance calculated by Cockcroft-Galt formula were determined. A diagnostic accuracy of serum concentrations of MPT and creatinine for normal renal function was analyzed by using receiver-operating characteristics (ROC) curves. In 82 subjects with normal renal function defined as calculated creatinine clearance ≥80mL/min (aged 6 to 68years), the correlations between age and/or urinary creatinine excretion, which is related to muscle mass, and serum concentrations of MPT or creatinine, were determined.ResultsIn the ROC curve, the area under the curve (AUC) in serum MPT concentration was significantly greater than that of creatinine (0.855 versus 0.800, respectively, P < 0.001) and the cut-off levels associated with the greatest diagnostic accuracy were 90ng/mL for serum MPT concentration and 0.70mg/dL for serum creatinine concentration. The sensitivity, specificity, and positive and negative predictive values were 69.5%, 85.1%, 83.8%, and 71.6% for serum MPT concentration, and 53.7%, 81.1%, 75.9%, and 61.2% for serum creatinine concentration. A close correlation existed between serum creatinine concentration and age (r = 0.798, P < 0.0001) in 23 subjects aged 20years or younger. Conversely, serum MPT concentration remained unchanged regardless of age (r=-0.135, P = 0.228). Furthermore, a close correlation existed between serum creatinine concentration and urinary creatinine excretion (r = 0.817, P < 0.0001), but not between serum MPT concentration and urinary creatinine excretion (r = 0.082, P = 0.461).ConclusionThe concentration of serum MPT is a more reliable diagnostic parameter than that of serum creatinine as a measure of normal renal function, and renal function can be compared in subjects independently of age and muscle mass when serum MPT concentration is measured.

Assessing renal graft function in clinical trials: Can tests predicting glomerular filtration rate substitute for a reference method?BackgroundIn clinical trials, comparison of renal graft function needs a rigorous determination of glomerular filtration rate (GFR). Since reference methods to measure GFR cannot be easily implemented, a number of tests predicting GFR are usually used. However, little is known about their validity in renal transplant patients. We aimed to compare the performances of six GFR tests with inulin clearance in this population.MethodsFive hundred consecutive inulin clearances performed in 294 renal transplant recipients with stable renal function were retrospectively selected. For each of them, we computed six estimates: the 24-hour creatinine clearance, the Cockcroft-Gault, Walser, Jelliffe, Nankivell, and Levey formulas. Their respective performance was assessed by correlation (simple linear regression), accuracy (dispersion of true error), and agreement (Bland and Altman method).ResultsEach GFR test closely correlated with inulin clearance (P < 0.0001). Comparisons between pairs of GFR tests did not show any significant difference in accuracy between the Levey, Jelliffe, and Walser formulas. Conversely, each of these formulas demonstrated a significant lower dispersion (P < 0.005) than the others. Nevertheless, all GFR tests displayed considerable lack of agreement with limits of agreement over 40mL/min/1.73m2 apart. The proportion of predicted GFR differing from inulin clearance by ± 10mL/min/1.73m2, ranged from 34% for the Jelliffe formula to 53% for the Nankivell's one.ConclusionNone of these formulas seems to be able to safely substitute for inulin clearance. In clinical trials, renal graft function should be preferably assessed using a reference method of GFR measurement.

Dietary flaxseed meal reduces proteinuria and ameliorates nephropathy in an animal model of type II diabetes mellitus.BackgroundEvidence is emerging that varying the type or source of dietary protein intake can have beneficial effects on chronic renal disease. Consumption of soybean and soy-based food products, as the source of plant protein, can retard the development and progression of chronic renal disease. We studied the obese spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat, a model of obesity and type II diabetes mellitus that consistently develops nephropathy resembling diabetic nephropathy. We specifically sought to determine whether changing the source of protein intake from animal protein, casein, to plant protein in the form of either soy protein concentrate or flaxseed protein in the diet has a different impact on renal function and nephropathy in this model.MethodsMale obese SHR/N-cp rats were randomly assigned to one of three diets containing either 20% casein, 20% soy protein concentrate, or 20% flaxseed meal. Except for the protein source, all three diets were identical and contained similar amounts of protein, fat, carbohydrates, minerals, and vitamins. All animals were maintained on these diets for 6months. At the end of the study, blood sampling and 24-hour urine collections were performed for renal functional measurements, and the kidneys were harvested and examined for histologic evaluation.ResultsAll three groups had similar amounts of food intake and body weight gain and exhibited fasting hyperglycemia and hyperinsulinemia. Plasma glucose levels did not differ among the three groups, but plasma insulin concentration was significantly lower in rats fed flaxseed meal than those fed either casein or soy protein concentrate. Mean plasma creatinine, creatinine clearance, and urinary urea excretion also did not differ significantly between the three groups. By contrast, urinary protein excretion was significantly lower (P < 0.01) in rats fed flaxseed than in rats fed either casein or soy protein concentrate. Morphologic analysis of renal structural lesions showed that the percentage of abnormal glomeruli with mesangial expansion and the tubulointerstitial score (an index of severity of tubulointerstitial damage) were significantly reduced in rats fed flaxmeal compared to those fed casein or soy protein concentrate.ConclusionWe conclude that dietary protein substitution with flaxseed meal reduces proteinuria and glomerular and tubulointerstitial lesions in obese SHR/N-cp rats and that flaxseed meal is more effective than soy protein in reducing proteinuria and renal histologic abnormalities in this model. The reduction in proteinuria and renal injury was independent of the amount of protein intake and glycemic control. Which dietary component(s) present in flaxseed meal is (are) responsible for the renal protective effect remains to be determined.

Bone disease in long-term adult kidney transplant patients with normal renal function.BackgroundIn successful renal transplantation, the degree of renal function recovery is usually incomplete and information is scarce about the abnormalities of mineral metabolism in long-term adult renal recipients with normal renal function. This study was designed to investigate bone mineral metabolism in patients with a long-term normal functioning kidney.MethodsTwenty-nine adult asymptomatic renal transplant (RT) recipients with stable graft function for more than 10 years and serum creatinine 70mL/min (x: 126 ± 55 mL/min) and Group B (N = 17; nine men, eight women) 70mL/min the prevalence of mineralization defect in the presence of normal serum levels of calcitriol suggested vitamin D resistance. Lumbar and femoral neck osteoporosis was present in 25% and 33% of patients in group A, and 23% and 53% in group B, respectively. T-score at lumbar spine was negatively correlated with months since transplantation. Patients under treatment with cyclosporine (CsA) showed increased concentrations of osteocalcin and D-pyr and higher lumbar bone mineral density (BMD), but bone histomorphometry was not influenced by CsA.ConclusionPatients with long-term renal transplantation with normal renal function frequently present with slight increases in PTH, but without an effect on bone histology. CsA did not induce changes in bone histology and delayed mineralization was frequently observed.

The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines suggest that clinicians use the estimated glomerular filtration rate (eGFR) measurements and minimize the use of timed urine creatinine clearance collection. The intent of this change was to improve recognition of chronic kidney disease. Here we used time-series modeling and intervention analyses to determine the effect of publication of the K/DOQI guidelines and the introduction of widespread eGFR reporting with prompts on physician ordering of 24-h urine collection for creatinine clearance. In this setting, clinical practice guidelines did not influence creatinine clearance testing; however, the direct introduction of eGFR reporting with prompts into physician workflow resulted in a sudden and significant 23.5% decrease in creatinine clearance collection over the 43 months analyzed. Thus, eGFR reporting with prompts may have produced a clinical practice change because it is integrated directly into physician workflow. Changing physician practice patterns may require more than publishing guidelines; rather it is more likely to occur through educational and structural changes to practice.

Measurement of renal function in pre-ESRD patients. The measurement of renal function in pre-dialysis patients is important in order to determine the appropriate time to begin renal replacement therapy, to forecast the start, and to compare, in groups of patients, the efficiency of different treatments that limit renal disease progression. The most reliable methods, such as inulin clearance or measurement by radioisotopes, are too awkward for the usual clinical follow-up of patients. Although much simpler and almost as reliable, the use of iohexol radiologic contrast does not allow the frequent monitoring of the patient either. The determinations of the plasmatic creatinine and its clearance or the estimate of the glomerular filtration rate by means of equations derived from the creatinine are the methods most often used in order to measure renal function, although not without problems in pre-dialysis. In order to try to overcome such problems, more precise equations and procedures, including the measurement of averaged urea-creatinine clearance or creatinine clearance with cimetidine, have been designed that better estimate the glomerular filtration rate. However, none of these methods is totally reliable in pre-dialysis. A new endogen marker, cystatin C, has advantages over creatinine, though more studies are needed in pre-dialysis in order to ascertain its use. The initial proposal of the National Kidney Foundation's Kidney Disease Outcome Quality Initiative (DOQI) guidelines to use weekly Kt/V and nutritional parameters to determine the time for starting renal replacement therapy has widened the prospects of the debate on the measurement of renal function in pre-dialysis, but further work is required to define their role in pre-dialysis patients' follow-up.

After its proposal as a marker of dialysis adequacy in the eighties of last century, Kt/ V urea helped to improve dialysis efficiency and to standardize the procedure. However, the concept was developed when dialysis was almost uniformly short and was applied thrice weekly with small pore cellulosic dialyzers. Since then dialysis evolved in the direction of many strategic alternatives, such as extended or daily dialysis, large pore high-flux dialysis, and convective strategies. Although still a useful baseline marker, Kt/ V urea no longer properly covers up for most of these modifications so that urea kinetics are hardly if at all representative for those of other solutes with a deleterious effect on morbidity and mortality of uremic patients. This is corroborated in several clinical studies showing a dissociation between removal of urea and that of other uremic toxins. In addition, randomized controlled trials showed no benefit of increasing Kt/ V urea . Finally, this parameter also hardly is evocative for metabolic or intestinal generation of toxins, for their removal by residual renal function and for the complex interaction of dialysis length with removal pattern and patient outcomes. We conclude that apart from being a baseline parameter of dialysis adequacy, Kt/ V urea insufficiently represents all novel strategic changes of modern dialysis. Kt/ V urea is too simple a concept for the complexities of uremia and of today's dialysis.

Tubular stress test detects subclinical reduction in renal functioning mass.BackgroundTo develop a test that would disclose subclinical impairment in renal function, we studied the increment in tubular secretion of creatinine (TSCr) induced by intravenous creatinine administration.MethodsStudies were done in 14 normal individuals, 7 kidney donors (KDs), and 11 transplant recipients (Tx), all of whom had normal creatinine levels (PCr

Effects of sodium artesunate, a new antimalarial drug, on renal function. Background Sodium artesunate is currently used in malaria treatment. Adverse effects of this drug have not been described, probably because they cannot be differentiated from malaria-related effects. Methods The effects on renal function of an acute infusion of sodium artesunate (12 mg/kg body weight) were studied in the rat with clearance techniques. We also evaluate the effect of sodium artesunate on chloride lumen-bath flux (Cl Jlb) in the isolated thick ascending limb of the loop of Henle (TALH) microperfused in vitro. Results Acute infusion of artesunate to the rat decreased inulin clearance, despite an increase in renal blood flow. These effects were associated with an increase in urinary excretion of sodium, chloride, potassium, and nitric oxide metabolites (NO 2 /NO 3 ). In water-loaded animals, artesunate increased sodium and water distal delivery and decreased free water clearance (C H 2 O ) factored for sodium and water delivery. Following hypertonic NaCl infusion, artesunate decreased free water excretion (TC H 2 O ) corrected by clearance of osmolarity (C Osm ). In vitro, artesunate 10 -6 and 10 -3 mol/L added to bath solution decreased chloride lumen-bath flux in isolated rabbit TALH in a dose-dependent manner, with the threshold effect at 10 -4 mol/L. This effect was completely blocked by N G -nitroL-arginine-metilester (L-NAME) 5mmol/L. Artesunate 10 -4 mol/L added to the perfusion solution did not change Cl Jlb. Conclusion These findings suggest that artesunate decreases glomerular filtration rate and increases renal blood flow and urinary excretion of Na, Cl, and K. These effects were due, at least in part, to the inhibition of Cl transport across cortical and medullary TALH, and were mediated by local production of nitric oxide, since it is associated with an increase in NO 2 /NO 3 urinary excretion and it is blocked by L-NAME in vitro.

Haptoglobin reduces renal oxidative DNA and tissue damage during phenylhydrazine-induced hemolysis. Background Haptoglobin knockout (Hp-/-) mice are more sensitive to phenylhydrazine-induced hemolysis than Hp+/+ mice. Methods Hemolysis was induced in Hp-/- and Hp+/+ mice using phenylhydrazine. Relative renal tissue damage and function were then assessed. Results Hp-/- mice had higher basal levels of renal lipid peroxidation, as evidenced by levels of malonaldehyde and 4-hydroxy-2(E)-nonenal (MDA/HNE). After the administration of phenylhydrazine, levels of 8-hydroxyguanine (but not other products of oxidative DNA damage) were significantly elevated in the renal DNA. There was also increased induction of heme oxygenase-1. The more severe renal damage in Hp-/- mice was also evident in the delayed erythropoietin gene expression and poorer renal clearance of 3 H-inulin. This reduction in glomerular filtration function in Hp+/+ and Hp-/- mice could be restored to baseline by vasodilators (prazosin or diazoxide), implicating renal vasoconstriction as a major mechanism of acute renal failure during induced hemolysis. Precipitation of hemoglobin in the kidney was not increased in Hp-/- mice. Conclusions Haptoglobin appears to play an important physiological role as an antioxidant, particularly during hemolysis.

Due to the shortage of organs, living donor acceptance criteria are becoming less stringent. An accurate determination of the glomerular filtration rate (GFR) is critical in the evaluation of living kidney donors and a value exceeding 80ml/min per 1.73m2 is usually considered suitable. To improve strategies for kidney donor screening, an understanding of factors that affect GFR is needed. Here we studied the relationships between donor GFR measured by 125I-iothalamate clearances (mGFR) and age, gender, race, and decade of care in living kidney donors evaluated at the Cleveland Clinic from 1972 to 2005. We report the normal reference ranges for 1057 prospective donors (56% female, 11% African American). Females had slightly higher mGFR than males after adjustment for body surface area, but there were no differences due to race. The lower limit of normal for donors (5th percentile) was less than 80 ml/min per 1.73m2 for females over age 45 and for males over age 40. We found a significant doubling in the rate of GFR decline in donors over age 45 as compared to younger donors. The age of the donors and body mass index increased over time, but their mGFR, adjusted for body surface area, significantly declined by 1.49±0.61 ml/min per 1.73m2 per decade of testing. Our study shows that age and gender are important factors determining normal GFR in living kidney donors.

Kidney transplanted children come of age. Background The aim of renal replacement therapy in children is to restore their potential for normal growth and development in order to reach mature adulthood. Because pediatric kidney transplantation started in the late 1960s, it is now possible to document the progress and outcome of these patients from transplantation in childhood to survival into adulthood. Methods In this single-center study, all 150 children born before December 1977 and having received a kidney transplant between 1970 and 1993 were selected for long-term follow-up. The mean age at transplantation was 12.1years (range 3.2 to 16.7), and the mean follow-up was 13.1years (range 2.0 to 25.0). In December 1995, 124 grown-up patients with a mean age of 25.4years (range 18.4 to 40.3) were alive, 89 with a functioning graft. Fifty had the first graft functioning longer than 10years. The fate of all patients was traced, and those living were analyzed in regard to their somatic and socioeconomic states. Results The actuarial 25-year survival rate for the patients was 81%, and for the first graft it was 31%. The best graft survival rates were observed after living related donation, pre-emptive transplantation, and immunosuppression with cyclosporine. The latter benefit, however, vanished after eight years. The mean creatinine clearance declined over the years from 76 to 45ml/min/1.73m 2 , and the incidence of hypertension increased to more than 80% of the patients. Malignancies occurred in 2.6%. Final height was stunted in 44% of noncystinotic patients, whereas all patients with cystinosis were extremely growth retarded. Twenty-seven percent suffered from additional disabilities. A majority of adult patients were rehabilitated in regard to education and socioeconomic status, and 14% were unemployed. Conclusions The results indicate that renal transplantation in children leads to a high degree of rehabilitation in adulthood. The life of a kidney transplant, however, is limited, which points out the need for more specific immunosuppression with fewer side-effects in order to reach the goal of lifelong graft function.

A theoretical four-compartment model to evaluate separate kidney technetium-99m-MAG 3 kinetics in humans . Background Pharmacokinetic modeling based on compartmentalization has provided a valuable tool to assess the clearance patterns of various glomerular and tubular agents. However, no models have been proposed thus far that combine vascular data and imaging data in order to gain a deeper knowledge on renal pathophysiology, and to obtain more diagnostic information of clinical relevance. To this aim, we propose a four-pool model for the evaluation of separate renal function. Methods In a group of ten normal volunteers and twenty patients with various renal diseases, we tested the four-pool model based on the identification of the two kidneys as two distinct pools. This approach made it possible to integrate the separate kidney contributions deriving from in vivo imaging data, and allows the researcher to quantitate many parameters specific to each kidney. Results The parameters TER R , TER L , MRT R , MRT L , ν R , ν L , k 3R-1 , k 3L-1 permit the normal from abnormal states of renal function to be differentiated, as well as monolateral from bilateral renal disease to be separated within the abnormal function group. Conclusions The proposed approach combines the advantages of plasma clearance methods with those derived by gamma-camera imaging, and makes it possible to quantitate the differential renal function. This feature may be clinically relevant in renal transplant donors, where full knowledge of renal pathophysiology could guide the procedure.

Role of endothelin in the pathophysiology of renal ischemia-reperfusion in normal rabbits. The present study addressed the acute effects of endothelin-1 on renal function and neutrophils accumulation in the setting of in vivo severe (60 min) acute ischemia/reperfusion. Ischemia/reperfusion decreased renal functional parameters and increased renal neutrophil accumulation and medullary congestion. All these parameters markedly improved with the intrarenal administration of anti-endothelin-1 antiserum. Comparatively, the intrarenal infusion of endothelin-1 decreased renal function and increased neutrophil accumulation. Abnormalities in renal histology were, however, less pronounced than with ischemia/reperfusion. In experiments using rabbit isolated perfused kidneys, endothelin-1 induced the accumulation of labeled neutrophils. This accumulation was similar to that observed in kidneys obtained after 60 minutes of ischemia plus 60 minutes of reperfusion. Both endothelin and ischemia/reperfusion effects were counteracted by an anti-endothelin antibody. In further in vitro studies, we found that endothelin-1-induced the expression of the CD 18 antigens on the neutrophil surface. In subsequent experiments based on this effect of ET-1 on CD18 antigens, a blockade of both ischemia/reperfusion-induced and endothelin-1-induced neutrophil accumulation was obtained by infusion an anti-CD18 antibody. In conclusion, our experiments disclosed the critical role of endothelin-1 as a major promoter of early neutrophil accumulation after ischemia/reperfusion, which occurred through an integrin-mediated mechanism.

Determination of residual renal function with iohexol clearance in hemodialysis patients. Residual renal function (RRF) may contribute significantly to the total dialysis prescription. Conventional quantitation of RRF in hemodialysis (HD) patients is measured by urea clearance and requires a 24-hour urine collection which is often difficult to perform and inaccurate. The renal clearance of iohexol was evaluated as an alternative method for RRF assessment (iohexol-derived RRF) in hemodialysis patients. An intravenous bolus of iohexol (12 ml; 300mg iodine/ml) was administered to 42 hemodialysis patients following routine HD. A single blood sample was obtained approximately 44 hours later (pre-HD) to determine the plasma clearance of iohexol using x-ray fluorescence methods. Total body clearance of iohexol (CTBio) and non-renal clearance of iohexol (CNRio) 2.87 ± 0.3ml/min (mean ± sem) were used to calculate iohexol-derived RRF (CTBio – CNRio). Iohexol-derived RRF determinations were then compared to urea clearance-derived RRF measurements. The RRF contribution to the dialysis prescription was also calculated utilizing iohexol-derived RRF compared to urea-derived RRF. Iohexol-derived RRF did not differ from urea-derived RRF (2.48 ± 0.3 vs. 2.64 ± 0.4 ml/min, P = 0.21). The RRF contribution to the weekly dialysis prescription (Kt/V) did not differ when iohexol-derived RRF was compared to urea-derived RRF (0.94 ± 0.1 vs. 0.93 ± 0.1, P = 0.9). Additionally, the effect of iohexol on RRF was assessed in 17 HD patients. Urea-derived RRF determinations one week after iohexol exposure did not differ from those measured one week prior to iohexol exposure (3.17 ± 0.6 vs. 2.91 ± 0.5 ml/min, respectively). Thus, renal clearance of iohexol can be an accurate and safe measure of RRF in HD patients and potentially simplify delivery of the dialysis prescription.

Constant infusion clearance techniques using exogenous renal markers are considered the gold standard for assessing the glomerular filtration rate. Here we describe a constant infusion clearance method in rats allowing the real-time monitoring of steady-state conditions using an automated closed-loop approach based on the transcutaneous measurement of the renal marker FITC-sinistrin. In order to optimize parameters to reach steady-state conditions as fast as possible, a Matlab-based simulation tool was established. Based on this, a real-time feedback-regulated approach for constant infusion clearance monitoring was developed. This was validated by determining hourly FITC-sinistrin plasma concentrations and the glomerular filtration rate in healthy and unilaterally nephrectomized rats. The transcutaneously assessed FITC-sinistrin fluorescence signal was found to reflect the plasma concentration. Our method allows the precise determination of the onset of steady-state marker concentration. Moreover, the steady state can be monitored and controlled in real time for several hours. This procedure is simple to perform since no urine samples and only one blood sample are required. Thus, we developed a real-time feedback-based system for optimal regulation and monitoring of a constant infusion clearance technique.

Many guidelines suggest that angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists (collectively referred to as renin, angiotensin, aldosterone system blockers (RAAS blockers)) are the preferred treatment for hypertension in most patients with chronic kidney disease (CKD). Improving the recognition of CKD with the introduction of eGFR reporting was intended to have more patients recognized with and treated for this disease. To quantify this, we examined trends in RAAS-blocker use over an 88-month period before and after routine eGFR reporting in southwestern Ontario, Canada. An intervention analysis with seasonal time-series modeling on linked health administrative data for 45,361 ambulatory residents with CKD (eGFR stages 3–5) older than 65 years was performed with a primary outcome of RAAS-blocker usage. The reporting of eGFR was associated with a significant increase in the use of RAAS blockers, as the prescription rate was 571 per 1000 patients with CKD prior to reporting but improved to 607 per 1000 after reporting. There was a significant increase in RAAS-blocker use attributable to eGFR reporting of 19 per 1000 CKD patients. Since about 8% of the adult population has CKD, this equates to about 15,200 new patients receiving RAAS-blocker treatment by 1 year after the introduction of eGFR reporting in community laboratories. Thus, eGFR reporting contributes to improved, guideline-appropriate care of older patients with CKD.

Experimental nephrotoxicity, hepatotoxicity and pharmacokinetics of cyclosporin G versus cyclosporin A. Cyclosporin G (CsG) is an analogue of cyclosporin A (CsA) with strong immunosuppressive activity. We compared these two drugs in a rat model in which salt depletion promotes irreversible renal interstitial fibrosis with renal dysfunction in animals given CsA for three weeks. When both drugs were given in the same dosage on a weight basis (15 mg/kg/day, subcutaneously), CsA blood levels were higher than CsG (3305 vs. 1824 ng/ml, P < 0.001). This could be explained by a higher CsG clearance (6.4 vs. 4.3 ml/min/kg in CsA, P < 0.0001) resulting in smaller CsG area under the curve. There was also lower renal and hepatic CsG tissue concentrations. CsA induced a dramatic decrease in GFR, 0.14 in CsA versus 0.67 ml/min/100g in control, P < 0.001, and increased urinary excretion of N-acetyl β-D-glucosaminidase (NAG), 21 in CsA versus 13 IU/gCr in control rats, P < 0.001. CsG-treated and control rats had similar GFR and urinary NAG. When CsA dosage was decreased to 7.5 mg/kg blood levels were similar to those found with CsG 15 mg/kg. CsA at this dose caused a reduced GFR (0.29 ml/min/100 g) and an increased urinary NAG (20 IU/gCr) (P < 0.01 vs. control for both). Both dosages of CsA induced considerable cortical and medullary injury (interstitial fibrosis and tubular atrophy), more severe than the histological damage found in CsG-treated rats. Neither drug promoted significant changes in liver function or histology. These results demonstrate that CsG caused less renal interstitial fibrosis and functional changes than CsA when the drugs were given at the same dosage or when similar blood levels of each drug were achieved.