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In this multicenter, prospective study of 288 children (half under 2 years of age) undergoing cardiac surgery, we evaluated whether the measurement of pre- and postoperative serum cystatin C (CysC) improves the prediction of acute kidney injury (AKI) over that obtained by serum creatinine (SCr). Higher preoperative SCr-based estimated glomerular filtration rates predicted higher risk of the postoperative primary outcomes of stage 1 and 2 AKI (adjusted odds ratios (ORs) 1.5 and 1.9, respectively). Preoperative CysC was not associated with AKI. The highest quintile of postoperative (within 6 h) CysC predicted stage 1 and 2 AKI (adjusted ORs of 6 and 17.2, respectively). The highest tertile of percent change in CysC independently predicted AKI, whereas the highest tertile of SCr predicted stage 1 but not stage 2 AKI. Postoperative CysC levels independently predicted longer duration of ventilation and intensive care unit length of stay, whereas the postoperative SCr change only predicted longer intensive care unit stay. Thus, postoperative serum CysC is useful to risk-stratify patients for AKI treatment trials. More research, however, is needed to understand the relation between preoperative renal function and the risk of AKI. [ABSTRACT FROM AUTHOR]

Tolvaptan and related V2-specific vasopressin receptor antagonists have been shown to delay disease progression in animal models of polycystic kidney disease. Slight elevations in serum creatinine, rapidly reversible after drug cessation, have been found in clinical trials involving tolvaptan. Here, we sought to clarify the potential renal mechanisms to see whether the antagonist effects were dependent on underlying renal function in 20 patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) before and after 1 week of daily split-dose treatment. Tolvaptan induced aquaresis (excretion of solute-free water) and a significant reduction in glomerular filtration rate (GFR). The serum uric acid increased because of a decreased uric acid clearance, and the serum potassium fell, but there was no significant change in renal blood flow as measured by para-aminohippurate clearance or magnetic resonance imaging (MRI). No correlation was found between baseline GFR, measured by iothalmate clearance, and percent change in GFR induced by tolvaptan. Blinded post hoc analysis of renal MRIs showed that tolvaptan significantly reduced total kidney volume by 3.1% and individual cyst volume by 1.6%. Preliminary analysis of this small cohort suggested that these effects were more noticeable in patients with preserved renal function and with larger cysts. No correlation was found between changes of total kidney volume and body weight or estimated body water. Thus, functional and structural effects of tolvaptan on patients with ADPKD are likely due to inhibition of V2-driven adenosine cyclic 3′,5′-monophosphate generation and its aquaretic, hemodynamic, and anti-secretory actions. [ABSTRACT FROM AUTHOR]

Studies of acute kidney injury usually lack data on pre-admission kidney function and often substitute an inpatient or imputed serum creatinine as an estimate for baseline renal function. In this study, we compared the potential error introduced by using surrogates such as (1) an estimated glomerular filtration rate of 75 ml/min per 1.73 m2 (suggested by the Acute Dialysis Quality Initiative), (2) a minimum inpatient serum creatinine value, and (3) the first admission serum creatinine value, with values computed using pre-admission renal function. The study covered a 12-month period and included a cohort of 4863 adults admitted to the Vanderbilt University Hospital. Use of both imputed and minimum baseline serum creatinine values significantly inflated the incidence of acute kidney injury by about half, producing low specificities of 77–80%. In contrast, use of the admission serum creatinine value as baseline significantly underestimated the incidence by about a third, yielding a low sensitivity of 39%. Application of any surrogate marker led to frequent misclassification of patient deaths after acute kidney injury and differences in both in-hospital and 60-day mortality rates. Our study found that commonly used surrogates for baseline serum creatinine result in bi-directional misclassification of the incidence and prognosis of acute kidney injury in a hospital setting. [ABSTRACT FROM AUTHOR]

Anti-glomerular basement membrane (GBM) autoantibodies are pathogenic in the development of anti-GBM disease. The main target antigen is the non-collagenous 1 domain (NC1) of collagen α3(IV); however, most antibodies can recognize the NC1 of collagens α1, α2, α4 and α5(IV). In this study, we analyzed the target antigens of anti-GBM autoantibodies to determine their relationship to the severity of renal damage. Natural anti-GBM autoantibodies were purified from 10 healthy individuals and from 57 patients with anti-GBM disease who were divided into groups based on the degree of renal damage defined by their serum creatinine at the time of diagnosis. We found that the sera of all 57 patients recognized α3(IV)NC1, while 23, 20, 28, and 48 patients also recognized the NC1 of collagens α1, α2, α4, and α5(IV), respectively. Natural anti-GBM autoantibodies recognized the NC1 of collagens α3 and α4(IV). The sera of 7 patients with the lowest level of renal damage mainly recognized the NC1 of collagens α3 and α5(IV). In the 20 patients with moderate and the 30 with severe renal damage, all five target antigens could be detected and most sera recognized three to five different α chains simultaneously. Regression analysis showed that only the level of autoantibodies against the NC1 of collagen α3(IV) was a significant independent risk factor for higher serum creatinine on diagnosis. Our study shows that autoantibodies to the NC1 of collagen α3(IV) were crucial in causing renal damage. Inter- and intra-molecular epitope spreading can occur during the development of human anti-GBM disease. [ABSTRACT FROM AUTHOR]

To predict development of acute kidney injury and its outcome we retrospectively studied children having cardiac surgery. Acute kidney injury (AKI) was defined using the serum creatinine criteria of the pediatric Risk Injury Failure Loss End-Stage (pRIFLE) kidney disease definition. We tested whether a small rise (less than 50%) in creatinine on post-operative days 1 or 2 could predict a greater than 50% increase in serum creatinine within 48 h in 390 children. AKI occurred in 36% of patients, mostly in the first 4 post-operative days. Using logistic regression, significant independent risk factors for AKI were bypass time, longer vasopressor use, and a tendency for younger age. Using Cox regression, AKI was independently associated with longer intensive care unit stay and duration of ventilation. Patients whose serum creatinine did not increase on post-operative days 1 or 2 were unlikely to develop AKI (negative predictive values of 87 and 98%, respectively). Percentage serum creatinine rise on post-operative day 1 predicted AKI within 48 h (area under the curve=0.65). Our study shows that AKI after pediatric heart surgery is common and is a risk factor for poorer outcome. Small post-operative increases in serum creatinine may assist in the early prediction of AKI. [ABSTRACT FROM AUTHOR]

A single-center prospective cohort study was designed to identify alterations of renal function during childhood in children born prematurely. A cohort of 143 such babies born over a 4-year period (birth weight less than 1000 g and/or less than 30 weeks of gestation) was prospectively included at birth. A mailing was sent to all parents to propose renal evaluation. Among the 50 included children, 23 had intra-uterine and 16 had extrauterine growth retardation. When comparing both of these groups to 11 children with appropriate pre- and postnatal growth at a mean follow-up of 7.6 years, both groups of growth-restricted children had slightly but significantly lower glomerular filtration rates, measured by inulin clearance, although both groups were still within the normal range for their ages. There were no differences for other renal parameters, neonatal therapies or complications, except for postnatal corticosteroid exposure. Children with extrauterine growth restriction were found to have significantly lower protein-energy intake during their first week of life than the intrauterine growth–restricted or the normotrophic children. Our study found that children with either intra- or extrauterine growth retardation are at risk of decreased glomerular filtration rates during childhood. Extrauterine growth restriction represents a new risk factor for long-term renal impairment in premature children.Kidney International (2009) 76, 445–452; doi:10.1038/ki.2009.201; published online 10 June 2009 [ABSTRACT FROM AUTHOR]

There is increasing evidence for a role of genetic predisposition in the etiology of kidney disease, but linkage scans have been poorly replicated. Here we performed a genome-wide linkage analysis of serum creatinine on 2859 individuals from isolated villages in South Tyrol (Italy), Rucphen (The Netherlands) and Vis Island (Croatia), populations that have been stable and permanently resident in their region. Linkage of serum creatinine levels to loci on chromosomes 7p14, 9p21, 11p15, 15q15-21, 16p13, and 18p11 was successfully replicated in at least one discovery population or in the pooled analysis. A novel locus was found on chromosome 10p11. Linkage to chromosome 22q13, independent of diabetes and hypertension, was detected over a region containing the non-muscle myosin heavy chain type II isoform A (MYH9) gene (LOD score=3.52). In non-diabetic individuals, serum creatinine was associated with this gene in two of the three populations and in meta-analysis (SNP rs11089788, P-value=0.0089). In populations sharing a homogeneous environment and genetic background, heritability of serum creatinine was higher than in outbred populations, with consequent detection of a larger number of loci than reported before. Our finding of a replicated association of serum creatinine with the MYH9 gene, recently linked to pathological renal conditions in African Americans, suggests that this gene may also influence kidney function in healthy Europeans.Kidney International (2009) 76, 297–306; doi:10.1038/ki.2009.135; published online 22 April 2009 [ABSTRACT FROM AUTHOR]

Paraoxonase-1 (PON1) is an HDL cholesterol–associated antioxidant enzyme, and some of its polymorphisms are linked with systemic oxidative stress and cardiovascular events. In this study, we genotyped seven single nucleotide polymorphisms (SNPs) within the PON1 gene and determined their association with chronic kidney disease in 2,968 individuals from the general Japanese population. We found that a missense SNP (rs662) with a G-to-A substitution leading to an amino acid substitution (G[Arg]/A[Gln]), was significantly associated with albuminuria and estimated glomerular filtration rate (eGFR), especially in women. The A/A genotype in women had the highest prevalence of albuminuria and the lowest values of adjusted eGFR. In contrast, such relationships were not detected in men. Multivariate regression analysis found that the A/A genotype was an independent and significant factor for albuminuria and renal insufficiency (eGFR less than 60 ml/min/1.73 m2). The serum PON1 activity was lowest in subjects with the A/A genotype. In biopsy specimens, immunohistochemical analysis found increased PON1 expression on the endothelial surface of sclerotic renal arterioles and glomerular capillaries in patients with hypertension or diabetes. Our study shows that this PON1 G-to-A substitution may be a key player in a common pathway to chronic kidney and cardiovascular diseases in women.Kidney International (2009) 76, 183–189; doi:10.1038/ki.2009.97; published online 8 April 2009 [ABSTRACT FROM AUTHOR]

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.Kidney International (2008) 74, 505–512; doi:10.1038/ki.2008.200; published online 21 May 2008 [ABSTRACT FROM AUTHOR]

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.Kidney International (2008) 73, 278–287; doi:10.1038/sj.ki.5002706; published online 28 November 2007 [ABSTRACT FROM AUTHOR]

There is an increased incidence of heart disease in patients with chronic nephrotic syndrome (NS), which may be attributable to the malnutrition and activated inflammatory state accompanying the sustained proteinuria. In this study, we evaluated renal function, cardiac morphometry, contractile function, and myocardial gene expression in the established puromycin aminonucleoside nephrosis rat model of NS. Two weeks after aminonucleoside injection, there was massive proteinuria, decreased creatinine clearance, and a negative sodium balance. Skeletal and cardiac muscle atrophy was present and was accompanied by impaired left ventricular (LV) hemodynamic function along with decreased contractile properties of isolated LV muscle strips. The expression of selected cytokines and proteins involved in calcium handling in myocardial tissue was evaluated by real time polymerase chain reaction. This revealed that the expression of interleukin-1β, tumor necrosis factor-α, and phospholamban were elevated, whereas that of cardiac sarco(endo)plasmic reticulum calcium pump protein was decreased. We suggest that protein wasting and systemic inflammatory activation during NS contribute to cardiac remodeling and dysfunction.Kidney International (2007) 71, 1240–1248; doi:10.1038/sj.ki.5002204; published online 25 April 2007 [ABSTRACT FROM AUTHOR]

Chronic kidney disease coexists with metabolic syndrome and this relationship may be apparent before overt manifestations of cardiovascular disease. To investigate early stages of the natural history of associations between renal function and metabolic syndrome, we phenotyped 1572 young (mean age=18.4 years), apparently healthy men for metabolic risk factors and estimated their creatinine clearance based on the Cockcroft–Gault equation. High metabolic risk (clustering of at least three metabolic risk factors) was revealed in 8.7% (137) of the subjects and was associated with a 6.9-fold increase in the odds of glomerular hyperfiltration (95% confidence interval (CI): 3.9–11.5) when compared to reference (from none to two metabolic risk factors). Overweight, elevated blood pressure, and low high-density lipoprotein (HDL) cholesterol increased the multivariate-adjusted odds ratio of glomerular hyperfiltration to 6.6 (95% CI: 3.8–11.6), 1.8 (95% CI: 1.0–3.0), and 2.5 (95% CI: 1.5–4.3), respectively. Systolic and diastolic blood pressures clustered together with leptin in the factor analysis and this blood pressure–adiposity component correlated with estimated creatinine clearance (r=0.329, P<0.0001) and explained on its own 10.2% of the variance in the estimated renal function. Our data reveal the silent epidemics of metabolic risk among young, apparently healthy men. Furthermore, the results indicate that high metabolic risk is associated with glomerular hyperfiltration before overt manifestations of cardiovascular disease.Kidney International (2007) 71, 816–821. doi:10.1038/sj.ki.5002160; published online 28 February 2007 [ABSTRACT FROM AUTHOR]

Missing data are a common problem in epidemiologic studies. This study had two aims: (a) to determine which method for imputing missing renal function data provides estimates closest to those made with complete data and (b) to determine which measure of renal function better estimates cardiovascular disease (CVD) risk. For these analyses, a subset of Strong Heart Study participants with complete data for renal function was identified. Data were randomly dropped from this complete set at three rates: 30, 45, and 60%. Five common techniques for handling missing data were compared: imputation using the mean, adjacent value (AV), single imputation, multiple imputation, and listwise deletion. Differences between the imputed sets and the complete set were determined for each method. Imputation methods were used to fill in missing values for serum creatinine (Scr) in one model and estimated glomerular filtration rate (eGFR) in another. For both Scr and eGFR, the AV method provided the most favorable results in predicting CVD risk, regardless of the rate of missing data.Kidney International (2007) 71, 701–705. doi:10.1038/sj.ki.5002105; published online 31 January 2007 [ABSTRACT FROM AUTHOR]

The sympathetic nervous system modulates renal function through its receptors namely β1 (cardiac output and renin release), α1 (systemic and renovascular constriction), and β2 renovascular dilation. Sympathetic overactivity is commonly seen in chronic kidney disease (CKD) and is an important contributor to increasing the risk of cardiovascular events as well as increasing renal disease progression. Recent evaluations of drug use in people with CKD shows a remarkably low percentage of patients receiving β-blockers, especially in more advanced stage CKD when cardiovascular risk is higher. This is in large part due to tolerability of these agents. Moreover, water-soluble β-blockers such as atenolol and metoprolol are dialyzable and require supplementation to avoid exacerbation of arrhythmias following dialysis. Newer vasodilating β-blockers have better tolerability and different effects on renal hemodynamics as well as metabolic variables. These effects are related to the relative α1-blocking effect of agents such as carvedilol and labetolol, with carvedilol having relatively greater α-blocking effects. Few studies evaluate β-blockers on cardiovascular risk in CKD patients. Studies with carvedilol demonstrate attenuated increases in albuminuria as well as reduction in cardiovascular events in CKD patients with hypertension. This paper reviews the animal and clinical trial data that evaluate β-blockers in CKD highlighting the vasodilating β-blockers. It is apparent that greater use of this drug class for blood pressure control would further enhance reduction of risk of heart failure, the most common cause of death in the first year of starting dialysis.Kidney International (2006) 70, 1905–1913. doi:10.1038/sj.ki.5001835; published online 4 October 2006 [ABSTRACT FROM AUTHOR]

The cardiorenal safety database from the Celecoxib Long-term Arthritis Safety Study (CLASS) was analyzed to examine whether supratherapeutic doses of celecoxib are associated with decreased renal function and blood pressure (BP) effects compared with standard doses of diclofenac and ibuprofen in osteoarthritis (OA) and rheumatoid arthritis (RA) patients.In total, 8059 patients were enrolled; 7968 received at least one dose of study drug (RA: N=2183; OA: N=5785). Patients received celecoxib, 400 mg twice a day (b.i.d.). (N=3987); ibuprofen, 800 mg three times a day. (N=1985); or diclofenac, 75 mg b.i.d. (N=1996). Effects measured included: investigator-reported hypertension, edema or congestive heart failure, clinically important BP elevations, incidence of patients starting new antihypertensive medication, and increases in serum creatinine or reductions in creatinine clearance. Celecoxib was associated with a similar incidence of hypertension or edema to diclofenac but significantly lower than ibuprofen. The celecoxib group had significantly fewer initiations of antihypertensives versus ibuprofen. Systolic BP increases of >20 mmHg and above 140 mmHg occurred significantly less often with celecoxib compared with ibuprofen or diclofenac. Changes in serum creatinine or estimated creatinine clearance occurred in a similar percentage of patients taking celecoxib or ibuprofen; modest differences were evident against diclofenac. In patients with mild prerenal azotemia, significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.7%), compared with diclofenac (7.3%; P<0.05) and ibuprofen (7.3%; P<0.05). A supratherapeutic dose of celecoxib was associated with an improved cardiorenal safety profile compared with standard doses of either ibuprofen or diclofenac.Kidney International (2006) 70, 1495–1502. doi:10.1038/sj.ki.5001766; published online 30 August 2006 [ABSTRACT FROM AUTHOR]

Progressive renal failure is one of the main complications in HbS/β-thalassemia (HbS/β-thal). Early identification of patients at high risk of developing renal failure is of great importance as it may allow specific measures to delay the progression of renal damage and thus reduce the incidence of end-stage renal failure and mortality. Early predictors of renal impairment in HbS/β-thal remain to explore. Within this context, we studied 87 compound HbS/β-thal patients (36 males/51 females; median age 39 years) and 30 healthy controls. In addition to conventional renal biochemistries we measured serum cystatin-C (Cys-C), urine N-acetyl-β-D-glucosaminidase (NAG) excretion and serum and urinary β2-microglobulin (β2-M). Cystatin-C, NAG and serum β2-M levels were higher in patients than controls. The incidence of patients with high levels of Cys-C, NAG, and β2-M was 32.1, 74.7, and 70.1% respectively, while only 6.8% of patients had increased serum creatinine levels. Cystatin-C and serum β2-M showed a strong correlation with creatinine clearance and age, while NAG positively correlated with proteinuria. An inverse correlation was also shown between hemoglobin and β2-M, NAG, and Cys-C levels. Seven patients with proteinuria received therapy with angiotensin-converting enzyme (ACE) inhibitors. Changes of poteinuria positively correlated with NAG levels. These results indicate that Cys-C is an accurate marker of renal dysfunction, and urinary NAG excretion can be considered as a reliable index of the tubular toxicity, and possible predictor of proteinuria and eventual renal impairment in HbS/β-thal patients. Furthermore, NAG measurement may be used for monitoring ACE-inhibitors therapy in HbS/β-thal patients with proteinuria.Kidney International (2006) 69, 2037–2042. doi:10.1038/sj.ki.5000248; published online 22 February 2006 [ABSTRACT FROM AUTHOR]

To guide the design of a nation-wide cohort study of chronic kidney disease in children, we determined how iohexol plasma disappearance curves could be used in children to measure glomerular filtration rate (GFR). Iohexol (5 ml) was administered intravenously and blood samples were obtained at 10, 20, 30, 60, 120, 240, 300, and 360 min after injection (N=29) and assayed by high performance liquid chromatography. Four urines were also collected following the injection. Intra-assay coefficient of variation (CV) in serum was 1.3% at 100 mg/l, 2.6% at 15 mg/l, and 3.4% for duplicate unknowns. GFR(9) was computed from iohexol dose and area under the nine-point blood disappearance curve, using double exponential modeling. Only 2.8% of 254 data points deviated by >3 CV from the curves. GFR(4) calculated from 10, 30, 120, and 300 min points correlated well with GFR(9) (r=0.999) and showed no bias (means±s.d. of GFR(9) and GFR(4)=59.3±36.3 and 59.4±36.0 ml/min per 1.73 m2). Relationship of GFR(9) and one-compartment GFR followed quadratic equation as previously reported by Brochner-Mortensen, allowing GFR to be calculated from 120 and 300 min points. This GFR(2) correlated well with GFR(9) (r=0.986). Estimated GFR from Schwartz height/creatinine formula correlated with GFR(9)(r=0.934) but overestimated GFR by 12.2 ml/min per 1.73 m2. Urine iohexol clearance was poorly correlated (r=0.770) with GFR(9) owing to variability in urine collections (median CV=24%). GFR can be measured accurately using four-point iohexol plasma disappearance (in most cases, two points suffice); estimated GFR and urinary clearances are less useful.Kidney International (2006) 69, 2070–2077. doi:10.1038/sj.ki.5000385; published online 12 April 2006 [ABSTRACT FROM AUTHOR]

Enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (r-hαGalA) enhances microvascular globotriaosylceramide clearance and improves clinical symptoms in patients with Fabry disease. We evaluated whether these effects are translated into a long-term benefit of kidney and heart function. We did a single center, prospective, open label study in 26 patients with Fabry disease (one early death, follow-up in 25 patients). r-α-GalA was administered in a dosage of 1 mg/kg body weight every second week. The effect of therapy on clinical end points (death, cardiac and cerebrovascular event, renal failure), cardiac and renal function monitored by Doppler echocardiography, 99Tc-GFR, and proteinuria was investigated. After a mean treatment time of 23±8 months, nine patients experienced 12 end points, including two deaths. All end points occurred in patients with impaired renal function (n=16; GFR 71±17 ml/min/1.73 m2). Despite ERT, renal function deteriorated to 60±23 ml/min/1.73 m2 (P=0.04) and left ventricular posterior wall thickness (PWT) did not change (14.0±2.1 vs 13.4±2.3 mm). In contrast, patients without impairment of renal function (n=9) had a more favorable outcome (no clinical events; GFR 115±18 vs 102±14 ml/min/1.73 m2, NS; PWT 11.7±1 and 10.7±0.7 mm, P=0.04). Proteinuria remained unchanged (1.34±0.94 vs 1.01±0.97 g/day, n=10). Patients with impaired renal function have a less favorable outcome and may develop cardiovascular and renal end points despite ERT.Kidney International (2006) 69, 1216–1221. doi:10.1038/sj.ki.5000208; published online 22 February 2006 [ABSTRACT FROM AUTHOR]

Brain natriuretic peptide (BNP) and endothelin-1 (ET-1) both exhibit natriuretic activity within the human kidney. Furthermore, they both act partly through activation of the endothelial nitric oxide pathway. Since ET-1 may cause vasodilation and natriuresis via stimulation of the ET-B receptor, the aim of the present study was to investigate whether renal ET-B receptors participate in the renal actions of BNP. In this placebo-controlled, crossover study, we infused BNP (4 pmol/kg/min) or placebo (i.v.) for 1 h, with or without co-infusion of the ET-B receptor antagonist BQ-788 (50 nmol/min) for 15 min on 4 separate days, in 10 healthy subjects (mean age 54±6 years.). During infusion, we measured effective renal plasma flow (ERPF), and glomerular filtration rate (GFR) using PAH/inulin clearance. Cardiac output was measured before and after infusion, using echocardiography. Blood pressure and heart rate (HR) were monitored as well. Urine and plasma samples were taken every hour to measure diuresis, natriuresis, cyclic 3′,5′ guanosine monophosphate, and ET-1 levels. BNP with or without ET-B receptor blockade increased natriuresis and diuresis. In addition, BNP alone increased GFR and filtered load, without changing ERPF. BQ-788 infusion did not affect renal hemodynamics or natriuresis. Neither BNP nor BQ-788 altered cardiac output, blood pressure, and heart rate. In conclusion, the present study shows that selective ET-B receptor blockade has no effect on the BNP-induced natriuresis and glomerular filtration rate.Kidney International (2006) 69, 864–868. doi:10.1038/sj.ki.5000215; published online 25 January 2006 [ABSTRACT FROM AUTHOR]

Appropriate selection of patients with atherosclerotic renovascular disease (ARVD) for revascularization might be improved if accurate non-invasive investigations were used to assess severity of pre-existing parenchymal damage. The purpose of this study was to evaluate the associations between magnetic resonance imaging (MRI)-measured renal morphological parameters and single-kidney glomerular filtration rate (GFR) in ARVD. Three-dimensional (3D)-MRI was performed on 35 ARVD patients. Renal bipolar length (BL), parenchymal volume, parenchymal (PT), and cortical thicknesses (CT) were measured in 65 kidneys. Thirteen kidneys were supplied by normal vessels, 13 had insignificant (<50%) renal artery stenosis (RAS), 33 significant (50%) RAS, and six complete vessel occlusion. All patients underwent radioisotopic measurement of single-kidney GFR (isoSK-GFR). Overall, 3D parameters such as parenchymal volume were better correlates of isoSK-GFR (r=0.86, P<0.001) than BL (r=0.78, P<0.001), PT (r=0.63, P<0.001) or CT (r=0.60, P<0.001). Kidneys with 50% RAS did show significant reduction in mean CT compared to those supplied by normal vessel (5.67±1.63 vs 7.28±1.80 mm, P=0.002; 22.1% reduction) and an even greater loss of parenchymal volume (120.65±47.15 vs 179.24±86.90 ml, P<0.001; 32.7% reduction) with no significant reduction in BL. In a proportion of 50% RAS kidneys, a disproportionately high parenchymal volume to isoSK-GFR was observed supporting a concept of ‘hibernating parenchyma’. 3D parameters of parenchymal volume are stronger correlates of isoSK-GFR than two-dimensional measures of BL, PT or CT. 3D morphological evaluation together with isoSK-GFR might be useful in aiding patient selection for renal revascularization. Kidneys with increased parenchymal volume to SK-GFR might represent a subgroup with the potential to respond beneficially to angioplasty.Kidney International (2006) 69, 715–722. doi:10.1038/sj.ki.5000118; published online 4 January 2006 [ABSTRACT FROM AUTHOR]

Background: Angiotensin-converting enzyme (ACE)2, a homologue of ACE, which is insensitive to ACE inhibitors and forms angiotensin-(1-7) [Ang-(1-7)] from angiotensin II (Ang II) with high efficiency was investigated in response to chronic blockade with lisinopril, losartan, and both drugs combined.Methods: Thirty-six adult Lewis rats were assigned to receive these medications in their drinking water for 2 weeks while their arterial pressure, water intake, and urine volume were recorded throughout the study. Measures of renal excretory variables included assessing excretion rates of angiotensin I (Ang I), Ang II and Ang-(1-7) while blood collected at the completion of the study was used for measures of plasma angiotensin concentrations. Samples from renal cortex were assayed for renin, angiotensinogen (Aogen), neprilysin, angiotensin types 1 and 2 (AT(1) and AT(2)) and mas receptor mRNAs by semiquantitative reverse transcriptase (RT) real-time polymerase chain reaction (PCR). ACE2 activity was determined as the rate of Ang II conversion into Ang-(1-7).Results: Comparable blood pressure reductions were obtained in rats medicated with either lisinopril or losartan, whereas both drugs produced a greater decrease in arterial pressure. Polyuria was recorded in all three forms of treatment associated with reduced osmolality but no changes in creatinine excretion. Lisinopril augmented plasma levels and urinary excretion rates of Ang I and Ang-(1-7), while plasma Ang II was reduced with no effect on urinary Ang II. Losartan produced similar changes in plasma and urinary Ang-(1-7) but increased plasma Ang II without changing urinary Ang II excretion. Combination therapy mimicked the effects obtained with lisinopril on plasma and urinary Ang I and Ang-(1-7) levels. Renal cortex Aogen mRNA increased in rats medicated with either lisinopril or the combination, whereas all three treatments produced a robust increase in renal renin mRNA. In contrast, ACE, ACE2, neprilysin, AT(1), and mas receptor mRNAs remained unchanged with all three treatments. Renal cortex ACE2 activity was significantly augmented in rats medicated with lisinopril or losartan but not changed in those given the combination.Conclusion: Our data revealed a role for ACE2 in Ang-(1-7) formation from Ang II in the kidney of normotensive rats as primarily reflected by the increased ACE2 activity measured in renal membranes from the kidney of rats given either lisinopril or losartan. The data further indicate that increased levels of Ang-(1-7) in the urine of animals after ACE inhibition or AT(1) receptor blockade reflect an intrarenal formation of the heptapeptide. [ABSTRACT FROM AUTHOR]

Both reduced filtration power and increased excretion of albumin in the urine are powerful markers for renal and cardiovascular progressive function loss. These risk markers indicate the risk above and beyond the conventional existing risk markers/factors. The risk is substantial, because both reduced filtration and microalbuminuria are highly prevalent in the general population, matching in prevalence with the most well-known risk factor, hypertension. Therapeutic interventions to preserve renal and cardiovascular function, such as with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, are highly effective, particularly in those patients that have reduced filtration power. In addition, short-term reduction of albuminuria that follows the renin-angiotensin-aldosterone-system intervention appears to be predictive of long-term cardiovascular and renal protection. In conclusion, estimated glomerular filtration rate as well as albumin excretion in the urine are powerful predictors for cardiovascular and renal outcome and should be used as such. Intervention and prevention could be aimed at not only at reducing conventional risk markers, but also at reducing albuminuria. [ABSTRACT FROM AUTHOR]

Dietary arginine supplementation attenuates renal damage after relief of unilateral ureteral obstruction in rats. Background. Progression of renal injury after relief of unilateral ureteral obstruction (UUO) has been demonstrated. Nitric oxide (NO) may be an effective intervention due to its vasodilatory, antifibrotic, and anti-apoptotic effects. Herein, we used dietary L-arginine (ARG) supplementation in a UUO relief model. Methods. This study comprised group 1, control (no treatment). All other rats were subject to 3-day UUO, which was then relieved, and the rats maintained for 7 additional days. Group 2, no additional treatment; group 3, L-ARG; group 4, L-NAME, NO synthase inhibitor; group 5, ARG and L-NAME. Urinary NO2/3 was quantified. GFR and ERPF were measured at day 10. Interstitial fibrosis and fibroblast expression, macrophage infiltration, tubular apoptosis, and proliferation, NOS expression, and the levels of tissue TGF-β were evaluated. Results. Urinary NO2/3 was significantly increased by ARG treatment and decreased by L-NAME. GFR and ERPF measured 7 days following relief were not significantly different in the previously obstructed kidneys (POK) of groups 2 and 3. L-NAME significantly reduced GFR and ERPF in the POK. ARG significantly reduced apoptosis, macrophage infiltration, and fibroblast expression in the POK. L-NAME exacerbated the effects on apoptosis and fibroblasts. Fibrosis was minimal in groups 1 through 3, but was significantly increased by L-NAME. ARG did not affect renal NOS expression and tissue TGF-β1 levels. Conclusion. Dietary ARG supplementation during UUO relief did not improve ERPF or GFR. However, renal damage, including fibrosis, apoptosis, and macrophage infiltration was significantly improved by ARG treatment. This suggests that increasing NO availability could be beneficial in the setting of UUO relief. [ABSTRACT FROM AUTHOR]

Mild renal insufficiency is associated with increased left ventricular mass in men, but not in women: An arterial stiffness–related phenomenon—The Hoorn Study. Background. Mild renal insufficiency has recently been recognized as an important risk factor for cardiovascular disease (CVD). The mechanisms underlying this association are incompletely understood. Increased left ventricular mass (LVM) is an independent risk factor for CVD, which is particularly common in end-stage renal disease (ESRD) and which has been shown to be associated with mild renal insufficiency. Increased arterial stiffness has also been shown to be an independent risk factor for CVD in ESRD and has also been associated with mild renal insufficiency. We hypothesized that the association between mild renal insufficiency and increased LVM could be mediated through increased arterial stiffness, and that this may be one of the pathways linking mild renal insufficiency to CVD. We therefore investigated, in a cross-sectional population-based study, the influence of increased arterial stiffness on the association between renal function and LVM. Methods. The study population consisted of 742 elderly individuals (373 men and 369 women). Renal function was estimated by the serum creatinine level in μmol/L; by the Cockcroft-Gault formula in mL/min and by the Modification of Diet in Renal Disease (MDRD) formula. LVM was obtained by echocardiography. Results. The mean estimates of renal function in men and women were, respectively, 103.7 (SD 17.0) and 86.8 (SD 11.2) μmol/L for the serum creatinine level; 63.4 (SD 12.9) and 61.4 (SD 11.0) mL/min/1.73 m2 for the Cockcroft-Gault formula; and 59.7 (SD 10.8) and 60.9 (SD 10.5) mL/min per 1.73 m2 for the MDRD formula. LVM was 93.1 (SD 26.4) g/m2 in men and 86.7 (SD 22.3) g/m2 in women. In men, impaired renal function, as estimated by the Cockcroft-Gault and the MDRD formula, was significantly associated with greater LVM after adjustment for age, glucose tolerance, hypertension, and prior CVD [regression coefficient β (95% CI), 1.28 (0.22 to 2.33) g/m2 and 1.63 (0.41 to 2.86) g/m2 per 5 mL/min/1.73 m2 decrease, respectively]. However, the association between impaired renal function and increased LVM was not statistically significant after adjustment for arterial stiffness estimates [regression coefficient β (95% CI), 0.02 (−1.60 to 1.64) g/m2 and 0.54 (−1.25 to 2.33) g/m2 per 5 mL/min/1.73 m2 decrease, respectively]. In women, impaired renal function was not significantly associated with greater LVM. Conclusion. Our study shows that in a general elderly population, even mild impairment of renal function is associated with adverse changes in left ventricular structure. In men, but not in women, this leads to greater LVM, a process that may be related to increases in arterial stiffness. Importantly, these novel findings suggest that such changes occur early in the process of renal functional deterioration, which may explain, in part, the increase in cardiovascular risk in men with mildly impaired renal function. [ABSTRACT FROM AUTHOR]

Circulating vitamin E, transforming growth factorβ1, and the association with renal disease susceptibility in two racial groups with type 2 diabetes. Background. End-stage renal disease caused by diabetes disproportionately affects patients of African origin. The biological mechanism(s) for this observation is unclear. Emerging data from cross-sectional studies suggest that increased oxidative stress and the cytokine, transforming growth factorβ1, are associated with this phenomenon. Therefore, a pathway involving these factors could alter the vulnerability to renal disease and impact adversely on the rate of loss of renal function. Methods. We assessed the relationship between renal function, oxidative stress, and transforming growth factorβ1 in 58 patients with type 2 diabetes of African and Caucasian origin over 174 patient-years of follow-up. Oxidative stress was assessed by measuring plasma lipid hydroperoxide and vitamin E in the postprandial state. Creatinine clearance was calculated from the Cockcroft-Gault equation. Patients received standardized management of hypertension, hyperglycemia, and hypercholesterolemia. Data were adjusted by multiple regression analysis to account for potential confounders. Results. Lipid hydroperoxide was higher and vitamin E lower, while there was no difference in fasting transforming growth factorβ1 between the African ( N= 22) and Caucasian ( N= 36) patients[5.1(1.2) vs. 4.3 (1.8)μmol/L; P= 0.02 and 29.8 (10.8) vs. 41.3(19.7)μmol/L; P= 0.02 and 6.33 (5.5) vs. 6.84 (3.9) ng/mL; P= 0.73], respectively. The mean (95% confidence interval) of the difference in creatinine clearance between the patients of African and Caucasian origin was−12.5 (−23.4 to−1.7) mL/min; P= 0.015 at baseline, the magnitude of which increased to−17.5 (−28.4 to−6.5) mL/min; P= 0.002 after 3 years. The fall in creatinine clearance from baseline among the patients of African origin was greater for lower levels of vitamin E (rho= 0.48; P= 0.03). Final plasma creatinine was significantly higher in the African patients compared with the Caucasian patients[109.0 (25.8) vs. 94.0 (20.0)μmol/L; P= 0.0017]. In regression analysis, vitamin E was a significant and independent predictor of plasma creatinine (t–3.17, P= 0.003). Conclusion. In these patients with type 2 diabetes, vitamin E is a determinant of renal function, and may explain some of the racial differences in renal disease susceptibility that precedes the divergence in incidence of end-stage renal disease. [ABSTRACT FROM AUTHOR]

The association between atherosclerotic risk factors and renal function in the general population. Background. Generalized atherosclerosis is increasingly recognized as an important cause of end-stage renal disease (ESRD). We questioned to what extent atherosclerotic risk factors determine renal function in the general population. Methods. We used baseline data of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study. A total of 8592 subjects, aged 28 to 75 years old, visited the outpatient clinic for blood pressure and anthropometric measurements, fasting blood sampling, and delivery of two 24-hour urine collections for creatinine clearance and albuminuria calculations. Design-based multivariate linear regression was used to estimate renal function. Results. In a multivariate model, male gender and body mass index (BMI) were associated with a higher renal function, while increasing diastolic blood pressure, serum triglycerides, use of antihypertensive or lipid-lowering medication were associated with a lower renal function. Age, systolic blood pressure, and plasma glucose showed an inverse U-shaped relationship with renal function. Cholesterol/high-density lipoprotein (HDL) ratio, smoking, and antidiabetic medication did not contribute to explain renal function. The atherosclerotic risk factors were related to renal function independently of albuminuria or C-reactive protein (CRP). Albuminuria and CRP itself were also related to renal function. Following gender and age, BMI, urinary albumin excretion (UAE), and plasma glucose had the strongest relation with renal function. Conclusion. We conclude that differences in renal function in the general population are (partly) explained by various atherosclerotic risk factors. Some risk factors are associated with elevated filtration, some with an impaired filtration, and others with both a higher and a lower renal function. [ABSTRACT FROM AUTHOR]

Determinants of cardiorenal damage progression in normotensive and never-treated hypertensive subjects. Background. In the present longitudinal study, we attempted to identify the determinants of cardiorenal damage progression in normotensive subjects (<140/90 mm Hg) and patients with never-treated essential hypertension. Methods. Renal hemodynamics and function and cardiac morphology were evaluated by isotopic techniques and echocardiography at baseline and after a median follow-up period of 5.2 years (range 3 to 13) in 30 normotensive and 33 hypertensive subjects. Results. The results are mean± SD. Among normotensive subjects at baseline, 50% became hypertensive during follow-up. In the whole population, multivariate analysis showed that age was the main determinant of the progression of systolic blood pressure. The yearly change in glomerular filtration rate (GFR) was exaggerated in hypertensive when compared to normotensive subjects at baseline (−1.22± 2.71 vs. 0.12± 2.08 mL/min/year, respectively) ( P= 0.033). In the whole population, only baseline systolic blood pressure remained correlated to the change in GFR, independently of GFR at baseline (model r2= 0.44) ( P< 0.0001). The observed increase in albuminuria was correlated with change in blood pressure only in hypertensive subjects at baseline. Left ventricular mass (LVM) progression was significant only in men and its determinants were basal plasma aldosterone, serum uric acid, and triglyceride and change in systolic blood pressure ( r2= 0.71) ( P< 0.0001). Conclusion. In a population of untreated subjects, baseline blood pressure as well as progression of blood pressure during follow-up are the main determinants of the decline in GFR, progression of albuminuria, and LVM. [ABSTRACT FROM AUTHOR]

Use of sirolimus and low-dose calcineurin inhibitor in lung transplant recipients with renal impairment: Results of a controlled pilot study.Background.Renal failure induced by calcineurin-inhibitor agents is a common complication of lung transplantation. Sirolimus, a macrolide immunosuppressant with a distinct mechanism of action, may prevent renal failure but was found to have a high infectious and toxicity rate in the only relevant study conducted so far. The aim of the present prospective pilot study was to assess the benefit of sirolimus combined with low-dose calcineurin inhibitors in this patient population.Methods.Sixteen lung transplant recipients with post-transplantation renal dysfunction were allocated to receive the standard immunosuppression regimen or a combination sirolimus/low-dose calcineurin-inhibitor regimen. Target trough levels of sirolimus were 4 to 8 ng/mL. Tacrolimus was tapered down to target trough levels of 4 to 8 ng/mL and cyclosporine to 80 to 120 ng/mL. Duration of follow-up was 18 months.Results.At the end of follow-up, the sirolimus group showed a significant improvement in creatinine clearance (42.6 mL/min vs. 32.5 mL/min,P= 0.05), whereas the control group showed a significant reduction (32.3 mL/min vs. 40.3 mL/min,P= 0.02). The difference between the groups was statistically significant (P<0.0001). Acute rejection episodes occurred in 2 patients in the sirolimus group and 1 patient in the control group (P= NS). Pneumonia developed in 6 study patients and 4 controls; all responded to antibiotics.Conclusion.Sirolimus combined with low-dose calcineurin inhibitors appears to be a safe and effective alternative immunosuppressive therapy to sirolimus alone in lung transplant recipients with renal failure. Graft function is preserved, and infection and drug toxicity rates are low. [ABSTRACT FROM AUTHOR]

Evaluation of pre-implantation kidney biopsies: Comparison of Banff criteria to a morphometric approach.Background.Donor glomerulosclerosis, interstitial fibrosis, and fibrous intimal thickening correlate with graft outcome. We evaluate chronic lesions in donor biopsies according to Banff criteria and with a morphometric technique to ascertain their predictive value on graft outcome.Methods.We evaluated 77 cadaveric donor biopsies according to Banff criteria. Glomerulosclerosis was expressed as the percentage of global sclerotic glomeruli. The following morphometric parameters were obtained: cortical interstitial volume fraction (Vvint/c), cortical glomerular volume fraction (Vvglom/c), mean glomerular volume (Vg), mean and maximal intimal arterial volume fraction (Vvintima/art), and Vvintima/art of the largest artery. We evaluated the correlation of histologic lesions with delayed graft function, 3 months' glomerular filtration rate (GFR), and death-censored graft survival.Results.Multivariate logistic regression showed that delayed graft function was associated with cv score[relative risk (RR) 4.2 and 95% CI 1.1 to 16.0) and glomerulosclerosis (RR 1.06 and 95% CI 1.01 to 1.13). Stepwise regression showed that Vvint/c and glomerulosclerosis were independent predictors of 3 months' GFR (R= 0.62,P= 0.0001). Repeated analysis not considering morphometric parameters showed that glomerulosclerosis, cv score and ci score were independent predictors of 3 months' GFR (R= 0.64,P= 0.0001). A donor chronic damage score was generated considering glomerulosclerosis, cv score and ci score. This score after adjusting for clinical variables was associated with 3 months' GFR (R= 0.71,P<0.0001) and death-censored graft survival (RR 2.2 and 95% CI 1.3 to 3.7).Conclusion.Combined evaluation of donor glomerulosclerosis, chronic vascular and interstitial damage according to Banff criteria allows a precise prediction of graft outcome. Morphometric evaluation of donor biopsies does not improve the predictive value of semiquantitative grading. [ABSTRACT FROM AUTHOR]

Liposome-mediated transfer of nitric oxide synthase gene improves renal function in ureteral obstruction in rats.Background.The protective effect of nitric oxide has been demonstrated in several renal disease models. We augmented renal nitric oxide production by transfer of the inducible nitric oxide synthase (iNOS) gene into rat kidney in controls and in unilateral ureteral obstruction (UUO).Methods.The human iNOS gene was inserted into a pcDNA 3.1-backbone plasmid with the FLAG epitope (FLAG-iNOS). In vitro, transduction of FLAG-iNOS was confirmed by Western blot and Griess reaction. In vivo, we transfected either FLAG-iNOS or control plasmid (CMV-LacZ), using cationic liposomes. Urinary nitric oxide metabolites and immunohistochemistry confirmed iNOS transduction. Renal function was also assessed.Results.In vitro, increased iNOS expression was demonstrated in human embryonic kidney (HEK293) cells, along with increased release of nitric oxide metabolites, NO2/NO3. In vivo, FLAG-iNOS was detected by polymerase chain reaction (PCR) up to 35 days after the transfection. Urine collection documented increased urinary NO2/NO3. Immunohistochemistry localized iNOS to collecting ducts, distal tubules, and glomerulus of the injected kidney. Renal function measured up to 21 days after transfection in control animals was not significantly different between the two groups. In contrast, renal function after 24 hours of UUO was significantly improved in FLAG-iNOS–treated animals.Conclusion.This study demonstrates the feasibility of liposome-mediated iNOS gene transfer into the kidney. Furthermore, the improvement of renal function in UUO demonstrates that the transfected iNOS gene is active and suggests that decreased iNOS activity contributes to the decreased renal function in UUO. This iNOS construct may have therapeutic utility in the pathophysiologic sequelae of UUO and other renal diseases. [ABSTRACT FROM AUTHOR]

Relation of urinary albumin excretion to coronary heart disease and low renal function: Role of blood pressure. Background. Previous studies report that urinary albumin excretion is associated with coronary heart disease (CHD). The present epidemiologic study investigated if ( 1) blood pressure status affects the association of urinary albumin excretion with CHD; and ( 2) urinary albumin excretion is associated with low renal function also. Methods. The cross-sectional association was analyzed of overnight urinary albumin excretion with prevalence of CHD (myocardial infarction and/or ischemia as defined by standard electrocardiogram) and low renal function (overnight creatinine clearance <60 mL/min) in a population sample of 1632 men and women with ages 45 to 64 years. Hypertension, hypercholesterolemia, smoking habit, and diabetes mellitus were included in analyses. Results. CHD prevalence was in the whole sample 8.2% ( N= 134), in the hypertensive subgroup 11.9% ( N= 79), and in the nonhypertensive subgroup 5.7% ( N= 55). For the association between urinary albumin excretion (logarithm-transformed due to skewed distribution) and CHD, the multivariate logistic coefficient with 95% CI was significant in the whole sample (+0.79, 95% CI =+0.32/+1.26, P < 0.001) and in the hypertensive subgroup (+0.97, 95% CI =+0.70/+1.24, P < 0.001), not in the nonhypertensive subgroup (−0.06, 95% CI =−0.80/+0.68, P= 0.997). Prevalence of low creatinine clearance was in the whole sample 4.0% ( N= 66), in the hypertensive subgroup 4.8% ( N= 32), and in the nonhypertensive subgroup 3.5% ( N= 34). [ABSTRACT FROM AUTHOR]

Mycophenolate mofetil in IgA nephropathy: Results of a 3-year prospective placebo-controlled randomized study. Background. Because humoral immunity is believed to play a pivotal role in the pathogenesis of IgA nephropathy (IgAN), a prospective placebo-controlled randomized study was started in patients with IgAN using mycophenolate mofetil (MMF). Methods. A total of 34 patients with IgAN were treated with salt intake restriction, angiotensin-converting enzyme (ACE) inhibition and MMF 2 g per day ( N= 21) or placebo ( N= 13). After 36 months of follow-up clinical, biochemical, and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis. Results. Therapy had to be stopped prematurely in five patients. Two patients (MMF group) evolved to end-stage renal disease (ESRD). There was no difference between groups in the percentage of patients with a decrease of 25% or more in the inulin clearance or with a serum creatinine increase of 50% or more over 3 years. There was also no significant difference between groups in annualized rate of change of serum creatinine, computed by linear regression analysis. No significant difference was noted between groups for inulin clearance, serum creatinine, proteinuria, blood pressure, or other parameters of renal function. Hemoglobin and C-reactive protein were significantly lower in the MMF group compared with the placebo group. As a function of time, a significant decline in both groups was noted of proteinuria, parenchymal thickness of the kidneys and C3d. Conclusion. In patients with IgAN at risk for progressive disease, no beneficial effect of 3-year treatment with MMF 2 g per day could be demonstrated on renal function/outcome or proteinuria. However, larger randomized studies are needed to confirm or reject these results. [ABSTRACT FROM AUTHOR]

The diagnostic value of serum concentrations of 2-(α-mannopyranosyl)- l-tryptophan for normal renal function. Background. We 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. Methods. A total of 156 subjects with serum creatinine concentration ≤1.60 mg/dL aged 0 to 88 years 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 ≥80 mL/min (aged 6 to 68 years), the correlations between age and/or urinary creatinine excretion, which is related to muscle mass, and serum concentrations of MPT or creatinine, were determined. Results. In 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 90 ng/mL for serum MPT concentration and 0.70 mg/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 20 years 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). Conclusion. The 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. [ABSTRACT FROM AUTHOR]

Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort Background. Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function. Standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to reliably measure renal cyst volumes. The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) is longitudinally observing ADPKD individuals using high-resolution magnetic resonance (MR) imaging to determine if change in renal and cyst volumes can be detected over a short period of time, and if they correlate with decline in renal function early in disease. Methods. Standardization studies were conducted in phantoms and four subjects at each participating clinical center. After, in the full-scale protocol, healthy ADPKD individuals 15 to 45 years old with creatinine clearance>70 mL/min underwent standardized MR renal imaging, renal iothalamate clearance, comprehensive clinical evaluation, and determination of 24-hour urinary albumin and electrolyte excretion. Stereology was used from T1-weighted images to quantify renal volume, and region-growing thresholding was used from T2-weighted images to determine cyst volume. Renal structures were evaluated in relation to demographic, clinical, and biochemical variables using means/medians, standard deviations, and Pearson correlations. Results. Reliability coefficients for MR renal and cyst volume measurements in phantoms were 99.9% and 89.2%, respectively. In the full-scale protocol, 241 ADPKD individuals (145 women and 96 men) were enrolled. Total renal, cyst, and % cyst volume were significantly greater in each decade group. Hypertensive individuals demonstrated greater renal, cyst, and % cyst volume than normotensive subjects. Age-adjusted renal (r = -0.31, P < 0.0001), cyst (r = -0.36, P < 0.0001), and % cyst volume (r = -0.35, P < 0.0001) were inversely related to glomerular filtration rate (GFR). Age-adjusted renal volume (r = 0.42, P < 0.0001), cystic (r = 0.39, P < 0.0001, and % cyst volume (r = 0.41, P < 0.0001) were related with urinary albumin excretion. Conclusion. MR measures of renal and cyst volume are reliable and accurate in patients with ADPKD. ADPKD is characterized by significant cystic involvement that increases with age. Structure (renal and cyst volume) and function (GFR) are inversely related and directly related with the presence of hypertension and urinary albumin excretion in individuals with normal renal function. [ABSTRACT FROM AUTHOR]

Therapeutic benefit of spironolactone in experimental chronic cyclosporine A nephrotoxicity. Background. Cyclosporine A (CsA) is an immunosuppressive drug used to prevent tissue allograft rejection. However, its long-term utilization is limited due to chronic nephrotoxicity for which no prevention is available. This study evaluated the effect of spironolactone on renal functional and structural alterations induced by CsA, and assessed whether the protective effect was associated with a reduction of transforming growth factor-β (TGF-β) and the change of extracellular matrix protein mRNA level. Methods. Male Wistar rats fed with low sodium diet were divided in four treatment groups: vehicle, CsA (30 mg/kg), spironolactone (20 mg/kg), or CsA+spironolactone. After 21 days, creatinine clearance (CCr ), blood CsA, arteriolopathy in renal tissue, and TGF-β, collagen I, collagen IV, fibronectin, and epidermal growth factor (EGF) mRNA levels in renal cortex were determined. Results. CsA reduced the CCr and up-regulated TGF-β, collagen I and fibronectin mRNA expression with a significant development of arteriolopathy, and reduced EGF mRNA levels. In contrast, spironolactone administration prevented the fall in renal function and TGF-β, collagen I, and fibronectin up-regulation, together with a reduction of arteriolopathy and tubulointerstitial fibrosis. Conclusion. Our data show that aldosterone plays an important role as a mediator of renal injury induced by CsA. Thus, mineralocorticoid receptor blockade may be a potential strategy to prevent CsA nephrotoxicity. [ABSTRACT FROM AUTHOR]

Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study. Background. Cardiovascular mortality is extremely high in end-stage renal disease. Cardiovascular mortality risk also is increased in selected (high-risk) individuals with mild to moderate impairment of renal function. It is not clear whether a similar association exists in the general population and, if so, through what mechanisms. We investigated the association of renal function with all-cause and cardiovascular mortality in a population-based cohort and explored potential mechanisms underlying any such relationship. Methods. An age-, sex-, and glucose-tolerance–stratified sample (N = 631) of a population-based cohort aged 50 to 75 years was followed prospectively. After up to 10.2 years of follow-up, 117 subjects had died (50 of cardiovascular causes). At baseline, renal function was estimated by the serum creatinine level, the Cockcroft-Gault formula and Levey's equation. Results. At baseline, the mean age was 64 ± 7 years, 48% were men, 55% had hypertension, and 27% (by design) had type 2 diabetes. Serum creatinine was 91.7 ± 19.0 μmol/L; creatinine clearance as estimated by the Cockroft-Gault formula was 72.5 ± 13.7 mL/min/1.73 m2 , and the glomerular filtration rate (GFR) estimated by Levey's equation was 67.8 ± 12.1 mL/min/1.73 m2 . Renal function was inversely associated with all-cause and with cardiovascular mortality. Relative risks (95% confidence intervals) were 1.08 (1.04 to 1.13) and 1.11 (1.07 to 1.16) per 5 μmol/L increase of serum creatinine; 1.07 (0.98 to 1.17) and 1.15 (1.01 to 1.31) for each decrease of 5 mL/min/1.73 m2 creatinine clearance; and 1.15 (1.05 to 1.26) and 1.26 (1.12 to 1.42) for each decrease of 5 mL/min/1.73 m2 of GFR. These associations remained after adjusting for age, sex, glucose tolerance status, hypertension, prior cardiovascular disease,... [ABSTRACT FROM AUTHOR]

Glomerular cell number in normal subjects and in type 1 diabetic patients. Background. The number of cells in glomeruli has been a challenging measure, especially in human kidneys, with only a small amount of tissue obtained by biopsy. However, the number of cells and their function are important determinants of renal function in health and disease. Methods. Modern morphometric techniques have now provided the means to determine the numerical density (Nv ) and number (with a measure of glomerular volume) of endothelial cells, mesangial cells, and podocytes in plastic-embedded renal tissue biopsied from nondiabetic subjects (N = 36) and type 1 diabetic patients (N = 46) over an extended age range from childhood through late adult. Results. Nv values for all glomerular cells varied only slightly with age and did not change within the range of glomerular lesions of diabetes studied. Thus, the increase in glomerular volume during childhood to a steady level thereafter was the primary determinant of total glomerular cell number. The number of mesangial cells and endothelial cells increased with age, reflecting the increase in all cells, while the podocytes remained unchanged in number over all ages studied (10 to 69 years). Numbers of total glomerular cells, mesangial cells, and endothelial cells were not changed with diabetes, while podocytes were fewer in number in diabetic patients of all ages, with reduced podocyte numbers even in diabetes of short duration. Conclusions. The essentially constant glomerular cell density in nondiabetic and diabetic subjects under different circumstances possibly indicates an underlying propensity for the glomerulus to regulate its architecture to maintain a constant number of cells per volume, no matter the size of the glomerulus or the severity of diabetic nephropathy studied in this set of patients. The reductions in podocyte numbers in both younger and older diabetic patients indicate a significant risk for functional abnormalities as diabetic nephropathy progresses. Moreover, these observations do not support the suggestion of marked increases in glomerular cell number (and especially mesangial cells) with the development and progression of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Developmental changes in multispecific organic anion transporter 1 expression in the rat kidney. Background. The cDNA of the multispecific organic anion transporter 1 (OAT1) responsible for the tubular secretion of organic anions was recently isolated. In the current study, we investigated the developmental changes in OAT1 expression in the rat kidney. Methods. Ontogenic expression of rat OAT1 was investigated by Northern blot, in situ hybridization, Western blot, and immunohistochemical analysis. In addition, para-aminohippurate (PAH) accumulation was measured using fetal, neonatal, and adult rat kidney slices. Results. In Northern blot analysis, OAT1 was detected as early as on embryonic day 18 in the fetal kidney. The expression level of OAT1 mRNA increased remarkably just after birth (postnatal day 0). In situ hybridization revealed OAT1 expression on embryonic day 19. In both the fetal and neonatal kidneys, OAT1 mRNA was localized in a relatively deep region in the cortex. Western blot analysis detected OAT1 protein on embryonic day 20, and the expression level increased after birth. Immunohistochemical analysis did not reveal OAT1 staining in the fetal kidneys. A faint signal of OAT1 protein was detected on postnatal day 0; thereafter, the expression level increased. In the functional study using kidney slices, low but definite probenecid-sensitive PAH accumulation was noted in fetal rat kidney on embryonic day 20. After birth, probenecid-sensitive PAH uptake was increased. Conclusions. The present study consistently demonstrates the remarkable increase of OAT1 expression after birth, and the immature excretory capacity of the proximal tubules of the neonatal kidney can be attributed, at least in part, to the low expression level of OAT1. [ABSTRACT FROM AUTHOR]

Chronic K depletion inhibits renal brush border membrane Na/sulfate cotransport. Background. The purpose of this study was to determine if dietary potassium (K) deficiency regulates renal proximal tubular sodium gradient-dependent sulfate transport (Na/Si cotransport) in the rat and, furthermore, determine if the regulation takes place at the level of the recently cloned Na/Si cotransport system (NaSi -1). Methods and Results. Rats treated chronically (seven days) with a K-deficient diet had a significant decrease in serum Si levels and an increase in fractional excretion of ultrafilterable Si , which paralleled a significant decrease in brush border membrane (BBM) Na/Si cotransport activity. The decrease in BBM Na/Si cotransport activity was associated with decreases in BBM NaSi -1 protein and renal cortical NaSi -1 mRNA abundance. In addition, in Xenopus oocytes injected with mRNA from kidney cortex slices of K-deficient rats, there was a significant reduction in the induced Na/Si cotransport, whereas there was no alteration in l-leucine uptake, suggesting that in K-deficient rats, there is a specific decrease in functional mRNA encoding the NaSi -1 mRNA. Conclusion. These findings indicate that chronic K deficiency leads to a reduction in serum Si levels and an increase fractional excretion of Si , and reduces Si reabsorption by down-regulating the expression of the proximal tubular Na/Si -1 cotransporter protein and mRNA. [ABSTRACT FROM AUTHOR]

Effect of indomethacin on the renal response to angiotensin II receptor blockade in healthy subjects. Background. Non-steroidal anti-inflammatory drugs are known to promote sodium retention and to blunt the blood pressure lowering effects of several classes of antihypertensive agents including beta-blockers, diuretics and angiotensin converting enzyme (ACE) inhibitors. The purpose of the present study was to investigate the acute and sustained effects of indomethacin on the renal response to the angiotensin II receptor antagonist valsartan and to the ACE inhibitor enalapril. Methods . Twenty normotensive subjects maintained on fixed sodium intake (100 mmol sodium/day) were randomized to receive for one week: valsartan 80 mg o.d., enalapril 20 mg o.d., valsartan 80 mg o.d. + indomethacin 50 mg bid and enalapril 20 mg o.d. + indomethacin 50 mg bid. This single-blind study was designed as a parallel (valsartan vs. enalapril) and cross-over trial (valsartan or enalapril vs. valsartan + indomethacin or enalapril + indomethacin). Renal hemodynamics and urinary electrolyte excretion were measured for six hours after the first and seventh administration of each treatment regimen. Results . The results show that valsartan and enalapril have comparable renal effects characterized by no change in glomerular filtration rate and significant increases in renal plasma flow and sodium excretion. The valsartan- and enalapril-induced renal vasodilation is not significantly blunted by indomethacin. However, indomethacin similarly abolishes the natriuresis induced by the angiotensin II antagonist and the ACE inhibitor. Conclusions . This observation suggests that although angiotensin receptor antagonists do not affect prostaglandin metabolism, the administration of a non-steroidal anti-inflammatory drug blunts the natriuretic response to angiotensin receptor blockade. [ABSTRACT FROM AUTHOR]

Localization of the prostacyclin receptor in human kidney. Background. Prostacyclin is an important mediator of renal hemodynamics. Furthermore, recent studies argue for a role of this arachidonic acid metabolite in the regulation of salt and water handling in the distal nephron. To gain insight into the network of prostacyclin signal transduction, we analyzed the intrarenal distribution of the prostacyclin receptor (IP receptor) in adult human kidney. Methods. Specific polyclonal antibodies against a synthetic peptide of the human IP receptor were generated. By means of immunohistology the localization of IP receptor protein was studied. The mRNA expression for IP receptor was analyzed by in situ hybridization using specific cRNA probes. Results. In human kidney sections both IP receptor-immunoreactive protein and mRNA were expressed in smooth muscle cells and endothelial cells. Expression of the IP receptor was observed in glomerular cells, namely mesangial cells, endothelial cells, and podocytes. Both mRNA and protein expression for IP receptor was observable in Tamm-Horsfall-negative distal tubules and collecting ducts. Conclusions. The vascular expression of the IP receptor is consistent with the known vasodilatory effect of prostacyclin in vascular beds. Glomerular expression argues for a role of this autacoid in the regulation of glomerular hemodynamics. The tubular distribution might point towards the involvement of prostacyclin in renal salt and water handling. [ABSTRACT FROM AUTHOR]

Despite the impressive reduction in early acute rejection rates over the past decades, chronic allograft dysfunction remains a key issue after renal transplantation. A number of factors, such as the quality of the original organ, ischemia/reperfusion injury, and/or (treated) acute rejection, will adversely affect renal structure, causing early (but often mild) tubular atrophy and interstitial fibrosis. It remains, however, controversial whether subclinical acute rejection or borderline changes imply a different functional prognosis with longer times of follow-up, if cases with late clinical acute rejection, inadequate dosing, and/or incompliance with drug prescription are excluded. Serum creatinine and immunosuppressant trough levels constitute the current standard biomarkers for assessing and renal function and systemic drug exposure, respectively. Serum creatinine is a notoriously unreliable marker for the glomerular filtration rate; changes in creatinine concentration occur late in disease progression and do not accurately represent the ongoing underlying renal damage. Trough level monitoring without information on the patient's absorption profile or the related systemic drug exposure is equally unreliable for guiding initial calcineurin inhibitor dosing or for controlling systemic drug exposure while tapering. Until more sophisticated biomarkers to guide clinical immunosupprression become available, protocol biopsies may prove to be most useful in patients with an increased risk for (late) acute rejection. [ABSTRACT FROM AUTHOR]

To evaluate cardiovascular disease (CVD) after renal transplantation we established a CVD database (no-intervention) including all patients transplanted among 2000–2002 in 14 hospitals from Spain (Renal Forum Group) ( n =2600). They were prospective followed annually thereafter and we present herein the most important results concerning survival figures and CVD at four years. Mean recipient age was 49.7±13.7 years: 16% retransplanted and 12.5% hyperimmunized. Tacrolimus, mycophenolate mofetil, and steroids was used in 63%. Acute rejection (AR) rate at 1 year was 14.8%. Graft and patient survival at 48 months were 85.6% (death censored) and 91.7% respectively. The first cause of graft loss was vascular in the first year, death with function during the 2–3 years, and chronic allograft nephropathy at the 4th year. Donor age, time on dialysis, acute tubular necrosis (ATN), AR, SCr at 6 months, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in the first year, and systolic blood pressure at 24 months were independent risk factors for graft loss at 4th year. The first cause of death was CVD (predominantly ischemic heart disease (IHD) in the first year). Recipient age, ATN, and SCr at 6 months were independent predictors of mortality. Despite worsening of donor age, comorbidity, and advanced age of recipients, survival figures at four years are considered good in our Spanish non-selected population. Cardiovascular mortality is the most important cause of death and graft loss particularly, IHD in the first year. Therefore, to decrease post-transplant mortality a careful cardiovascular evaluation and treatment in the waiting list and a close follow-up of patients after transplantation is mandatory. [ABSTRACT FROM AUTHOR]

Tubulointerstitial damage and progression of renal failure . The present work reviews the mechanisms and close association between glomerular and tubular damage and its relationship to renal functional impairment. In addition, we present an overview of the pathways involved in the progression of tubulointerstitial fibrosis and a brief summary of the treatments used to retard the progression to end-stage renal failure. [ABSTRACT FROM AUTHOR]

Risk factors associated with the deterioration of renal function after kidney transplantation Renal function early after transplantation is associated with a large number of risk factors, including donor age and acute rejection. During the 1990s, donor age increased and the incidence of acute rejection decreased. Renal function between the third and sixth month improved slightly, while renal function deterioration between the third or sixth month and the 12th month improved significantly. This modification coincides with the introduction of mycophenolate mofetil and tacrolimus. The tendency for sustained renal improvement early after transplantation became more evident after the introduction of anti-calcineurin–free regimens. Studies of protocol biopsies have shown that there is an increase of glomerular volume after transplantation and that a larger glomerular volume at 4 months is associated with a better glomerular filtration rate. This adaptation mechanism is impaired in patients with chronic allograft nephropathy or in patients with high cyclosporin levels. Taken together, these data suggest that the steady improvement of renal allograft function may be partly explained by a better glomerular adaptation after transplantation because of the avoidance of the vasoconstrictive effect of anti-calcineurinic agents, and a significant decrease in the prevalence of chronic allograft nephropathy early after transplantation. [ABSTRACT FROM AUTHOR]

An elevated urinary albumin excretion predicts de novo development of renal function impairment in the general population. Background We questioned which factors determine the risk for developing renal function impairment. To that purpose, we studied the incidence of newly diagnosed impaired renal function (GFR <60 mL/min/1.73m 2 ) in the PREVEND cohort ( N =8592), which is enriched for the presence of albuminuria, and which was first studied in 1997–1998. Of this cohort, 6894 subjects were studied again four years later. Methods Subjects with known renal disease, GFR <60 mL/min, missing GFR values, or sediment abnormalities at the first screening were excluded from the present analysis ( N =872). We examined whether albuminuria is associated with the de novo development of an impaired renal function. GFR was 90.3 (SD 16.3) mL/min/1.73m 2 at baseline, and 11.6% of the subjects had an albuminuria of more than 30 mg/day. Results After a follow-up of four years, 253 subjects (4.2%) were found to have a GFR <60 mL/min/1.73m 2 . The subjects with newly diagnosed impaired GFR were older, had a higher blood pressure, serum cholesterol, plasma glucose, and urinary albumin excretion at the first examination, and had a lower GFR to start with than those with a GFR >60 at the second evaluation. Subjects with de novo impaired GFR had a comparable BMI and smoked less frequently compared with subjects with GFR >60. In multivariate analysis, urinary albumin excretion was independently predictive for the risk of developing an impaired GFR ( P =0.001). Conclusion Also in the general population, measurement of urinary albumin excretion may prove to be a valuable tool to detect subjects at risk for later development of renal failure, independent of the presence of other cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Therapeutic implications and new perspectives for essential hypertension and renal damage. The kidney can suffer the consequences of a persistently elevated blood pressure. In fact end-stage renal failure caused by essential hypertension appears to be one of the most prevalent etiologies in patients entering a dialysis program. Blood pressure control is needed in order to prevent the progressive loss of renal function. Target blood pressure control has been established at values as low as 125/75 mm Hg for patients with proteinuria above 1 g/day. Attainment of this target level usually requires the combination of two or more drugs. However, the possibility that differences exist among the different classes of antihypertensive drugs beyond their capacity to simply lower blood pressure remains to be clearly elucidated. The fact that the presence of chronic renal failure is also accompanied by an enhanced cardiovascular risk potentiates the need to explore the renoprotective and cardiovascular protective capacity of the different classes of antihypertensive drugs, in patients with essential hypertension and some degree of renal involvement, characterized by the presence of microalbuminuria, proteinuria and/or an elevated serum creatinine. [ABSTRACT FROM AUTHOR]