Aparecido B. Pereira

Influence of Muscle Mass and Physical Activity on Serum and Urinary Creatinine and Serum Cystatin C

BACKGROUND AND OBJECTIVES For addressing the influence of muscle mass on serum and urinary creatinine and serum cystatin C, body composition was assessed by skinfold thickness measurement and bioelectrical impedance analyses. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 170 healthy individuals (92 women, 78 men) were classified as sedentary or with mild or moderate/intense physical activity. Blood, 24-h urine samples, and 24-h food recall were obtained from all individuals. RESULTS Serum and urinary creatinine correlated significantly with body weight, but the level of correlation with lean mass was even greater. There was no significant correlation between body weight and lean mass with cystatin C. Individuals with moderate/intense physical activity presented significantly lower mean body mass index (23.1 +/- 2.5 versus 25.7 +/- 3.9 kg/m(2)) and higher lean mass (55.3 +/- 10.0 versus 48.5 +/- 10.4%), serum creatinine (1.04 +/- 0.12 versus 0.95 +/- 0.17 mg/dl), urinary creatinine (1437 +/- 471 versus 1231 +/- 430 mg/24 h), protein intake (1.4 +/- 0.6 versus 1.1 +/- 0.6 g/kg per d), and meat intake (0.7 +/- 0.3 versus 0.5 +/- 0.4 g/kg per d) than the sedentary individuals. Conversely, mean serum cystatin did not differ between these two groups. A multivariate analysis of covariance showed that lean mass was significantly related to serum and urinary creatinine but not with cystatin, even after adjustment for protein/meat intake and physical activity. CONCLUSIONS Cystatin C may represent a more adequate alternative to assess renal function in individuals with higher muscle mass when mild kidney impairment is suspected.

NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele

Mutations in NPHS2, encoding podocin, have been identified in childhood onset focal and segmental glomerulosclerosis (FSGS). The role of NPHS2 in adult disease is less well defined. We studied 30 families with FSGS and apparent autosomal recessive inheritance and 91 individuals with primary FSGS. We screened family members for NPHS2 mutations. NPHS2 mutations appeared to be responsible for disease in nine of these families. In six families, the affected individuals were compound heterozygotes for a nonconservative R229Q amino acid substitution. This R229Q variant has an allele frequency of 3.6% in a control population. In these families, R229Q was the only mutation identified on one of the two disease-associated NPHS2 alleles. We used in vitro-translated podocin and purified nephrin to investigate the effect of R229Q on their interaction and found decreased nephrin binding to the R229Q podocin. These data suggest that this common polymorphism contributes to the development of FSGS. Chromosomes bearing the R229Q mutation share a common haplotype defining an approximately 0.2-Mb region. R229Q appears to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. Identification of R229Q mutations may be of clinical importance, as NPHS2-associated disease appears to define a subgroup of FSGS patients unresponsive to corticosteroids.

Pre- and post-transplant anti-myosin and anti–heat shock protein antibodies and cardiac transplant outcome

BACKGROUND The purpose this study was to investigate the relationship of anti-myosin and anti-heat shock protein immunoglobulin G (IgG) serum antibodies to the original heart disease of cardiac transplant recipients, and also to rejection and patient survival after cardiac transplantation. METHODS Anti-myosin and anti-heat shock protein (anti-hsp) IgG antibodies were evaluated in pre-transplant sera from 41 adult cardiac allograft recipients and in sequential post-transplant serum samples from 11 recipients, collected at the time of routine endomyocardial biopsies during the first 6 months after transplantation. In addition, the levels of these antibodies were determined from the sera of 28 healthy blood donors. RESULTS Higher anti-myosin antibody levels were observed in pre-transplant sera than in sera from normal controls. Moreover, patients with chronic Chagas heart disease showed higher anti-myosin levels than patients with ischemic heart disease, and also higher levels, although not statistically significant, than patients with dilated cardiomyopathy. Higher anti-hsp levels were also observed in patients compared with healthy controls, but no significant differences were detected among the different types of heart diseases. Higher pre-transplant anti-myosin, but not anti-hsp, levels were associated with lower 2-year post-transplant survival. In the post-transplant period, higher anti-myosin IgG levels were detected in sera collected during acute rejection than in sera collected during the rejection-free period, whereas anti-hsp IgG levels showed no difference between these periods. CONCLUSIONS The present findings are of interest for post-transplant management and, in addition, suggest a pathogenic role for anti-myosin antibodies in cardiac transplant rejection, as has been proposed in experimental models of cardiac transplantation.

Proximal tubular dysfunction is associated with chronic allograft nephropathy and decreased long-term renal-graft survival.

Background: Chronic allograft nephropathy is the major cause of graft loss after the first year of transplantation. Although many conditions are associated with its development, there is no method that can anticipate its risk in patients with good renal function. Methods: We prospectively studied 92 renal-transplant recipients with good and stable allograft function and correlated the development of chronic allograft nephropathy and graft loss with their levels of urinary retinol binding protein (uRBP). Patients were divided in two groups regarding the level of their tubular protein: high, above 0.400 mg/L, and normal levels, 0.400 mg/L or less. Results: Forty-eight (52%) patients had high levels of uRBP. At the enrollment time, patients with high and normal uRBP had comparable serum creatinine and cyclosporine trough levels. During a 5-year follow-up period, chronic allograft nephropathy was detected in 23 (25%) patients, 19 (82.6%) of whom had high levels of uRBP. Five-year chronic allograft nephropathy-free and graft survivals were significantly worse in patients with higher levels of uRBP than in patients with normal levels (57.5% vs. 89.9% P=0.0004; 70.7% vs. 100%, respectively, P=0.0002). High levels of uRBP were the strongest factor associated with the development of chronic allograft nephropathy (RR=5.3, 95% confidence interval 1.45–19.58, P=0.012). Conclusions: Among renal-transplant patients with good and stable graft function, high levels of uRBP identify those having a high risk of developing chronic allograft nephropathy.

Urinary Retinol-Binding Protein as a Prognostic Marker in Glomerulopathies

Tubulointerstitial involvement seems to have a decisive influence on the progression of glomerular diseases. We have prospectively evaluated the levels of urinary retinol-binding protein (urRBP), a marker of proximal tubular dysfunction, in patients with different glomerulopathies (GPs) and correlated these levels with disease progression. By studying 238 patients with GPs, we found that urRBP tend to be lower in minimal change disease, glomerular hematuria and poststreptococcal glomerulonephritis as compared to focal segmental glomerulosclerosis, membranous nephropathy and membranoproliferative glomerulonephritis. By following 149 patients for up to 10 years, we have concluded that high levels of urRBP can identify patients who will progress with loss of renal function (defined as doubling of serum creatinine level) and that a urRBP level >1 mg/l was an efficient and independent indicator of poor prognosis as shown by multivariate analysis. This prediction was possible at a time when serum creatinine and creatinine clearance were still in the normal range. Our data suggest that this laboratory test adds important clinical information to the follow-up of GPs.

Early detection of heart transplant patients with increased risk of ciclosporin nephrotoxicity

Chronic nephrotoxic effects from ciclosporin are a common clinical complication after heart transplantation and frequently lead to progressive renal failure. There is no laboratory test to predict development of chronic renal failure in heart transplant patients. We analysed urinary retinol-binding protein (uRBP) concentration, to assess proximal tubular dysfunction, in 36 clinically stable heart transplant patients. We detected a subgroup of 13 patients who had high concentrations of uRBP, good renal function, and a high risk of developing progressive renal failure compared with patients with normal uRBP (relative risk 3.87, p=0.003).

Prediction of steroid responsiveness in the idiopathic nephrotic syndrome using urinary retinol-binding protein and beta-2-microglobulin

OBJECTIVES To determine the prevalence of early proximal tubular dysfunction, measured by urinary excretion of retinol-binding protein (RBP) and beta-2-microglobulin (B2M), in patients with the idiopathic nephrotic syndrome and to investigate the value of these tests in predicting steroid responsiveness. DESIGN Before-after trial with 8-week treatment period. SETTING Tertiary referral center. PATIENTS Sequential sample of 37 patients with the idiopathic nephrotic syndrome caused by minimal change disease, focal segmental glomerulosclerosis, or mesangial proliferative glomerulonephritis. INTERVENTION All patients were treated with prednisone as one dose of 1 to 1.5 mg/kg body weight per day for 8 weeks. MEASUREMENTS Urinary RBP was measured by an immunoenzymometric assay and B2M, by an enzyme-linked immunosorbent assay. Remission of the nephrotic syndrome after steroid treatment was the main outcome variable. RESULTS Elevated levels of urinary RBP and B2M before treatment were detected in 65% and 75% of the patients, respectively. Median urinary RBP and B2M, before treatment, were significantly higher in the steroid-unresponsive group than in the responsive group (P less than 0.01). In the steroid-responsive group, urinary RBP and B2M levels decreased significantly after remission (P less than 0.01). In the steroid-unresponsive group, the likelihood ratios for urinary RBP greater than 4000 micrograms/g creatinine and for B2M greater than 3000 micrograms/g creatinine were 3.8 and 3.0, respectively. The probability was 100% that values of RBP of less than 1300 micrograms/g creatinine and B2M of less than 130 micrograms/g creatinine were from steroid-responsive patients. Multivariate analysis confirmed that higher urinary levels of RBP and B2M were associated with a lower likelihood of steroid responsiveness, independent of age and histologic diagnosis. CONCLUSIONS Proximal tubular dysfunction is frequent in patients with the idiopathic nephrotic syndrome. Pretreatment urinary RBP and B2M levels may be helpful in identifying nephrotic patients who are more likely to be responsive to steroids.

Predictive value of urinary retinol binding protein for graft dysfunction after kidney transplantation.

UNLABELLED High concentrations of retinol binding protein (RBP) are found in the urine of patients with tubulointerstitial injury. We evaluated the predictive value of urinary RBP (RBPu) for development graft dysfunction after kidney transplantation. METHODS Serum creatinine and RBPu were prospectively measured at months 3, 6, and 12 in 221 kidney transplant patients. Baseline graft function was defined as the lowest serum creatinine value during the first 3 months after transplantation. Graft dysfunction was assessed at 1 year as a >-20% or >-30% change in the inverse creatinine ((Delta)1/Cr) compared to baseline value at month 3. RESULTS Among 183 patients with normal graft function (Cr </= 1.6 mg/dL) the mean (Delta)1/Cr from month 3 to 12 was -17 +/- 22% (-80% to + 44%). Using a receiver operating characteristic (ROC) analysis, concentrations higher than 0.6 mg/L showed the best predictive value for diagnosis of graft dysfunction at 1 year. Mean (Delta)1/Cr from month 3 to 12 was -13 +/- 20% for those with RBP < 0.6 mg/L vs -20 +/- 23% in those with RBPu > 0.6 mg/L (95% CI = -13% to -1.3%, P =.018). The percentage of patients with >-20% or >-30% (Delta)1/Cr was higher among patients with RBPu > 0.6 mg/L (34% vs 47%, P =.042; 21% vs 34%, P =.035). RBPu > 0.6 mg/L was the only variable independently associated with >-30% (Delta)1/Cr at 1 year, with an odds ratio (OR) of 1.95 (95% CI 0.99 to 3.80, P =.05). CONCLUSIONS RBPu may serve as a surrogate marker for graft dysfunction early after transplantation for patients with normal graft function, allowing early institution of intervention therapies to prolong allograft survival.

Urinary Retinol-Binding Protein as a Prognostic Marker in the Treatment of Nephrotic Syndrome

We studied the urinary levels of retinol-binding protein (urRBP), an index of proximal tubular dysfunction, in patients with nephrotic syndrome before and approximately 2 months after the beginning of steroid therapy as a predictor of response to therapy which included for some patients courses of immunosuppressive drugs. Those patients with minimal-change disease, mesangial proliferative glomerulonephritis, and focal-segmental glomerulosclerosis who had normal pretreatment urRBP levels were responsive to treatment; occasionally, responsive patients had an initially elevated urRBP level which normalized during treatment. Contrariwise, those patients with abnormally high levels of urRBP which did not normalize during treatment did not respond to treatment. The chance of a patient with minimal-change disease, mesangial proliferative glomerulonephritis, or focal-segmental glomerulosclerosis and a pretreatment urRBP level equal to or >1.0 mg/l being resistant to steroid treatment is 30 times that of a patient with a urRBP level <1.0 mg/l and even higher, if we consider the levels obtained during treatment.

Race Adjustment for Estimating Glomerular Filtration Rate Is Not Always Necessary

Background: Estimated glomerular filtration rate (eGFR) is very important in clinical practice, although it is not adequately tested in different populations. We aimed at establishing the best eGFR formulas for a Brazilian population with emphasis on the need for race correction. Methods: We evaluated 202 individuals with chronic kidney disease (CKD) and 42 without previously known renal lesions that were additionally screened by urinalysis. Serum creatinine and plasma clearance of iohexol were measured in all cases. GFR was estimated by the Mayo Clinic, abbreviated Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas, and creatinine clearance was estimated by the Cockcroft-Gault (CG) formula. Plasma clearance of iohexol was used as the gold standard for GFR determination and for the development of a Brazilian formula (BreGFR). Results: Measured and estimated GFR were compared in 244 individuals, 57% female, with a mean age of 41 years (range 18–82). Estimates of intraclass correlation coefficients among the plasma clearance of iohexol and eGFR formulas were all significant (p < 0.001) and corresponded to the following scores: CG 0.730; obesity-adjusted CG 0.789; Mayo Clinic 0.804; MDRD 0.848; MDRD1 (without race adjustment) 0.846; CKD-EPI 0.869; CKD-EPI1 (without race adjustment) 0.876, and BreGFR 0.844. Conclusions: All cited eGFR formulas showed a good correlation with the plasma clearance of iohexol in the healthy and diseased conditions. The formulas that best detected reduced eGFR were the BreGFR, CKD-EPI, and CKD-EPI1 formulas. Notably, the race correction included in the MDRD and CKD-EPI formulas was not necessary for this population, as it did not contribute to more accurate results.