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.

Are urinary levels of free light chains of immunoglobulins useful markers for differentiating between systemic lupus erythematosus and infection?

INTRODUCTION: Active systemic lupus erythematosus (SLE) and infection are often hard to distinguish. We evaluated the urinary levels of free light chains of immunoglobulins (urFLCIg) as a possible laboratory marker to differentiate those conditions. METHODS: We evaluated 43 patients with lupus nephritis (16-63 years old), with or without concurrent infection (12 with infection), 14 with infectious disease without SLE and 20 with idiopathic Fanconi's syndrome. The Systemic Lupus Erythematosus Disease Activity Index was utilized to establish activity of disease. Levels of urFLCIg kappa and lambda were determined by an immunoenzymometric assay developed in our institution. In order to evaluate proximal tubular dysfunction which could be responsible for increased levels of urFLCIg, we determined the low-molecular-weight protein urRBP. RESULTS: Levels of urFLCIg in healthy volunteers (median kappa 1.57 mg/l; lambda 0.96 mg/l), inactive SLE (5.36; 4.93) and active SLE (11.82; 23.59) were significantly different; urFLCIg levels or urFLCIg/urRBP ratios could not separate patients with infection from those with SLE. CONCLUSION: Our data show that convoluted proximal tubular dysfunction was not responsible for the increase in urFLCIg levels. UrFLCIg determination was useful in the detection of SLE activity, but was unable to distinguish activity from infection in this condition.

Should adolescents with glomerulopathies be treated as children or adults?

BACKGROUND: Glomerular diseases are an important cause of end-stage renal disease, especially among young adults. However, clinical and epidemiological surveys involving adolescent populations are scarce. AIM: To determine the pattern of glomerulopathies (GP) in adolescents submitted to renal biopsy. METHODS: A retrospective study of patients' records of the Glomerulopathy Section, UNIFESP (Brazil), was performed RESULTS: Among 72 adolescents (12-18 years) with GP, 15.6 +/- 1.5 years, 58.3% females, the most frequent clinical manifestation was nephrotic syndrome (NS, 71%) and focal segmental glomerulosclerosis (FSGS) was the main histological pattern (24%), followed by minimal change disease (MCD, 19.5%). After comparing the main causes of NS in adolescents with those of adults, we found no statistically significant differences in clinical presentation or outcome. Renal failure-free survival of 1 and 5 years for all GP corresponded to 87.9 and 73.6%, respectively (88.5 and 76.3% for NS). CONCLUSIONS: NS was the main manifestation; FSGS and MCD were the most common histological diagnoses. Our data suggest the GP and particularly the NS pattern in adolescents is similar to that of adults, pointing to the need for an adaptation in diagnostic and treatment protocols for this age group, a pattern which corresponds more closely to that of adults.

O laboratório clínico no rastreamento de doenças renais / The clinical pathology laboratory and the screening of renal diseases

Testes diagnósticos podem ser usados para rastreamento de anormalidades diversas, desde que sejam de aplicação fácil, não sejam dispendiosos, tenhamalta sensibilidade e boa especificidade. Vale ressaltar que, nesse contexto, é importante que a detecção de alguma anormalidade leve a uma conduta quealtere o prognóstico do indivíduo. Recentemente várias organizações ligadas à Nefrologia têm defendido a aplicação de procedimentos de rastreamento, com vistas à detecção precoce de pacientes com lesões renais e à adoção subseqüente de medidas que prolonguem a sobrevida do indivíduo sem necessidade de terapia substitutiva da função renal. Destacam-se entre os testes de maior aplicabilidade no rastreamento da doença renal crônica:dosagem sérica de creatinina, pesquisa de proteinúria e de microalbuminúria, e mesmo o exame completo de urina. São aqui discutidas peculiaridadesdesses testes e as situações em que seu uso está indicado para fins de triagem.

Diagnostic tests can be used for screening of several abnormalities, since they are of easy application, non expensive, and they have high specificity and sensitivity. In such context it is important that the detection of some abnormality conduct to measures with potential to change the prognosis of the indivi -dual. Recently many organizations related to Nephrology have supported the application of screening procedures in order to detect early patients with renal lesions and to use subsequently measures that increase survival of the individual without renal substitutive therapy. The tests more applicable for scree -ning of chronic renal disease are: determination of serum creatinine, proteinuria and microalbuminuria, and even a complete urinalysis. Here we discuss peculiar aspects of these tests and situations in which their use is indicated for screening.

NPHS2 mutations in adult patients with primary focal segmental glomerulosclerosis.

BACKGROUND: Mutations in the NPHS2 gene encoding the protein podocin have recently been found in a recessive form of steroid-resistant nephrotic syndrome. Focal segmental glomerulosclerosis (FSGS) was the histologic diagnosis in many of the patients harboring these mutations. FSGS is a heterogeneous glomerular lesion with diverse origins and outcomes. Although mutational analysis in children permits the identification of an unresponsive group before initiating treatment, there is not much information on adult-onset patients with FSGS. METHODS: We performed NPHS2 gene mutational analysis in 39 adult Brazilian patients with primary FSGS, and evaluated the clinical course of the disease and response to treatment; in addition, we performed urinary screening in 44 relatives of these patients. RESULTS: In this group, only 1 patient (with familial FSGS) had a mutation in the NPHS2 gene with double heterozygosity. The absence of mutations in all other patients evaluated suggests its rarity in sporadic cases of adult-onset (steroid sensitive or resistant) FSGS in our population. CONCLUSIONS: Our results suggest that the analysis of the NPHS2 gene mutation is not indicated as a routine diagnostic procedure in our population for adult-onset patients with FSGS.

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.

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.

NPHS2 R229Q functional variant is associated with microalbuminuria in the general population.

BACKGROUND: Microalbuminuria is a risk factor for developing end-stage renal disease and cardiovascular events. Mutations in NPHS2 have been shown to cause autosomal-recessive nephrotic syndrome. Recently, a functional polymorphism of this gene (R229Q) was described and associated with a maturity-onset form of nephrotic syndrome. We have investigated whether the carrier status of this novel genetic variant is associated with microalbuminuria in individuals from the general population. METHODS: Demographic, cardiovascular risk factors, and renal phenotypes in 1577 individuals from a cross-sectional-based study were collected following the general guidelines of the WHO-MONICA project (monitoring trends and determinants in cardiovascular diseases). Blood and urine samples were obtained. Microalbuminuria was determined using a semiquantitative protocol, and DNA was extracted from peripheral lymphocytes. RESULTS: A strong association was found between the 229Q allele and microalbuminuria (P= 0.008). The presence of the 229Q allele was still associated with a 2.77-fold increased risk of presenting microalbuminuria even after adjustment for age, ethnicity, hypertension, obesity, and diabetes in a multiple logistic regression model. In addition, a statistically significant interaction was identified between the presence of the 229Q allele and body mass index (BMI) (P= 0.01), suggesting an additive effect between the 229Q allele and other risk factors for microalbuminuria. CONCLUSION: These data have important implications for the understanding of microalbuminuria in the general population and may contribute to better ways of disease prediction and prevention.

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.

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.

A locus for adolescent and adult onset familial focal segmental glomerulosclerosis on chromosome 1q25-31.

Focal segmental glomerulosclerosis is a nonspecific renal lesion observed both as a primary (idiopathic) entity and in a secondary form, typically in association with reduced functional renal mass. Familial forms have been observed and two loci for autosomal dominant FSGS have been mapped. This study shows that an adolescent/adult form of recessive FSGS maps to a locus on chromosome 1q25-31, which overlaps with a region previously identified as harboring a locus for an early childhood onset recessive form of nephrotic syndrome (SRN1). Evaluation of a large family demonstrated linkage with a maximum two-point lod score of 3.98 at D1S254 and D1S222. Lod score calculations support the conclusion of linkage in four of five additional families. Haplotype analysis suggests that this FSGS gene is located in a 19-cM region flanked by D1S416 and D1S413, of which 6 cM overlaps with SRN1, suggesting that these distinct clinical subsets of kidney disease may be allelic. These regions may also overlap with the syntenic region of the glomerulosclerosis susceptibility locus in the BUF/Mna rat. Because the presentation of FSGS may be subtle, inherited FSGS may be much more common than generally realized and grossly underestimated because of the absence of clear familial patterns. This result increases the suspicion that polymorphisms at this locus may contribute to sporadic FSGS.

Glomerulonefrite associada à infecçäo pelo vírus da hepatite C / Glomerulonephritis associated with hepatitis C virus infection

Descrevem-se pacientes com glomerulonefrites (GNs) associadas à infecçäo pelo vírus da hepatite C (HCV). Entre agosto de 93 e julho de 96 foram observados 4 pacientes, com idade mediana de 41 anos, sendo 2 do sexo masculino. Pesquisaram-se o anti-HCV por ensaio imuno-enzimático e o HCV-RNA por PCR. Também foram pesquisadas crioglobulinas séricas, hemácias dismórficas no sedimento urinário e proteinúria de 24h. Viremia, crioglobulinas, hematúria e proteinúria foram observadas nos 4 pacientes. As biópsias hepáticas revelaram atividade inflamatória nos 3 pacientes em que foram realizadas e as do rim revelaram glomerulonefrite membranoproliferativa em 3 e glomerulonefrite proliferativa mesangial em 1 paciente. Dois pacientes vêm recebendo antivirais (IFN associado à ribavirina) e evoluindo com melhora. A presença de viremia e de hepatite concomitante com as alteraçöes urinárias constituem indícios do envolvimento viral na glomerulopatia. Tais achados säo reforçados pela melhora das alteraçöes urinárias durante o tratamento específico. Conclui-se que a pesquisa de marcadores virais em pacientes com GNs assume relevância na medida em que pode modificar a conduta terapêutica