Compromiso renal en artritis idiopática juvenil (AIJ) en una población de pacientes colombianos

La artritis idiopática juvenil AIJ es la entidad más frecuente de las enfermedades reumatológicas en la infancia. No se conoce la prevalencia global del compromiso renal en los pacientes con AIJ, considerándose de rara ocurrencia. Objetivo: Describir el compromiso renal en niños con diagnóstico de artritis idiopática juvenil (AIJ) en la Clínica Infantil Colsubsidio atendidos en el periodo comprendido entre marzo de 2006 y marzo de 2010 Materiales y métodos: Estudio retrospectivo descriptivo de serie de casos. Pacientes de la Clínica Infantil Colsubsidio con diagnóstico de AIJ, con posterior revisión sistemática de las historias clínicas. Se introdujeron los datos a una base creada en Excel 2007 y se realizó el análisis estadístico con el programa estadístico STATA 10.1 Resultados: 35 pacientes del género masculino (30.43%) y 80 del femenino (69.57%). Con una mediana de edad de 7 años . La prevalencia de compromiso renal para esta población fue de 30.43%. con diferencias estadísticamente significativas en las variables relación proteinuria / creatinuria y proteinuria de 24 horas .Se realizó biopsia renal en 3 pacientes (2.61% de la población) con nefropatía de cambios mínimos. Se encontraron diferencias estadísticamente significativas en cuanto al uso de prednisolona, metotrexate oral y metotrexate intravenoso. Conclusiones: El compromiso renal representa una complicación importante y no tan infrecuente en los paciente que padecen AIJ. Se observó una mayor prevalencia en los pacientes con AIJ que usaron prednisolona y metotrexate endovenoso, sin que esto represente una asociación causal. Se sugiere la realización de un estudio prospectivo.

Collectives of diagnostic biomarkers identify high-risk subpopulations of hematuria patients: exploiting heterogeneity in large-scale biomarker data

Background: Ineffective risk stratification can delay diagnosis of serious disease in patients with hematuria. We applied a systems biology approach to analyze clinical, demographic and biomarker measurements (n = 29) collected from 157 hematuric patients: 80 urothelial cancer (UC) and 77 controls with confounding pathologies.

Methods: On the basis of biomarkers, we conducted agglomerative hierarchical clustering to identify patient and biomarker clusters. We then explored the relationship between the patient clusters and clinical characteristics using Chi-square analyses. We determined classification errors and areas under the receiver operating curve of Random Forest Classifiers (RFC) for patient subpopulations using the biomarker clusters to reduce the dimensionality of the data.

Results: Agglomerative clustering identified five patient clusters and seven biomarker clusters. Final diagnoses categories were non-randomly distributed across the five patient clusters. In addition, two of the patient clusters were enriched with patients with ‘low cancer-risk’ characteristics. The biomarkers which contributed to the diagnostic classifiers for these two patient clusters were similar. In contrast, three of the patient clusters were significantly enriched with patients harboring ‘high cancer-risk” characteristics including proteinuria, aggressive pathological stage and grade, and malignant cytology. Patients in these three clusters included controls, that is, patients with other serious disease and patients with cancers other than UC. Biomarkers which contributed to the diagnostic classifiers for the largest ‘high cancer- risk’ cluster were different than those contributing to the classifiers for the ‘low cancer-risk’ clusters. Biomarkers which contributed to subpopulations that were split according to smoking status, gender and medication were different.

Conclusions: The systems biology approach applied in this study allowed the hematuric patients to cluster naturally on the basis of the heterogeneity within their biomarker data, into five distinct risk subpopulations. Our findings highlight an approach with the promise to unlock the potential of biomarkers. This will be especially valuable in the field of diagnostic bladder cancer where biomarkers are urgently required. Clinicians could interpret risk classification scores in the context of clinical parameters at the time of triage. This could reduce cystoscopies and enable priority diagnosis of aggressive diseases, leading to improved patient outcomes at reduced costs. © 2013 Emmert-Streib et al; licensee BioMed Central Ltd.

Standardization of diagnostic biomarker concentrations in urine; the hematuria caveat

Sensitive and specific urinary biomarkers can improve patient outcomes in many diseases through informing early diagnosis. Unfortunately, to date, the accuracy and translation of diagnostic urinary biomarkers into clinical practice has been disappointing. We believe this may be due to inappropriate standardization of diagnostic urinary biomarkers. Our objective was therefore to characterize the effects of standardizing urinary levels of IL-6, IL-8, and VEGF using the commonly applied standards namely urinary creatinine, osmolarity and protein. First, we report results based on the biomarker levels measured in 120 hematuric patients, 80 with pathologically confirmed bladder cancer, 27 with confounding pathologies and 13 in whom no underlying cause for their hematuria was identified, designated “no diagnosis”. Protein levels were related to final diagnostic categories (p = 0.022, ANOVA). Osmolarity (mean = 529 mOsm; median = 528 mOsm) was normally distributed, while creatinine (mean = 10163 µmol/l, median = 9350 µmol/l) and protein (0.3297, 0.1155 mg/ml) distributions were not. When we compared AUROCs for IL-6, IL-8 and VEGF levels, we found that protein standardized levels consistently resulted in the lowest AUROCs. The latter suggests that protein standardization attenuates the “true” differences in biomarker levels across controls and bladder cancer samples. Second, in 72 hematuric patients; 48 bladder cancer and 24 controls, in whom urine samples had been collected on recruitment and at follow-up (median = 11 (1 to 20 months)), we demonstrate that protein levels were approximately 24% lower at follow-up (Bland Altman plots). There was an association between differences in individual biomarkers and differences in protein levels over time, particularly in control patients.

Proteinuria predicts relapse in adolescent and adult minimal change disease

OBJECTIVE: This study sought to outline the clinical and laboratory characteristics of minimal change disease in adolescents and adults and establish the clinical and laboratory characteristics of relapsing and non-relapsing patients.METHODS: We retrospectively evaluated patients with confirmed diagnoses of minimal change disease by renal biopsy from 1979 to 2009; the patients were aged >13 years and had minimum 1-year follow-ups.RESULTS: Sixty-three patients with a median age (at diagnosis) of 34 (23-49) years were studied, including 23 males and 40 females. At diagnosis, eight (12.7%) patients presented with microscopic hematuria, 17 (27%) with hypertension and 17 (27%) with acute kidney injury. After the initial treatment, 55 (87.3%) patients showed complete remission, six (9.5%) showed partial remission and two (3.1%) were nonresponders. Disease relapse was observed in 34 (54%) patients who were initial responders (n = 61). In a comparison between the relapsing patients (n = 34) and the non-relapsing patients (n = 27), only proteinuria at diagnosis showed any significant difference (8.8 (7.1-12.0) vs. 6.0 (3.6-7.3) g/day, respectively, p = 0.001). Proteinuria greater than 7 g/day at the initial screening was associated with relapsing disease.CONCLUSIONS: In conclusion, minimal change disease in adults may sometimes present concurrently with hematuria, hypertension, and acute kidney injury. The relapsing pattern in our patients was associated with basal proteinuria over 7 g/day.

Proteinuria predicts relapse in adolescent and adult minimal change disease

OBJECTIVE: This study sought to outline the clinical and laboratory characteristics of minimal change disease in adolescents and adults and establish the clinical and laboratory characteristics of relapsing and non-relapsing patients. METHODS: We retrospectively evaluated patients with confirmed diagnoses of minimal change disease by renal biopsy from 1979 to 2009; the patients were aged >13 years and had minimum 1-year follow-ups. RESULTS: Sixty-three patients with a median age (at diagnosis) of 34 (23-49) years were studied, including 23 males and 40 females. At diagnosis, eight (12.7%) patients presented with microscopic hematuria, 17 (27%) with hypertension and 17 (27%) with acute kidney injury. After the initial treatment, 55 (87.3%) patients showed complete remission, six (9.5%) showed partial remission and two (3.1%) were nonresponders. Disease relapse was observed in 34 (54%) patients who were initial responders (n = 61). In a comparison between the relapsing patients (n = 34) and the non-relapsing patients (n = 27), only proteinuria at diagnosis showed any significant difference (8.8 (7.1-12.0) vs. 6.0 (3.6-7.3) g/day, respectively, p = 0.001). Proteinuria greater than 7 g/day at the initial screening was associated with relapsing disease. CONCLUSIONS: In conclusion, minimal change disease in adults may sometimes present concurrently with hematuria, hypertension, and acute kidney injury. The relapsing pattern in our patients was associated with basal proteinuria over 7 g/day.

Metodi di misurazione e implicazioni dell'albuminuria e della proteinuria nel cane

La proteinuria è un marker di danno renale nel cane. L’obiettivo dello studio è di valutare la capacità del dipstick urinario e dell’UPC di diagnosticare precocemente l’albuminuria nel cane. Sono stati raccolti 868 campioni di urina, con sedimento spento e assenza di ematuria, nell’Ospedale Didattico Veterinario della Facoltà di Medicina Veterinaria di Bologna. Per 550 campioni è stata effettuata l’analisi delle urine, la misurazione dell’UPC e dell’UAC, mentre UPC e UAC sono stati misurati in tutti gli 868 campioni. I campioni di urina sono stati analizzati con il metodo dipstick mediante lettura automatizzata. Utilizzando come valore di riferimento l’UAC è stata valutata l’accuratezza diagnostica del dipstick urinario e dell’UPC. L’intervallo di riferimento dell’UAC (0-0,024) è stato determinato utilizzando 60 cani sani. I dati raccolti sono stati classificati utilizzando differenti cut-off per il peso specifico urinario (1012 o 1030), per la proteinuria al dipstick (30 o 100 mg/dl), per l’UPC (0,2) e per l’UAC (0,024). Sono stati valutati l’agreement diagnostico e la correlazione di Spearman tra dipstick, UPC e UAC. E’ stata stimata l’accuratezza diagnostica misurando l’area al di sotto della curva di ROC nell’analisi dell’UAC. Il livello di significatività è stato definito per p < 0,05. Indipendentemente dal peso specifico urinario, l’agreement diagnostico tra dipstick, UPC e UAC è risultato forte (k=0,62 e k=0,61, rispettivamente; p<0,001) con valori di dipstick ≥30 mg/dl, debole (k=0,27 e k=0,26, rispettivamente; p<0,001) con valori di dipstick ≥100 mg/dl. L’accuratezza diagnostica del dipstick messa a confronto con UPC e con UAC è molto buona (AUC 0,84 e 0,84, rispettivamente; p<0,001) e i risultati negativi al dipstick presentano il 100% di sensitività. UPC e UAC sono fortemente correlate (r=0,90; p<0,001). Mettendo a confronto UPC e UAC, l’accuratezza diagnostica è risultata eccellente (AUC 0,94; p<0,001), con massima sensitività e specificità per UPC≥0.3.

Tenofovir-associated proteinuria

Proteinuria was observed in 27% of 153 patients taking tenofovir for more than 1 year. Concomitant protease inhibitor therapy and cumulative tenofovir exposure were independently associated with proteinuria in this cohort. Proteinuria was reversible in 11 of 12 patients who ceased tenofovir because of proteinuria without altering other medications. Clinicians should be aware that tenofovir can cause reversible proteinuria in patients with HIV.

Fucoidan inhibits the development of proteinuria in active Heymann nephritis

Fucoidan, the sulphated polysaccharide extracted from brown seaweed, has various biological activities. The effect of fucoidan on the formation of proteinuria and renal functions in active Heymann nephritis was investigated in this study. Active Heymann nephritis was induced by administering brush border protein of rat proximal uriniferous tubules (FX1A). Fucoidan was administered by oral intubation to Heymann nephritis rats at three doses (50, 100 and 200 mg/kg) once daily for 4 weeks. The elevated urinary protein excretion and plasma creatinine due to the induction of Heymann nephritis were significantly reduced by fucoidan at doses of 100 and 200 mg/kg. The results indicated that fucoidan has a renoprotective effect on active Heymann nephritis and is a promising therapeutic agent for nephritis. Copyright (c) 2005 John Wiley F Sons, Ltd.

Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.

The impact of biomarkers in multivariate algorithms for bladder cancer diagnosis in patients with hematuria

BACKGROUND: We appraised 23 biomarkers previously associated with urothelial cancer in a case-control study. Our aim was to determine whether single biomarkers and/or multivariate algorithms significantly improved on the predictive power of an algorithm based on demographics for prediction of urothelial cancer in patients presenting with hematuria. METHODS: Twenty-two biomarkers in urine and carcinoembryonic antigen (CEA) in serum were evaluated using enzyme-linked immunosorbent assays (ELISAs) and biochip array technology in 2 patient cohorts: 80 patients with urothelial cancer, and 77 controls with confounding pathologies. We used Forward Wald binary logistic regression analyses to create algorithms based on demographic variables designated prior predicted probability (PPP) and multivariate algorithms, which included PPP as a single variable. Areas under the curve (AUC) were determined after receiver-operator characteristic (ROC) analysis for single biomarkers and algorithms. RESULTS: After univariate analysis, 9 biomarkers were differentially expressed (t test; P

Tracking down the cause of proteinuria in primary care

Proteinuria originates from the kidney and occurs as a result of injury to either the glomerulus or the renal tubule or both. It is relatively common in the general population with reported point prevalence of up to 8% but the prevalence falls to around 2% on repeated testing. Chronic glomerular injury resulting in proteinuria may be secondary to prolonged duration of diabetes or hypertension. A tubular origin of proteinuria may be associated with inflammation of renal tubules triggered by prescribed drugs or ingested toxins. In the absence of obvious clues to the cause of persistent proteinuria on history or clinical examination it is worthwhile reviewing the patient's prescribed drugs to identify any potentially nephrotoxic agents e.g. NSAIDs. NICE guidelines recommend screening for proteinuria in individuals at higher risk for chronic kidney disease (CKD). These include patients with diabetes, hypertension, cardiovascular disease, connective tissue disorders, a family history of renal disease and those prescribed potentially nephrotoxic drugs. Patients with sudden onset of lower limb oedema and associated proteinuria should have a serum albumin level measured to exclude the nephrotic syndrome. Renal tract ultrasound will measure kidney size, and detect scarring associated with chronic pyelonephritis or prior renal stone disease which can cause proteinuria.

Prevalencia de nefropatía de cambios mínimos en biopsia renal en niños con síndrome nefrótico idiopático en una institución en Bogotá

Introducción: El síndrome nefrótico idiopático es una entidad con una tasa de prevalencia de 16/100.000 niños, en la cual ocurre pérdida de proteínas a través del filtro glomerular; la proteinuria > 40mg/sc/hora, se acompaña de edema, hipoproteinemia, albumina < 2,5g/dL. La ausencia de datos de prevalencia de nefropatía de cambios mínimos en nuestro medio limita la perspectiva real para lograr un manejo integral de nuestros niños y el enfoque a seguir por parte del grupo de pediatría. Materiales y métodos: Estudio de corte transversal descriptivo, se revisan historias clínicas de los niños con síndrome nefrótico idiopático con biopsia renal, que asistieron a la consulta de nefrología pediátrica en la Fundación Cardio Infantil durante un período de 14 años. Resultados: La prevalencia de nefropatía de cambios mínimos en nuestro subgrupo de pacientes con biopsia renal es de 24,2%. En esta, se presentaron 50% con hematuria macroscópica y 43,7% con hematuria microscópica. La insuficiencia renal crónica se presentó en un sólo paciente con 6,25% y la corticoresistencia en 3 pacientes con 18,7%. Discusión: La prevalencia de nefropatía de cambios mínimos en nuestra población es la tercera parte de lo reportado en la literatura mundial en población general con síndrome nefrótico idiopático. Esta prevalencia menor en nuestro estudio se puede deber posiblemente por tratarse la población de nuestro estudio un subgrupo de pacientes con indicación de biopsia renal además de ser la Fundación Cardio Infantil, central de referencia que llegan remitidos patologías más complejas.