Association of Urinary Vitamin D Binding Protein and Neutrophil Gelatinase-Associated Lipocalin with Steroid Responsiveness in Idiopathic Nephrotic Syndrome of Childhood.

Idiopathic nephrotic syndrome (NS) is one of the most common kidney diseases of childhood. In this study, we assessed urine Vitamin-D binding protein (VDBP) and neutrophil gelatinase-associated lipocalin (NGAL) levels as a predictor of steroid responsiveness in idiopathic NS. This cross-sectional study included children with steroid-resistant NS (SRNS) (n = 28), steroid-sensitive NS (SSNS) (n = 28), and healthy controls (n = 28). Urine levels of VDBP and NGAL were measured using a commercially available ELISA kit and normalized to urine creatinine (Cr). Urine microalbumin (MALB) was measured using nephelometer, and MALB/Cr was calculated. Urine Vitamin-D binding protein (uVDBP) and urine neutrophil gelatinase-associated lipocalin (uNGAL) levels were statistically significantly higher (P < 0.001) in patients with SRNS (701.12 ± 371.64 ng/mL and 28.42 ± 15.40 ng/mL, respectively) than in patients with SSNS (252.87 ± 66.34 ng/mL and 8.86 ± 5.54 ng/mL, respectively) and normal controls (34.74 ± 14.10 ng/mL and 6.79 ± 1.32 ng/mL, respectively). Estimated glomerular filtration rate shows a significant negative correlation with MALB/Cr, uVDBP, and uNGAL. However, uVDBP and uNGAL showed a much higher discriminatory ability for differentiating SRNS from MALB/Cr. uVDBP and uNGAL at the cutoff value of 303.81 and 13.1 ng/mL, respectively, yielded the optimal sensitivity (82% and 86%) and specificity (78% and 89%) to distinguish SRNS from SSNS. Urine levels of VDBP and NGAL can predict steroid responsiveness in patients with idiopathic NS.

Steroid-resistant nephrotic syndrome: a persistent challenge for pediatric nephrology.

Steroid-resistant nephrotic syndrome remains a challenge to treat, but various efforts are underway to better understand the pathogenesis and improve patient outcomes. This review provides an update on the newer advances in understanding the molecular etiologies for a variety of podocyte abnormalities, potential circulating factors that may initiate and sustain the steroid-resistant state, genetic mutations, and precision medicine treatment modalities in this continuously perplexing disorder.

Study of nephrotic syndrome in children: importance of light, immunoflourescence and electron microscopic observations to a correct classification of glomerulopathies.

OBJECTIVE: To evaluate the contribution of electron microscopy (EM) to the accurate diagnosis of glomerulopathies in childhood nephrotic syndrome (NS) in a developing country. METHODS: The study was carried out at the Histopathology Department, Sindh Institute of Urology and Transplantation (SIUT) from April 2007 to March 2008. All children (≤18 years) presenting with NS were included. Patients' demographic, clinical, laboratory, and biopsy data were retrieved from case records and biopsy reports. Renal biopsies were studied by light microscopy, immunoflourescence, and EM. RESULTS: The mean age of 74 children was 11.34, 4.85 years, EM was useful in 97.2% of cases, being essential in 31% and helpful in 66.2% cases. CONCLUSION: The results demonstrate that the ultrastructural study is both helpful and essential to a correct classification of glomerular diseases underlying NS in children in nearly all cases and whenever feasible this should be used in the pathologic evaluation of renal biopsies.

Severity of nephrotic IgA nephropathy according to the Oxford classification.

BACKGROUND: IgA nephropathy with nephrotic syndrome (nephrotic IgAN) is a rare form of IgAN. Its prognosis and response to steroid therapy are still controversial because the differential diagnosis between nephrotic IgAN and minimal change nephrotic syndrome with IgA depositions is sometimes confused. METHODS: In this retrospective cohort analysis, we accurately diagnosed 42 cases of nephrotic IgAN (4.4%) from 954 IgAN patients, according to the Oxford classification. We analyzed the clinical and histological data, prognosis, and response to steroid therapy. RESULTS: In nephrotic IgAN, mean estimated glomerular filtration rate (eGFR) was 51.1 ± 24.6 ml/min, proteinuria was 5.71 ± 2.56 g/day, and urinary red blood cells were 51.0 ± 37.8 high power field. Both active and chronic histological lesions were observed. Cumulative renal survival rate was significantly lower in nephrotic IgAN than in non-nephrotic IgAN (the control group consisted of 47 non-nephrotic IgAN patients diagnosed between 1995 and 1996) (log-rank test: P < 0.0001). The cases with steroid therapy significantly improved their prognosis, though their male-to-female ratio and blood pressure level measured at renal biopsy were significantly lower than in the cases without steroid therapy. Steroid therapy was particularly effective in cases with low-grade tubular atrophy and interstitial fibrosis (T-grade in Oxford classification). Without steroid therapy, lower eGFR and higher T-grade were independent risk factors for severe outcome by multivariate Cox regression. CONCLUSION: Nephrotic IgAN is a very severe form of IgAN, with renal dysfunction, massive hematuria, and active and chronic histopathological lesions. Renal outcome is severe; however, steroid therapy can improve prognosis in cases with higher eGFR and lower T-grade, according to the Oxford classification.

Semiología renal y genitourinaria en pediatría: segunda parte / Nephrologoy and urology semiology in children: second part

Entre las patologías renales en niños, se encuentra la injuria renal aguda; que es la pérdida súbita de la función renal; el síndrome nefrótico que es el espectro más grave de proteinuria; el síndrome nefrítico caracterizado por la riada edema, hematuria macro o microscópica e hipertensión arterial.

Among the renal pathology in children is acute kidney injury, which is the sudden loss of kidney function, the nephrotic syndrome is the most severe spectrum of proteinuria, the nephrotic syndrome characterized by the triad of edema, macro or microscopic hematuria and arterial hypertension.

Changes in glomerular mesangium in kidneys with congenital nephrotic syndrome of the Finnish type.

Congenital nephrotic syndrome of the Finnish type (NPHS1, CNF) is an autosomal recessive disease caused by mutations in a major podocyte protein, nephrin. NPHS1 is associated with heavy proteinuria and the development of glomerular scarring. We studied the cellular and molecular changes affecting the glomerular mesangium in NPHS1 kidneys. Marked hyperplasia of mesangial cells (MC) was mainly responsible for the early mesangial expansion in NPHS1 glomeruli. The levels of the proliferation marker, mindbomb homolog 1 and the major MC mitogen, platelet-derived growth factor, and its receptors, however, were quite normal. Only a small number of cells were positive for CD68 (marker for phagocytic cells) and CD34 (marker for mesenchymal precursor cells) in the NPHS1 mesangium. MCs strongly expressed alpha-smooth muscle actin, indicating myofibloblast transformation. The expression levels of the profibrotic mediators osteopontin and transforming growth factor beta were up-regulated in NPHS1 glomeruli by 3.2 and 1.6-fold, respectively, compared to the controls. The synthesis by MCs of the typical fibroblast products collagen I, fibronectin, and tenascin, however, was low, and the extracellular matrix increase was caused by the accumulation of a normal MC product, collagen IV. The results indicate that severe glomerular sclerosis can develop without major qualitative cellular or molecular changes in the mesangium.

Management of childhood onset nephrotic syndrome.

The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Children's Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a children's primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

Congenital nephrotic syndrome.

When presented with an edematous infant who may be experiencing a severe infection, particularly an unusual one, it is important to include nephrotic syndrome in the differential diagnosis. Because drastic measures may be required to manage this illness, it is important to be able to recognize symptoms, compile needed diagnostic data, and commence appropriate treatment. A referred pediatric nephrologist can aid in diagnosis, direct management, and educate and support parents. The nephrologist is also instrumental in guiding ongoing care and preparing the infant for transplantation when it becomes necessary.

[Congenital and infantile nephrotic syndrome]. / Syndromes néphrotiques congénitaux et infantiles.

Congenital nephrotic syndrome is present at birth or appears during the first three months of life and infantile nephrotic syndrome during the first year. Finnish type congenital nephrotic syndrome is an autosomal recessive disease. Nephrotic syndrome is present at birth, severe and does not respond to therapy. Infectious and nutritional complications are frequent. Renal function deteriorates necessitating a dialysis-transplantation program. Between age five and eight. The disease does not recur after transplantation. Diffuse mesangial sclerosis is the second cause of congenital and infantile nephrotic syndrome. It may be isolated or part of a Denys-Drash syndrome (association of the nephropathy with male pseudohermaphroditism and Wilm's tumor). Nephrotic syndrome is resistant to therapy. Renal failure develops in early childhood. Therapy is aimed to prevent oedema, denutrition, infections and thrombosis. Proteinuria does not recur after renal transplantation. Other causes are less frequent.

Influence of nephrotic state on the infectious profile in childhood idiopathic nephrotic syndrome

OBJETIVO: Caracterizar as infecções, em pacientes com Síndrome Nefrótica Idiopática. PACIENTES E MÉTODOS: Foram analisados, os prontuários de 92 crianças e adolescentes com Síndrome Nefrótica Idiopática . Os tipos de infecções foram agrupados em: Infecções de Vias Aéreas Superiores , Pnemonia, Infecções Cutâneas, Peritonite, Diarréia, Infecção do Trato Urinário, Herpes Vírus e Outros. Os pacientes foram divididos, em dois grupos: Grupo I (córtico-sensíveis)-n=75, com quatro subgrupos; IA (episódio único)-n=10; IB (recidivantes infreqüentes)-n=5; IC (recidivantes freqüentes)-n=14 e ID (córtico-dependentes) n=46; e Grupo II (córtico-resistentes)-n=17. Comparou-se a densidade de incidência de infecções nos períodos com proteinúria negativa e nefrótica. No período com proteinúria nefrótica, comparou-se a densidade de incidência de infecções dos grupos e subgrupos entre si. Da mesma forma, no período com proteinúria negativa. RESULTADO: A análise revelou maior densidade de incidência de infecções, no período com proteinúria nefrótica, em todos os grupos e subgrupos, com exceção do subgrupo IA. No período com proteinúria nefrótica, os subgrupos IC, ID e o grupo II, apresentaram maior densidade de incidência de infecções, quando comparados ao subgrupo IA. No período com proteinúria negativa, não houve diferença na densidade de incidência de infecções entre os grupos e subgrupos. As Infecções de Vias Aéreas Superiores foram os processos infecciosos mais freqüentes. CONCLUSÃO: O estado nefrótico, manifesto através de recidivas freqüentes, dependência ou resistência aos corticosteróides, conferiu ao pacientes com Síndrome Nefrótica Idiopática , maior susceptibilidade à infecções. O resultado deste estudo reforça que a melhor prevenção anti-infecciosa nesta doença é o controle do estado nefrótico.

[The dependence of the progression of chronic glomerulonephritis on the clinical and morphological types of glomerulonephritis and on the tubulointerstitial changes]. / Zavisimost' progressirovaniia khronicheskogo glomerulonefrita ot klinicheskogo i morfologicheskogo tipov glomerulonefrita i tubulointerstitsial'nykh izmenenii.

Progression of chronic glomerulonephritis (CGN) is strongly associated with morphologic type of the disease, tubulointerstitial changes, some clinical syndromes. The aim of the study was to trace relations between the onset of chronic renal failure within 7 years since the diagnosis (fast progression of CGN--FP CGN), CGN clinical variant according to M. Ia. Ratner et al. classification (1987) and histomorphological changes in the renal biopsy. Unfavorable clinical types (active nephritic types and nephrotic-hypertensive type) proved dominating predictor of FP CGN not only because of close relationship between these type and FP CGN but also due to FP CGN occurrence in morphologically unfavorable morphological types and tubulointerstitial changes in line with concomitant unfavorable clinical types.

Síndrome nefrótico en infantes y adolescentes: revisión bibliográfica / Nefrótico syndrome in infants and adolescents: bibliographical overhaul

Presenta una revisión bibliográfica, describe el síndrome nefrótico durante la infancia y la adolescencia desde su definición, pasando por su clasificación y ciertas consideraciones generales, detallando su etiología, fisio e histopatología, consideraremos sus manifestaciones clínicas, finalizaremos con el esquema terapéutico y su pronóstico.

The nonspecificity of focal segmental glomerulosclerosis. The defining characteristics of primary focal glomerulosclerosis, mesangial proliferation, and minimal change.

We performed a detailed clinical review and pathologic analysis of the kidney biopsies of 134 children with nephrotic syndrome or asymptomatic proteinuria. This analysis challenges some of our concepts about the classification of conditions associated with these disorders. The presence of focal segmental sclerotic lesions does not define a unique disorder in childhood. Some children with such lesions will have unaffected glomeruli that are ultrastructurally completely normal. These patients, predominately black adolescents, present either with nephrotic syndrome or asymptomatic proteinuria. We classify this disorder as primary focal segmental glomerulosclerosis (FSGS) and have never found it to recur after transplantation. Most other children with FSGS have 1 of 2 specific glomerulopathies. Those with minimal change have generalized fusion of podocyte foot processes. Those with mesangial proliferation have similar foot process changes combined with mesangial expansion and proliferation and, frequently, thinning of the lamina densa and tubuloreticular inclusions. The presence of segmental lesions in these glomerulopathies appears to be nothing more than a marker of severity. Children with these glomerulopathies are generally younger white children, virtually all of whom have nephrotic syndrome. These disorders have a strong propensity to recur after transplantation. The presence of mesangial labeling of IgM or C1q has no significance in any of these 3 disorders. The classification of disorders associated with nephrotic syndrome or asymptomatic proteinuria must concentrate less on the presence or absence of focal sclerosis and more on the histologic appearance of the rest of the glomeruli.

Nephrotic syndrome in Trinidadian children.

57 children with idiopathic nephrotic syndrome who were seen at two hospitals in Trinidad between 1989 and 1995 (median follow-up period, 38 months) were classified according to their response to glucocorticoids. 27 (47%) were two to six years old at presentation; 37 (65%) were of East Indian descent, 7 (12%) were of African descent, and 12 (21%) were of mixed race. 55 (96%) responded to glucocorticoids. Renal biopsies in 15 patients revealed membranoproliferative glomerulonephritis and membranous nephropathy in the two patients who had not responded to glucocorticoids. Ten patients showed mesangial hypercellularity, associated with immunoglobulin deposits in 7 cases. Age, presentation with nephrotic features, mesangial hypercellularity and immunoglobulin deposits did not predict for unresponsiveness to glucocorticoids. These findings may be explained by the predominance of East Indians in the study group.

Post-transplantation nephrosis in congenital nephrotic syndrome of the Finnish type.

Congenital nephrotic syndrome of the Finnish type (CNF) is an autosomal recessively inherited disease manifesting as massive proteinuria, edema and ascites in the neonatal period. The disease is believed to be limited to the kidneys and recurrences after renal transplantation have not been reported. At our center 29 transplantations have been performed on 28 CNF patients. One to 33 months after transplantation, seven grafts (24%) of six patients have developed a steroid-resistant nephrotic syndrome. The clinical data and renal histology of these patients were analyzed in order to elucidate the cause of the proteinuria. At the onset of six of the seven episodes of nephrosis, the patient had evidence of a preceding CMV- or EBV-infection and the remaining patient had sinusitis. Upon light and electron microscopy examination, endothelial swelling of the glomerular capillaries resembling transplant glomerulopathy (TG) was seen, but unlike TG, the glomerular basement membranes were normal. The response of proteinuria to steroid or cyclophosphamide therapy was poor, with total remission in only two patients and partial remission in one patient, all treated with methylprednisolone and cyclophosphamide immediately after the diagnosis. Four grafts have been lost. Our data show that CNF patients have an increased tendency for post-transplantation nephrosis.

A follow up study of adult nephrotic syndrome in Nigerians: outcome and predictors of endstage renal failure.

Clinical data from 88 patients who presented with the nephrotic syndrome and biopsy proven glomerular disease were analysed to determine the outcome after 8 years of follow up, and to find out the influence of glomerular histology, sex, age, plasma creatinine, creatinine clearance, hypertension, 24-hour urinary protein excretion and microscopic haematuria, on the clinical course and outcome. The results showed that at the end of follow up (8 years), 13 patients (14.8%) had died from renal failure while 24 patients (27.2%) were in chronic renal failure. Persistent renal disease was still present in 29 patients (33.0%). Of the whole group (88), mortality and endstage renal failure were highest amongst patients with focal segmental glomerulosclerosis and membrano-proliferative glomerulonephritis. Male sex, hypertension, impaired plasma creatinine and creatinine clearance in patients from these two groups were associated with progression to chronic renal failure and death from uraemia. At final observation hypertension and microscopic haematuria were marked features of these two histological groups. Prognosis in minimal change nephropathy was quite good with remission occurring in 20 patients (66.6%); persistent renal disease however occurred in 8 patients (26.6%) while 1 patient died from uraemia.

[The prognosis of the accelerated progression of chronic glomerulonephritis]. / Prognozirovanie uskorennogo progressirovaniia khronicheskogo glomerulonefrita.

Based on the data of the 20-year follow-up of 146 patients suffering from intracapillary chronic glomerulonephritis (CGN) verified with the aid of nephrobiopsy, the conclusion was made about the necessity of distinguishing rapid-progressing CGN. In such pattern of CGN, chronic renal failure may occur for up to 5 years since the disease onset. A significant relationship was established between the incidence of rapid-progressing CGN and the morphological and clinical types as well as tubulointerstitial alterations. The clinical types included the active and inactive nephritic, nephrotic and nephrotic-hypertonic types. A regressive analysis made according to the Cox method permitted one to establish that the clinical type of CGN is the most reliable factor of predicting rapid-progressing disease.