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.

Efficacy of leflunomide combined with prednisone in the treatment of refractory nephrotic syndrome.

OBJECTIVE: To assess the safety and clinical efficacy of leflunomide (LEF) and prednisone on refractory nephrotic syndrome (RNS). METHODS: A total of 52 patients with RNS were treated for 24 weeks between 2010 and 2014 in our hospital. In the treated group, 26 patients were treated with LEF and prednisone, and, in the control group, 26 patients were treated with cyclophosphamide (CTX) and prednisone. During the treatment, 24 h urinary protein excretion and the serum levels of albumin and cholesterol, and kidney function were assayed before and after the therapy. Adverse reactions during treatment were recorded. RESULTS: In the LEF group, the medication was markedly effective in eight cases and effective in nine cases; the total efficacy rate was 65.30%. In the CTX group, the treatment was markedly effective in six cases and effective in nine cases; the total efficacy rate was 57%. There were no significant differences between the results of the total efficacy rate (p > .05). The 24 h urinary protein excretion and serum cholesterol levels in both groups decreased after therapy and the serum levels of albumin in both groups increased after therapy. There were significant differences between the results for the 24 h urinary protein excretion, serum levels of albumin and cholesterol in the two groups (p < .05). The treatments were well tolerated in both groups. CONCLUSION: LEF combined with prednisone has a certain efficacy on the RNS and displays few adverse reactions. A large-sample, randomized double-blind controlled study and long-term follow-up are needed to verify the efficacy of LEF combined with prednisone.

Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome.

BACKGROUND: Rituximab (RTX) is a promising option for treating childhood-onset steroid-dependent (SDNS), frequently relapsing (FRNS), and steroid-resistant (SRNS) nephrotic syndrome. METHODS: We retrospectively surveyed RTX treatment for these conditions to evaluate its indications, efficacy and adverse events. Questionnaires were sent to 141 hospitals in Japan. RESULTS: Seventy-four patients (52 SDNS; 3 FRNS; 19 SRNS) were treated with RTX because of resistance to various immunosuppressive agents. Most patients received a single administration of RTX (85%). Forty-one of 53 SDNS/FRNS (77%) and 5 of 17 SRNS (29%) patients successfully discontinued prednisolone (16 SDNS/FRNS and 6 SRNS achieved their first discontinuation since onset), and 17 out of 53 SDNS/FRNS patients (31%) discontinued cyclosporine. However, 28 of the 53 patients (51%) relapsed. Although immunosuppressive agents did not extend B cell depletion, relapses were significantly less if immunosuppressive agents were continued after RTX (P = 0.006; hazard ratio = 0.2). Among the SRNS patients, complete (n = 6) and partial remission (n = 6) were achieved. No life-threatening adverse events were experienced. CONCLUSIONS: Although this was a multi-center survey where treatment of nephrotic syndrome varied between centers, the steroid-sparing effect of RTX in SDNS/FRNS was excellent. If single administration of RTX is chosen, continuation of immunosuppressive agents is recommended for prevention of relapse.

Clinical presentation & management of glomerular diseases: hematuria, nephritic & nephrotic syndrome.

Because the differential diagnosis for glomerulonephritis (GN) is broad, using a classification schema is helpful to narrow the causes of GN in a systematic manner. The etiology of glomerulonephritis can be classified by their clinical presentation (nephrotic, nephritic, rapidly progressive GN, chronic GN) or by histopathology. GN may be restricted to the kidney (primary glomerulonephritis) or be a secondary to a systemic disease (secondary glomerulonephritis). The nephrotic syndrome is defined by the presence of heavy proteinuria (protein excretion greater than 3.0 g/24 hours), hypoalbuminemia (less than 3.0 g/dL), and peripheral edema. Hyperlipidemia and thrombotic disease may be present. The nephritic syndrome is associated with hematuria and proteinuria and abnormal kidney function and carries poorer prognosis and is typically associated with hypertension. The predominant cause of the nephrotic syndrome in children is minimal change disease. The most common causes of nephritic syndrome are post infectious GN, IgA nephropathy and lupus nephritis. Chronic GN is slowly progressive and is associated with hypertension and gradual loss of kidney function. Treatment includes non-specific measure aimed at controlling hypertension, edema, proteinuria and disease modifying immunosuppression.

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.

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.

Molecular stratification of idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome (INS) describes a group of pathologies of the renal glomerulus that result in the classic triad of heavy proteinuria, oedema and hypoalbuminaemia. The disease has historically been defined by evidence of distinctive histological changes in the absence of clinical evidence of a distinct pathological driver. However, the current classification is not based on any systematic mechanistic understanding of biological processes, and therefore current treatment regimens are broad, iterative and nonspecific. Over the past 20 years delineation of the underlying biology of the target cell in INS - the glomerular podocyte - has transformed our understanding of the mechanisms that contribute to breakdown of the glomerular filtration barrier and the development of INS. It is increasingly clear that nephrotic syndrome caused by monogenic mutations is distinct from immune-driven disease, which in some cases is mediated by circulating factors that target the podocyte. The combination of systems biology and bioinformatics approaches, together with powerful laboratory models and ever-growing patient registries has potential to identify disease 'signatures' that reflect the underlying molecular mechanism of INS on an individual basis. Understanding of such processes could lead to the development of targeted therapies.

Childhood nephrotic syndrome in tropical Africa: then and now.

This descriptive and comparative review examines the changing epidemiology, treatment, renal and patient outcome of childhood nephrotic syndrome (NS) in tropical Africa (TpAfr). In the 1960s to 1980s, corticosteroid-resistant non-minimal change disease (nMCD) including quartan malaria nephropathy (QMN) was the dominant renal histopathology type. The overall incidence of NS was 0.35-1.34% of hospital admissions. Median age at onset of NS ranged between 4.0 and 12.0 years while the mean (SD) age range was 5.8 (3.8) to 10.3 (4.8) years across studies. The male: female ratio was 1.6:1.0. The overall mean (SD) incidence of idiopathic minimal change disease (MCD) [21.6 (18.6%)] compared with idiopathic nMCD [59.1 (25.7%)] demonstrates significant dominance of the latter (p = 0.0001). Post-1989, the following mean (SD) incidences of histopathological types were: MCD 20.4 (17.7%), focal segmental glomerulosclerosis 39.0 (26.3%), membranoproliferative glomerulonephritis 25.4 (16.8%), proliferative glomerulonephritis 16.7 (27.0%) and membranous nephropathy 7.4 (4.5%). While the mean (SD) proportion of steroid resistance (SR) [73.5 (19.2%)] was significantly greater than the mean complete remission (CR) [26.5 (19.2%)] during 1960-1989 (p=0.005), mean (SD) SR [27.4 (25.3%)] was significantly lower than mean (SD) CR [66.1 (28.0%)] post-1989 (p < 0.001). Unlike QMN, hepatitis B virus, HIV infection, sickle cell disease and systemic lupus erythematosus are now increasingly being associated with NS in TpAfr. Mean (SD) renal survival post-1989 was 58.3 (37.0%) while all-cause mortality was 9.8%. Children with NS now survive better than before, reflecting improved access to healthcare and transition to a clinical pattern favouring idiopathic NS and increased sensitivity to corticosteroids.

[Evaluation of therapeutic strategies in congenital nephrotic syndrome of the Finnish type]. / Evaluación de las estrategias terapéuticas en el síndrome nefrótico congénito tipo finlandés.

INTRODUCTION: Congenital nephrotic syndrome of the Finnish type (CNFS) is caused by mutations in the nephrin gene. This disease manifests as massive proteinuria, gross peripheral edema, and ascites during the first weeks of life. In the last few years the prognosis has improved due to new treatment strategies: antiproteinuria drugs, intensive nutrition, nephrectomy, dialysis, and renal transplantation. The aim of this study was to determine the impact of these therapeutic measures. PATIENTS AND METHOD: We performed a descriptive retrospective epidemiological study of 12 patients diagnosed with CNSF between January 1985 and August 2005. We included patients aged less than 14 years old with massive proteinuria and generalized edema during the neonatal period, a large placenta (> 25 % of birth weight), and normal glomerular filtration rate during the first 6 months of life, in whom other causes of congenital nephrotic syndrome were ruled out. RESULTS: The diagnosis was established after a median period of 17 days (range 6-30). The most commonly used treatments were albumin infusions (91.7 %), angiotensin-converting enzyme inhibitors (66.7 %), and indomethacin (58.3 %). Dialysis was started in 58.3 %, at a median age of 3.76 years (2.81-7.6). The main complication was acute peritonitis (85.7 %). Renal transplantation was performed in 58.3 % of the patients; of these, 71.4 % have normal renal function after a median follow-up of 3.73 years (0.8-6.3). The median plasma albumin level during the pretransplant period was 0.17 g/dL (0.12-0.28). Plasma cholesterol and triglyceride levels decreased significantly after renal transplantation (p = 0.043). Fifty percent of the patients achieved adequate height and weight for their age and gender. Mortality was 33.3 %. CONCLUSION: Antiproteinuria drugs and intensive nutritional therapy improve clinical control and delay the start of dialysis and renal transplantation, increasing the probability of success.

[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.

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.

The influence of hypoalbuminemia in the generation of nephrotic hyperlipidemia.

Lipoprotein measurements in a group of 29 patients with massive proteinuria and without hypoalbuminemia, were compared with those observed in matched controls and patients with overt nephrotic syndrome to assess the influence of plasma albumin concentration and proteinuria in modulating blood lipid levels. Plasma apoprotein B and apo B containing lipoproteins were not increased in proteinuric normoalbuminemic patients. There was a good correlation between plasma albumin and oncotic pressure (r = 0.937; P < 0.001). Plasma oncotic pressure was inversely correlated with plasma apoprotein B in nephrotic patients (r = -0.44, P = 0.017) but not in normoalbuminemics (r = 0.17, P = 0.369), suggesting that plasma albumin affects apoprotein B secretion. Other findings, however, indicate that multiple processes are ocurring simultaneously in these patients. There was an accumulation of very low- and intermediate density lipoproteins in normoalbuminemics, suggesting a residual defect in the lipoprotein removal. Also, raised (P < 0.05) lipoprotein(a) levels respect to controls (median, 0.15 g/l) were noted in both, normoalbuminemics (median, 0.72 g/l) and hypoalbuminemics (median, 0.84 g/l) with similar degree of proteinuria (6.4 vs. 6.6 g/24 h), suggesting that other mechanisms may be operative in lipoprotein(a) derangements. Our findings suggest that there is no unique mechanism in the pathogenesis of nephrotic hyperlipidemia but that both hypoalbuminemia and proteinuria can have a distinct contribution, individually or in combination.

Pathologic classification of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is defined as a clinical-pathologic syndrome manifesting proteinuria and focal and segmental glomerular sclerosis with foot process effacement. The pathologic approach to the classification of FSGS is complicated by the existence of primary (idiopathic) forms and multiple subcategories with etiologic associations, including human immunodeficiency virus (HIV)-associated nephropathy, heroin nephropathy, familial forms, drug toxicities, and a large group of secondary FSGS mediated by structural-functional adaptations to glomerular hyperfiltration. A number of morphologic variants of primary and secondary focal sclerosis are now recognized, including FSGS not otherwise specified (NOS), perihilar, cellular, tip, and collapsing variants. The defining features of these morphologic variants and of the major subcategories of FSGS are discussed with emphasis on distinguishing light microscopic patterns and clinical-pathologic correlations.

Epidemiology and natural course of idiopathic nephrotic syndrome.

The term "idiopathic nephrotic syndrome" is poorly defined and is used to refer to a variety of glomerular lesions. This article seeks to clarify the situation by considering the case for treating minimal-change nephropathy, focal and segmental glomerulosclerotic lesions, and mesangioproliferative lesions with predominantly IgM deposition as separate disease entities. In children, nephrotic syndrome has a pattern different from that in adults, in whom a wider pathogenetic spectrum is seen. There is support for the use of prospective clinicopathological data as the basis of identifying those patients with nephrotic syndrome who will progress to end-stage renal failure. Very heavy, persisting proteinuria is one marker of such progression and is also an indicator of metabolic complications, such as cardiovascular disease, which further increase the risks of mortality and morbidity in this group of patients.

Clinical and histopathologic findings in adults with the nephrotic syndrome.

The clinical and histopathologic findings in 225 Irish adults with nephrotic syndrome were reviewed. Membranous nephropathy was the most common lesion found (28%), followed by proliferative glomerulonephritis (17%), and focal sclerosing glomerulonephritis (16%). Minimal change disease was the least frequent cause for idiopathic nephrotic syndrome (12%). The major secondary cause of nephrotic syndrome was amyloidosis (13%). The patients were analysed for the predictive value of the level of renal function, presence or absence of hypertension, and the degree of proteinuria. It was not possible to determine the nature of the underlying lesion giving rise to the nephrotic syndrome using any of these variables. There was also no significant difference between primary and secondary glomerular disease with regard to these factors. It is concluded that renal biopsy remains the only definitive method of establishing the underlying lesion causing idiopathic nephrotic syndrome.