Idiopathic Steroid-resistant nephrotic syndrome (iSRNS) is a common problem in pe- diatric nephrology. About 10% - 20% of children with nephrotic syndrome have idi- opathic steroid resistant nephrotic syndrome (iSRNS)    . About 50 percent of patients with iSRNS will progress to end-stage renal disease (ESRD)  . It is a point which makes difficult to manage these patients. This study was thus designed to determine the spectrum of histopathological patterns in children presenting with iSRNS at our center. In this way, doing renal biopsy is mandatory to confirm histopathologic pattern of disease. These histological variants of nephrosis may be found alone or in any combination on sequential biopsies in each patient. Therefore, evaluation for iSRNS depends in an adequate renal biopsy to determine the underlying histology. However in the most literatures, primary focal segmental glomerulosclerosis has been reported as the main leading cause indicating poor outcome and warranting more ag- gressive therapy  . Results of studies by the International Study of Kidney Disease in Children (ISKDC) revealed focal and segmental glomerulosclerosis (FSGS), mesen- gial proliferative glomerulonephritis (MPGN) and minimal change disease (MCD) as the respective morphologic lesions seen in 70%, 44% and 7% of children with iSRNS. . Also, it demonstrated that clinical corticosteroid response had a high predictive accuracy for outcome than renal histological findings in children with idiopathic nephrotic syndrome . The glomerular morphologic pattern and treatment outcome of iSRNS in Iranian children in North-west of Iran have not been previously defined. In this study, we conducted to compare the histopathologic distribution of different sub- types’ glomerular morphologic patterns in iSRNS and outcome of patients after thera- py.
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Subjects were patients with steroid resistant nephrotic syndrome (SRNS) who visited the pediatric nephrology division of several educational hospitals in Indonesia. The inclusion criteria were Indonesian, aged between 1 - 14 years old, with primary SRNS. This study was approved by the ethical committee of the Faculty of Medicine, Universitas Padjadjaran/Dr. Hasan Sadikin General Hospital, Bandung. The definitions for nephrotic syndrome (NS) and steroid resistant nephrotic syndrome (SRNS) used were definitions as defined by the International Study of Kidney Disease in Children (ISKDC) criteria, i.e. edema, severe proteinuria, and hypoalbuminemia (<2.5 g/dL) for NS  while SRNS was defined as NS patients who do not achieve remission after the full- dose single drug prednisone therapy during the first four weeks . NS and SRNS were diagnosed by pediatric nephrologists or pediatricians supervised by pediatric nephrologists. Renal insufficiency was defined as an estimated glomerulo filtration rates (eGFR) of <90 mL/min per 1.73 m 2 . Data analysis was performed using SPSS TM version 20.0. Fisher’s Exact Test was used to determine the correlation between NPHS2 polymorphisms and clinical manifestations, i.e. eGFR, hematuria, and hypertension.
A 5-year-old nonconsanguineous girl of African American and Hispanic origin presented with nephrotic syndrome, in- cluding nephrotic-range proteinuria (UPC of > 29 mg/mg), edema, and hypoalbuminemia. Her initial serum cre- atinine was 654 μmol/L. Other pertinent laboratory evaluation at time of presentation included albumin of 19 g/L, BUN of 38 mmol/L, potassium of 6 mmol/L, bi- carbonate of 12 mmol/L, calcium of 1.7 mmol/L, phos- phorus of 2.5 mmol/L, and parathyroid hormone of 396 ng/L. She was oligoanuric and hemodialysis was initiated. An ultrasound of her kidneys showed diffuse echogenicity and loss of corticomedullary differentiation (Fig. 1). Her history was significant for developmental delay and short stature. Her proteinuria presented in the setting of a previous respiratory illness but was not investigated. She has a normal-looking face and without dys- morphic features which was confirmed by the hospi- tal’s geneticist. An ophthalmological examination did not show cataract or retinal changes. She has normal looking ears and exhibited normal hearing. She was normocephalic and did not have an exam consistent with GAMOS and no uro-genital anomalies were
Lipids, including sphingolipids, have been shown to control steroid hormone biosynthesis in adrenal glands. Sphingolipid intermediates ceramide and sphingosine have been demon- strated to reduce steroidogenesis in vitro (26–28). Sphingosine has been reported to interact directly with the orphan nuclear receptor steroidogenic factor-1 (SF-1; NR5A1), which plays a role in both the acute phase of steroidogenesis and in adrenal and gonadal development (28). In binding to SF-1, sphingosine main- tains the transcription factor in an inactive conformation. The sphingosine intermediate S1P, however, has been demonstrated to induce transcription of several steroidogenic factors (29). Thus, sphingolipid intermediates may have some role in modu- lating steroidogenesis and potentially adrenal development. We saw increased plasma S1P and ceramide levels in patient 5, and we anticipate that SGPL1 deficiency would lead to cytosolic accu- mulation of sphingolipid intermediates. Studies of tissues from SGPL1-deficient mice demonstrate an accumulation of S1P (22, 25, 30). While S1P is largely considered a proproliferative signal- ing molecule and ceramide proapoptotic in normal physiology, studies have demonstrated that pathological accumulation of S1P in the cytosol can induce apoptosis (31).
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As an immune disease, primary nephrotic syndrome is usually treated with adrenocortical hormone and cyto- toxic drugs in clinic. For patients whose clinical symp- toms are not remitted completely or partially after being treated with hormone of standard dosage (1 mg/kg/d) for at least 3 months, they are diagnosed with steroid-resis- tant nephrotic syndrome (SRNS) . SRNS is usually presented, pathologically, as minimal change disease (MCD), mesangial proliferative glomerulonephritis (Me- sPGN) and focal segmental glomerulosclerosis (FSGS), with a few of membranous nephropathy and individual of non-IgA mesangial proliferative glomerulonephritis, which is difficult to be treated and generally immunosuppre- ssive agents such as cyclophosphamide and cyclosporine
participate in coenzyme Q 10 (CoQ 10 ) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ 10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ 10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ 10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ 10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ 10 biosynthesis may be treatable with CoQ 10 .
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It is not a single disease entity, and attempts to portray it as a uniform entity has led to some confusion in the literature with regard to natural history. FSGS is always a histopathologic diagnosis, and its clinical presentation will vary according to the etiology or cause of the histologic lesion. FSGS may manifest in a fashion that is indistinguishable from MCN, but it may be found only after years of clinical nephrotic syndrome when earlier biopsies have been interpreted as MCN. FSGS is a known consequence of hyper filtration and is regularly seen in patients with reflux nephropathy and in some patients with a single kidney who’s other has been lost because of conditions such as multicystic dysplastic kidney disease.
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A total of 480 children with primary nephrotic syndrome were admitted in BSMMU during the study period. Forty three (43) children were randomly selected who were aged 1-15 yrs. Among them, 19 had steroid resistant nephrotic syndrome (SRNS) leveled as group B and 24 were steroid sensitive nephrotic syndrome (SSNS) leveled as group C, in SSNS group 11 children had FRNS +SDNS, (Group C1) and 13 had infrequent relapsing nephrotic syndrome IFRNS, (Group C2). Among the 19 children with SRNS, the histological reports on biopsy were mesangial proliferative glomerulonephritis (9 children), MCNS (3 children), focal segmental glomerulosclerosis (3children), membranoproliferative glomerulonephritis (2 children) and membranous glomerulonephritis (2 children). Children below one year and above 15 years and those with congenital nephrotic syndrome, nephrotic syndrome secondary to systemic disease like systemic lupus erythromatosis, hepatitis B, Henoch Schonlein purpura, falciparum malaria, lymphoma or amylodosis were excluded from the study. Those with severe protein energy malnutrition or Down’s syndrome were also excluded.
Biomarkers are useful tools for diagnosis and prognostication in both childhood and adult idiopathic nephrotic syndrome, as well as for differentiating SRNS from SSNS. Currently, clinical and histological features are still dependable guides for predicting disease responsiveness to steroid therapy. However, biomarkers can now be utilized to predict renal outcome in the disease, as well as to promptly identify those patients who would respond to immunosuppressive therapy. Although progress has been made in demonstrating the prognostic and discriminatory roles of these biomarkers, their limited availability in most laboratories has precluded a complete paradigm shift from the conventional renal biopsy. Nevertheless, further longitudinal studies are still required to establish their usefulness as noninvasive predictors of disease response to immunosuppressive therapy.
MCN generally responds well to steroids with over 90% response rate while steroid resistance occurs in 7 – 10% of cases. 12 Its mean prevalence rate of about 14% among SRNS patients in West Africa agrees with this well-estab- lished ﬁ gure. But in South Africa, MCN appears to have the same frequency and steroid-resistance rate with FSGS. 43 Historically, the degenerative glomerular lesions of FSGS were those observed in the progression of MCN (hitherto known as “ lipoid nephrosis ” ), and it was later noted that these patients with MCN had an accelerated clinical trajec- tory (with possible transformation to FSGS). 52 This may explain the similarity in the frequencies of both histopatho- logic subtypes, although this conclusion remains conjec- tural. Nevertheless, the rising prevalence rate of steroid- resistant FSGS in South Africa and in the West African sub-region, could be attributed to the current pandemic of the human immunode ﬁ ciency virus (HIV). In virus-asso- ciated FSGS, HIV-1 is the most implicated virus which is strongly linked with this histopathologic subtype (espe- cially the collapsing glomerular variant of FSGS) as it directly infects the podocytes. 5,53 Interestingly, the effect of HIV on podocytes is strongest in individuals with two APOL1 risk alleles, with a high odds ratio reported in South Africa. 53 Remarkably, subjects with HIV-associated nephropathy (HIVAN) have one or two APOL1 risk alleles. 49 Although APOL1-associated FSGS constitutes a
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Abstract: The prevalence of childhood steroid-resistant nephrotic syndrome (SRNS) ranges from 35% to 92%. This steroid resistance among Nigerian children also reflects underlying renal histopathology, revealing a rare minimal-change disease and a varying burden of membranop- roliferative glomerulonephritis and focal segmental glomerulosclerosis (FSGS). FSGS tends to progress to end-stage kidney disease, which requires dialysis and/or renal transplantation. While knowledge of the molecular basis of NS is evolving, recent data support the role of mutant genes that otherwise maintain the structural and functional composition of the glomerular filtration barrier to account for many monogenic forms of FSGS. With the advent of next-generation sequencing, >39 genes are currently associated with SRNS, and the number is likely to increase in the near future. Monogenic FSGS is primarily resistant to steroids, and this foreknowledge obviates the need for steroids, other immunosuppressive therapy, and renal biopsy. Therefore, a multidisciplinary collaboration among cell biologists, molecular physiologists, geneticists, and clinicians holds prospects of fine-tuning the management of SRNS caused by known mutant genes. This article describes the genetics of NS/SRNS in childhood and also gives a narrative review of the challenges and opportunities for molecular testing among children with SRNS in Nigeria. For these children to benefit from genetic diagnosis, Nigeria must aspire to have and develop the manpower and infrastructure required for medical genetics and genomic medicine, leveraging on her existing experiences in genomic medicine. Concerted efforts can be put in place to increase the number of enrollees in Nigeria’s National Health Insurance Scheme (NHIS). The scope of the NHIS can be expanded to cater for the expensive bill of genetic testing within or outside the structure of the National Renal Care Policy proposed by Nigerian nephrologists. Keywords: child, humans, nephrotic syndrome, genetic testing
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In this study, we evaluated the clinical charac- teristics and response to steroid therapy of patients with FSGS and primary MCD. It was discovered that patients with FSGS were older than those with MCD, but there was no differ- ence in ages as well as gender between these two groups. Actually, MCD in childhood is prob- ably more common in males, but there is appar- ently no gender difference in adults. Moreover, during follow-up, all patients had nephrotic syn- drome, and few in these two groups were sub- mitted to renal biopsy when the proteinuria level was still less than 3.5 g/24 h . What was known to all was that less than 10% of MCD patients did not have nephrotic protein- uria when the disease disappeared, while such percentage could reach to 30% in FSGS patients . In this study, initial levels of pro- teinuria in patients with MCD (average 7.9 g/24 h) were higher than those with FSGS (average 5.1 g/24 h). A study analyzed mean levels of proteinuria on patients with MCD was at 10 g/24 h and serum creatinine of 1.4 mg/dL, which was similar to the levels detected in the study (7.9 g/24 h and 1.1 mg/dL, respectively) . It also showed an incidence of hyperten- sion in adults with MCD that reaches forty per- cent. However, 13% of MCD patients had hyper- tension in the study. This percentage is higher in cases of FSGS.
A. calcineurin inhibitor (CNI) as initial therapy for children with SRNS: CNI therapy be continued for a minimum of 6 months and then stopped if a partial or complete remission of proteinuria is not achieved. CNI is to be continued for a minimum of 12 months when at least a partial remission is achieved by 6 months. Low-dose corticosteroid therapy be combined with CNI therapy. Complete and partial remissions are less common in the presence of nephrotic syndrome associated with podocin mutations 63,64,65 . CNI therapy may induce at least a partial remission in these patients. Tacrolimus was compared with cyclosporine in one study 66 . and showed no significant difference in proteinuria control. The frequency of nephrotoxicity, hypertension, and diabetes mellitus were not different between cyclosporine and tacrolimus in this trial. Hypertrichosis and gingival hyperplasia were significantly more common with cyclosporine than with tacrolimus.
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Purpose: The pathophysiology of hypogammaglobulinemia in nephrotic syndrome (NS) remains unknown. We evaluated the differences in the distribution of anti-bacterial antibodies and anti-viral antibodies, and those of immune antibodies and natural antibodies in steroid-sensitive NS. Materials and Methods: We examined the antibody status of 18 children who had routine vaccinations. The levels of immnunoglobulin G (IgG), the IgG subclasses, and the antibodies induced by vaccinations such as diphtheria-pertussis-tetanus and measles-mumps- rubella were analyzed in children with steroid-sensitive NS. Results: There was a positive correlation between the albumin and IgG values (r = 0.6, p < 0.01), and the four IgG subclasses were all evenly depressed in the nephrotic children during the acute stage of the disease. The antibodies induced by bacterial antigens were depressed and the seropositivity of anti-viral antibodies tended to be lower than those of age-matched control children during the acute stage. The depressed immune antibody status recovered rapidly in the remission stage of NS, despite corticosteroid treatment. Conclusion: IgG levels correlated positively with albumin levels, and all antibodies, including immune and natural antibodies, were depressed in the acute stage of NS. Our results suggest that hypogammaglobulinaemia in NS may be associated with intravascular homeostasis of oncotic pressure.
Children with the diagnosis of SSNS were recruited from the Pediatric Nephrology Clinic at Doernbecher Children’s Hospital at Oregon Health Sciences University. Fifteen English-speaking families with children ranging from 3 to 16 years of age agreed to participate. Five additional families declined participation. Rea- sons for not participating included lack of time and discomfort completing psychological surveys. There were no significant dif- ferences in demographic characteristics (ie, age and sex of child, duration of diagnosis, and parent marital status) between partic- ipants and nonparticipants. The majority of respondents were mothers (87%). A total of 10 participants completed the study. Of the 5 children who did not complete the study, 1 was rediagnosed as steroid resistant and 4 did not relapse during the 16-month course of the investigation. At entry, parental educational level, occupation, and marital status were determined. The Hollings- head Index of Social Class was used to calculate social status (A. B. Hollingshead, unpublished manuscript, 1975). The study protocol was approved by the institutional review boards at Oregon Health Sciences University and Washington State University. Informed consent was obtained from each child’s parent or guardian.
NPS is an autosomal dominant disorder characterized by orthopedic manifestations. In our case, NPS was difficult to diagnose early for the following reasons: 1) nephrotic syndrome developed prior to overt orthopedic symp- toms; 2) she had no family history; and 3) renal pathology revealed only non-specific findings in the GBM at an early stage of NPS nephropathy. Based on the presence of orthopedic symptoms, we performed a genetic analysis, detected a de novo mutation in LMX1B without this mutation in her parents, and discontinued unnecessary steroid treatments.
Approximately 90% of children with nephrotic syndrome is INS. INS in children is characterized by high sensitivity to steroids and about 77% had minimal change disease.  Approximately 80% of children with steroid-sensitive NS (SSNS) have one or more relapses, and about 50% have frequent relapses and/or steroid dependence [4,5,6] requiring higher exposure to steroids. INS includes multiple histologic types: minimal change disease, mesangial proliferation, focal segmental glomerulosclerosis, membranous nephropathy, and membranoproliferative glomerulonephritis. Minimal change disease is characterized by remitting and relapsing course and its stricking susceptibility to corticosteroid therapy. Patients who have frequent relapse or steroid dependent, it is difficult to obtain remission. Prolonged use of steroids can cause significant side-effects such as hypertension, obesity, cataracts, psychosis, striae and growth failure.  Long term use of steroid has so many complications so other alternative medicine has to be introduced for obtain remission. Cyclophosphamide has been chosen by many centers as first line treatment for children suffering from SDNS along with low dose of steroid to reduce complications of long term high dose of steroid. Several studies have reported prolonged remission in these cases when cyclophosphamide was given along with steroids. But there is no uniform opinion regarding the dose and duration of cyclophosphamide treatment. Also hazards like bone marrow depression, increased susceptibility to infections, haemorrhagic cystitis, alopecia, gonadal failure and malignancy are associated with daily cyclophosphamide regimen. Response to cyclophosphamide was more dependent on histopathological pattern and age of onset of cyclophosphamide treatment. [8,9] Biopsy was not a pre- requisite before starting cyclophosphamide therapy. The percentage of cumulative sustained remission was similar in children who received treatment without biopsy versus those who had prior biopsy. 
Nephrotic syndrome is also called nephrosis. NS usually begins between the age of 2 and 5 years. It is characterized by proteinuria, hypo- albuminimia, hyperlipidemia and edema. A condition in which the kidneys leak large and abnormal amounts of protein into the urine. With the loss of protein in the urine, this leads to puffiness of the eyelids, feet and ankles, and eventually the abdomen. Main reason of NS is still unclear. Idiopathic nephrotic syndrome (INS) is the most frequent form of Nephrotic syndrome in children representing more than 90 percent of cases between 1 and 10 years of age and 50 percent after 10 years of age . Majority of patient with minimal change disease >90% are sensitive to long term steroid therapy. However, 50% of mesengial proliferation and 30% of focal segmental glomerulosclerosis response to steroid therapy . Most of the children respond very well to steroid treatment. Remission can be achieved with in two weeks. Most children will have at least one relapse or recurrence of protein in the urine. Around 10% of children have secondary nephrotic syndrome with significant lesions. Some children doesnot respond to steroid and considered as SRNS while some children relapse after lowering dose or stopping steroid and considered as SDNS. In practice immunosuppressant drugs such as Cyclophosphamide and CsA has been used as a second line drug who doesnot respond with steroid alone. However these immune- suppressant drugs like CsA have high remission rate but they also have high relapse rate and high resistant rate nowadays. So this has become a troublesome for the patients and doctors too. CNIs such as tacrolimus can be an alternative drug as it has high remission and low relapse rate.
used methylprednisolone pulse therapy in addition to CsA and prednisone in patients with FSGS. The results of this protocol treatment were encouraging with a response rate of around 85.7%. However, the number of patients reported in this study was small (seven) and so valid conclusions cannot be drawn. In summary, all these studies have sug- gested that CsA improves steroid sensitivity in steroid- resistant nephrotic children and recommend the use of combination cyclosporine-prednisone in the management of steroid-resistant nephrotic syndrome.
In summary, the role of the podocyte is crucial in under- standing of the pathogenesis of nephrotic syndrome. The development, migration, basement membrane interaction, and regeneration of the podocyte are all critical processes in the maintenance of foot process integrity. Genetic mutations in any one of these processes can lead to the phenotype of nephrotic syndrome, and more specifically, mutations in genes coding for key podocyte proteins (NPHS2, PLCE1, ACTN4, and TRPC6) cause FSGS, the histopathologic finding most commonly associated with SRNS. 12 In all, 24