Diagnosis and management of nephrotic syndrome.
McCloskey Oonagh,Maxwell Alexander P
The Practitioner
Nephrotic syndrome is defined by a triad of clinical features: oedema, substantial proteinuria (> 3.5 g/24 hours) and hypoalbuminaemia (< 30 g/L). It is often associated with hyperlipidaemia, thromboembolism and an increased risk of infection. Nephrotic syndrome develops following pathological injury to renal glomeruli. This may be a primary problem, with a disease specific to the kidneys, or secondary to a systemic disorder such as diabetes mellitus. The most common cause in children is minimal change glomerulonephritis. In white adults, nephrotic syndrome is most frequently due to membranous nephropathy whereas in populations of African ancestry the most common cause of nephrotic syndrome is focal segmental glomerulosclerosis. Diabetic nephropathy is the most common multisystem disease that can cause nephrotic syndrome. Patients typically present with periorbital oedema (most noticeable in the morning) or dependent pitting oedema (more common later in the day). Proteinuria should be documented by a quantitative measurement e.g. urine protein: creatinine ratio (PCR) or albumin: creatinine ratio (ACR). PCR > 300-350 mg/mmol indicates nephrotic range proteinuria. Urgent referral to a nephrologist (ideally within 2 weeks) is necessary and a renal biopsy is usually performed. This will establish what form of glomerular disease is responsible. Additional tests may be undertaken to assess if nephrotic syndrome is secondary to another disorder e.g. systemic lupus erythematosus or amyloidosis.
Urinary CD80 excretion is a predictor of good outcome in children with primary nephrotic syndrome.
Ling Chen,Liu Xiaorong,Shen Ying,Chen Zhi,Fan Jianfeng,Jiang Yeping,Meng Qun
Pediatric nephrology (Berlin, Germany)
BACKGROUND:The level of urinary cluster of differentiation 80 (uCD80) is elevated in most children with minimal change disease (MCD) as opposed to focal segmental glomerulosclerosis (FSGS) during the acute phase. The objective of this follow-up study was to evaluate whether uCD80 elevation is actually associated with MCD and whether it signals better prognosis. METHODS:We evaluated uCD80 levels and a series of putative progression factors in a cohort of 64 patients with nephrotic syndrome (NS) seen between 2011 and 2016. We monitored progression of chronic kidney disease (CKD), assessed as a glomerular filtration rate of < 90 ml/min/1.73 m for at least 3 months. Patients were classified according to uCD80 level and to the progression rate as calculated by Kaplan-Meier survival analysis and Cox's regression analysis. RESULTS:During a mean follow-up period of 4.8 ± 0.6 (range 3.5-6.0) years, 13 children (20%) evolved to at least CKD stage 2. The 64 patients with NS and normal baseline renal function were divided into two groups based on uCD80 excretion, i.e. below or above a defined cutoff (< or > 328.98 ng/g creatinine). The predicted response to immunosuppression therapy was 34.5 and 100% in the low- and high-uCD80 excretion, respectively (p < 0.001). Progression to CKD was 41.4 vs. 2.9% in NS patients (p < 0.001). Using the Cox model, only uCD80 excretion (p = 0.013, relative risk 6.171) predicted progression to CKD. CONCLUSIONS:Urinary CD80 predicts progression and remission in children with NS. The use of uCD80 as a prognostic marker facilitates the identification of high-risk patients at an early stage and may lead to better treatment selection.
10.1007/s00467-018-3885-7
Acute kidney injury in idiopathic nephrotic syndrome of childhood is a major risk factor for the development of chronic kidney disease.
Yaseen Afshan,Tresa Vina,Lanewala Ali Asghar,Hashmi Seema,Ali Irshad,Khatri Sabeeta,Mubarak Muhammed
Renal failure
BACKGROUND:Acute kidney injury (AKI) is an important complication of idiopathic nephrotic syndrome (INS) and is associated with adverse outcomes, especially the development of chronic kidney disease (CKD). We aimed to determine the clinical profile of children with INS who developed AKI and its short-term outcome. MATERIAL AND METHODS:This prospective study was conducted from March 2014 to October 2015. A total of 119 children of INS (age: 2-18 years) fulfilling the pediatric RIFLE criteria for the diagnosis of AKI were enrolled and followed up for 3 months to determine the outcome. Factors predisposing to CKD were studied. RESULTS:The mean age at presentation was 8.8 ± 3.59 years and males were 74 (62.2%). At presentation, 61 (51.3%) children were in Risk category, 43 (36.1%) in Injury category, and 15 (12.6%) in Failure category. Most of them (41.2%) had steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) on histopathology (33.6%). Infections were the major predisposing factor for AKI in 67 (56.3%) cases. Drug toxicity was the next common, found in 52 (43.7%) children. A total of 65 (54.6%) children recovered from AKI, while 54 (45.4%) did not. CKD developed in 49 (41.2%) non-recovered cases and 5 (4.2%) children succumbed to acute illness. SRNS, cyclosporine use, FSGS on histology, and drug toxicity were significant factors associated with the development of CKD. CONCLUSION:AKI associated with INS is a reversible condition in most cases but it can progress to CKD, especially among those who have SRNS, FSGS, and drug toxicity.
10.1080/0886022X.2016.1277743
Association of HLA-DQA1 gene polymorphisms with the risk of children primary nephrotic syndrome in Chinese population.
Zhu Bingbing,Zhang Ruifeng,Yang Huandan,Yuan Tingting,Lv Juan,Peng Qianqian,Tian Lijun
Journal of clinical laboratory analysis
BACKGROUND:The association between gene polymorphisms and the risk of primary nephrotic syndrome (PNS) is uncovering recently. This study aims to investigate the relationship between single nucleotide polymorphisms (SNPs) on HLA-DQA1 gene and the risk of PNS. METHODS:In this study, we genotyped eight single nucleotide polymorphisms (SNPs) in the HLA-DQA1 gene in 501 PNS patients and 532 healthy people in Chinese population. Then we analyzed associations of these SNPs with the clinical features in primary nephrotic syndrome of children in Chinese population. RESULTS:Significant associations with PNS were found on missense SNP rs1129740 (GG vs AA, odds ratio (OR) = 1.987, 95% confidence interval (CI) = 1.468-2.652, P = 0.00177049) and rs1047992 (AA vs GG, OR = 1.857, 95% CI = 1.325-2.391, P = 1.1073E-10) of the HLA-DQA1 gene. CONCLUSIONS:This work suggests SNPs of HLA-DQA1 are risk factors for PNS in Chinese population, which implies roles of immune response in the pathogenesis of PNS.
10.1002/jcla.22623
Elevation of plasma-soluble HLA-G in childhood nephrotic syndrome is associated with IgE.
Liu Yanqing,Lai Meimei,Lou Yunyan,Han Qiuyue,Yang Qing,Chen Minguang,Li Jingbo,Wang Huiyan,Yan Weihua,Zheng Xiaoqun
Annals of clinical biochemistry
Background Nephrotic syndrome is related to immune system dysfunction. Soluble human leukocyte antigen-G has been suggested to have an immunomodulatory role. Additionally, human leukocyte antigen-G expression may be influenced by the 14-base pair insertion/deletion polymorphism. However, this molecule has not been investigated in nephrotic syndrome. Methods Fifty-five children with nephrotic syndrome were enrolled: 24 primary nephrotic syndrome patients and 31 recurrent nephrotic syndrome patients. A group of 120 healthy subjects were included as reference controls. Additionally, 22 patients in nephrotic syndrome remission after treatments were also included. Both nephrotic syndrome patients and healthy subjects were genotyped for the 14-base pair insertion/deletion polymorphism. Plasma soluble human leukocyte antigen-G concentrations and serum immunoglobulin concentrations were determined. Results Nephrotic syndrome patients showed significantly higher levels of both soluble human leukocyte antigen-G and immunoglobulin E compared to normal controls. Nephrotic syndrome patients presented a higher frequency of the -14-base pair allele than did normal controls. Soluble human leukocyte antigen-G concentrations in remission patients were dramatically lower compared to in nephrotic syndrome patients. Moreover, soluble human leukocyte antigen-G and immunoglobulin E were moderately correlated in nephrotic syndrome patients. Conclusions The present study demonstrated that plasma soluble human leukocyte antigen-G concentrations were significantly elevated and that a relationship between serum total immunoglobulin E in nephrotic syndrome patients and the human leukocyte antigen-G -14-base pair allele may be a risk factor for nephrotic syndrome. These findings suggest that soluble human leukocyte antigen-G may be used as a monitoring marker for nephrotic syndrome patients' condition.
10.1177/0004563216637625
Molecular stratification of idiopathic nephrotic syndrome.
Nature reviews. Nephrology
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.
10.1038/s41581-019-0217-5
The effect of systemic corticosteroids on the innate and adaptive immune system in children with steroid responsive nephrotic syndrome.
Baris Hatice Ezgi,Baris Safa,Karakoc-Aydiner Elif,Gokce Ibrahim,Yildiz Nurdan,Cicekkoku Dilek,Ogulur Ismail,Ozen Ahmet,Alpay Harika,Barlan Isil
European journal of pediatrics
UNLABELLED:The severity and duration of immunosuppression caused by corticosteroids (CSs) usage have not been extensively studied. We aimed to investigate the effects of CSs on the various compartments of immune system in relation to timing of initiation and persistence of therapy. Pediatric patients with idiopathic nephrotic syndrome (NS) treated with 2 mg/kg/day prednisolone and healthy control (HC) were enrolled. Blood samples were drawn for immunologic analyses at baseline and at the first and second weeks and first, second, and third months of CS therapy in addition to first and second weeks and first, second, and third months of discontinuation. Fourteen patients (M/F, 7/7) between 1 and 8 years old were evaluated. Untreated NS exhibited high absolute lymphocyte count (ALC)(p = 0.010), absolute CD3(+) T cells (p = 0.020) and absolute CD8(+) T cells (p = 0.006) compared to HC. Suppression in ALC was observed and nadir value was noted at first month of therapy compared to baseline (p = 0.002). The CD4(+) (p = 0.036) and CD8(+) T cell (p = 0.013) counts decreased significantly at the first week of treatment compared to baseline. While baseline B cell counts was indifferent from HC, gradually increased in 2 weeks of CS initiation and decreased during the treatment with a statistical significance compared to HC (p = 0.010). However, after cessation of CS, B cell counts continued to decline and found to be significantly different than baseline at first week (p = 0.008) and at third month (p = 0.040). CONCLUSION:Apart from baseline lymphocyte subset changing observed in untreated NS patients, our data implies that T cells were suppressed very early in the CS treatment. Interestingly, depressed B cell counts were detected later but persisted even after CS cessation. Due to early decrease in T cells, it would be beneficial to assume the patients as immunosuppressed at the very beginning of CS treatment to avoid infections. WHAT IS KNOWN:• Corticosteroids (CSs) are widely used for a variety of diseases including nephrotic syndrome, which is related with complex immune disturbance including T and B cells dysfunctions. • CSs induce neutrophilic leukocytosis concomitant with lymphopenia and eosinopenia leading to immunosupression. What is New: • T cell subsets and proliferation are susceptible to CSs more than B cells; however, the reversibility is faster with dose reduction in CS. • The change of B cells and B cell subtypes (CD27 (+) memory) shows prolonged effect of CSs on B cells which may alter antibody production even after 3 months of CSs cessation.
10.1007/s00431-016-2694-x
FCGR2A single nucleotide polymorphism confers susceptibility to childhood-onset idiopathic nephrotic syndrome.
Rossi Giovanni M,Bonatti Francesco,Adorni Alessia,Alberici Federico,Bodria Monica,Bonanni Alice,Ghiggeri Gian M,Martorana Davide,Vaglio Augusto
Immunology letters
Childhood-onset idiopathic nephrotic syndrome affects 1.15-3.4 children/100,000 children/year in Western Countries. Immune-mediated mechanisms, particularly T cell-mediated, are thought to play a key pathogenic role. The genetic basis of the disease is still poorly understood. We tested the association between single nucleotide polymorphisms (SNPs) of four genes encoding Fc gamma receptors (FCGR2A, FCGR2B, FCGR3A, FCGR3B) and idiopathic nephrotic syndrome in a case-control study of paediatric patients. Children with idiopathic nephrotic syndrome (aged 1-16 years) were included. FCGR2A rs1801274 and FCGR3A rs396991 SNPs were genotyped using real-time PCR with the TaqMan method, while FCGR2B rs1050501 and FCGR3B NA1/NA2 were genotyped using Sanger sequencing. Fisher's exact test was used to explore genetic association. We enrolled 103 idiopathic nephrotic syndrome patients and 181 healthy controls. A significant association was found between idiopathic nephrotic syndrome and FCGR2A rs1801274 SNP (both with the T allele and the TT genotype, p value=0.0009, OR 1.81, 95% CI 1.27-2.59 and p value=0.0007, OR 2.39, 95% CI 1.44-3.99, respectively). No associations were found for the remaining SNPs. Fc gamma receptors might modulate response to rituximab; since 60 of the enrolled patients were treated with rituximab, we also tested the association between the studied SNPs and rituximab efficacy in this patient subgroup, but found only a weak association with FCGR2A CC genotype (p value=0.03). The FCGR2A rs1801274 SNP in the gene encoding the activating receptor CD32A confers susceptibility to idiopathic nephrotic syndrome.
10.1016/j.imlet.2017.11.002