Nephrotic syndrome is defined by nephrotic-range proteinuria (≥40 mg/m
2
/hour or urine protein/creatinine ratio ≥200 mg/mL or 3+ protein on urine dipstick), hypoalbuminaemia (<25 g/L) and oedema. ...This review focuses on the classification, epidemiology, pathophysiology, management strategies and prognosis of idiopathic nephrotic syndrome of childhood, and includes a brief overview of the congenital forms.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting from 1.15 to 16.9 per 100,000 children per year globally. It is characterized by massive proteinuria, ...hypoalbuminemia, and/or concomitant edema. Approximately 85–90% of patients attain complete remission of proteinuria within 4–6 weeks of treatment with glucocorticoids, and therefore, have steroid-sensitive nephrotic syndrome (SSNS). Among those patients who are steroid sensitive, 70–80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapses or become dependent on glucocorticoids to maintain remission. The dose and duration of steroid treatment to prolong time between relapses remains a subject of much debate, and patients continue to experience a high prevalence of steroid-related morbidity. Various steroid-sparing immunosuppressive drugs have been used in clinical practice; however, there is marked practice variation in the selection of these drugs and timing of their introduction during the course of the disease. Therefore, international evidence-based clinical practice recommendations (CPRs) are needed to guide clinical practice and reduce practice variation. The International Pediatric Nephrology Association (IPNA) convened a team of experts including pediatric nephrologists, an adult nephrologist, and a patient representative to develop comprehensive CPRs on the diagnosis and management of SSNS in children. After performing a systematic literature review on 12 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, recommendations were formulated and formally graded at several virtual consensus meetings. New definitions for treatment outcomes to help guide change of therapy and recommendations for important research questions are given.
Aim
This study aimed to investigate the incidence of relapse and FR/SDNS in Chinese children with SSNS and to develop clinical prediction models for relapse and FR/SDNS.
Methods
This retrospective ...cohort study involved 339 newly onset SSNS patients between 2006 and 2016. The incidence of relapse and FR/SDNS were estimated using the Kaplan–Meier method. Prediction models were constructed based on Cox proportional‐hazards regression.
Results
The median follow‐up time was 8.7 years. The cumulative incidence of relapse at 1‐, 2‐, and 5‐year was 51.0%, 62.5%, and 66.6%. The cumulative incidence of FR/SDNS at 1‐, 2‐, and 5‐year was 18.4%, 29.0%, and 32.9%. The final prediction model for first relapse included four variables (serum albumin, triglycerides, IgM, and time to first remission). The model's discriminative ability was low (Harrell's C index = 0.62). The final prediction model for FR/SDNS included four variables (serum albumin, lipoprotein(a), time to first remission, and time to first relapse). The discrimination and calibration of the prediction model for FR/SDNS were acceptable (Harrell's C index = 0.73, Brier score at 1‐ and 2‐year were 0.11 and 0.17).
Conclusion
The first relapse and FR/SDNS mainly occurred in the first 2 years after initial SSNS onset. The prediction model for relapse developed using common clinical parameters performed poorly, while the prediction model for FR/SDNS might be useful.
Summary at a Glance
The incidence of relapse in Chinese children with SSNS might not be as high as previously reported in cohort studies or randomized controlled trials of other countries. Besides, this study developed a valuable prediction model for FR/SDNS in SSNS children using common clinical and laboratory variables.
Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected ...causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.
Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.
In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel.
,
,
, and
were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.
Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.
Nephrotic syndrome results in hyperlipidemia and profound alterations in lipid and lipoprotein metabolism. Serum cholesterol, triglycerides, apolipoprotein B (apoB)–containing lipoproteins (very ...low-density lipoprotein VLDL, immediate-density lipoprotein IDL, and low-density lipoprotein LDL), lipoprotein(a) (Lpa), and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio are increased in nephrotic syndrome. This is accompanied by significant changes in the composition of various lipoproteins including their cholesterol-to-triglyceride, free cholesterol–to-cholesterol ester, and phospholipid-to-protein ratios. These abnormalities are mediated by changes in the expression and activities of the key proteins involved in the biosynthesis, transport, remodeling, and catabolism of lipids and lipoproteins including apoproteins A, B, C, and E; 3-hydroxy-3-methylglutaryl-coenzyme A reductase; fatty acid synthase; LDL receptor; lecithin cholesteryl ester acyltransferase; acyl coenzyme A cholesterol acyltransferase; HDL docking receptor (scavenger receptor class B, type 1 SR-B1); HDL endocytic receptor; lipoprotein lipase; and hepatic lipase, among others. The disorders of lipid and lipoprotein metabolism in nephrotic syndrome contribute to the development and progression of cardiovascular and kidney disease. In addition, by limiting delivery of lipid fuel to the muscles for generation of energy and to the adipose tissues for storage of energy, changes in lipid metabolism contribute to the reduction of body mass and impaired exercise capacity. This article provides an overview of the mechanisms, consequences, and treatment of lipid disorders in nephrotic syndrome.
Idiopathic nephrotic syndrome is the most frequent glomerular disease in children in most parts of the world. Children with steroid-sensitive nephrotic syndrome (SSNS) generally have a good prognosis ...regarding the maintenance of normal kidney function even in the case of frequent relapses. The course of SSNS is often complicated by a high rate of relapses and the associated side effects of repeated glucocorticoid (steroid) therapy. The following recommendations for the treatment of SSNS are based on the comprehensive consideration of published evidence by a working group of the German Society for Pediatric Nephrology (GPN) based on the systematic Cochrane reviews on SSNS and the guidelines of the KDIGO working group (Kidney Disease - Improving Global Outcomes).
Steroid-resistant nephrotic syndrome (SRNS) represents the second most frequent cause of chronic kidney disease in the first three decades of life. It manifests histologically as focal segmental ...glomerulosclerosis (FSGS) and carries a 33% risk of relapse in a renal transplant. No efficient treatment exists. Identification of single-gene (monogenic) causes of SRNS has moved the glomerular epithelial cell (podocyte) to the center of its pathogenesis. Recently, mutations in >30 recessive or dominant genes were identified as causing monogenic forms of SRNS, thereby revealing the encoded proteins as essential for glomerular function. These findings helped define protein interaction complexes and functional pathways that could be targeted for treatment of SRNS. Very recently, it was discovered that in the surprisingly high fraction of ∼30% of all individuals who manifest with SRNS before 25 years of age, a causative mutation can be detected in one of the ∼30 different SRNS-causing genes. These findings revealed that SRNS and FSGS are not single disease entities but rather are part of a spectrum of distinct diseases with an identifiable genetic etiology. Mutation analysis should be offered to all individuals who manifest with SRNS before the age of 25 years, because (i) it will provide the patient and families with an unequivocal cause-based diagnosis, (ii) it may uncover a form of SRNS that is amenable to treatment (e.g. coenzyme Q
), (iii) it may allow avoidance of a renal biopsy procedure, (iv) it will further unravel the puzzle of pathogenic pathways of SRNS and (v) it will permit personalized treatment options for SRNS, based on genetic causation in way of 'precision medicine'.
Idiopathic membranous nephropathy (INM) remains a common cause of the nephrotic syndrome in adults. The autoimmune nature of IMN was clearly delineated in 2009 with the identification of the ...glomerular-deposited IgG to be a podocyte receptor, phospholipase A2 receptor (PLA2R) in 70% to 75% of cases. This anti-PLA2R autoantibody, predominantly the IgG4 subclass, has been quantitated in serum using an enzyme-linked immunosorbent assay and has been used to aid diagnosis and monitor response to immunosuppressive therapy. In 2014, a second autoantigen, thrombospondin type 1 domain–containing 7A (THSD7A), was identified. Immunostaining of biopsy specimens has further detected either PLA2R or THSD7A antigen in the deposited immune complexes in 5% to 10% of cases autoantibody seronegative at the time of biopsy. Therefore, the term IMN should now be superseded by the term primary or autoimmune MN (AMN) (anti-PLA2R or anti-THSD7A positive) classifying ∼80% to 90% of cases previously designated IMN. Cases of secondary MN associated with other diseases show much lower association with these autoantibodies, but their true incidence in secondary cases still needs to be defined. How knowledge of the autoimmune mechanism and the sequential measurement of these autoantibodies is likely to change the clinical management and trajectory of AMN by more precisely defining its diagnosis, prognosis, and treatment is discussed. Their application early in the disease course to new and old therapies will provide additional precision to AMN management. We also review innovative therapeutic approaches on the horizon that are expected to lead to our ultimate goal of improved patient care in A(I)MN.
Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9–30% in selected series. Using whole exome sequencing we ...sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.
WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype–phenotype correlations of 61 patients with ...WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype–phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.
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