Cause Of Glomerular Disease Research Articles

Potential Role of Mineralocorticoid Receptor Antagonists in Nondiabetic Chronic Kidney Disease and Glomerular Disease.

Glomerular disease is a leading cause of CKD and ESKD. Although diabetic kidney disease is the most common cause of glomerular disease, nondiabetic causes include malignancy, systemic autoimmune conditions, drug effects, or genetic conditions. Nondiabetic glomerular diseases are rare diseases, with a paucity of high-quality clinical trials in this area. Furthermore, late referral can result in poor patient outcomes. This article reviews the current management of nondiabetic glomerular disease and explores the latest developments in drug treatment in this area. Current treatment of nondiabetic glomerular disease aims to manage complications (edema, hypertension, proteinuria, hyperlipidemia, hypercoagulability, and thrombosis) as well as target the underlying cause of glomerular disease. Treatment options include renin-angiotensin-aldosterone system inhibitors, statins/nonstatin alternatives, loop diuretics, anticoagulation agents, immunosuppressives, and lifestyle and dietary modifications. Effective treatment of nondiabetic glomerular disease is limited by heterogeneity and a lack of understanding of the disease pathogenesis. Sodium-glucose cotransporter-2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs, such as finerenone), with their broad anti-inflammatory and antifibrotic effects, have emerged as valuable therapeutic options for a range of cardiorenal conditions, including CKD. ns-MRAs are an evolving drug class of particular interest for the future treatment of nondiabetic glomerular disease, and there is evidence that these agents may improve kidney prognosis in various subgroups of patients with CKD. The benefits offered by ns-MRAs may present an opportunity to reduce the progression of CKD from a spectrum of glomerular disease. Several novel ns-MRA are in clinical development for both diabetic and nondiabetic CKD.

#1494 Immunotactoid glomerulopathy: a comprehensive analysis of three cases

Abstract Background Immunotactoid glomerulopathy (ITG) is an uncommon cause of glomerular disease encountered in approximately 0.06% of native kidney biopsies. This fibrillary disease is strongly associated with haematologic disorders, including lymphoma (mainly chronic lymphocytic leukaemia/small lymphocytic lymphoma), monoclonal gammopathy, and multiple myeloma. It is usually managed with oral steroids and/or treatment of an underlying lymphoproliferative disorder. Here, we report three cases of ITG, all female patients with varying severity of the disease, timing of malignancy and required treatment. Case Scenarios: Case 1: A 76-year-old lady with no significant medical background presented in May 2020 with confusion and progressive peripheral oedema. She had AKI (serum creatinine 210 µmol/L from baseline 68 µmol/L) and a sodium of 104 mmol/l. Urine PCR was 1182 mg/mmol. She was admitted to the ITU, where hyponatraemia was managed with a good clinical response. Blood screening showed negative immune, myeloma and virology screens. Complement was low. A renal biopsy showed a diagnosis of ITG. She had an extensive malignancy screen, but no malignancy was detected. She was started on prednisolone 60 mg once daily and eventually weaned off the drug by March 2021, as she maintained remission of her disease. Two years after her initial presentation, she was seen by the ophthalmologist for a right lacrimal gland mass. This was excised, and a biopsy revealed a MALT Lymphoma. Case 2: A 50-year-old lady with splenomegaly being investigated under the haematology service was referred to our renal clinic for proteinuria in June 2019. Her serum creatinine was within normal limits, and her UPCR was 302 mg/mmol. She had no paraprotein in her blood, low serum immunoglobulins, low C3 and a negative viral screen. Perindopril, initiated by her GP, was up-titrated. Renal biopsy revealed features in keeping with Immunotactoid Glomerulopathy, and completed haematological investigations revealed Chronic Lymphocytic Leukaemia. Her UPCR peaked at 842 mg/mmol before reducing to 190 mg/mmol within a year after treatment with Veneclotax and Rituximab after not tolerating FCR (Fludarabine, Cyclophosphamide, Rituximab) Chemotherapy. Case 3: A 69-year-old lady presented to the renal clinic with proteinuria in September 2018. She had a background of breast cancer diagnosed in 2007 (She had surgical resection followed by radiotherapy). Her 24-hour urine protein was 2g, and UPCR was 155 mg/mmol. Serum creatinine was 81 µmol/l and eGFR 66 ml/min. P- ANCA was positive, while PR3 and ANA were negative. She had bilateral leg oedema due to long-standing lymphedema. The biopsy report showed immunotactoid glomerulopathy. Regular surveillance of previous breast cancer with mammography and CT-CAP has shown no evidence of malignancy recurrence, hepatitis virology and paraprotein were negative, and C3/C4 were within normal limits. She had improved UPCR and maintained normal kidney function on full-dose Losartan. Conclusion Immunotactoid Glomerulopathy is a rare form of glomerular disease with a strong association with lymphoproliferative malignancies, which may precede, occur concomitantly or present years after the initial diagnosis. This common association highlights the need for diligence in screening for malignancy in each case, and it is a reason for careful follow-up of these patients. Treatment of underlying disorders is associated with positive renal outcomes, and in some cases, there is a good response to steroids.

#1166 ACTION3 pivotal Phase 3 & open-label extension study assessing DMX-200 in adult & paediatric patients with focal segmental glomerulosclerosis (FSGS)

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a major cause of glomerular disease that affects both adults and children. FSGS can rapidly progress to end-stage kidney disease. Lack of safe and effective treatment represents a significant unmet need for patients with FSGS. Development of treatments has been hampered by complexities including the rare nature of the disease, varying drivers of pathogenesis, and the evolving diagnostic and clinical trial designs, necessitating innovative research approaches. DMX-200 (repagermanium) is a C-C motif chemokine receptor 2 (CCR2) pathway inhibitor. Activation of the angiotensin II type 1 receptor (AT1R) and CCR2 have been independently implicated in the pathogenesis and progression of FSGS. These receptors form a functional complex so inhibition of both receptors may provide an efficient approach to FSGS treatment. In vivo data shows co-administration of DMX-200 and the angiotensin receptor blocker (ARB) irbesartan demonstrated a synergistic reduction in proteinuria, macrophage infiltration, and podocyte loss compared with vehicle or either antagonist alone. A subsequent Phase 2a cross-over study (NCT03649152) in N = 8 patients with biopsy-proven primary FSGS showed that the combination of DMX-200 and irbesartan (compared to placebo) was well tolerated with most patients experiencing a reduction in proteinuria. Based on these data, the global Phase 3 study (ACTION3) was initiated to confirm the proteinuria lowering effects of DMX-200 and assess effects on eGFR decline. ACTION3 is a randomised, placebo-controlled, double-blind, long-duration study of FSGS patients and on completion will provide a resource for the wider nephrology community and advocacy groups on the natural history of FSGS patients and the effects of a CCR2-inhibitor on the background of an ARB. Here we present the baseline data from the first 90 patients enrolled in ACTION3 at 12th January 2024. Method The ACTION3 (NCT05183646) study is a pivotal Phase 3, multicentre study of the efficacy and safety of DMX-200, 120 mg twice daily compared with placebo in adult patients with biopsy-proven FSGS receiving maximal tolerated ARB, with persistent proteinuria >1.5g/ day and eGFR >25 ml/min/1.73 m2. The study plans to enroll approximately 286 patients with primary FSGS, genetic FSGS and FSGS of undetermined cause with the primary objective of evaluating the efficacy of DMX-200 in percent change in 24-hour urine PCR and eGFR slope. The initial 104-week randomized period will be extended in a 2-year open label extension study. A futility analysis by an Independent Data Monitoring Committee following the first 72 patients completing 35 weeks of treatment confirm that continuation of the study is non-futile. Results The study is actively recruiting at 71 sites in 11 countries listed in Table 1. Demographic data of randomised patients is listed in Table 2. Patients are predominantly male (65%), with an average age of 46.6 yrs. and mean eGFR 56.3 ± 27.6 (ml/min/1.73 m2). The study is expanding recruitment into additional countries in the Asia Pacific, Europe, and Latin American regions. Further, the study protocol has sought and received regulatory approval to enroll adolescent patients aged 12-18 in Argentina, Mexico, UK and the US. Conclusion DMX-200 (repagermanium) has shown encouraging signs of safety and efficacy in combination with an ARB for the treatment of FSGS. The contributing countries and baseline characteristics of the patients enrolled in ACTION3 are similar to the populations studied in other recent FSGS trials. No clinically significant safety concerns have been observed in patients enrolled to date in the ACTION3 Phase 3 study.

Clinicopathological Characteristics of Adult IgA Nephropathy in the United States

IgA nephropathy (IgAN) is a progressive autoimmune kidney disease and a leading cause of glomerular disease that can result in kidney failure (KF). The median age at diagnosis is 35 to 37 years and approximately 50% of patients will progress to KF within 20 years. We aimed to enhance the understanding of renal histology and chronic kidney disease (CKD) stage at the time of IgAN diagnosis using a large real-world biopsy cohort. This retrospective cohort study evaluated biopsy data and clinical characteristics from adult patients within the US who were diagnosed with IgAN between January 1, 2016 to May 31, 2020. Descriptive statistics were summarized and relationship(s) between each Oxford Classification (MEST-C) component score with 24-hour proteinuria or CKD stage were examined using regression analysis. A total of 4375 patients (mean age 47.7 years, 62.7% male) met eligibility criteria. Mild to moderate mesangial hypercellularity (47.3%), segmental sclerosis (65.0%), tubular atrophy≥25% (57.4%), and crescents (18.5%) were identified; and 74.6% of patients were at CKD stage≥3. Proteinuria≥1 g/d was associated with higher MEST-C scores, and the odds of mesangial hypercellularity, segmental sclerosis, tubular atrophy, and crescents increased with CKD stage. Most patients with IgAN in our US cohort were diagnosed at CKD stage≥3 and had high MEST-C scores and proteinuria that are suggestive of significant disease burden at the time of kidney biopsy. Strategies are required to raise awareness and promote earlier detection of asymptomatic urinary abnormalities before extensive irreversible kidney damage has occurred.

#5344 EPIDEMIOLOGY OF GLOMERULAR DISEASES IN THE PRE- AND POST-COVID-19 ERA IN CENTRAL QUEENSLAND, AUSTRALIA

Abstract Background and Aims Development of new onset and recurrent glomerular diseases (GD) following Covid-19 infection or vaccination are increasingly reported in the literature with various proposed pathogenic mechanisms. Australia reported its first case of Covid-19 in January 2020. Currently in Australia, there has been 11.3 million cases of Covid-19 infection and 98% of individuals aged ≥ 16 years received at least 1 dose of Covid-19 vaccination. However, there are no studies in Australia that evaluate the risk of GD after Covid-19 infection or vaccination. We compared kidney biopsy results pre- (01/01/2017-31/12/2019) and post- (01/01/2020-31/12/2022) Covid-19 era to assess for potential changes in the epidemiology of kidney biopsy-proven GD. Method In this single-centred retrospective study, all renal biopsies performed in Central Queensland (CQ) between 01/01/2017 and 31/12/2022 were reviewed. This pilot study is a subset of Queensland Kidney Biopsy Registry which has captured all renal biopsies of adults residing in CQ with a regional population of 220,912 with a land area of 497,714 km2. Results Eighty-seven percent of the CQ population received at least one dose of Covid-19 vaccination and 53,234 cases of Covid-19 infection were confirmed by rapid antigen test (RAT) as of the end of January 2023. The total number of kidney biopsies performed pre- and post-Covid-19 era were 47 vs 58, respectively, and the majority were native kidney biopsies (94% vs 95%) in CQ whereby the number of nephrologists in the respective catchment areas and access availability to kidney biopsies remained similar. The mean age of patients was 55.3 years (standard deviation, SD 16.4) vs 55.6 years (SD 15.6) and the majority were males (70% vs 62%) and Caucasians (77% vs 76%). No case of recurrent GD was diagnosed in pre-Covid-19 era whereas 5 cases of recurrent GD {2 membranous nephropathy, 1 minimal change disease, 1 lupus nephritis class III-IV, and 1 ANCA associated vasculitis (AAV)} in post-Covid-19 era, p = 0.025. The commonest cause of GD in the pre-Covid-19 era was IgA nephropathy (IgAN) whereas diabetic nephropathy and AAV was the most common GD during the post-Covid-19 era. The incidence of IgAN decreased from 12 cases (18.1 cases/million person years) in pre-Covid-19 era to 3 cases (4.5 cases/million person years) in the post-Covid-19 era (incidence rate ratio, IRR of 0.25, 95% CI 0.05-0.93, p = 0.020). The incidence of diabetic nephropathy increased from 1 case (1.5 cases million person years) during the three years pre-Covid-19 era to 13 cases (19.6 cases/million person years) for three years post-Covid-19 era (IRR of 13.1, 95% CI 1.95-552.47, p = 0.001). In the post-Covid-19 era, the mean age of patients with diabetic nephropathy was 51.2 years (SD 11.9) and the majority were indigenous Australian (n = 8, 62%) with poor diabetic control. They had kidney biopsies for nephrotic range proteinuria with or without acute kidney injury and haematuria. The incidence of AAV increased from 3 cases (4.5 cases/million person years) during the three years pre-Covid-19 era to 10 cases (15.1 cases/million person years) for three years post-Covid-19 era (IRR of 3.4, 95% CI 0.86-18.85, p = 0.052). In the post-Covid-19 era, the mean age of patients with AAV was 68.4 years (SD 16.1) with Caucasian (n = 10, 100%). PR3-AAV (n = 5) and MPO-AAV (n = 5) are equally prevalent, and 3 patients (30%) had concomitant pulmonary complications. Three cases of AAV each occurred in the first and second years and 4 cases in the third year during the post-Covid-19 era. There was no increase in the incidence rate for other types of glomerular diseases. Conclusion Our findings suggest the frequency of incident and recurrent GD may vary with the emergence of Covid-19 and steps taken to minimise viral complications that include primary preventative measures via vaccination. Larger epidemiological studies are required to better elucidate the risk of Covid-19 infection and vaccination in relation to GD.

Loss of the collagen IV modifier prolyl 3-hydroxylase 2 causes thin basement membrane nephropathy.

The glomerular filtration barrier (GFB) produces primary urine and is composed of a fenestrated endothelium, a glomerular basement membrane (GBM), podocytes, and a slit diaphragm. Impairment of the GFB leads to albuminuria and microhematuria. The GBM is generated via secreted proteins from both endothelial cells and podocytes and is supposed to majorly contribute to filtration selectivity. While genetic mutations or variations of GBM components have been recently proposed to be a common cause of glomerular diseases, pathways modifying and stabilizing the GBM remain incompletely understood. Here, we identified prolyl 3-hydroxylase 2 (P3H2) as a regulator of the GBM in an a cohort of patients with albuminuria. P3H2 hydroxylates the 3′ of prolines in collagen IV subchains in the endoplasmic reticulum. Characterization of a P3h2ΔPod mouse line revealed that the absence of P3H2 protein in podocytes induced a thin basement membrane nephropathy (TBMN) phenotype with a thinner GBM than that in WT mice and the development of microhematuria and microalbuminuria over time. Mechanistically, differential quantitative proteomics of the GBM identified a significant decrease in the abundance of collagen IV subchains and their interaction partners in P3h2ΔPod mice. To our knowledge, P3H2 protein is the first identified GBM modifier, and loss or mutation of P3H2 causes TBMN and focal segmental glomerulosclerosis in mice and humans.

A novel frameshift homozygous mutation in FAT1 gene causes ptosis, nephropathy, and syndactyly in an Emirati family: case report and literature review

Background: Single gene mutations are important causes of glomerular disease in children. Of these genes, mutations in the FAT1 gene have been recently described in the literature as a cause of nephropathy in isolated form or multisystem involvement. The spectrum of renal disease associated with FAT1 gene mutations varies from asymptomatic proteinuria and hematuria to severe nephrotic syndrome and end-stage renal disease. Case Presentation: In this case report, we describe a 3-year-old child and two other family members with a novel frameshift homozygous mutation in the FAT1 gene consistent with the diagnosis of autosomal recessive colobomatous-microphthalmia, ptosis, nephropathy, and syndactyly syndrome with variable expression of the phenotype. Conclusion: This report adds to the genotype-phenotype correlation, highlighting the clinical importance of considering FAT1 gene defects as part of the differential diagnosis for congenital ptosis, syndactyly and nephropathy, especially with multiple affected family members.

Crk1/2 and CrkL play critical roles in maintaining podocyte morphology and function

Podocytes are actin-rich epithelial cells whose effacement and detachment are the main cause of glomerular disease. Crk family proteins: Crk1/2 and CrkL are reported to be important intracellular signaling proteins that are involved in many biological processes. However, the roles of them in maintaining podocyte morphology and function remain poorly understood. In this study, specific knocking down of Crk1/2 and CrkL in podocytes caused abnormal cell morphology, actin cytoskeleton rearrangement and dysfunction in cell adhesion, spreading, migration, and viability. The p130Cas, focal adhesion kinase, phosphatidylinositol 3-kinase/Akt, p38 and JNK signaling pathways involved in these alterations. Furthermore, knocking down CrkL alone conferred a more modest phenotype than did the Crk1/2 knockdown and the double knockdown. Kidney biopsy specimens from patients with focal segmental glomerulosclerosis and minimal change nephropathy showed downregulation of Crk1/2 and CrkL in glomeruli. In zebrafish embryos, Crk1/2 and CrkL knockdown compromised the morphology and caused abnormal glomerular development. Thus, our results suggest that Crk1/2 and CrkL expression are important in podocytes; loss of either will cause podocyte dysfunction, leading to foot process effacement and podocyte detachment.

P0246MEMBRANOUS NEPHROPATHY IN THE ELDERLY : EPIDEMIOLOGY, DIAGNOSIS AND MANAGEMENT

Abstract Background and Aims The aging of the population and the increase in life expectancy have led to increasing numbers of elderly patients so greater numbers of elderly patients with chronic kidney diseases are surviving longer. Membranous nephropathy (MN) is the most important cause of glomerular disease in older patients (≥65 years). The aim of this study is to describe the epidemiological and clinical profile of elderly patients with MN and to analyze the diagnostic and management approach. Method We conducted a retrospective descriptive study in the nephrology department at Charles Nicolle hospital over a period of 44 years. All older patients (≥65 years) with histologically proven MN were included in this study. Results Thirty patients were collected. The mean age was 69.43 years (65-78 years) with a male predominance (sex ratio: 2.3) and low socio-economic level in 83.3% of cases. Sixteen patients were smokers (55.3%), 5 ethyl patients (16.7%), diabetes was present in 3 patients (10%) and hypertension in 11 patients (36.7%). Two cases of neoplasm were present, namely one case of prostatic adenocarcinoma and one case of gallbladder adenocarcinoma, all were diagnosed and treated along one year and ten years respectively, before the diagnosis of MN. The circumstances of discovery was dominated by oedema in 27 cases (86.27%), hypertension in 11 cases (36.7%) and elevated creatinine level in 9 cases (30%). Deep venous thrombosis was the circumstance of discovery in one case. At the time of diagnosis, the clinico-biological picture was dominated by high systolic blood pressure in 21 cases (67.6%), anasarca in 7 cases (23.3%), proteinuria in all cases and hematuria in 20 cases (66.6%). Biology revealed nephrotic syndrome (NS) in 28 cases (87.11%), hypercholesterolemia in 23 cases (76.6%), high serum creatinine in 14 cases (46.6%) with an average creatinine level of 123,85 µmol/l, anemia in 17 cases (56.6%) and anti-neutrophil cytoplasmic antibodies were positive in one case. MN was confirmed by a kidney biopsy in all cases. Twenty-two patients had idiopathic MN (IMN) and 2 patients had secondary MN. In fact, MN was associated with multiple myeloma in one case and secondary to hepatitis B in other case. Symptomatic treatment was indicated in all patients. Patients with secondary MN received etiopathogenic treatment. For the IMN, immunosuppressive therapy started early for 12 patients (40%) because of the severe NS and the deterioration of renal function. Eight patients (26.6%) received corticosteroids alone, three patients received corticosteroid with mycofenolate mofetil and one patient received corticosteroid with ciclosporin. We noted complete remission in 6 patients and end renal stage disease in 5 patients. Conclusion In studies of glomerular disease in the elderly, MN was the most common cause of NS. The clinical presentation is similar in older and younger patients, but older patients more often present with kidney failure and severe NS.

CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease

Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. Multicenter prospective cohort study. Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. Current follow-up can only detect large differences in ESKD and death outcomes. Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.

Synopsis of Sweet! Mouse Models of Diabetic Kidney Disease.

Diabetes mellitus (types 1 and 2) is the leading cause of glomerular disease and end-stage renal disease in most developed countries, with estimates that one-third of people living with diabetes will develop diabetic kidney disease (DKD). The current standard of care medications slow but do not arrest progression of kidney disease, and therefore, therapy for DKD is a highly unmet medical need for patients. To discover and test novel and durable new therapies, it is necessary to develop animal models of human DKD, which authentically recapitulate the human disease state and provide translatable efficacy to human patients. Here, we review selected mouse models of human DKD, which demonstrate many of the features of type 2 human DKD.

Glomerular Diseases in Children.

Unique challenges exist in the diagnosis and treatment of glomerular diseases with their onset during childhood. Mounting evidence supports the notion that earlier onset cases occur due to larger numbers of genetic risk alleles. Nearly all causes of adult-onset glomerulonephritis, nephrotic syndrome, and thrombotic microangiopathy have also been described in children, although the prevalence of specific causes differs. Postinfectious glomerulonephritis, Henoch-Schönlein purpura nephritis, and minimal change disease remain the most common causes of glomerular disease in younger children in the United States and can be diagnosed clinically without need for biopsy. IgA nephropathy is the most common pediatric glomerular disease diagnosed by kidney biopsy and is considered the most common chronic glomerulopathy worldwide. In both developing and developed countries, there is a strong relationship between infectious diseases and nephritis onset or relapse. Although research has led to a better understanding of how to classify and manage glomerular diseases in children, the need for disease-specific biomarkers of activity and chronicity remains a hurdle. The strength of the immune system and the growth and maturation that occurs during adolescence are unique and require age-specific approaches to disease management.

Renal and Cardiovascular Morbidities Associated with APOL1 Status among African-American and Non-African-American Children with Focal Segmental Glomerulosclerosis.

African-American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression, and cardiovascular morbidity in children. We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease. A total of 140 AA children in the CKiD study were genotyped. High risk (HR) APOL1 genotypes were present in 24% of AA children (33/140) and were associated with FSGS, p < 0.001. FSGS was the most common cause of glomerular disease in children with HR APOL1 (89%; 25/28). Of 32 AA children with FSGS, 25 (78%) had HR APOL1. Compared to children with low risk APOL1 and FSGS (comprising 36 non-AA and 7 AA), children with HR APOL1 developed FSGS at a later age, 12.0 (IQR: 9.5, 12.5) vs. 5.5 (2.5, 11.5) years, p = 0.004, had a higher prevalence of uncontrolled hypertension (52 vs. 33%, p = 0.13), left ventricular hypertrophy (LVH) (53 vs. 12%, p < 0.01), C-reactive protein > 3 mg/l (33 vs. 15%, p = 0.12), and obesity (48 vs. 19%, p = 0.01). There were no differences in glomerular filtration rate, hemoglobin, iPTH, or calcium-phosphate product. AA children with HR APOL1 genotype and FSGS have increase prevalence of obesity and LVH despite a later age of FSGS onset, while adjusting for socioeconomic status. Treatment of obesity may be an important component of chronic kidney disease and LVH management in this population.

Prognostic factors for mortality in pediatric acute poststreptococcal glomerulonephritis

Background Acute post-streptococcal glomerulonephritis (APSGN) is one of the most common causes of glomerular disease in developing countries, including Indonesia. It can lead to end stage renal failure and higher mortality rates. To decrease morbidity and mortality, it is important to understand the prognostic factors affecting the disease.Objective To identify prognostic factors affecting outcomes in pediatric APSGN patients.Methods Study data were collected from medical records of patients with APSGN hospitalized in Wahidin Sudirohusodo Hospital, Makassar in 2009-2013. Possible prognotic factors analyzed were gender, age, nutritional status, level of consciousness, as well as proteinuria, hemoglobin, serum albumin, urea, and creatinine levels.Results Of 86 subjects, 82 (95.3%) survived and 4 (4.7%) died. Fifty-three (61.6%) patients were male and 33 (38.4%) were female. Subjects’ ages ranged from 3.42 to 14.67 years, with a mean age of 9.36 years. Multivariate analysis revealed serum creatinine level &gt;1.5 mg/dL to be an independent prognostic factor for mortality in children with APSGN (AOR 15.43; 95%CI 1.31 to 181.7; P=0.03).Conclusion High serum creatinine level is an independent prognostic factor for poor outcomes in children with APSGN. [Paediatr Indones. 2016;56:166-70.].

Frequency of kidney diseases and clinical indications of pediatric renal biopsy: A single center experience.

Kidney biopsy occupies a fundamental position in the management of kidney diseases. There are very few renal pathology studies available in the literature from developing world. This study scrutinized the frequency and clinicopathological relationship of kidney biopsies done at the kidney center from 1997 to 2013 amongst pediatric patients. Kidney allograft biopsy were excluded. The specimen was examined under light microscopy and immunofluorescence while electron microscopy was not done. The study includes 423 patients, mean age was 10.48 ± 4.58 years, males 245 (57.9%) were more than females 178 (42.1%). Nephrotic syndrome 314 (74.2%) was the most common clinical presentation followed by acute nephritic syndrome 35 (8.3%) and acute renal failure 24 (5.7%). Primary glomerulonephritis (PGN) was the most common group of diseases, seen in 360 (85.1%) followed by secondary glomerulonephritis (SGN) in 27 (6.4%) and tubulointerstitial nephritis in 21 (5.0%). Among PGN, minimal change disease (MCD) was the most dominant disease, with 128 (30.3%) cases followed by focal segmental glomerulosclerosis FSGS in 109 (25.8%) and membranous glomerulonephropathy in 27 (6.4%). Lupus nephritis (LN) was the leading cause of glomerular disease in SGN followed by hemolytic uremic syndrome. In conclusion, MCD is the most common histological finding, especially in younger children and FSGS is second to it. SGN is rare, and the most common disease in this category is LN while tubulointerstitial and vascular diseases are infrequent.

Translating genetic findings in hereditary nephrotic syndrome: the missing loops.

Nephrotic syndrome (NS) is a clinicopathological entity characterized by proteinuria, hypoalbuminemia, peripheral edema, and hyperlipidemia. It is the most common cause of glomerular disease in children and adults. Although the molecular pathogenesis of NS is not completely understood, data from the study of familial NS suggest that it is a "podocytopathy." Virtually all of the genes mutated in hereditary NS localize to the podocyte or its secreted products and the slit diaphragm. Since the completion of human genome sequence and the advent of next generation sequencing, at least 29 causes of single-gene NS have been identified. However, these findings have not been matched by therapeutic advances owing to suboptimal in vitro and in vivo models for the study of human glomerular disease and podocyte injury phenotypes. Multidisciplinary collaboration between clinicians, geneticists, cell biologists, and molecular physiologists has the potential to overcome this barrier and thereby speed up the translation of genetic findings into improved patient care.

Recurrent focal segmental glomerulosclerosis after kidney transplantation.

Focal segmental glomerulosclerosis (FSGS) is an important cause of glomerular disease in children and adolescents and nearly 50 % of affected patients will progress to end-stage kidney disease over a 5 to 10-year period. Unfortunately, there is no established treatment for disease in the native kidney. Moreover, up to 55 % of patients develop recurrent disease after receiving a kidney transplant, with a substantially higher risk in patients who have already experienced recurrent disease in a prior transplant. A number of clinical and laboratory factors have been identified as risk factors for this complication. In addition, new investigations into podocyte biology and circulating permeability factors have shed light on the cause of recurrent the disease. While a number of novel therapeutic agents have been applied in the management of this problem, there still is no proven treatment. In this review, we summarize recent advances in the epidemiology, pathophysiology, and treatment of recurrent FSGS in pediatric patients who have received a kidney transplant.

Glomerular diseases outcome at one year in a tertiary care centre.

Objectives:To determine outcome in primary and secondary glomerular diseases at one year follow up.Methods:Study design is observational cohort, done in out-patient department, Dow Iinternational Medical College, DUHS. All information gathered on a proforma. All patients with dipstick positive proteinuria and clinical glomerular disease were included in study. Patients with no proteinuria were excluded so were patients with stage 5 CKD. Patients were followed for proteinuria and renal insufficiency at completion of one year follow up. Statistical analysis was done on SPSS version 16.Result:Total number of patients who completed one year follow up was 173. Mean age of patients was 51.67+ 10.16 (range 15 to 75 years). Ninety two (53.2%), were males and 81(46.8%) were females, ratio being 1.1: 1.0. Mean weight of our patients was 67.43+ 14.13 Kg, (35 to 107 kg). Commonest cause of glomerular disease in our patient was diabetic nephropathy which was seen in 94.2% patients. Commonest associated problem with glomerular disease was hypertension seen in 66.5% of patients. Four out of 173 patients had stage 5 CKD at end of follow up at one year while quantitativ proteinuria remained same at one year follow up.Conclusion:One year follow up is critical for patients with glomerular disease associated with stage 4 CKD as progression to end stage renal failure may be seen within one year in these patients.

Prognostic Factor of Ureum and Creatinine Serum of Acute Post Streptococcal Glomerulonephritis in Children

Introduction: Acute post streptococcal glomerulonephritis is one of the commonest causes of glomerular disease in developing countries. Ureum and creatinine examination not only can be used to support the diagnosis but also to identify and detect early organs disturbances and predict the patient prognosis. Objective: This study aims to observe the ureum and creatinine serum level in APSGN children and its relationship with the outcomes. Methods: A retrospective cohort design regarding the prognostic value of serum ureum and creatinine levels for APSGN children outcomes. The data was collected from medical records of APSGN children treated at Dr. Wahidin Sudirohusodo Hospital Makassar from 2009-2013. Results: There is no significant correlation between the outcome and sex (p=0.961), nutritional status (p=1.000), and age (p=0.108). There is a significant difference both in early ureum levels to outcome with p=0.003 and in early creatinine levels to outcome with p=0.020. There is tendency to decreased levels of ureum and creatinine serum of survival group (p=0.000) while hospitalization and trend of increased or stagnan levels of ureum and creatinine serum of non survival group while hospitalization. Multivariate analyses indicated that serum ureum levels <119 mg/dl is an independent prognostic factor for APSGN outcomes in children with p=0.032, OR 1.021, and CI 95% 1.002-1.041. Conclusion: It seems that serum ureum is an independent prognostic factor for APSGN, where serum ureum levels <119 mg/dl and creatinine levels <1.3 mg/dl have a good prognosis. Out of the 95 patients as sampled, there were 90 (94.7%) cured, and 5 (5.2%) patients died.

Early Focal Segmental Glomerulosclerosis as a Cause of Renal Allograft Primary Nonfunction

Background. Primary focal segmental glomerulosclerosis (FSGS) is one of the commonest causes of glomerular disease and if left untreated will often progress to established renal failure. In many cases the best treatment option is renal transplantation; however primary FSGS may rapidly recur in renal allografts and may contribute to delayed graft function. We present a case of primary nonfunction in a renal allograft due to biopsy-proven FSGS. Case Report. A 32-year-old man presented with serum albumin of 22 g/L, proteinuria quantified at 12 g/L, and marked peripheral oedema. Renal biopsy demonstrated tip-variant FSGS. Despite treatment, the patient developed progressive renal dysfunction and was commenced on haemodialysis. Cadaveric renal transplantation was undertaken; however this was complicated by primary nonfunction. Renal biopsies failed to demonstrate evidence of acute rejection but did demonstrate clear evidence of FSGS. The patient was treated to no avail. Discussion. Primary renal allograft nonfunction following transplantation is often due to acute kidney injury or acute rejection. Recurrent FSGS is recognised as a phenomenon that drives allograft dysfunction but is not traditionally associated with primary nonfunction. This case highlights FSGS as a potentially aggressive process that, once active in the allograft, may prove refractory to targeted treatment. Preemptive therapies in patients deemed to be at high risk of recurrent disease may be appropriate and should be considered.