Guidelines for Genetic Testing and Management of Alport Syndrome

Genetic testing for pathogenic COL4A3–5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3–COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.

Protective Effect of Keluoxin against Diabetic Nephropathy in Type 2 Diabetic Mellitus Models

Diabetic nephropathy (DN) is a chronic kidney disease that develops in patients with diabetes mellitus (DM). Renal dysfunction and persistent proteinuria are the main clinical features of DN. Podocyte injury is an important cause of persistent proteinuria and diabetic kidney disease (DKD) progression. Traditional Chinese patent medicines can improve renal function by enhancing autophagy and promoting apoptosis. Keluoxin is a Chinese patent medicine that has the effect of invigorating qi and nourishing yin, activating blood, and eliminating blood stasis. Therefore, we hypothesized that Keluoxin may have a protective effect against diabetic nephropathy in rats with type 2 DM. Rats induced with diabetes through streptozocin (STZ) injection and a high-fat and high-sugar diet were treated with Keluoxin (0.63 g/kg/day) for 8 weeks, and renal function, biochemical indicators, and histopathological changes in renal tissues were observed. Immunofluorescence staining and western blot analysis were used to detect the expression of autophagy-related proteins. The results showed that Keluoxin reduced blood glucose and lipid levels, improved renal function, and alleviated renal histopathological changes in rats with DN. The therapeutic effect was similar to that of Irbesartan (15.6 mg/kg/day). It is inferred that the mechanism works through reducing the obstruction of downstream pathways of autophagy by improving the lysosomal degradation function and alleviating podocyte injury. This study demonstrates that Keluoxin could regulate autophagy in podocytes, alleviate kidney injury in rats with DN, and have a protective effect on renal function; its mechanism can thus be a potential therapy for DN.

Mycoplasma pneumoniae Infection Associated C3 Glomerulopathy Presenting as Severe Crescentic Glomerulonephritis

C3 glomerulopathy (C3GP) is a group of diseases caused by a deregulated complement system, which encompasses both dense deposit disease and C3 glomerulonephritis. Renal manifestations of C3GP are primarily of proliferative glomerulonephritis, and only a few case reports of crescentic glomerulonephritis (CGN) in association with C3GP are available. Here is a case of an adult South-Asian female, who was diagnosed as seropositive acute Mycoplasma pneumoniae infection, with associated systemic manifestations, including immune-type extravascular haemolysis and nephrotic range proteinuria. Subsequent renal biopsy revealed CGN with disrupted Bowman’s capsules and necrotizing lesions. Immunofluorescence showed coarse granular mesangial C3 deposits with negative IgM, IgG, IgA, and C1q. The immunomorphological phenotype raised two possibilities including C3GP and infection-related glomerulonephritis (IRGN). Persistent proteinuria with no evidence of resolution even after 6 months of follow-up favoured C3GP over IRGN. The patient proceeded to end-stage renal failure requiring renal replacement despite aggressive immunosuppression. This case illustrates the rare association of CGN with C3GP induced by Mycoplasma pneumoniae infection, highlighting the importance of correct diagnosis as well as timely identification of triggering factors in CGN on patient outcome.

A Novel LMX1B Variant Identified in a Patient Presenting with Severe Renal Involvement and Thin Glomerular Basement Membrane

We report a case of nail-patella syndrome (NPS) with unusual thinning of the glomerular basement membrane (GBM) associated with a novel heterozygous variant in the <i>LMX1B</i> gene. A 43-year-old female patient with a previous diagnosis of NPS, referred to our hospital for persistent proteinuria, underwent a renal biopsy, which revealed minor glomerular abnormalities. She underwent a second renal biopsy at the age of 56 owing to the presence of persistent proteinuria and decline in serum albumin, meeting the diagnostic criteria for nephrotic syndrome. Light microscopy demonstrated glomerulosclerosis and cystic dilatation of the renal tubules. Notably, electron microscopy revealed unusual thinning of the GBM, which is quite different from typical biopsy findings observed in patients with NPS, characterized by thick GBM with fibrillary material and electron-lucent structures. Comprehensive genetic screening for 168 known genes responsible for inherited kidney diseases using a next-generation sequencing panel identified a novel heterozygous in-frame deletion-insertion (c.723_729delinsCAAC: p.[Ser242_Lys243delinsAsn]) in exon 4 of the <i>LMX1B</i> gene, which may account for the disrupted GBM structure. Further studies are warranted to elucidate the complex genotype-phenotype relationship between <i>LMX1B</i> and proper GBM morphogenesis.

Determination of prevalence of asymptomatic proteinuria and haematuria in 5-15 year aged school children in southern India

Background: Chronic renal diseases remain major cause of morbidity and mortality in young children. Although idiopathic nephrotic syndrome takes on chronic course other histopathological variants can lead to rapid progression of disease. Proteinuria in children can be physiological. Hematuria in children is always should be investigated. Persistent proteinuria in children should be investigated for any significant progressive renal disease after excluding orthostatic proteinuria. Although many countries adopt high risk screening in pediatric age group many eastern countries advocate school screening for asymptomatic proteinuria and hematuria using dipstick urine screening.Methods: A 6 month cross sectional study of asymptomatic children aged 5-15 years in metropolitan school for dipstick urine analysis for proteinuria and hematuria.Results: The ratio of male and female children in the study is 1.2:1 (total-1999, male-1056, and female-934). Age group ranged from 5 to 15 with mean 12.13 and standard deviation (SD)-2.46. Maximum number of students in the study are above 10 years of age. Children with isolated asymptomatic proteinuria have significant differences due to their sex (p value-0.005) and hematuria (p value-0.007). Prevalence of asymptomatic proteinuria is 9.8% and hematuria is 1.05%. Prevalence of persistent proteinuria is 1.35%.Conclusions: Prevalence of asymptomatic proteinuria and hematuria can be determined using dipstick urine analysis in school children. Mass screening is cost effective and feasible only if persistent cases of proteinuria are followed up, ruling out orthostatic proteinuria. Although study is feasible, it is cumbersome. High risk screening is the best cost effective method.

An Update on Targeted Treatment of IgA Nephropathy: An Autoimmune Perspective

Immunoglobulin (Ig) A nephropathy (IgAN) is the commonest form of primary glomerulonephritis worldwide and is, considered a significant cause of end-stage renal disease in young adults. The precise pathogenesis of IgAN is unclear. The clinical and pathological features vary significantly between individuals and races, which makes treating IgAN difficult. Currently, the therapeutic strategies in IgAN are still optimal blood pressure control and proteinuria remission to improve the renal function in most cases. Immunosuppressive drugs such as corticosteroids can be considered in patients with persistent proteinuria and a high risk of renal function decline; however, they include a high toxicity profile. Therefore, the safety and selectivity of medications are critical concerns in the treatment of IgAN. Various pharmacological therapeutic targets have emerged based on the evolving understanding of the autoimmune pathogenesis of IgAN, which involves the immune response, mucosal immunity, renal inflammation, complement activation, and autophagy; treatments based on these mechanisms have been explored in preclinical and clinical studies. This review summarizes the progress concerning targeted therapeutic strategies and the relevant autoimmune pathogenesis in IgAN.

Proteinuria and Psoriasis Risk: A Nationwide Population-Based Study

Psoriasis, a chronic inflammatory dermatosis, has been associated with chronic kidney disease or end-stage renal disease. However, the association of the changes or amount of proteinuria with psoriasis development has not been evaluated. Using the Korean National Health Screening database, we assessed psoriasis development until 2018 in 6,576,851 Koreans who underwent health examinations in 2009 and 2011. Psoriasis was defined using the International Classification of Diseases, 10th revision (ICD-10) code L40. The risk of psoriasis was evaluated according to change in proteinuria (never [Neg (no proteinuria)/Neg], new [Neg/Pos (proteinuria present)], past [Pos/Neg] and persistent [Pos/Pos] proteinuria) and the proteinuria amount. During a median 7.23-year follow-up, 162,468 (2.47%) individuals developed psoriasis. After adjustments, the hazard ratio (HR) for psoriasis was higher in the persistent proteinuria group (1.32 [1.24–1.40]) than in the never proteinuria group. The past proteinuria group showed better renal outcome (1.03 [1.00–1.07]) than the new (1.05 [1.01–1.07]) and never proteinuria (reference, 1.00) groups did. The amount of random urine proteinuria was associated with increased HR for psoriasis. Subgroup analyses for age, sex, estimated glomerular filtration rate (eGFR), hypertension and diabetes showed that the persistent proteinuria group had a higher risk of psoriasis than the never proteinuria group, especially at eGFR < 60 mL/min/1.73 m2. Persistent proteinuria is associated with psoriasis risk, and the proteinuria amount significantly affects psoriasis development.

Serum-Urine Matched Metabolomics for Predicting Progression of Henoch-Schonlein Purpura Nephritis

Henoch-Schonlein purpura nephritis (HSPN) is a common glomerulonephritis secondary to Henoch-Schonlein purpura (HSP) that affects systemic metabolism. Currently, there is a rarity of biomarkers to predict the progression of HSPN. This work sought to screen metabolic markers to predict the progression of HSPN via serum-urine matched metabolomics. A total of 90 HSPN patients were enrolled, including 46 HSPN (+) patients with severe kidney damage (persistent proteinuria &gt;0.3 g/day) and 44 HSPN (–) patients without obvious symptoms (proteinuria &lt; 0.3 g/day). Untargeted metabolomics was determined by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q/TOF-MS). A total of 38 and 50 differential metabolites were, respectively, identified in serum and urine from the comparison between HSPN (+) and HSPN (–) patients. Altered metabolic pathways in HSPN (+) mainly included glycerophospholipid metabolism, pyruvate metabolism, and citrate cycle. A panel of choline and cis-vaccenic acid gave areas under the curve of 92.69% in serum and 72.43% in urine for differential diagnosis between HSPN (+) and HSPN (–). In addition, the two metabolites showed a significant association with clinical indices of HSPN. These results suggest that serum-urine matched metabolomics comprehensively characterized the metabolic differences between HSPN (+) and HSPN (–), and choline and cis-vaccenic acid could serve as biomarkers to predict HSPN progression.

MO1014PROSPECTIVE STUDY OF SAFETY AND EFFECTIVENESS OF OFATUMUMAB AS A TREATMENT IN REFRACTORY NEPHROTIC SYNDROME (CORTICODEPENDENT AND CORTICORRESISTANT)

Background and Aims Ofatumumab (OFA) is an anti-CD-20 monoclonal antibody useful in nephrotic syndrome refractory to conventional treatments and rituximab (RTX). Our objective is to evaluate the response and safety in patients with nephrotic syndrome (NS) treated with Ofatumumab. Method A prospective descriptive study of 2 years duration (2017-2019) in children with NS refractory to first-line therapies who received treatment with anti-CD20 monoclonal antibodies. To do this, we divided the cohort into 3 groups: Patients with corticodependent NS (CDNS) without response or with adverse effects associated with first-line treatment that preclude its use (Group 1); Corticosteroid-resistant SN (CRNS) (Group 2) and SN with post-transplant recurrence (Group 3). In them, the results of safety and remission rate were evaluated. Results Thirty-three patients (21 with SNCD, 11 with SNCR, and 1 with SN recurrence in transplantation) were included and administered anti-CD20. The male / female ratio was 2: 1 and the mean age at diagnosis was 5.2 years. 100% of the children (33) received RTX and 18.2% (6) OFA. The RTX achieved complete remission in 87.9% (29) and 48.3% of these did not present new relapses after 70 months of follow-up. 100% of Group 1 presented complete remission after RTX, although 52.4% (11) presented at least 1 relapse after 22.9 months (mean 2.5 relapses). In group 2, 72.72% (8) complete remission and 27.2% (3) partial, with persistent proteinuria. 36.4% (4) presented relapse after 17 months of treatment (mean 1 relapse). Of the 6 who received OFA, 83.3% presented complete remission (1 SNCR and 4 SNCD) and 1 patient (SNCD) presented relapse at 24 months (mean follow-up 1 year). The other case, a 13-year-old girl with recurrence of focal segmental glomerulosclerosis (FSGS) in kidney transplantation, presented partial remission after one year of treatment in association with immunoadsorption sessions. Regarding safety, adverse reactions occurred in 6% (2): allergic reaction with 2nd dose of RTX and cytokine release syndrome with 1st dose of OFA. Conclusion Ofatumumab in our series has proven to be an effective and safe drug in difficult-to-manage NS, achieving complete remission in 5 patients who had not previously responded to Rituximab

Clinical and Genetic Characteristics of Atypical Hemolytic Uremic Syndrome in Children: A Chinese Cohort Study

<b><i>Background:</i></b> Atypical hemolytic uremic syndrome (aHUS) is a rare but critical illness. To this date, few studies have reported on the disease in Chinese children. <b><i>Methods:</i></b> We studied a Chinese pediatric cohort to delineate the clinical characteristics, genotypes, and prognosis. Ninety-one patients with aHUS were enrolled in this study. <b><i>Results:</i></b> Fifty-nine children (64.8%) had anti-complement-factor-H autoantibody-associated aHUS (anti-CFH aHUS). Of these children, 21 (46.7%) had complement factor-H-related protein 1 (CFHR1) homozygous deletion, and most patients with CFHR1 homozygous deletion also had complement factor-H-related protein 3 (CFHR3) homozygous deletions (76.2%). Using gene sequencing of 15 candidate genes, we identified 14 genetic variants in 46 aHUS patients, including 5 pathogenic or like pathogenic variants and 9 variants of uncertain significance. The average follow-up time was 46.1 ± 28 months. Among patients with anti-CFH aHUS, there was a correlation between CFHR1 homozygous deletion and patients with persistent proteinuria (odds ratio [OR] 6.954, 95% confidence interval [CI] 1.033–46.821, <i>p</i> = 0.046). As of the last follow-up, ESRD or deaths occurred in 3.6% of the children with anti-CFH aHUS and 26.7% of children with aHUS who were negative for anti-CFH. <b><i>Conclusions:</i></b> Anti-complement-factor-H antibody positivity is the main cause of morbidity in Chinese children with aHUS. There may be a correlation between CFHR1 homozygous deletion and persistent proteinuria. Comprehensive assessment of anti-CFH antibodies and genetic variants is essential for the management of aHUS children.