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Author(s): Richard Klaus [sup.1] , Teresa K. Barth [sup.2] , Axel Imhof [sup.2] , Franziska Thalmeier [sup.1] , Bärbel Lange-Sperandio [sup.1] Author Affiliations: (1) https://ror.org/05591te55, grid.5252.0, 0000 0004 1936 973X, [...], Background Urinary proteomics identifies the totality of urinary proteins and can therefore help in getting an early and precise diagnosis of various pathological processes in the kidneys. In infants, non-invasive urine collection is most commonly accomplished with a urine bag or clean catch. The influence of those two collection methods on urinary proteomics was assessed in this study. Methods Thirty-two urine samples were collected in infants using urine bag and clean catch within 24 h. Nine boys and seven girls with a mean age of 4.3 ± 2.9 months were included (5 x post-pyelonephritis, 10 x non-kidney disease, 1 x chronic kidney disease (CKD)). Liquid chromatography-mass spectrometry (LC-MS/MS) was performed in data-independent acquisition (DIA) mode. Protein identification and quantification were achieved using Spectronaut. Results A total of 1454 urinary proteins were detected. Albumin and [alpha]-1-microglobulin were detected the most. The 18 top-abundant proteins accounted for 50% of total abundance. The number of proteins was slightly, but insignificantly higher in clean catch (957 ± 245) than in bag urine (876 ± 255). The median intensity was 1.2 x higher in the clean catch. Overall, differential detection of proteins was 29% between the collection methods; however, it diminished to 3% in the 96 top-abundant proteins. Pearson's correlation coefficient was 0.81 ± 0.11, demonstrating a high intraindividual correlation. A principal component analysis and a heat map showed clustering according to diagnoses and patients rather than to the collection method. Conclusion Urinary proteomics shows a high correlation with minor variation in low-abundant proteins between the two urine collection methods. The biological characteristics overrule this variation.

Background Impaired kidney concentration capacity is present in half of the patients with autosomal dominant polycystic kidney disease (ADPKD). The kidney concentrating capacity was further impaired within the animal model of autosomal recessive polycystic kidney disease (ARPKD). To date, only one small study has investigated it in children having ARPKD. Therefore, we aimed to study the kidney concentrating ability in a larger cohort of children with ARPKD. Methods Eighteen children (median age 8.5 years, range 1.3-16.8) were retrospectively investigated. A standardized kidney concentrating capacity test was performed after the application of a nasal drop of desmopressin (urine osmolality > 900 mOsmol/kg). The glomerular filtration rate was estimated using the Schwartz formula (eGFR) and blood pressure (BP) was measured as office BP. Results Kidney concentrating capacity was decreased (urine osmolality < 900 mOsmol/kg) in 100% of children with ARPKD. The median urine osmolality after desmopressin application was 389 (range 235-601) mOsmol/kg. Sixteen patients (89%) were defined as hypertensive based on their actual BP level or their use of antihypertensive drugs. The maximum amounts of urinary concentration correlated significantly with eGFR (r = 0.72, p < 0.0001) and hypertensive scores (r = 0.50, p < 0.05), but not with kidney size. Twelve patients (67%) were defined as having CKD stages 2-4. The median concentrating capacity was significantly lower in children within this group, when compared to children with CKD stage 1 possessing a normal eGFR (544 mOsmol/kg, range 413-600 mOsmol/kg vs. 327 mOsmol/kg, range 235-417 mOsmol/l, p < 0.001). Conclusions Impaired kidney concentrating capacity is present in most children with ARPKD and is associated with decreased eGFR and hypertension. Graphical abstract, Author(s): Tomás Seeman [sup.1] [sup.2] [sup.3] , Kveta Bláhová [sup.2] , Filip Fencl [sup.2] , Richard Klaus [sup.1] [sup.2] , Bärbel Lange-Sperandio [sup.1] , Gabriela Hrcková [sup.4] , Ĺudmila Podracká [...]

Background: Anti-GBM disease is a rare vasculitis mediated by pathogenic antibodies against collagen IV. Anti-GBM disease presents with rapid progressive glomerulonephritis and leads to kidney failure if untreated. KDIGO recommends plasma exchanges (PEX) for antibody elimination and steroids plus cyclophosphamide (CTX) to suppress antibody production. CTX is associated with severe side effects including gonadal toxicity. Rituximab (RTX) and mycophenolate mofetil (MMF) might be a less toxic but equally efficient alternative to CTX. Studies in pediatric anti-GBM disease patients receiving RTX and MMF instead of CTX are lacking. Methods: A retrospective survey in 8 tertiary German centers was performed. The clinical data of patients diagnosed between 2014 and 2022 were collected and analyzed. Results: Five adolescent patients treated with PEX and RTX and/or MMF due to anti-GBM disease were analyzed. All patients had anti-GBM antibodies, hematuria, glomerular proteinuria, and pulmonary hemorrhage. eGFR was 124 ml/min/1.73 m2 (range 47–162), and all patients were non-dialysis-dependent but with relevant histological kidney affection (mean crescents on kidney biopsy 77%). Antibody clearance was achieved after 13 PEX cycles (range 6–31). Four out of 5 patients received methylprednisolone pulses. All patients received oral prednisolone and MMF, and four patients received a median of 4 RTX doses (range 2–4). After a mean follow-up of 27 months, 4/5 patients had conserved or improved kidney function, while one patient (20%) developed kidney failure. Conclusions: In this small series of pediatric non-dialysis-dependent anti-GBM disease patients, first-line treatment with RTX and MMF showed a favorable kidney outcome in 4/5 cases and had an acceptable side effect profile. [ABSTRACT FROM AUTHOR]

Background Congenital nephrotic syndrome (CNS) is primarily a monogenetic disease, with the majority of cases due to changes in five different genes: the nephrin (NPHS1), podocin (NPHS2), Wilms tumor 1 (WT1), laminin ß2 (LAMB2), and phospholipase C epsilon 1 (PLCE1, NPHS3) gene. Usually CNS is not responsive to immunosuppressive therapy, but treatment with ACE inhibitors, AT1 receptor blockade and/or indomethacin can reduce proteinuria. If the disease progresses to end-stage renal disease, kidney transplantation is the therapy of choice. Case-Diagnosis Here, we present the case of a 4-month-old girl with congenital nephrotic syndrome. Upon admission, the patient presented with life-threatening anasarca, hypoalbuminemia, proteinuria, and impaired growth. There was no evidence of an infectious or immunological etiology. The genetic evaluation revealed a heterozygous variant in NPHS1 (p.Arg207Trp), in NPHS2 (p.Ser95Phe) as well as in PLCE1 (p.Ala1045Ser) and did not explain CNS. In addition to daily parenteral albumin infusions plus furosemide, a pharmacological antiproteinuric therapy was started to reduce protein excretion. Based on the genetic results, immunosuppressive therapy with prednisolone was initiated, but without response. However, following cyclosporine A treatment, the patient achieved complete remission and now has good renal function, growth, and development. Conclusions A profound search for the cause of CNS is necessary but has its limitations. The therapeutic strategy should be adapted when the etiology remains unclear., Author(s): Anna Eichinger [sup.1] , Sabine Ponsel [sup.1] , Carsten Bergmann [sup.2] , Roman Günthner [sup.3] [sup.4] , Julia Hoefele [sup.3] , Kerstin Amann [sup.5] , Bärbel Lange-Sperandio [sup.1] Author [...]

Background Alport syndrome (ATS) is a progressive hereditary nephropathy characterized by hematuria and proteinuria. It can be associated with extrarenal manifestations. In contrast, thin basement membrane nephropathy (TBMN) is characterized by microscopic hematuria, is largely asymptomatic, and is rarely associated with proteinuria and end-stage renal disease. Mutations have been identified in the COL4A5 gene in ATS and in the COL4A3 and COL4A4 genes in ATS and TBMN. To date, more than 1000 different mutations in COL4A5, COL4A3, and COL4A4 are known. Methods In this study mutational analysis by exon sequencing and multiplex ligation-dependent probe amplification was performed in a large European cohort of families with ATS and TBMN. Results Molecular diagnostic testing of 216 individuals led to the detection of 47 novel mutations, thereby expanding the spectrum of known mutations causing ATS and TBMN by up to 10 and 6 %, respectively, depending on the database. Remarkably, a high number of ATS patients with only single mutations in COL4A3 and COL4A4 were identified. Additionally, three ATS patients presented with synonymous sequence variants that possible affect correct mRNA splicing, as suggested by in silico analysis. Conclusions The results of this study clearly broaden the genotypic spectrum of known mutations for ATS and TBMN, which will in turn now facilitate future studies into genotype-phenotype correlations. Further studies should also examine the significance of single heterozygous mutations in COL4A3 and COL4A4 and of synonymous sequence variants associated with ATS., Author(s): Stefanie Weber[sup.1] , Katja Strasser[sup.1] , Sabine Rath[sup.2] , Achim Kittke[sup.2] , Sonja Beicht[sup.2] , Martin Alberer[sup.3] , Bärbel Lange-Sperandio[sup.4] , Peter F. Hoyer[sup.1] , Marcus R. Benz[sup.5] , [...]

Thin basement membrane nephropathy (TBMN) and Alport syndrome (ATS) are genetically heterogeneous conditions characterized by structural abnormalities in the glomerular basement membrane (GBM). TBMN presents with hematuria, minimal proteinuria, and normal renal function. Although TBMN is an autosomal dominant disease (COL4A3 and COL4A4), ATS can be inherited X-linked (COL4A5), autosomal recessive, or autosomal dominant (both COL4A3 and COL4A4). The clinical course of TBMN is usually benign, whereas ATS typically results in end-stage renal disease (ESRD). Nevertheless, there is a broad spectrum of clinical phenotypes caused by mutations in COL4A3 or COL4A4. We report an Italian family who presented with hematuria and mild proteinuria. Mutational analysis showed a novel heterozygous mutation p.G291E in exon 15 of the COL4A3 gene. Many different mutations in COL4A3 and COL4A4 that cause TBMN have already been identified, but most genetic variability in these genes has been found to cause autosomal ATS. A valid genotype-phenotype correlation for TBMN or ATS is not yet known. Therefore, it is important to identify new mutations by direct sequencing to clarify their clinical importance, to assess the prognosis of the disease, and to avoid renal biopsy. Keywords Thin basement membrane nephropathy * Late-onset ESRD * Proteinuria * Hematuria, Introduction Thin basement membrane nephropathy (TBMN) is the most common cause of inherited renal disease. The exact epidemiology is not known, but has been reported to be as high as [...]

Byline: Barbel Lange-Sperandio (1), Klaus Mohring (2), Frank Gutzler (3), Otto Mehls (1) Keywords: Familial Mediterranean fever; Polyarteritis nodosa; Henoch Schonlein syndrome Abstract: Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent and self-limited attacks of serosal inflammation with abdominal pain, chest pain, and arthritis usually accompanied by fever. Different vasculitides such as polyarteritis nodosa (PAN) and Henoch-Schonlein syndrome (HSS) may be associated with FMF. We report two sisters of a Turkish family with FMF who developed distinct vasculitides. The younger sister developed severe PAN with perirenal hematoma at the age of 13 years, the older sister presented with severe HSS and acute renal failure at the age of 19 years. Neither sister developed amyloidosis until the age of 30 years. This observation suggests that early events in the pathogenesis of PAN and HSS are generally quite similar. Author Affiliation: (1) Division of Pediatric Nephrology, University Children&apos;s Hospital, INF 150, 69120, Heidelberg, Germany (2) Department of Urology, University of Heidelberg, 69120, Heidelberg, Germany (3) Department of Internal Medicine, University of Heidelberg, 69120, Heidelberg, Germany Article History: Registration Date: 30/01/2004 Received Date: 15/09/2003 Accepted Date: 14/01/2004 Online Date: 11/03/2004

Author(s): Marcus R. Benz [sup.1] , Holger Schmid [sup.2 ] , Stefan Heinen [sup.3] [sup.4] , Bärbel Lange-Sperandio [sup.1] , Julia Hoefele [sup.1 ] , Thomas Sitter [sup.2] , Peter [...]

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening microangiopathy, frequently causing kidney failure. Inhibition of the terminal complement complex with eculizumab is the only licensed treatment but mostly requires long-term administration and risks severe side effects. The underlying genetic cause of aHUS is thought to influence the severity of initial and recurring episodes, with milder courses in patients with mutations in membrane cofactor protein (MCP). Methods: Twenty pediatric cases of aHUS due to isolated heterozygous MCP mutations were reported from 12 German pediatric nephrology centers to describe initial presentation, timing of relapses, treatment, and kidney outcome. Results: The median age of onset was 4.6 years, with a female to male ratio of 1:3. Without eculizumab maintenance therapy, 50% (9/18) of the patients experienced a first relapse after a median period of 3.8 years. Kaplan-Meier analysis showed a relapse-free survival of 93% at 1 year. Four patients received eculizumab long-term treatment, while 3 patients received short courses. We could not show a benefit from complement blockade therapy on long term kidney function, independent of short-term or long-term treatment. To prevent 1 relapse with eculizumab, the theoretical number-needed-to-treat (NNT) was 15 for the first year and 3 for the first 5 years after initial presentation. Conclusion: Our study shows that heterozygous MCP mutations cause aHUS with a risk of first relapse of about 10% per year, resulting in large NNTs for prevention of relapses with eculizumab. More studies are needed to define an optimal treatment schedule for patients with MCP mutations to minimize the risks of the disease and treatment. [ABSTRACT FROM AUTHOR]

Background: Children presenting with proliferative lupus nephritis (LN) are treated with intensified immunosuppressive protocols. Data on renal outcome and treatment toxicity is scare. Methods: Twelve-month renal outcome and comorbidity were assessed in 79 predominantly Caucasian children with proliferative LN reported to the Lupus Nephritis Registry of the German Society of Paediatric Nephrology diagnosed between 1997 and 2015. Results: At the time of diagnosis, median age was 13.7 (interquartile range 11.8–15.8) years; 86% showed WHO histology class IV, nephrotic range proteinuria was noted in 55%, and median estimated glomerular filtration rate amounted to 75 ml/min/1.73 m2. At 12 months, the percentage of patients with complete and partial remission was 38% and 41%, respectively. Six percent of patients were non-responders and 15% presented with renal flare. Nephrotic range proteinuria at the time of diagnosis was associated with inferior renal outcome (odds ratio 5.34, 95% confidence interval 1.26–22.62, p = 0.02), whereas all other variables including mode of immune-suppressive treatment (e.g., induction treatment with cyclophosphamide (IVCYC) versus mycophenolate mofetil (MMF)) were not significant correlates. Complications were reported in 80% of patients including glucocorticoid toxicity in 42% (Cushingoid appearance, striae distensae, cataract, or osteonecrosis), leukopenia in 37%, infection in 23%, and menstrual disorder in 20%. Growth impairment, more pronounced in boys than girls, was noted in 78% of patients. Conclusions: In this cohort of juvenile proliferative LN, renal outcome at 12 months was good irrespectively if patients received induction treatment with MMF or IVCYC, but glucocorticoid toxicity was very high underscoring the need for corticoid sparing protocols. [ABSTRACT FROM AUTHOR]