Repetitive administration of rituximab can achieve and maintain clinical remission in patients with MCD or FSGS.

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are glomerulopathies associated with nephrotic syndrome. Primary forms of these diseases are treated with various regimes of immunosuppression. Frequently relapsing or glucocorticoid-dependent courses remain challenging. Here, a B-cell-depleting strategy with rituximab represents a salvage option although data are sparse in the adult population. In particular, there is limited evidence on the efficacy of restoring remission after initial successful treatment with rituximab and whether patients benefit from an individualized, relapse-based approach. We identified 13 patients who received multiple therapies with rituximab from the FOrMe-registry (NCT03949972), a nationwide registry for MCD and FSGS in Germany, or from the University Hospital of Cologne. Disease status, changes in serum creatinine, proteinuria, and time to relapse were evaluated. Relapse-free survival was compared to the patients' previous therapy regimens. Through all treatment cycles, an improvement of disease activity was shown leading to a complete remission in 72% and partial remission in 26% after 3 ([Formula: see text]0.001) and 6 months ([Formula: see text]0.001). Relapse-free survival increased from 4.5 months (95%-CI 3-10 months) to 21 months (95%-CI 16-32 months) ([Formula: see text]0.001) compared to previous immunosuppression regimens with no loss in estimated glomerular filtration over time (p = 0.53). Compared to continuous B-cell depletion, an individualized relapse-based approach led to a reduced rituximab exposure and significant cost savings. Relapse-based administration of rituximab in patients with MCD/FSGS with an initial good clinical response did not result in a decreased efficacy at a median follow-up duration of 110 months. Thus, reinduction therapies may provide an alternative to continuous B-cell-depletion and reduce the long-term side effects of continuous immunosuppression.

Humoral immune response and live-virus neutralization of the SARS-CoV-2 omicron (BA.1) variant after COVID-19 mRNA vaccination in children and young adults with chronic kidney disease.

BACKGROUND: Data on humoral immune response to standard COVID-19 vaccination are scarce in adolescent patients and lacking for children below 12 years of age with chronic kidney disease including kidney transplant recipients. METHODS: We therefore investigated in this retrospective two-center study (DRKS00024668; registered 23.03.2021) the humoral immune response to a standard two-dose mRNA vaccine regimen in 123 CKD patients aged 5-30 years. A live-virus assay was used to assess the serum neutralizing activity against the SARS-CoV-2 omicron (BA.1) variant. RESULTS: Children aged 5-11 years had a comparable rate and degree of immune response to adolescents despite lower vaccine doses (10 µg vs. 30 µg BNT162b2). Treatment with two (odds ratio 9.24) or three or more (odds ratio 17.07) immunosuppressants was an independent risk factor for nonresponse. The immune response differed significantly among three patient cohorts: 48 of 77 (62.3%) kidney transplant recipients, 21 of 26 (80.8%) patients on immunosuppressive therapy, and 19 of 20 (95.0%) patients with chronic kidney disease without immunosuppressive therapy responded. In the kidney transplant recipients, immunosuppressive regimens comprising mycophenolate mofetil, an eGFR of < 60 mL/min/1.73 m2, and female sex were independent risk factors for nonresponse. Two of 18 (11.1%) and 8 of 16 (50.0%) patients with an anti-S1-RBD IgG of 100-1411 and > 1411 BAU/mL, respectively, showed a neutralization activity against the omicron variant. CONCLUSION: A standard mRNA vaccine regimen in immunosuppressed children and adolescents with kidney disease elicits an attenuated humoral immune response with effective live virus neutralization against the omicron variant in approximately 10% of the patients, underlying the need for omicron-adapted vaccination. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical Aspects of the Subsequent SARS-CoV-2 Waves in Children from 2020 to 2022-Data from a Local Cohort in Cologne, Germany (n = 21,635).

Almost two and a half years after the appearance of the first cases of SARS-CoV-2 in December 2019, more than 500 million people have been infected with SARS-CoV-2 and over 6 million have died of it worldwide. In terms of the pediatric cohort, it already became evident at an early stage that the infection causes milder symptoms in children and rarely runs a fatal course. OBJECTIVE: This work presents data gathered over a period of over two years in patients between the age of 0 and 18 years. The aim is to provide information on the clinical aspects of the five different SARS-CoV-2 waves. METHODS: Between 13 March 2020 and 22 April 2022, all nucleic acid amplification tests (NAATs) of children who received a swab for SARS-CoV-2 at our clinic were included. Data were collected on standardized questionnaires. The analysis of the data was anonymized and retrospective. RESULTS: We investigated 21,635 NAATs, of which 1028 of the tests were positive (4.8%). The highest rate of positive results was observed in the fifth wave (541/2.292 NAATs (23.6%)). Most of the children who were hospitalized were hospitalized in wave three (22.9%). The availability of a vaccine was followed by a decrease in positive NAATs in the corresponding age group thereafter. CONCLUSIONS: These data underline the fact that children infected with SARS-CoV-2, regardless of which VOC, are often only mildly affected. Vaccinations seem to remain the key to avoid massive numbers of infected people and a potential collapse of the healthcare systems.

Phenotypic Variability in Siblings With Autosomal Recessive Polycystic Kidney Disease.

Introduction: Autosomal recessive polycystic kidney disease (ARPKD) is a rare monogenic disorder characterized by early onset fibrocystic hepatorenal changes. Previous reports have documented pronounced phenotypic variability even among siblings in terms of patient survival. The underlying causes for this clinical variability are incompletely understood. Methods: We present the longitudinal clinical courses of 35 sibling pairs included in the ARPKD registry study ARegPKD, encompassing data on primary manifestation, prenatal and perinatal findings, genetic testing, and family history, including kidney function, liver involvement, and radiological findings. Results: We identified 70 siblings from 35 families with a median age of 0.7 (interquartile range 0.1-6.0) years at initial diagnosis and a median follow-up time of 3.5 (0.2-6.2) years. Data on PKHD1 variants were available for 37 patients from 21 families. There were 8 patients from 7 families who required kidney replacement therapy (KRT) during follow-up. For 44 patients from 26 families, antihypertensive therapy was documented. Furthermore, 37 patients from 24 families had signs of portal hypertension with 9 patients from 6 families having substantial hepatic complications. Interestingly, pronounced variability in the clinical course of functional kidney disease was documented in only 3 sibling pairs. In 17 of 20 families of our cohort of neonatal survivors, siblings had only minor differences of kidney function at a comparable age. Conclusion: In patients surviving the neonatal period, our longitudinal follow-up of 70 ARPKD siblings from 35 families revealed comparable clinical courses of kidney and liver diseases in most families. The data suggest a strong impact of the underlying genotype.

Morbidity of Respiratory Syncytial Virus (RSV) Infections: RSV Compared With Severe Acute Respiratory Syndrome Coronavirus 2 Infections in Children Aged 0-4 Years in Cologne, Germany.

The aim of this retrospective analysis was to provide information on how infections with respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) differ in symptoms, clinical course, outcome, and utilization of hospital care. We investigated 748 polymerase chain reaction results from symptomatic children aged 0-4 years in Cologne, Germany. One hundred sixty-nine patients tested positive for RSV (22.6%) and 24 children for SARS-CoV-2 (3.2%). Symptomatic patients with RSV infection were hospitalized significantly longer. RSV-positive patients needed oxygen supplementation significantly more often as well as high-flow therapy. With regard to care efforts, RSV-infected patients put higher pressure on the hospital and utilized more hospital resources.

The role of the immune system in idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia and usually responds well to steroids. However, relapses are frequent, which can require multi-drug therapy with deleterious long-term side effects. In the last decades, different hypotheses on molecular mechanisms underlying INS have been proposed and several lines of evidences strongly indicate a crucial role of the immune system in the pathogenesis of non-genetic INS. INS is traditionally considered a T-cell-mediated disorder triggered by a circulating factor, which causes the impairment of the glomerular filtration barrier and subsequent proteinuria. Additionally, the imbalance between Th17/Tregs as well as Th2/Th1 has been implicated in the pathomechanism of INS. Interestingly, B-cells have gained attention, since rituximab, an anti-CD20 antibody demonstrated a good therapeutic response in the treatment of INS. Finally, recent findings indicate that even podocytes can act as antigen-presenting cells under inflammatory stimuli and play a direct role in activating cellular pathways that cause proteinuria. Even though our knowledge on the underlying mechanisms of INS is still incomplete, it became clear that instead of a traditionally implicated cell subset or one particular molecule as a causative factor for INS, a multi-step control system including soluble factors, immune cells, and podocytes is necessary to prevent the occurrence of INS. This present review aims to provide an overview of the current knowledge on this topic, since advances in our understanding of the immunopathogenesis of INS may help drive new tailored therapeutic approaches forward.

The Alpha Variant (B.1.1.7) of SARS-CoV-2 in Children: First Experience from 3544 Nucleic Acid Amplification Tests in a Cohort of Children in Germany.

In May 2021, the Alpha variant (B.1.1.7) of SARS-CoV-2 was found in 91% of the SARS-CoV-2 cases in Germany. Not much is known about the symptoms, courses of disease, and infectiousness in pediatric patients with the Alpha variant. OBJECTIVE: The aim of this retrospective analysis was to gain information on the infection with the Alpha variant in children and adolescents. METHODS: Between 12 January 2021 and 3 June 2021, all nucleic acid amplification tests (NAATs) of children who received a swab for SARS-CoV-2 were included. Data were collected on standardized questionnaires. The analysis of data was anonymized and retrospective. RESULTS: We investigated 3544 NAATs; 95 children were tested positive (2.7%) for SARS-CoV-2. For the sub-analysis, 65 children were analyzed. In 59 children, the Alpha variant was found (90.8%), and 54.2% (n = 32/59) were symptomatic. The most common symptoms were fever, cough, and rhinitis. The median Ct value was 24.0 (min 17.0; max 32.7). CONCLUSIONS: We can underline early findings that children are still less effected by SARS-CoV-2 infection with the spread of the Alpha variant. We found no evidence that children infected with the Alpha variant showed more severe symptoms or suffered from a more severe clinical course than those infected with the wild type.

Expanding the Spectrum of FAT1 Nephropathies by Novel Mutations That Affect Hippo Signaling.

INTRODUCTION: Disease-causing mutations in the protocadherin FAT1 have been recently described both in patients with a glomerulotubular nephropathy and in patients with a syndromic nephropathy. METHODS: We identified 4 patients with FAT1-associated disease, performed clinical and genetic characterization, and compared our findings to the previously published patients. Patient-derived primary urinary epithelial cells were analyzed by quantitative polymerase chain reaction (qPCR) and immunoblotting to identify possible alterations in Hippo signaling. RESULTS: Here we expand the spectrum of FAT1-associated disease with the identification of novel FAT1 mutations in 4 patients from 3 families (homozygous truncating variants in 3, compound heterozygous missense variants in 1 patient). All patients show an ophthalmologic phenotype together with heterogeneous renal phenotypes ranging from normal renal function to early-onset end-stage kidney failure. Molecular analysis of primary urine-derived urinary renal epithelial cells revealed alterations in the Hippo signaling cascade with a decreased phosphorylation of both the core kinase MST and the downstream effector YAP. Consistently, we found a transcriptional upregulation of bona fide YAP target genes. CONCLUSION: A comprehensive review of the here identified patients and those previously published indicates a highly diverse phenotype in patients with missense mutations but a more uniform and better recognizable phenotype in the patients with truncating mutations. Altered Hippo signaling and de-repressed YAP activity might be novel contributing factors to the pathomechanism in FAT1-associated renal disease.

Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.

Prevalence of COVID-19 Among Children and Adolescents While Easing Lockdown Restrictions in Cologne, North Rhine-Westphalia, Germany.

BACKGROUND: In Germany, widespread full closures of schools and day care facilities were part of lockdown measures to control the spread of coronavirus disease 2019 (COVID-19). In the state of North Rhine-Westphalia closures took place on March 16, 2020 and were gradually eased from end of April 2020 until beginning of June 2020. OBJECTIVE: This study aims to evaluate the prevalence of COVID-19 among children and adolescents during the reopening period of schools and day care facilities in Cologne, North Rhine-Westphalia, Germany. It further depicts medical history and results of physical examinations of pediatric patients undergoing a test for severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2). METHODS: Testing for SARS-CoV-2 was carried out by a naso- and / or oropharyngeal swab by local pediatricians at the time of presentation. Samples were analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR). Medical history and physical examination results were retrospectively analyzed. RESULTS: 525 children and adolescents presented mainly with mild upper respiratory tract infections. Three patients were diagnosed with COVID-19. Their medical history and examination results did not stand out from the other patients. CONCLUSION: A precautious stepwise opening of schools and day care facilities was not associated with the occurrence of a relevant prevalence of COVID-19 among children and adolescents. However, a low general prevalence of COVID-19 at the end of the observation period has to be taken into account. Systematic testing might enable adjusted regulations in favor of full closures, especially in the light of increasing evidence for pediatric patients constituting a low-risk group for COVID-19.

Severe neurological outcomes after very early bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD).

To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4-15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort.

Risk Factors for Early Dialysis Dependency in Autosomal Recessive Polycystic Kidney Disease.

OBJECTIVE: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis. STUDY DESIGN: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life. RESULTS: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys. CONCLUSIONS: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD.

A case report on the exceptional coincidence of two inherited renal disorders: ADPKD and Alport syndrome
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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of dialysis-requiring end-stage renal disease in adults and is characterized by the slowly progressing replacement of renal tissue by focal macrocysts. Alport syndrome (AS; hereditary nephritis) is a rare, inherited disorder of the basement membrane associated with hematuria, proteinuria, and loss of kidney function as well as sensorineural hearing loss and ocular abnormalities. Here, we report on a family in which both ADPKD and AS are present. In a male patient, both -ADPKD and AS coincided. This patient shows the very rare coexistence of two severe, inherited renal disorders and illustrates the importance of considering additional diagnoses in the setting of positive family history for a common hereditary disorder.
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Challenges in establishing genotype-phenotype correlations in ARPKD: case report on a toddler with two severe PKHD1 mutations.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) constitutes an important cause of pediatric end stage renal disease and is characterized by a broad phenotypic variability. The disease is caused by mutations in a single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1), which encodes a large transmembrane protein of poorly understood function called fibrocystin. Based on current knowledge of genotype-phenotype correlations in ARPKD, two truncating mutations are considered to result in a severe phenotype with peri- or neonatal mortality. Infants surviving the neonatal period are expected to carry at least one missense mutation. CASE-DIAGNOSIS/TREATMENT: We report on a female patient with two truncating PKHD1 mutations who survived the first 30 months of life without renal replacement therapy. Our patient carries not only a known stop mutation, c.8011C>T (p.Arg2671*), but also the previously reported c.51A>G PKHD1 sequence variant of unknown significance in exon 2. Using functional in vitro studies we have confirmed the pathogenic nature of c.51A>G, demonstrating activation of a new donor splice site in intron 2 that results in a frameshift mutation and generation of a premature stop codon. CONCLUSIONS: This case illustrates the importance of functional mutation analyses and also raises questions regarding the current belief that the presence of at least one missense mutation is necessary for perinatal survival in ARPKD.

Effect of mycophenolic acid in experimental, nontransplant glomerular diseases: new mechanisms beyond immune cells.

Mycophenolic acid (MPA) was introduced into clinical practice as immunosuppressive drug therapy to prevent allograft rejection. Since then, its clinical application has widened. Our goal was to review the lessons learned from experimental nontransplant glomerular disease models on the mechanisms of MPA therapy. T and B lymphocytes are preferentially dependent on de novo purine synthesis. By inhibiting the rate-limiting enzyme of de novo purine synthesis, MPA depletes the pool of deoxyguanosine triphosphate (dGTP) and inhibits proliferation of these immune cells. Furthermore, MPA can also induce apoptosis of immune cells and is known to inhibit synthesis of fucose- and mannose-containing membrane glycoproteins altering the surface expression and binding ability of adhesion molecules. However, MPA exerts a direct effect also on nonimmune cells. Mesangial cells are partially dependent on de novo purine biosynthesis and are thus susceptible to MPA treatment. Additionally, MPA can inhibit apoptosis in podocytes and seems to be beneficial in preserving the expression of nephrin and podocin, and by attenuation of urokinase receptor expression leads to decreased foot-process effacement. In summary, our manuscript sheds light on the molecular mechanisms underlying the antiproteinuric effect of MPA. Overall, MPA is an excellent treatment option in many immunologic glomerulopathies because it possesses immunosuppressive properties, has a remarkable effect on nonimmune cells and counteracts the proliferation of mesangial cells, expansion of mesangial matrix, and foot-process effacement of podocytes combined with a low systemic toxicity.

Rationale, design and objectives of ARegPKD, a European ARPKD registry study.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare but frequently severe disorder that is typically characterized by cystic kidneys and congenital hepatic fibrosis but displays pronounced phenotypic heterogeneity. ARPKD is among the most important causes for pediatric end stage renal disease and a leading reason for liver-, kidney- or combined liver kidney transplantation in childhood. The underlying pathophysiology, the mechanisms resulting in the observed clinical heterogeneity and the long-term clinical evolution of patients remain poorly understood. Current treatment approaches continue to be largely symptomatic and opinion-based even in most-advanced medical centers. While large clinical trials for the frequent and mostly adult onset autosomal dominant polycystic kidney diseases have recently been conducted, therapeutic initiatives for ARPKD are facing the challenge of small and clinically variable cohorts for which reliable end points are hard to establish. METHODS/DESIGN: ARegPKD is an international, mostly European, observational study to deeply phenotype ARPKD patients in a pro- and retrospective fashion. This registry study is conducted with the support of the German Society for Pediatric Nephrology (GPN) and the European Study Consortium for Chronic Kidney Disorders Affecting Pediatric Patients (ESCAPE Network). ARegPKD clinically characterizes long-term ARPKD courses by a web-based approach that uses detailed basic data questionnaires in combination with yearly follow-up visits. Clinical data collection is accompanied by associated biobanking and reference histology, thus setting roots for future translational research. DISCUSSION: The novel registry study ARegPKD aims to characterize miscellaneous subcohorts and to compare the applied treatment options in a large cohort of deeply characterized patients. ARegPKD will thus provide evidence base for clinical treatment decisions and contribute to the pathophysiological understanding of this severe inherited disorder.