Publications by authors named "Oliver Gross"

96 Publications

Detrusor sphincter dyssynergia: can a more specific definition distinguish between patients with and without an underlying neurological disorder?

Spinal Cord 2021 May 7. Epub 2021 May 7.

Department of Neuro-Urology, Balgrist University Hospital, University of Zürich, Zürich, Switzerland.

Study Design: Cross-sectional study.

Objectives: To evaluate if specific definitions of detrusor sphincter dyssynergia (DSD) might distinguish between individuals with spinal cord injury (SCI) and those with no underlying neurological disorder (NO ND).

Setting: Single tertiary university SCI center.

Methods: A series of 153 individuals, 81 with traumatic SCI and 72 with NO ND, were prospectively evaluated and included in this study. All individuals underwent a clinical neuro-urological examination, a neurophysiological work-up and a video-urodynamic investigation and were diagnosed with DSD as defined by the International Continence Society (ICS). We determined the DSD grades/types according to the classifications by Yalla (grade 1-3), Blaivas (type 1-3) and Weld (type 1-2). Distribution of the DSD grades/types were compared between SCI and NO ND individuals. Associations between the various DSD grades/types and clinical parameters, such as risk factors for upper urinary tract damage (all individuals) or lower extremity motor scores, SCI injury levels and severity scores (only SCI group), were assessed.

Results: The distribution of all DSD types were similar between groups (p > 0.05). None of the DSD classifications allowed risk assessment for upper urinary tract damage. A significant association between DSD type and other clinical parameters could not be found (p > 0.05).

Conclusions: None of the investigated DSD definitions can distinguish between patients with SCI and with NO ND. The more complex DSD classifications by Yalla, Blaivas or Weld cannot compete with the ICS binary yes-no definition which is pragmatic and straightforward for managing patients in daily clinical practice.

Sponsorship: None.
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http://dx.doi.org/10.1038/s41393-021-00635-3DOI Listing
May 2021

Collagen IV dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture's and Alport diseases.

J Biol Chem 2021 Mar 24:100590. Epub 2021 Mar 24.

Dept. of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA; Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN, USA; Aspirnaut Program, Vanderbilt University Medical Center, Nashville, TN; Dept. of Pathology, Microbiology and Immunology, Vanderbilt University Med. Center, Nashville, TN, USA; Dept. of Biochemistry, Vanderbilt University, Nashville, TN, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN, USA; Dept. of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. Electronic address:

Diseases of the glomerular basement membrane (GBM), such as Goodpasture's disease (GP) and Alport syndrome (AS), are a major cause of chronic kidney failure and an unmet medical need. Collagen IV is an important architectural element of the GBM that was discovered in previous research on GP and AS. How this collagen enables GBM to function as a permselective filter and how structural defects cause renal failure remain an enigma. We found a distinctive genetic variant of collagen IV in both a familial GP case and four AS kindreds that provided insights into these mechanisms. The variant is an 8-residue appendage at the C-terminus of the α3 subunit of the α345 hexamer. A knock-in mouse harboring the variant displayed GBM abnormalities and proteinuria. This pathology phenocopied AS, which pinpointed the α345 hexamer as a focal point in GBM function and dysfunction. Crystallography and assembly studies revealed underlying hexamer mechanisms, as described in Companion Papers II and III. Bioactive sites on the hexamer surface were identified where pathogenic pathways of GP and AS converge, and, potentially, that of diabetic nephropathy (DN). We conclude that the hexamer functions include signaling and organizing macromolecular complexes, which enable GBM assembly and function. Therapeutic modulation or replacement of α345 hexamer could therefore be a potential treatment for GBM diseases, and this knock-in mouse model is suitable for developing gene therapies.
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http://dx.doi.org/10.1016/j.jbc.2021.100590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100070PMC
March 2021

Genotype-phenotype correlations and nephroprotective effects of RAAS inhibition in patients with autosomal recessive Alport syndrome.

Pediatr Nephrol 2021 Mar 27. Epub 2021 Mar 27.

Department of Pediatrics, Peking University First Hospital, No. 1 Xi An Men Da Jie, Beijing, 100034, China.

Background: Autosomal recessive Alport syndrome (ARAS) is caused by pathogenic variants in both alleles of either COL4A3 or COL4A4 genes. Reports on ARAS are rare due to small patient numbers and there are no reports on renin-angiotensin-aldosterone system (RAAS) inhibition therapy in ARAS.

Methods: Retrospective study in 101 patients with ARAS from Chinese Registry Database of Hereditary Kidney Diseases and European Alport Registry. Genotype-phenotype correlations and nephroprotective effects of RAAS inhibition in ARAS were evaluated.

Results: Median age was 15 years (range 1.5-46 years). Twelve patients progressed to stage 5 chronic kidney disease (CKD5) at median age 20.5 years. Patients without missense variants had both higher prevalence and earlier onset age of hearing loss, nephrotic-range proteinuria, more rapid decline of eGFR, and earlier onset age of CKD5 compared to patients with 1 or 2 missense variants. Most patients (79/101, 78%) currently are treated with RAAS inhibitors; median age at therapy initiation was 10 years and mean duration 6.5 ± 6.0 years. Median age at CKD5 for untreated patients was 24 years. RAAS inhibition therapy delayed CKD5 onset in those with impaired kidney function (T-III) to median age 35 years, but is undefined in treated patients with proteinuria (T-II) due to low number of events. No treated patients with microalbuminuria (T-I) progressed to CKD5. ARAS patients with 1 or 2 missense variants showed better response to treatment than patients with non-missense-variants.

Conclusions: Our study provides the first evidence for early use of RAAS inhibition therapy in patients with ARAS. Furthermore, genotype in ARAS correlates with response to therapy in favor of missense variants.
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http://dx.doi.org/10.1007/s00467-021-05040-9DOI Listing
March 2021

A glycine substitution in the collagenous domain of Col4a3 in mice recapitulates late onset Alport syndrome.

Matrix Biol Plus 2021 Feb 30;9:100053. Epub 2020 Dec 30.

Center of Excellence in Biobanking and Biomedical Research, Molecular Medicine Research Center, University of Cyprus Medical School, Cyprus.

Alport syndrome (AS) is a severe inherited glomerulopathy caused by mutations in the genes encoding the α-chains of type-IV collagen, the most abundant component of the extracellular glomerular basement membrane (GBM). Currently most AS mouse models are knockout models for one of the collagen-IV genes. In contrast, about half of AS patients have missense mutations, with single aminoacid substitutions of glycine being the most common. The only mouse model for AS with a homozygous knockin missense mutation, Col4a3-p.Gly1332Glu, was partly described before by our group. Here, a detailed in-depth description of the same mouse is presented, along with another compound heterozygous mouse that carries the glycine substitution with a knockout allele. Both mice recapitulate essential features of AS, including shorten lifespan by 30-35%, increased proteinuria, increased serum urea and creatinine, pathognomonic alternate GBM thinning and thickening, and podocyte foot process effacement. Notably, glomeruli and tubuli respond differently to mutant collagen-IV protomers, with reduced expression in tubules but apparently normal in glomeruli. However, equally important is the fact that in the glomeruli the mutant α3-chain as well as the normal α4/α5 chains seem to undergo a cleavage at, or near the point of the mutation, possibly by the metalloproteinase MMP-9, producing a 35 kDa C-terminal fragment. These mouse models represent a good tool for better understanding the spectrum of molecular mechanisms governing collagen-IV nephropathies and could be used for pre-clinical studies aimed at better treatments for AS.
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http://dx.doi.org/10.1016/j.mbplus.2020.100053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930875PMC
February 2021

Mutations in Are a Novel Cause of Galloway-Mowat Syndrome.

J Am Soc Nephrol 2021 Mar 16;32(3):580-596. Epub 2021 Feb 16.

Institute of Human Genetics, Faculty of Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background: Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease.

Methods: Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. and studies determined the functional significance of the mutations identified.

Results: Three biallelic variants of the transcriptional regulator were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in embryos disrupted pronephric development. Human wild-type RNA rescued the disruption, but the three variants did not. Finally, CRISPR-mediated knockout of in human podocytes led to dysregulation of several renal developmental genes.

Conclusions: Variants in can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.
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http://dx.doi.org/10.1681/ASN.2020040490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920168PMC
March 2021

Correction to: Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020.

Pediatr Nephrol 2021 Mar;36(3):731

Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany.

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http://dx.doi.org/10.1007/s00467-020-04892-xDOI Listing
March 2021

Response to: Diagnosis of Alport syndrome, is there a role for skin biopsy?

Pediatr Nephrol 2021 Apr 7;36(4):1031. Epub 2021 Jan 7.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

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http://dx.doi.org/10.1007/s00467-020-04872-1DOI Listing
April 2021

Characterization of Sensorineural Hearing Loss in Children with Alport Syndrome.

Life (Basel) 2020 Dec 18;10(12). Epub 2020 Dec 18.

Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, 37075 Göttingen, Germany.

Most adults with Alport syndrome (AS) suffer from progressive sensorineural hearing loss. However, little is known about the early characteristics of hearing loss in children with AS. As a part of the EARLY PRO-TECT Alport trial, this study was the first clinical trial ever to investigate hearing loss in children with AS over a timespan of up to six years Nine of 51 children (18%) had hearing impairment. Audiograms were divided into three age groups: in the 5-9-year-olds, the 4-pure tone average (4PTA) was 8.9 decibel (dB) ( 15) in those with normal hearing and 43.8 dB ( 2, 12%) in those with hearing impairment. Among the 10-13-year-olds, 4PTA was 4.8 dB (healthy, 12) and 41.4 dB (hearing impaired, 6.33%). For the 14-20-year-olds, the 4PTA was 7.0 dB (healthy; 9) and 48.2 dB (hearing impaired, 3.25%). On average, hearing thresholds of the hearing impaired group increased, especially at frequencies between 1-3 kHz. In conclusion, 18% of children developed hearing loss, with a maximum hearing loss in the audiograms at 1-3 kHz. The percentage of children with hearing impairment increased from 10% at baseline to 18% at end of trial as did the severity of hearing loss.
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http://dx.doi.org/10.3390/life10120360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766141PMC
December 2020

[COVID-19 and the kidneys-Clinical aspects].

Authors:
Oliver Gross

Nephrologe 2020 Dec 11:1-6. Epub 2020 Dec 11.

Klinik für Nephrologie und Rheumatologie, Universitätsmedizin Göttingen, Robert-Koch Str. 40, 37075 Göttingen, Deutschland.

The aim of this article is to explain the clinical benefits of the growing knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the lungs, SARS-CoV‑2 can invade multiple cell types in other organs, such as the kidneys and replicate there. Important damaging pathways of the virus, such as vascular endotheliitis, thrombotic events and systemic cytokine release are still incompletely understood. Coronavirus disease 2019 (COVID-19) is a systemic disease that necessitates intensive medical care and in particular, internal medicine involvement and represents a major challenge for all disciplines of internal medicine. Among these, nephrology in particular is involved in the fight against COVID-19 in a variety of ways: urine investigations can provide indications of multiple organ involvement, endotheliitis, microthrombi and microcirculation damage, etc. Experience with low serum albumin levels and antithrombin III activity in nephrotic patients helps to point out the decreasing effects of loop diuretics and heparin to other specialist disciplines. Nephrological knowledge of the complications of hypoalbuminemia and "resistance" to diuretics must lead to an early implementation of renal replacement procedures in order to be able to prevent mechanical ventilation in COVID-19 intensive care patients with increased extracellular lung fluid. The kidneys can be used as a seismograph for severe courses of COVID-19 and nephrological knowledge can be brought to use to optimize the intensive medical care for critically ill patients. Both together have the potential to considerably reduce morbidity and mortality further.
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http://dx.doi.org/10.1007/s11560-020-00470-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731728PMC
December 2020

Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020.

Pediatr Nephrol 2021 Mar 6;36(3):711-719. Epub 2020 Nov 6.

Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany.

In 2013, we published a set of clinical practice recommendations for the treatment of Alport syndrome in this journal. We recommended delaying the initiation of angiotensin-converting enzyme inhibition until the onset of overt proteinuria or, in some cases, microalbuminuria. Developments that have occurred over the past 7 years have prompted us to revise these recommendations. We now recommend the initiation of treatment at the time of diagnosis in males with X-linked Alport syndrome and in males and females with autosomal recessive Alport syndrome. We further recommend starting treatment at the onset of microalbuminuria in females with X-linked Alport syndrome and in males and females with autosomal dominant Alport syndrome. This article presents the rationale for these revisions as well as recommendations for diagnostic tactics intended to ensure the early diagnosis of Alport syndrome.
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http://dx.doi.org/10.1007/s00467-020-04819-6DOI Listing
March 2021

Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial.

Clin Genet 2021 Jan 25;99(1):143-156. Epub 2020 Oct 25.

Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.
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http://dx.doi.org/10.1111/cge.13861DOI Listing
January 2021

Isocyanide adducts of tri- and tetravalent uranium metallocenes supported by tetra(isopropyl)cyclopentadienyl ligands.

Dalton Trans 2020 Sep;49(34):11971-11977

Department of Chemistry, University of California, Berkeley, California 94720, USA. and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

Reaction of the uranium(iii) metallocenium salt [(CpiPr4)2U][B(C6F5)4] with tert-butyl isocyanide (tBuNC) yielded the dicationic uranium(iv) complex [(CpiPr4)2U(CNtBu)4][B(C6F5)4]2 (1), which displays a linear metallocene geometry. Use of crude mixtures of [(CpiPr4)2U][B(C6F5)4], which contain a soluble source of iodide, led instead to isolation of the monocationic uranium(iv) iodide complex [(CpiPr4)2U(I)(CNtBu)2][B(C6F5)4] (2). Adduct formation with no change in oxidation state was observed upon addition of tBuNC to the neutral uranium(iii) species (CpiPr4)2UI, resulting in isolation of (CpiPr4)2U(I)(CNtBu) (3). X-ray crystallographic and IR spectroscopic studies both showed effects ascribed to the presence of multiple strongly donating isocyanide ligands in 1.
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http://dx.doi.org/10.1039/d0dt02005bDOI Listing
September 2020

TASCI-transcutaneous tibial nerve stimulation in patients with acute spinal cord injury to prevent neurogenic detrusor overactivity: protocol for a nationwide, randomised, sham-controlled, double-blind clinical trial.

BMJ Open 2020 08 13;10(8):e039164. Epub 2020 Aug 13.

Department of Trauma, University Hospital Zürich, Zürich, Switzerland.

Introduction: Neurogenic lower urinary tract dysfunction (NLUTD), including neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia, is one of the most frequent and devastating sequelae of spinal cord injury (SCI), as it can lead to urinary incontinence and secondary damage such as renal failure. Transcutaneous tibial nerve stimulation (TTNS) is a promising, non-invasive neuromodulatory intervention that may prevent the emergence of the C-fibre evoked bladder reflexes that are thought to cause NDO. This paper presents the protocol for TTNS in acute SCI (TASCI), which will evaluate the efficacy of TTNS in preventing NDO. Furthermore, TASCI will provide insight into the mechanisms underlying TTNS, and the course of NLUTD development after SCI.

Methods And Analysis: TASCI is a nationwide, randomised, sham-controlled, double-blind clinical trial, conducted at all four SCI centres in Switzerland. The longitudinal design includes a baseline assessment period 5-39 days after acute SCI and follow-up assessments occurring 3, 6 and 12 months after SCI. A planned 114 participants will be randomised into verum or sham TTNS groups (1:1 ratio), stratified on study centre and lower extremity motor score. TTNS is performed for 30 min/day, 5 days/week, for 6-9 weeks starting within 40 days after SCI. The primary outcome is the occurrence of NDO jeopardising the upper urinary tract at 1 year after SCI, assessed by urodynamic investigation. Secondary outcome measures assess bladder and bowel function and symptoms, sexual function, neurological structure and function, functional independence, quality of life, as well as changes in biomarkers in the urine, blood, stool and bladder tissue. Safety of TTNS is the tertiary outcome.

Ethics And Dissemination: TASCI is approved by the Swiss Ethics Committee for Northwest/Central Switzerland, the Swiss Ethics Committee Vaud and the Swiss Ethics Committee Zürich (#2019-00074). Findings will be disseminated through peer-reviewed publications.

Trial Registration Number: NCT03965299.
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http://dx.doi.org/10.1136/bmjopen-2020-039164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430472PMC
August 2020

After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy.

Kidney Int 2020 10 22;98(4):1044-1052. Epub 2020 May 22.

Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany. Electronic address:

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.
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http://dx.doi.org/10.1016/j.kint.2020.04.046DOI Listing
October 2020

COVID-19-associated nephritis: early warning for disease severity and complications?

Lancet 2020 05 6;395(10236):e87-e88. Epub 2020 May 6.

Institute of Infection Control and Infectious Diseases, University Medical Center Göttingen, Göttingen 37075, Germany.

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http://dx.doi.org/10.1016/S0140-6736(20)31041-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202828PMC
May 2020

Clinical trial recommendations for potential Alport syndrome therapies.

Kidney Int 2020 06 6;97(6):1109-1116. Epub 2020 Apr 6.

Department of Nephrology and Hypertension, The Cleveland Clinic, Cleveland, Ohio, USA.

Alport syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport syndrome community, as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry representatives, academic researchers, clinicians, regulatory agency representatives, and-most critically-patients with Alport syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.
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http://dx.doi.org/10.1016/j.kint.2020.02.029DOI Listing
June 2020

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome.

Kidney Int 2020 06 17;97(6):1275-1286. Epub 2020 Jan 17.

Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.

Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12-2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.
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http://dx.doi.org/10.1016/j.kint.2019.12.015DOI Listing
June 2020

Determining the fragility of bulk metallic glass forming liquids via modulated DSC.

J Phys Condens Matter 2020 Apr 1;32(32):324004. Epub 2020 Apr 1.

Chair of Metallic Materials, Saarland University, Campus C6.3, 66123 Saarbrücken, Germany.

Temperature modulated DSC is used to study the fragility of three different bulk metallic glass forming liquids. Through applying various modulation frequencies, the dynamic glass transition shifts in temperature, allowing to determine the temperature dependence of the average relaxation time for each system. The resulting fragilities are compared with fragility investigations in literature obtained using thermo-mechanical analysis and the heating rate dependence of the calorimetric glass transition. Different methods to compare the data are evaluated and discussed.
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http://dx.doi.org/10.1088/1361-648X/ab8526DOI Listing
April 2020

Ultrafast scanning calorimetry of newly developed Au-Ga bulk metallic glasses.

J Phys Condens Matter 2020 Mar 23;32(32):324001. Epub 2020 Mar 23.

Chair of Metallic Materials, Saarland University, Campus C6.3, 66123 Saarbrücken, Germany.

The isothermal crystallization times and critical cooling rates of the liquid phase are determined for the two bulk metallic glass forming alloys AuAgPdCuSi and AuAgPdCuGaSi by using fast differential scanning calorimetry, covering the whole timescale of the crystallization event of the metallic melt. In the case of AuAgPdCuSi, a typical crystallization nose was observed, whereas for the AuAgPdCuGaSi, a more complex crystallization behavior with two distinct crystallization noses was found. Even for the complex crystallization behavior of the AuAgPdCuGaSi alloy it is shown that the minimal isothermal nose time [Formula: see text] does allow for a quantification of the macroscopic critical thickness. It is discussed in contrast to the critical cooling rate, which is found to allow less exact calculations of the critical thickness and thus does not correlate well with the critical cooling rate from macroscopic experiments. Additionally the crystallization data of AuAgPdCuSi was modeled using classical nucleation theory with the Johnson-Mehl-Avrami-Kolmogorov (JMAK) equation, enabling a determination of the interfacial energy.
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http://dx.doi.org/10.1088/1361-648X/ab8252DOI Listing
March 2020

Bulk metallic glass formation in the (Ti,Zr)-(Ni,Cu)-S system.

J Phys Condens Matter 2020 Jun;32(26):264003

Chair of Metallic Materials, Saarland University, Saarbrücken, Germany. Amorphous Metal Solutions GmbH, Homburg, Germany.

New bulk glass-forming alloy compositions, exceeding a critical casting thickness of 1 mm, are developed in the (quasi-ternary) (Ti,Zr)-(Ni,Cu)-S system. The ternary eutectic composition TiNiCu is stepwise modified through additions of S (0-8 at%) and Zr (0-22.5 at%) at the expense of Ni and Ti, respectively. By increasing the plate thickness of the casted samples from 500 µm to 1.25 mm, the primary precipitating phases are identified which is for the best glass-formers (e.g. TiZrNiCuS) an icosahedral phase. In calorimetric experiments, several exothermic crystallization events are observed upon heating glassy samples. The first exothermic event, obscuring the glass transition, is attributed to the formation of the icosahedral phase. As the icosahedral phase forms upon heating and cooling for the best glass-formers, the origin of the increased glass-forming ability might be attributed to a pronounced icosahedral short-range order in the liquid state, impeding the formation of the stable crystalline phases.
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http://dx.doi.org/10.1088/1361-648X/ab7c15DOI Listing
June 2020

The Hypomorphic Variant p.(Gly624Asp) in as a Possible Cause for an Unexpected Severe Phenotype in a Family With X-Linked Alport Syndrome.

Front Pediatr 2019 26;7:485. Epub 2019 Nov 26.

Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany.

Alport syndrome (AS) is a progressive kidney disorder leading to end stage renal disease (ESRD). Extrarenal symptoms like hearing loss and ocular changes can be observed. Approximately 85% of the patients carry pathogenic variants in (X-linked inheritance). The variant c.1871G>A, p.(Gly624Asp) in is described in the literature as a hypomorphic variant associated with thin basement membrane nephropathy (TBMN). ESRD was only seen rarely at a median age of 50 years and extrarenal manifestations have only been described in single cases. This is a report on a family with X-linked AS. In the female index patient, microscopic hematuria, and proteinuria were observed beginning at the age of 20 years and 41 years, respectively. Microscopic hematuria was also present in the daughter (from 6th month of life), the son (from 22nd month of life), the mother and the maternal grandniece. Proteinuria was observed in the maternal aunt and paternal grandmother. The father of the index patient, a paternal uncle and a second cousin presented with ESRD at the age of 49, 34, and 70 years of life, respectively. Extrarenal manifestations were absent in the whole family. In the index patient, her children and her mother molecular diagnostics were performed using Sanger and exome sequencing. In all examined family members the variant c.1871G>A, p.(Gly624Asp) in was identified. With the exception of the index patient, who was homozygous for this variant, all family members carried the variant heterozygously, or hemizygously. A different or additional monogenic hereditary nephropathy could not be detected by exome sequencing of the index patient. This is the first report of a patient with the variant p.(Gly624Asp) in in a homozygous state. The variant was previously reported as a mild variant requiring dialysis in less than 10%. The family presented, however, with a more severe clinical course. We therefore suggest to question the term "hypomorphic" in the context of the variant p.(Gly624Asp) although molecular diagnostics could not be done in all affected family members.
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http://dx.doi.org/10.3389/fped.2019.00485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887795PMC
November 2019

The importance of clinician, patient and researcher collaborations in Alport syndrome.

Pediatr Nephrol 2020 05 1;35(5):733-742. Epub 2019 May 1.

Wellcome Centre for Cell-Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.

Alport syndrome is caused by mutations in the genes COL4A3, COL4A4 or COL4A5 and is characterised by progressive glomerular disease, sensorineural hearing loss and ocular defects. Occurring in less than 1:5000, Alport syndrome is a rare genetic disorder but still accounts for > 1% of the prevalent population receiving renal replacement therapy. There is also increasing awareness about the risk of chronic kidney disease in individuals with heterozygous mutations in Alport syndrome genes. The mainstay of current therapy is the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, yet potential new therapies are now entering clinical trials. The 2017 International Workshop on Alport Syndrome in Glasgow was a pre-conference workshop ahead of the 50th anniversary meeting of the European Society for Pediatric Nephrology. It focussed on updates in clinical practice, genetics and basic science and also incorporated patient perspectives. More than 80 international experts including clinicians, geneticists, researchers from academia and industry, and patient representatives took part in panel discussions and breakout groups. This report summarises the workshop proceedings and the relevant contemporary literature. It highlights the unique clinician, patient and researcher collaborations achieved by regular engagement between the groups.
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http://dx.doi.org/10.1007/s00467-019-04241-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096363PMC
May 2020

Identification of platelet-derived growth factor C as a mediator of both renal fibrosis and hypertension.

Kidney Int 2019 05 28;95(5):1103-1119. Epub 2019 Feb 28.

Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.

Platelet-derived growth factors (PDGF) have been implicated in kidney disease progression. We previously found that PDGF-C is upregulated at sites of renal fibrosis and that antagonism of PDGF-C reduces fibrosis in the unilateral ureteral obstruction model. We studied the role of PDGF-C in collagen 4A3 ("Alport") mice, a model of progressive renal fibrosis with greater relevance to human kidney disease. Alport mice were crossbred with PDGF-C mice or administered a neutralizing PDGF-C antibody. Both PDGF-C deficiency and neutralization reduced serum creatinine and blood urea nitrogen levels and mitigated glomerular injury, renal fibrosis, and renal inflammation. Unexpectedly, systolic blood pressure was also reduced in both Alport and wild-type mice treated with a neutralizing PDGF-C antibody. Neutralization of PDGF-C reduced arterial wall thickness in the renal cortex of Alport mice. Aortic rings isolated from anti-PDGF-C-treated wildtype mice exhibited reduced tension and faster relaxation than those of untreated mice. In vitro, PDGF-C upregulated angiotensinogen in aortic tissue and in primary hepatocytes and induced nuclear factor κB (NFκB)/p65-binding to the angiotensinogen promoter in hepatocytes. Neutralization of PDGF-C suppressed transcript expression of angiotensinogen in Alport mice and angiotensin II receptor type 1 in Alport and wildtype mice. Finally, administration of neutralizing PDGF-C antibodies ameliorated angiotensin II-induced hypertension in healthy mice. Thus, in addition to its key role in mediating renal fibrosis, we identified PDGF-C as a mediator of hypertension via effects on renal vasculature and on the renin-angiotensin system. The contribution to both renal fibrosis and hypertension render PDGF-C an attractive target in progressive kidney disease.
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http://dx.doi.org/10.1016/j.kint.2018.11.031DOI Listing
May 2019

Kidney Injury by Variants in the Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis.

Int J Mol Sci 2019 Jan 26;20(3). Epub 2019 Jan 26.

Clinic of Nephrology and Rheumatology, University Medical Center Goettingen, 37075 Goettingen, Germany.

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases.
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http://dx.doi.org/10.3390/ijms20030519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386959PMC
January 2019

Pure Bipolar Plasma Vaporization of the Prostate: Results from a Prospective 3D Ultrasound Volumetry Study with Clinical Outcome After 3 Years.

J Endourol 2019 02 1;33(2):107-112. Epub 2019 Feb 1.

Department of Urology, University Hospital Zürich, University of Zürich, Zürich Switzerland.

Introduction And Objectives: Bipolar plasma vaporization (BPV) has been shown to be a low-morbidity alternative to conventional transurethral resection of the prostate (TURP). Improved functional short-term outcome and a postoperative prostate volume reduction comparable to TURP have been reported. However, comprehensive mid- or long-term results following BPV are still lacking.

Methods: A consecutive series of men who underwent pure BPV in a tertiary care academic center was prospectively investigated. Clinical parameters [International Prostate Symptom Score with Quality-of-Life domain, peak urinary flow rate (Qmax), postvoid residual volume, and prostate-specific antigen] as well as prostate volume (assessed by planimetric volumetry following transrectal 3D-ultrasound) were recorded preoperatively and regularly after BPV (after catheter removal, 6 weeks, 6 months, 1 year, and 3 years). Statistical analysis was performed using the Wilcoxon signed-rank test. All p-values ≤0.05 were considered significant.

Results: Seventy-five men were included in this prospective investigation. Their median (interquartile range) prostate volume was 41.0 mL (30.6-57.4 mL). In the first year after BPV, the prostate volume continuously decreased over time and the relative volume reduction was 52.2% after 12 months. Subsequently, the volume reduction remained stable with 50.7% after 3 years. All investigated outcome parameters improved significantly after the procedure and remained so after 3 years. Reoperations due to persistent or regrown adenoma were not necessary. Six (8.0%) and five patients (6.6%) developed a de novo urethral stricture or bladder neck contracture, respectively.

Conclusions: Three years after pure BPV of the prostate, a durable prostate volume reduction in combination with a stable improvement of functional outcome parameters was detectable in our prospective study. The low morbidity of the procedure and the possibility to perform BPV under ongoing platelet aggregation inhibition confirms its role as minimally invasive alternative to conventional TURP.
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http://dx.doi.org/10.1089/end.2018.0700DOI Listing
February 2019

The Bonding Situation in the Dinuclear Tetra-Hydrido Complex [{CpFe}(μ-H)] Revisited by Hard X-Ray Spectroscopy.

Inorg Chem 2019 May 31;58(10):6609-6618. Epub 2018 Dec 31.

Faculty of Science , Paderborn University , Warburger Straße 100 , 33098 Paderborn , Germany.

High energy resolution fluorescence detected XANES (HERFD-XANES) and valence-to-core X-ray emission spectroscopy (VtC-XES) are introduced as powerful tools to investigate hydride-iron interaction, the possible iron-iron bond, and iron spin state of the dinuclear tetra-hydrido complex [{CpFe}(μ-H)] (1H, Cp = η-C iPr) by thoroughly accessing the geometric and electronic structure of this complex in comparison to the nonhydride reference [CpCpFe] (1, Cp = CH). The so far observed most intense hydride induced signals in the pre-edge feature of the HERFD-XANES and in the VtC-XES spectra at the iron K-edge allow a precise analysis of the LUMO and HOMO states, respectively, by application of time-dependent density function theory (TD-DFT) and density functional theory (DFT) calculations. The results of these calculations are further employed to understand the oxidation state, spin states, and potential Fe-Fe bonds in this complex.
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http://dx.doi.org/10.1021/acs.inorgchem.8b03032DOI Listing
May 2019

Expert consensus guidelines for the genetic diagnosis of Alport syndrome.

Pediatr Nephrol 2019 07 9;34(7):1175-1189. Epub 2018 Jul 9.

Genetics, Guy's Hospital, Viapath, London, UK.

Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.
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http://dx.doi.org/10.1007/s00467-018-3985-4DOI Listing
July 2019

Inhibition of autophagy significantly increases the antitumor effect of Abiraterone in prostate cancer.

World J Urol 2019 Feb 27;37(2):351-358. Epub 2018 Jun 27.

Laboratory for Tissue Engineering and Stem Cell Therapy, Department of Urology, University Hospital Zürich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland.

Purpose: Abiraterone acetate (AA) plus prednisone is an approved treatment of advanced prostate cancer (PCa). Autophagy is linked to drug resistance in numerous types of cancers. We hypothesized, that upregulation of autophagy is one of the mechanisms by which PCa cells survive AA anti-tumor treatment and therefore evaluated the potential effect of a combination with autophagy inhibition.

Methods: Human PCa LNCaP cell lines were cultured in steroid-free medium and treated with AA. Autophagy was inhibited by 3-methyladenine, chloroquine and ATG5 siRNA knock-down. Cell viability and apoptosis was assessed by flow cytometry and fluorescence microscopy, and autophagy was monitored by immunohistochemistry, AUTOdot and Western blotting.

Results: Western blot revealed upregulation of ATG5 and LC3 II with a reduction of p62 protein expression in AA-treated cells, indicating upregulation of autophagy. These data were supported by results obtained with immunocytochemistry and AUTOdot assays. Using flow cytometry, we showed that combining AA with autophagy inhibition significantly impaired cell viability (1.3-1.6-fold, p < 0.001) and increased apoptosis (1.4-1.5-fold, p < 0.001) compared to AA treatment alone.

Conclusions: AA activates autophagy as a cytoprotective mechanism in LNCaP prostate cancer cells and targeting of autophagy enhances the antitumor effect of the compound.
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http://dx.doi.org/10.1007/s00345-018-2385-5DOI Listing
February 2019