TY  - JOUR
AB  - Understanding normal aging of kidney function is pivotal to help distinguish individuals at particular risk for chronic kidney disease. Glomerular filtration rate (GFR) is typically estimated via serum creatinine (eGFRcrea) or cystatin C (eGFRcys). Since population-based age-group-specific reference values for eGFR and eGFR-decline are scarce, we aimed to provide such reference values from population-based data of a wide age range. In four German population-based cohorts (KORA-3, KORA-4, AugUR, DIACORE), participants underwent medical exams, interview, and blood draw up to five times within up to 25 years. We analyzed eGFRcrea and eGFRcys cross-sectionally and longitudinally (12,000 individuals, age 25-95 years). Cross-sectionally, we found age-group-specific eGFRcrea to decrease approximately linearly across the full age range, for eGFRcys up to the age of 60 years. Within age-groups, there was little difference by sex or diabetes status. Longitudinally, linear mixed models estimated an annual eGFRcrea decline of -0.80 [95% confidence interval -0.82, -0.77], -0.79 [-0.83, -0.76], and -1.20 mL/min/1.73m2 [-1.33, -1.08] for the general population, "healthy" individuals, or individuals with diabetes, respectively. Reference values for eGFR using cross-sectional data were shown as percentile curves for "healthy" individuals and for individuals with diabetes. Reference values for eGFR-decline using longitudinal data were presented as 95% prediction intervals for "healthy" individuals and for individuals with diabetes, obesity, and/or albuminuria. Thus, our results can help clinicians to judge eGFR values in individuals seen in clinical practice according to their age and to understand the expected range of annual eGFR-decline based on their risk profile.
AU  - Herold, J.M.*
AU  - Wiegrebe, S.*
AU  - Nano, J.
AU  - Jung, B.*
AU  - Gorski, M.*
AU  - Thorand, B.
AU  - Koenig, W.*
AU  - Zeller, T.*
AU  - Zimmermann, M.E.*
AU  - Burkhardt, R.*
AU  - Banas, B.*
AU  - Küchenhoff, H.*
AU  - Stark, K.J.*
AU  - Peters, A.
AU  - Böger, C.A.*
AU  - Heid, I.M.*
C1  - 71386
C2  - 56089
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 699-711
TI  - Population-based reference values for kidney function and kidney function decline in 25- to 95-year-old Germans without and with diabetes.
JO  - Kidney Int.
VL  - 106
IS  - 4
PB  - Elsevier Science Inc
PY  - 2024
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Cognitive impairment is common in extracerebral diseases such as chronic kidney disease (CKD). Kidney transplantation reverses cognitive impairment, indicating that cognitive impairment driven by CKD is therapeutically amendable. However, we lack mechanistic insights allowing development of targeted therapies. Using a combination of mouse models (including mice with neuron-specific IL-1R1 deficiency), single cell analyses (single nuclei RNA sequencing and single cell thallium autometallography), human samples and in vitro experiments we demonstrate that microglia activation impairs neuronal potassium homeostasis and cognition in CKD. CKD disrupts the barrier of brain endothelial cells in vitro and the blood-brain barrier in vivo, establishing that the uremic state modifies vascular permeability in the brain. Exposure to uremic conditions impairs calcium homeostasis in microglia, enhances microglial potassium efflux via the calcium-dependent channel KCa3.1, and induces p38-MAPK associated IL-1β maturation in microglia. Restoring potassium homeostasis in microglia using a KCa3.1-specific inhibitor (TRAM34) improves CKD-triggered cognitive impairment. Likewise, inhibition of the IL-1β receptor 1 (IL-R1) using anakinra or genetically abolishing neuronal IL-1R1 expression in neurons prevent CKD-mediated reduced neuronal potassium turnover and CKD-induced impaired cognition. Accordingly, in CKD mice, impaired cognition can be ameliorated by either preventing microglia activation or inhibiting IL-1R-signaling in neurons. Thus, our data suggest that potassium efflux from microglia triggers their activation, which promotes microglia IL-1β release and IL-1R1-mediated neuronal dysfunction in CKD. Hence, our study provides new mechanistic insight into cognitive impairment in association with CKD and identifies possible new therapeutic approaches.
AU  - Zimmermann, S.*
AU  - Mathew, A.*
AU  - Bondareva, O.
AU  - Elwakiel, A.*
AU  - Waldmann, K.*
AU  - Jiang, S.*
AU  - Rana, R.*
AU  - Singh, K.*
AU  - Kohli, S.*
AU  - Shahzad, K.*
AU  - Biemann, R.*
AU  - Roskoden, T.*
AU  - Storsberg, S.D.*
AU  - Mawrin, C.*
AU  - Krügel, U.*
AU  - Bechmann, I.*
AU  - Goldschmidt, J.*
AU  - Sheikh, B.
AU  - Isermann, B.*
C1  - 71399
C2  - 56107
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 1101-1116
TI  - Chronic kidney disease leads to microglial potassium efflux and inflammasome activation in the brain.
JO  - Kidney Int.
VL  - 106
IS  - 6
PB  - Elsevier Science Inc
PY  - 2024
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knock-out mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knock-out of Foxd2 in ureteric-bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift towards a stromal cell identity. Histology of Foxd2 knock-out mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.
AU  - Riedhammer, K.M.*
AU  - Nguyen, T.T.*
AU  - Koşukcu, C.*
AU  - Calzada-Wack, J.
AU  - Li, Y.*
AU  - Batzir, N.A.*
AU  - Saygılı, S.*
AU  - Wimmers, V.*
AU  - Kim, G.J.*
AU  - Chrysanthou, M.*
AU  - Bakey, Z.*
AU  - Sofrin-Drucker, E.*
AU  - Kraiger, M.
AU  - Sanz-Moreno, A.
AU  - Amarie, O.V.
AU  - Rathkolb, B.
AU  - Klein-Rodewald, T.
AU  - Garrett, L.
AU  - Hölter, S.M.
AU  - Seisenberger, C.
AU  - Haug, S.*
AU  - Schlosser, P.*
AU  - Marschall, S.
AU  - Wurst, W.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Wuttke, M.*
AU  - Hrabě de Angelis, M.
AU  - Ćomić, J.*
AU  - Doğan, N.*
AU  - Özlük, Y.*
AU  - Taşdemir, M.*
AU  - Ağbaş, A.*
AU  - Canpolat, N.*
AU  - Orenstein, N.*
AU  - Çalışkan, S.*
AU  - Weber, R.G.*
AU  - Bergmann, C.*
AU  - Jeanpierre, C.*
AU  - Saunier, S.*
AU  - Lim, T.Y.*
AU  - Hildebrandt, F.*
AU  - Alhaddad, B.*
AU  - Basel-Salmon, L.*
AU  - Borovitz, Y.*
AU  - Wu, K.*
AU  - Antony, D.*
AU  - Matschkal, J.*
AU  - Schaaf, C.W.*
AU  - Renders, L.*
AU  - Schmaderer, C.*
AU  - Rogg, M.*
AU  - Schell, C.*
AU  - Meitinger, T.*
AU  - Heemann, U.*
AU  - Köttgen, A.*
AU  - Arnold, S.J.*
AU  - Ozaltin, F.*
AU  - Schmidts, M.*
AU  - Hoefele, J.*
C1  - 69025
C2  - 53810
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 844-864
TI  - Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).
JO  - Kidney Int.
VL  - 105
IS  - 4
PB  - Elsevier Science Inc
PY  - 2023
SN  - 0085-2538
ER  - 

TY  - JOUR
AU  - Bissinger, R.*
AU  - Bohnert, B.N.
AU  - Nemkov, T.*
AU  - Artunc, F.
C1  - 64312
C2  - 51900
SP  - 649-650
TI  - The authors reply.
JO  - Kidney Int.
VL  - 101
IS  - 3
PY  - 2022
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, MitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.
AU  - Drovandi, S.*
AU  - Lipska-Ziętkiewicz, B.S.*
AU  - Ozaltin, F.*
AU  - Emma, F.*
AU  - Gulhan, B.*
AU  - Boyer, O.*
AU  - Trautmann, A.*
AU  - Zietkiewicz, S.*
AU  - Xu, H.*
AU  - Shen, Q.*
AU  - Rao, J.L.*
AU  - Riedhammer, K.M.*
AU  - Heemann, U.*
AU  - Hoefele, J.*
AU  - Stenton, S.
AU  - Tsygin, A.N.*
AU  - Ng, K.H.*
AU  - Fomina, S.*
AU  - Benetti, E.*
AU  - Aurelle, M.*
AU  - Prikhodina, L.*
AU  - Schijvens, A.M.*
AU  - Tabatabaeifar, M.*
AU  - Jankowski, M.*
AU  - Baiko, S.*
AU  - Mao, J.*
AU  - Feng, C.*
AU  - Deng, F.*
AU  - Rousset-Rouviere, C.*
AU  - Stańczyk, M.*
AU  - Bałasz-Chmielewska, I.*
AU  - Fila, M.*
AU  - Durkan, A.M.*
AU  - Levart, T.K.*
AU  - Dursun, I.*
AU  - Esfandiar, N.*
AU  - Haas, D.*
AU  - Bjerre, A.*
AU  - Anarat, A.*
AU  - Benz, M.R.*
AU  - Talebi, S.*
AU  - Hooman, N.*
AU  - Ariceta, G.*
AU  - Schaefer, F.*
C1  - 65036
C2  - 52136
SP  - 592-603
TI  - Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy.
JO  - Kidney Int.
VL  - 102
IS  - 3
PY  - 2022
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Primary Coenzyme Q10 (CoQ10) deficiency is an ultra-rare disorder caused by defects in genes involved in CoQ10 biosynthesis leading to multidrug-resistant nephrotic syndrome as the hallmark kidney manifestation. Promising early results have been reported anecdotally with oral CoQ10 supplementation. However, the long-term efficacy and optimal prescription remain to be established. In a global effort, we collected and analyzed information from 116 patients who received CoQ10 supplements for primary CoQ10 deficiency due to biallelic pathogenic variants in either the COQ2, COQ6 or COQ8B genes. Median duration of follow up on treatment was two years. The effect of treatment on proteinuria was assessed, and kidney survival was analyzed in 41 patients younger than 18 years with chronic kidney disease stage 1-4 at the start of treatment compared with that of an untreated cohort matched by genotype, age, kidney function, and proteinuria. CoQ10 supplementation was associated with a substantial and significant sustained reduction of proteinuria by 88% at 12 months. Complete remission of proteinuria was more frequently observed in COQ6 disease. CoQ10 supplementation led to significantly better preservation of kidney function (5-year kidney failure-free survival 62% vs. 19%) with an improvement in general condition and neurological manifestations. Side effects of treatment were uncommon and mild. Thus, our findings indicate that all patients diagnosed with primary CoQ10 deficiency should receive early and life-long CoQ10 supplementation to decelerate the progression of kidney disease and prevent further damage to other organs.
AU  - Drovandi, S.*
AU  - Lipska-Ziętkiewicz, B.S.*
AU  - Ozaltin, F.*
AU  - Emma, F.*
AU  - Gulhan, B.*
AU  - Boyer, O.*
AU  - Trautmann, A.*
AU  - Xu, H.*
AU  - Shen, Q.*
AU  - Rao, J.*
AU  - Riedhammer, K.M.*
AU  - Heemann, U.*
AU  - Hoefele, J.*
AU  - Stenton, S.
AU  - Tsygin, A.N.*
AU  - Ng, K.H.*
AU  - Fomina, S.*
AU  - Benetti, E.*
AU  - Aurelle, M.*
AU  - Prikhodina, L.*
AU  - Schreuder, M.F.*
AU  - Tabatabaeifar, M.*
AU  - Jankowski, M.*
AU  - Baiko, S.*
AU  - Mao, J.*
AU  - Feng, C.*
AU  - Liu, C.*
AU  - Sun, S.*
AU  - Deng, F.*
AU  - Wang, X.*
AU  - Clavé, S.*
AU  - Stańczyk, M.*
AU  - Bałasz-Chmielewska, I.*
AU  - Fila, M.*
AU  - Durkan, A.M.*
AU  - Levart, T.K.*
AU  - Dursun, I.*
AU  - Esfandiar, N.*
AU  - Haas, D.*
AU  - Bjerre, A.*
AU  - Anarat, A.*
AU  - Benz, M.R.*
AU  - Talebi, S.*
AU  - Hooman, N.*
AU  - Ariceta, G.*
AU  - Schaefer, F.*
C1  - 65475
C2  - 52314
SP  - 604-612
TI  - Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency.
JO  - Kidney Int.
VL  - 102
IS  - 3
PY  - 2022
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
AU  - Gorski, M.*
AU  - Rasheed, H.*
AU  - Teumer, A.*
AU  - Thomas, L.F.*
AU  - Graham, S.E.*
AU  - Sveinbjornsson, G.*
AU  - Winkler, T.W.*
AU  - Günther, F.*
AU  - Stark, K.J.*
AU  - Chai, J.F.*
AU  - Tayo, B.O.*
AU  - Wuttke, M.*
AU  - Li, Y.*
AU  - Tin, A.*
AU  - Ahluwalia, T.S.*
AU  - Ärnlöv, J.*
AU  - Asvold, B.O.*
AU  - Bakker, S.J.L.*
AU  - Banas, B.*
AU  - Bansal, N.*
AU  - Biggs, M.L.*
AU  - Biino, G.*
AU  - Böhnke, M.*
AU  - Boerwinkle, E.*
AU  - Bottinger, E.P.*
AU  - Brenner, H.*
AU  - Brumpton, B.M.*
AU  - Carroll, R.J.*
AU  - Chaker, L.*
AU  - Chalmers, J.*
AU  - Chee, M.L.*
AU  - Cheng, C.Y.*
AU  - Chu, A.Y.*
AU  - Ciullo, M.*
AU  - Cocca, M.*
AU  - Cook, J.P.*
AU  - Coresh, J.*
AU  - Cusi, D.*
AU  - de Borst, M.H.*
AU  - Degenhardt, F.*
AU  - Eckardt, K.U.*
AU  - Endlich, K.*
AU  - Evans, M.K.*
AU  - Feitosa, M.F.*
AU  - Franke, A.*
AU  - Freitag-Wolf, S.*
AU  - Fuchsberger, C.*
AU  - Gampawar, P.*
AU  - Gansevoort, R.T.*
AU  - Ghanbari, M.*
AU  - Ghasemi, S.*
AU  - Giedraitis, V.*
AU  - Gieger, C.
AU  - Gudbjartsson, D.F.*
AU  - Hallan, S.*
AU  - Hamet, P.*
AU  - Hishida, A.*
AU  - Ho, K.*
AU  - Hofer, E.*
AU  - Holleczek, B.*
AU  - Holm, H.*
AU  - Hoppmann, A.*
AU  - Horn, K.*
AU  - Hutri-Kähönen, N.*
AU  - Hveem, K.*
AU  - Hwang, S.J.*
AU  - Ikram, M.A.*
AU  - Josyula, N.S.*
AU  - Jung, B.*
AU  - Kähönen, M.*
AU  - Karabegović, I.*
AU  - Khor, C.C.*
AU  - Koenig, W.*
AU  - Kramer, H.*
AU  - Krämer, B.K.*
AU  - Kühnel, B.
AU  - Kuusisto, J.*
AU  - Laakso, M.*
AU  - Lange, L.A.*
AU  - Lehtimäki, T.*
AU  - Li, M.*
AU  - Lieb, W.*
AU  - Lifelines Cohort Study*
AU  - Lind, L.*
AU  - Lindgren, C.M.*
AU  - Loos, R.J.F.*
AU  - Lukas, M.A.*
AU  - Lyytikäinen, L.P.*
AU  - Mahajan, A.*
AU  - Matias-Garcia, P.R.
AU  - Meisinger, C.
AU  - Meitinger, T.
AU  - Melander, O.*
AU  - Milaneschi, Y.*
AU  - Mishra, P.P.*
AU  - Mononen, N.*
AU  - Morris, A.P.*
AU  - Mychaleckyj, J.C.*
AU  - Nadkarni, G.N.*
AU  - Naito, M.*
AU  - Nakatochi, M.*
AU  - Nalls, M.A.*
AU  - Nauck, M.*
AU  - Nikus, K.*
AU  - Ning, B.*
AU  - Nolte, I.M.*
AU  - Nutile, T.*
AU  - O'Donoghue, M.L.*
AU  - O'Connell, J.*
AU  - Olafsson, I.*
AU  - Orho-Melander, M.*
AU  - Parsa, A.*
AU  - Pendergrass, S.A.*
AU  - Penninx, B.W.J.H.*
AU  - Pirastu, M.*
AU  - Preuss, M.H.*
AU  - Psaty, B.M.*
AU  - Raffield, L.M.*
AU  - Raitakari, O.T.*
AU  - Rheinberger, M.*
AU  - Rice, K.M.*
AU  - Rizzi, F.*
AU  - Rosenkranz, A.R.*
AU  - Rossing, P.*
AU  - Rotter, J.I.*
AU  - Ruggiero, D.*
AU  - Ryan, K.A.*
AU  - Sabanayagam, C.*
AU  - Salvi, E.*
AU  - Schmidt, H.*
AU  - Schmidt, R.*
AU  - Scholz, M.*
AU  - Schöttker, B.*
AU  - Schulz, C.A.*
AU  - Sedaghat, S.*
AU  - Shaffer, C.M.*
AU  - Sieber, K.B.*
AU  - Sim, X.*
AU  - Sims, M.*
AU  - Snieder, H.*
AU  - Stanzick, K.J.*
AU  - Thorsteinsdottir, U.*
AU  - Stocker, H.R.*
AU  - Strauch, K.
AU  - Stringham, H.M.*
AU  - Sulem, P.*
AU  - Szymczak, S.*
AU  - Taylor, K.D.*
AU  - Thio, C.H.L.*
AU  - Tremblay, J.*
AU  - Vaccargiu, S.*
AU  - van der Harst, P.*
AU  - van der Most, P.J.*
AU  - Verweij, N.*
AU  - Völker, U.*
AU  - Wakai, K.*
AU  - Waldenberger, M.
AU  - Wallentin, L.*
AU  - Wallner, S.*
AU  - Wang, J.*
AU  - Waterworth, D.M.*
AU  - White, H.D.*
AU  - Willer, C.J.*
AU  - Wong, T.Y.*
AU  - Woodward, M.*
AU  - Yang, Q.*
AU  - Yerges-Armstrong, L.M.*
AU  - Zimmermann, M.*
AU  - Zonderman, A.B.*
AU  - Bergler, T.*
AU  - Stefansson, K.*
AU  - Böger, C.A.*
AU  - Pattaro, C.*
AU  - Köttgen, A.*
AU  - Kronenberg, F.*
AU  - Heid, I.M.*
C1  - 65554
C2  - 52326
SP  - 624-639
TI  - Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.
JO  - Kidney Int.
VL  - 102
IS  - 3
PY  - 2022
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Anemia is a common complication of chronic kidney disease, affecting the quality of life of patients. Among various factors, such as iron and erythropoietin deficiency, reduced red blood cell (RBC) lifespan has been implicated in the pathogenesis of anemia. However, mechanistic data on in vivo RBC dysfunction in kidney disease are lacking. Herein, we describe the development of chronic kidney disease-associated anemia in mice with proteinuric kidney disease resulting from either administration of doxorubicin or an inducible podocin deficiency. In both experimental models, anemia manifested at day 10 and progressed at day 30 despite increased circulating erythropoietin levels and erythropoiesis in the bone marrow and spleen. Circulating RBCs in both mouse models displayed altered morphology and diminished osmotic-sensitive deformability together with increased phosphatidylserine externalization on the outer plasma membrane, a hallmark of RBC death. Fluorescence-labelling of RBCs at day 20 of mice with doxorubicin-induced kidney disease revealed premature clearance from the circulation. Metabolomic analyses of RBCs from both mouse models demonstrated temporal changes in redox recycling pathways and Lands' cycle, a membrane lipid remodeling process. Anemic patients with proteinuric kidney disease had an increased proportion of circulating phosphatidylserine-positive RBCs. Thus, our observations suggest that reduced RBC lifespan, mediated by altered RBC metabolism, reduced RBC deformability, and enhanced cell death contribute to the development of anemia in proteinuric kidney disease.
AU  - Bissinger, R.*
AU  - Nemkov, T.*
AU  - D Alessandro, A.*
AU  - Grau, M.*
AU  - Dietz, T.*
AU  - Bohnert, B.N.
AU  - Essigke, D.*
AU  - Wörn, M.*
AU  - Schaefer, L.*
AU  - Xiao, M.*
AU  - Beirne, J.M.*
AU  - Kalo, M.Z.*
AU  - Schork, A.
AU  - Bakchoul, T.*
AU  - Omage, K.*
AU  - Kong, L.*
AU  - González-Menéndez, I.*
AU  - Quintanilla-Martinez, L.*
AU  - Fehrenbacher, B.*
AU  - Schaller, M.*
AU  - Dhariwal, A.*
AU  - Birkenfeld, A.L.
AU  - Grahammer, F.*
AU  - Qadri, S.M.*
AU  - Artunc, F.
C1  - 63038
C2  - 51225
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 1227-1239
TI  - Proteinuric chronic kidney disease is associated with altered red blood cell lifespan, deformability and metabolism.
JO  - Kidney Int.
VL  - 100
IS  - 6
PB  - Elsevier Science Inc
PY  - 2021
SN  - 0085-2538
ER  - 

TY  - JOUR
AU  - Bohnert, B.N.
AU  - Büttner-Herold, M.*
AU  - Amann, K.*
AU  - Schork, A.
AU  - Birkenfeld, A.L.
AU  - Guthoff, M.
AU  - Heyne, N.
AU  - Nadalin, S.*
AU  - Artunc, F.
C1  - 61631
C2  - 50358
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 1031-1032
TI  - The Case | A 74-year-old liver transplant recipient with nephrotic-range proteinuria.
JO  - Kidney Int.
VL  - 99
IS  - 4
PB  - Elsevier Science Inc
PY  - 2021
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
AU  - Gorski, M.*
AU  - Jung, B.*
AU  - Li, Y.*
AU  - Matias-Garcia, P.R.
AU  - Wuttke, M.*
AU  - Coassin, S.*
AU  - Thio, C.H.L.*
AU  - Kleber, M.E.*
AU  - Winkler, T.W.*
AU  - Wanner, V.*
AU  - Chai, J.F.*
AU  - Chu, A.Y.*
AU  - Cocca, M.*
AU  - Feitosa, M.F.*
AU  - Ghasemi, S.*
AU  - Hoppmann, A.*
AU  - Horn, K.*
AU  - Li, M.*
AU  - Nutile, T.*
AU  - Scholz, M.*
AU  - Sieber, K.B.*
AU  - Teumer, A.*
AU  - Tin, A.*
AU  - Wang, J.*
AU  - Tayo, B.O.*
AU  - Ahluwalia, T.S.*
AU  - Almgren, P.*
AU  - Bakker, S.J.L.*
AU  - Banas, B.*
AU  - Bansal, N.*
AU  - Biggs, M.L.*
AU  - Boerwinkle, E.*
AU  - Bottinger, E.P.*
AU  - Brenner, H.*
AU  - Carroll, R.J.*
AU  - Chalmers, J.*
AU  - Chee, M.L.*
AU  - Cheng, C.Y.*
AU  - Coresh, J.*
AU  - de Borst, M.H.*
AU  - Degenhardt, F.*
AU  - Eckardt, K.U.*
AU  - Endlich, K.*
AU  - Franke, A.*
AU  - Freitag-Wolf, S.*
AU  - Gampawar, P.*
AU  - Gansevoort, R.T.*
AU  - Ghanbari, M.*
AU  - Gieger, C.
AU  - Hamet, P.*
AU  - Ho, K.*
AU  - Hofer, E.*
AU  - Holleczek, B.*
AU  - Xian Foo, V.H.*
AU  - Hutri-Kähönen, N.*
AU  - Hwang, S.J.*
AU  - Ikram, M.A.*
AU  - Josyula, N.S.*
AU  - Kähönen, M.*
AU  - Khor, C.C.*
AU  - Koenig, W.*
AU  - Kramer, H.*
AU  - Krämer, B.K.*
AU  - Kühnel, B.
AU  - Lange, L.A.*
AU  - Lehtimäki, T.*
AU  - Lieb, W.*
AU  - Loos, R.J.F.*
AU  - Lukas, M.A.*
AU  - Lyytikäinen, L.P.*
AU  - Meisinger, C.
AU  - Meitinger, T.
AU  - Melander, O.*
AU  - Milaneschi, Y.*
AU  - Mishra, P.P.*
AU  - Mononen, N.*
AU  - Mychaleckyj, J.C.*
AU  - Nadkarni, G.N.*
AU  - Nauck, M.*
AU  - Nikus, K.*
AU  - Ning, B.*
AU  - Nolte, I.M.*
AU  - O'Donoghue, M.L.*
AU  - Orho-Melander, M.*
AU  - Pendergrass, S.A.*
AU  - Penninx, B.W.J.H.*
AU  - Preuss, M.H.*
AU  - Psaty, B.M.*
AU  - Raffield, L.M.*
AU  - Raitakari, O.T.*
AU  - Rettig, R.*
AU  - Rheinberger, M.*
AU  - Rice, K.M.*
AU  - Rosenkranz, A.R.*
AU  - Rossing, P.*
AU  - Rotter, J.I.*
AU  - Sabanayagam, C.*
AU  - Schmidt, H.*
AU  - Schmidt, R.*
AU  - Schöttker, B.*
AU  - Schulz, C.A.*
AU  - Sedaghat, S.*
AU  - Shaffer, C.M.*
AU  - Strauch, K.
AU  - Szymczak, S.*
AU  - Taylor, K.D.*
AU  - Tremblay, J.*
AU  - Chaker, L.*
AU  - van der Harst, P.*
AU  - van der Most, P.J.*
AU  - Verweij, N.*
AU  - Völker, U.*
AU  - Waldenberger, M.
AU  - Wallentin, L.*
AU  - Waterworth, D.M.*
AU  - White, H.D.*
AU  - Wilson, J.G.*
AU  - Wong, T.Y.*
AU  - Woodward, M.*
AU  - Yang, Q.*
AU  - Yasuda, M.*
AU  - Yerges-Armstrong, L.M.*
AU  - Zhang, Y.*
AU  - Snieder, H.*
AU  - Wanner, C.*
AU  - Böger, C.A.*
AU  - Köttgen, A.*
AU  - Kronenberg, F.*
AU  - Pattaro, C.*
AU  - Heid, I.M.*
C1  - 61233
C2  - 49766
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 926-939
TI  - Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.
JO  - Kidney Int.
VL  - 99
IS  - 4
PB  - Elsevier Science Inc
PY  - 2021
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Increased plasma concentrations of proprotein convertase subtilisin/kexin type 9 or PCSK9, which reduces hepatic uptake of low-density lipoprotein by downregulation of the low-density lipoprotein receptor, have been reported in nephrotic patients and might contribute to hyperlipidemia in nephrotic syndrome. The results of the study by Molina-Jijon et al. found that renal PCSK9 expression was upregulated in the collecting duct of nephrotic patients and animals, suggesting that the kidney might be a major source for plasma PCSK9 in nephrotic syndrome.
AU  - Artunc, F.
C1  - 60787
C2  - 49751
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 1393-1395
TI  - Kidney-derived PCSK9-a new driver of hyperlipidemia in nephrotic syndrome?
JO  - Kidney Int.
VL  - 98
IS  - 6
PB  - Elsevier Science Inc
PY  - 2020
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - High circulating fibroblast growth factor 23 (FGF23) levels are probably a major risk factor for cardiovascular disease in chronic kidney disease. FGF23 interacts with the receptor FGFR4 in cardiomyocytes inducing left ventricular hypertrophy. Moreover, in the liver FGF23 via FGFR4 increases the risk of inflammation which is also found in chronic kidney disease. In contrast, X-linked hypophosphatemia is characterized by high FGF23 circulating levels due to loss of function mutations of the phosphate-regulating gene with homologies to an endopeptidase on the X chromosome (PHEX), but is not characterized by high cardiovascular morbidity. Here we used a novel murine X-linked hypophosphatemia model, the PhexC733RMhda mouse line, bearing an amino acid substitution (p.Cys733Arg) to test whether high circulating FGF23 in the absence of renal injury would trigger cardiovascular disease. As X-linked hypophosphatemia patient mimics, these mice show high FGF23 levels, hypophosphatemia, normocalcemia, and low/normal vitamin D levels. Moreover, these mice show hyperparathyroidism and low circulating soluble alpha Klotho levels. At the age of 27 weeks we found no left ventricular hypertrophy and no alteration of cardiac function as assessed by echocardiography. These mice also showed no activation of the calcineurin/NFAT pathway in heart and liver and no tissue and systemic signs of inflammation. Importantly, blood pressure, glomerular filtration rate and urea clearance were similar between genotypes. Thus, the presence of high circulating FGF23 levels alone in the absence of renal impairment and normal/high phosphate levels is not sufficient to cause cardiovascular disease.
AU  - Pastor-Arroyo, E.M.*
AU  - Gehring, N.H.*
AU  - Krudewig, C.*
AU  - Costantino, S.*
AU  - Bettoni, C.*
AU  - Knöpfel, T.*
AU  - Sabrautzki, S.
AU  - Lorenz-Depiereux, B.
AU  - Pastor, J.*
AU  - Strom, T.M.
AU  - Hrabě de Angelis, M.
AU  - Camici, G.G.*
AU  - Paneni, F.*
AU  - Wagner, C.A.*
AU  - Rubio-Aliaga, I.*
C1  - 53483
C2  - 44667
CY  - 360 Park Ave South, New York, Ny 10010-1710 Usa
SP  - 49-59
TI  - The elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease risk.
JO  - Kidney Int.
VL  - 94
IS  - 1
PB  - Elsevier Science Inc
PY  - 2018
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Volume retention in nephrotic syndrome has been linked to activation of the epithelial sodium channel (ENaC) by proteolysis of its γ-subunit following urinary excretion of serine proteases such as plasmin. Here we tested whether pharmacological inhibition of urinary serine protease activity might protect from ENaC activation and volume retention in nephrotic syndrome. Urine from both nephrotic mice (induced by doxorubicin injection) and nephrotic patients exhibited high aprotinin-sensitive serine protease activity. Treatment of nephrotic mice with the serine protease inhibitor aprotinin by means of subcutaneous sustained-release pellets normalized urinary serine protease activity and prevented sodium retention, as did treatment with the ENaC inhibitor amiloride. In the kidney cortex from nephrotic mice, immunofluorescence revealed increased apical γ-ENaC staining, normalized by aprotinin treatment. In Xenopus laevis oocytes heterologously expressing murine ENaC, aprotinin had no direct inhibitory effect on channel activity but prevented proteolytic channel activation. Thus, our study shows that volume retention in experimental nephrotic syndrome is related to proteolytic ENaC activation by proteasuria and can be prevented by treatment with aprotinin. Hence, inhibition of urinary serine protease activity might become a therapeutic approach to treat patients with nephrotic-range proteinuria.
AU  - Bohnert, B.N.
AU  - Menacher, M.*
AU  - Janessa, A.*
AU  - Wörn, M.*
AU  - Schork, A.
AU  - Daiminger, S.*
AU  - Kalbacher, H.*
AU  - Häring, H.-U.
AU  - Daniel, C.*
AU  - Amann, K.*
AU  - Sure, F.*
AU  - Bertog, M.*
AU  - Haerteis, S.*
AU  - Korbmacher, C.*
AU  - Artunc, F.
C1  - 52157
C2  - 43783
CY  - New York
SP  - 159-172
TI  - Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome.
JO  - Kidney Int.
VL  - 93
IS  - 1
PB  - Elsevier Science Inc
PY  - 2017
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.
AU  - Gorski, M.*
AU  - Tin, A.*
AU  - Garnaas, M.*
AU  - McMahon, G.M.*
AU  - Chu, A.Y.*
AU  - Tayo, B.O.*
AU  - Pattaro, C.*
AU  - Teumer, A.*
AU  - Chasman, D.I.*
AU  - Chalmers, J.*
AU  - Hamet, P.*
AU  - Tremblay, J.*
AU  - Woodward, M.*
AU  - Aspelund, T.*
AU  - Eiriksdottir, G.*
AU  - Gudnason, V.*
AU  - Harris, T.B.*
AU  - Launer, L.J.*
AU  - Smith, A.V.*
AU  - Mitchell, B.D.*
AU  - O'Connell, J.R.*
AU  - Shuldiner, A.R.*
AU  - Coresh, J.*
AU  - Li, M.*
AU  - Freudenberger, P.*
AU  - Hofer, E.*
AU  - Schmidt, H.*
AU  - Schmidt, R.*
AU  - Holliday, E.G.*
AU  - Mitchell, P.*
AU  - Wang, J.J.*
AU  - de Boer, I.H.*
AU  - Li, G.*
AU  - Siscovick, D.S.*
AU  - Kutalik, Z.*
AU  - Corre, T.*
AU  - Vollenweider, P.*
AU  - Waeber, G.*
AU  - Gupta, J.*
AU  - Kanetsky, P.A.*
AU  - Hwang, S.J.*
AU  - Olden, M.*
AU  - Yang, Q.*
AU  - de Andrade, M.*
AU  - Atkinson, E.J.*
AU  - Kardia, S.L.*
AU  - Turner, S.T.*
AU  - Stafford, J.M.*
AU  - Ding, J.*
AU  - Liu, Y.*
AU  - Barlassina, C.*
AU  - Cusi, D.*
AU  - Salvi, E.*
AU  - Staessen, J.A.*
AU  - Ridker, P.M.*
AU  - Grallert, H.
AU  - Meisinger, C.
AU  - Müller-Nurasyid, M.
AU  - Krämer, B.K.*
AU  - Kramer, H.*
AU  - Rosas, S.E.*
AU  - Nolte, I.M.*
AU  - Penninx, B.W.*
AU  - Snieder, H.*
AU  - Fabiola Del Greco, M.*
AU  - Franke, A.*
AU  - Nöthlings, U.*
AU  - Lieb, W.*
AU  - Bakker, S.J.*
AU  - Gansevoort, R.T.*
AU  - van der Harst, P.*
AU  - Dehghan, A.*
AU  - Franco, O.H.*
AU  - Hofman, A.*
AU  - Rivadeneira, F.*
AU  - Sedaghat, S.*
AU  - Uitterlinden, A.G.*
AU  - Coassin, S.*
AU  - Haun, M.*
AU  - Kollerits, B.*
AU  - Kronenberg, F.*
AU  - Paulweber, B.*
AU  - Aumann, N.*
AU  - Endlich, K.*
AU  - Pietzner, M.*
AU  - Völker, U.*
AU  - Rettig, R.*
AU  - Chouraki, V.*
AU  - Helmer, C.*
AU  - Lambert, J.C.*
AU  - Metzger, M.*
AU  - Stengel, B.*
AU  - Lehtimäki, T.*
AU  - Lyytikäinen, L.-P.*
AU  - Raitakari, O.*
AU  - Johnson, A.*
AU  - Parsa, A.*
AU  - Bochud, M.*
AU  - Heid, I.M.
AU  - Goessling, W.*
AU  - Köttgen, A.*
AU  - Kao, W.H.*
AU  - Fox, C.S.*
AU  - Böger, C.A.*
C1  - 42933
C2  - 35874
CY  - New York
SP  - 1017–1029
TI  - Genome-wide association study of kidney function decline in individuals of European descent.
JO  - Kidney Int.
VL  - 87
IS  - 5
PB  - Nature Publishing Group
PY  - 2015
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin β receptor (LTβR) signaling is crucial for the formation of lymphoid tissue, and inhibition of LTβR signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LTβR signaling could also have a role in renal injury. Renal biopsies from patients with GN were found to express both LTα and LTβ ligands, as well as LTβR. The LTβR protein and mRNA were localized to tubular epithelial cells, parietal epithelial cells, crescents, and cells of the glomerular tuft, whereas LTβ was found on lymphocytes and tubular epithelial cells. Human tubular epithelial cells, mesangial cells, and mouse parietal epithelial cells expressed both LTα and LTβ mRNA upon stimulation with TNF in vitro. Several chemokine mRNAs and proteins were expressed in response to LTβR signaling. Importantly, in a murine lupus model, LTβR blockade improved renal function without the reduction of serum autoantibody titers or glomerular immune complex deposition. Thus, a preclinical mouse model and human studies strongly suggest that LTβR signaling is involved in renal injury and may be a suitable therapeutic target in renal diseases.
AU  - Seleznik, G.M.*
AU  - Seeger, H.*
AU  - Bauer, J.
AU  - Fu, K.*
AU  - Czerkowicz, J.*
AU  - Papandile, A.*
AU  - Poreci, U.*
AU  - Rabah, D.*
AU  - Ranger, A.*
AU  - Cohen, C.D.*
AU  - Lindenmeyer, M.*
AU  - Chen, J.*
AU  - Edenhofer, I.*
AU  - Anders, H.J.*
AU  - Lech, M.*
AU  - Wüthrich, R.P.*
AU  - Ruddle, N.H.*
AU  - Moeller, M.J.*
AU  - Kozakowski, N.*
AU  - Regele, H.*
AU  - Browning, J.L.*
AU  - Heikenwälder, M.
AU  - Segerer, S.*
C1  - 46969
C2  - 39093
SP  - 113–126
TI  - The lymphotoxin β receptor is a potential therapeutic target in renal inflammation.
JO  - Kidney Int.
VL  - 89
IS  - 1
PY  - 2015
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - There is increasing evidence for a role of genetic predisposition in the etiology of kidney disease, but linkage scans have been poorly replicated. Here we performed a genome-wide linkage analysis of serum creatinine on 2859 individuals from isolated villages in South Tyrol (Italy), Rucphen (The Netherlands) and Vis Island (Croatia), populations that have been stable and permanently resident in their region. Linkage of serum creatinine levels to loci on chromosomes 7p14, 9p21, 11p15, 15q15-21, 16p13, and 18p11 was successfully replicated in at least one discovery population or in the pooled analysis. A novel locus was found on chromosome 10p11. Linkage to chromosome 22q13, independent of diabetes and hypertension, was detected over a region containing the non-muscle myosin heavy chain type II isoform A (MYH9) gene (LOD score = 3.52). In non-diabetic individuals, serum creatinine was associated with this gene in two of the three populations and in meta-analysis (SNP rs11089788, P-value = 0.0089). In populations sharing a homogeneous environment and genetic background, heritability of serum creatinine was higher than in outbred populations, with consequent detection of a larger number of loci than reported before. Our finding of a replicated association of serum creatinine with the MYH9 gene, recently linked to pathological renal conditions in African Americans, suggests that this gene may also influence kidney function in healthy Europeans.
AU  - Pattaro, C.*
AU  - Aulchenko, Y.S.*
AU  - Isaacs, A.*
AU  - Vitart, V.*
AU  - Hayward, C.*
AU  - Franklin, C.S.*
AU  - Polasek, O.*
AU  - Kolcic, I.*
AU  - Biloglav, Z.*
AU  - Campbell, S.*
AU  - Hastie, N.*
AU  - Lauc, G.*
AU  - Meitinger, T.
AU  - Oostra, B.A.*
AU  - Gyllensten, U.*
AU  - Wilson, J.F.*
AU  - Pichler, I.*
AU  - Hicks, A.A.*
AU  - Campbell, H.*
AU  - Wright, A.F.*
AU  - Rudan, I.*
AU  - van Duijn, C.M.*
AU  - Riegler, P.*
AU  - Marroni, F.*
AU  - Pramstaller, P.P.*
C1  - 550
C2  - 26709
SP  - 297-306
TI  - Genome-wide linkage analysis of serum creatinine in three isolated European populations.
JO  - Kidney Int.
VL  - 76
IS  - 3
PB  - Nature Publ. Group
PY  - 2009
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Macrophages and dendritic cells are heterogenous and highly plastic bone marrow-derived cells that play major roles in renal diseases. We characterized these cells using immunohistochemistry in 55 renal biopsies from control patients or patients with glomerulonephritis as an initial step towards postulating specific roles for these cells in kidney disease. In proliferative glomerulonephritis numerous CD68 positive (pan monocyte, macrophage and dendritic marker) cells were found in both glomeruli and the tubulointerstitial space, however, a myeloid dendritic cell marker (DC-SIGN) was identified only in the tubulointerstitium. A significant number of plasmacytoid dendritic cells (identified as BDCA-2 positive cells) were seen at sites of interstitial inflammation, including follicular aggregates of inflammatory cells. Langerin positive cells (a marker of Langerhans' cells) were detectable but rare. The area of either CD68 or DC-SIGN positive interstitial cells correlated with serum creatinine. Low levels of DC-SIGN, DC-LAMP and MHC class II mRNA were present in the tubulointerstitial space in controls and increased only in that region in proliferative glomerulonephritis. We demonstrate that the CD68 positive cells infiltrating the glomerulus lack dendritic cell markers (reflecting macrophages), whereas in the tubulointerstitial space the majority of CD68 positive cells are also DC-SIGN positive (reflecting myeloid dendritic cells). Their number correlated with serum creatinine, which further emphasizes the significance of interstitial DCs in progressive glomerular diseases.
AU  - Segerer, S.*
AU  - Heller, F.*
AU  - Lindenmeyer, M.T.*
AU  - Schmid, H.*
AU  - Cohen, C.D.*
AU  - Draganovici, D.*
AU  - Mandelbaum, J.*
AU  - Nelson, P.J.*
AU  - Gröne, H.J.*
AU  - Gröne, E.F.*
AU  - Figel, A.-M.
AU  - Nößner, E.
AU  - Schlöndorff, D.*
C1  - 2180
C2  - 25397
SP  - 37-46
TI  - Compartment specific expression of dendritic cell markers in human glomerulonephritis.
JO  - Kidney Int.
VL  - 74
IS  - 1
PB  - Nature Publ. Group
PY  - 2008
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - Lipoprotein(a) (Lp(a)) consists of a low-density lipoprotein-like particle and a covalently linked highly glycosylated protein, called apolipoprotein(a) (apo(a)). Lp(a) derives from the liver but its catabolism is still poorly understood. Plasma concentrations of this highly atherogenic lipoprotein are elevated in hemodialysis (HD) patients, suggesting the kidney to be involved in Lp(a) catabolism. We therefore compared the in vivo turnover rates of both protein components from Lp(a) (i.e. apo(a) and apoB) determined by stable-isotope technology in seven HD patients with those of nine healthy controls. The fractional catabolic rate (FCR) of Lp(a)-apo(a) was significantly lower in HD patients compared with controls (0.164+/-0.114 vs 0.246+/-0.067 days(-1), P=0.042). The same was true for the FCR of Lp(a)-apoB (0.129+/-0.097 vs 0.299+/-0.142 days(-1), P=0.005). This resulted in a much longer residence time of 8.9 days for Lp(a)-apo(a) and 12.9 days for Lp(a)-apoB in HD patients compared with controls (4.4 and 3.9 days, respectively). The production rates of apo(a) and apoB from Lp(a) did not differ significantly between patients and controls and were even lower for patients when compared with controls with similar Lp(a) plasma concentrations. This in vivo turnover study is a further crucial step in understanding the mechanism of Lp(a) catabolism: the loss of renal function in HD patients causes elevated Lp(a) plasma levels because of decreased clearance but not increased production of Lp(a). The prolonged retention time of Lp(a) in HD patients might importantly contribute to the high risk of atherosclerosis in these patients.
AU  - Frischmann, M.E.*
AU  - Kronenberg, F.
AU  - Trenkwalder, E.*
AU  - Schaefer, J.R.*
AU  - Schweer, H.*
AU  - Dieplinger, B.*
AU  - Koenig, P.*
AU  - Ikewaki, K.*
AU  - Dieplinger, H.*
C1  - 3275
C2  - 24605
SP  - 1036-1043
TI  - In vivo turnover study demonstrates diminished clearance of lipoprotein(a) in hemodialysis patients.
JO  - Kidney Int.
VL  - 71
IS  - 10
PB  - Nature Publ. Group
PY  - 2007
SN  - 0085-2538
ER  - 

TY  - JOUR
AB  - rogressive renal vascular sclerosis is a key feature of chronic kidney disease (CKD). Adiponectin, an adipokine with potent anti-inflammatory and antiatherosclerotic properties, is associated with insulin resistance, type II diabetes and cardiovascular disease. In this study, we evaluated the predictive value of adiponectin for the progression of CKD in patients enrolled in the Mild to Moderate Kidney Disease Study. The primary end point was defined as a doubling of the baseline serum creatinine and/or terminal renal failure in 177 patients who completed a prospective follow-up of 7 years. Patients who reached a progression endpoint (n=65) were significantly older, had higher baseline serum creatinine, proteinuria and adiponectin concentrations and more components of the metabolic syndrome. A gender-stratified Cox model revealed adiponectin in men as a significant predictor of progression after adjustment for age, glomerular filtration rate, and proteinuria. Male patients with adiponectin levels above their ROC analysis-derived optimal cutoff of 4 mug/ml had a significantly faster progression than patients below this point. This prospective long-term study in patients with CKD indicates high adiponectin as a novel independent predictor of disease progression in men but not in women. Our observation may be relevant for other conditions of progressive vascular sclerosis and diabetic nephropathy.
AU  - Kollerits, B.*
AU  - Fliser, D.*
AU  - Heid, I.M.
AU  - Ritz, E.*
AU  - Kronenberg, F.*
C1  - 4139
C2  - 24509
SP  - 1279-1286
TI  - Gender-specific association of adiponectin as a predictor of progression of chronic kidney disease: The Mild to Moderate Kidney Disease Study.
JO  - Kidney Int.
VL  - 71
IS  - 12
PB  - Nature Publ. Group
PY  - 2007
SN  - 0085-2538
ER  - 

TY  - JOUR
AU  - Segerer, S.*
AU  - Henger, A.*
AU  - Schmid, H.*
AU  - Ketzler, M.*
AU  - Draganovici, D.*
AU  - Brandt, U.*
AU  - Nößner, E.
AU  - Nelson, P.J.*
AU  - Kerajaschke, D.*
AU  - Schlöndorff, D.*
AU  - Regele, H.*
C1  - 2847
C2  - 24065
SP  - 1765-1773
TI  - Expression of the chemokine receptor CXCR1 in human glomerular disease.
JO  - Kidney Int.
VL  - 69
PY  - 2006
SN  - 0085-2538
ER  - 

TY  - JOUR
AU  - Haiman, M.*
AU  - Salvenmoser, W.*
AU  - Scheiber, K.*
AU  - Lingenhel, A.*
AU  - Rudolph, C.*
AU  - Schmitz, G.*
AU  - Kronenberg, F.
AU  - Dieplinger, H.*
C1  - 3132
C2  - 23134
SP  - 1130-1136
TI  - Immunohistochemical localization of apolipoprotein A-IV in human kidney tissue.
JO  - Kidney Int.
VL  - 68
PY  - 2005
SN  - 0085-2538
ER  - 

TY  - JOUR
AU  - Kronenberg, F.
AU  - Lingenhel, A.
AU  - Lhotta, K.
AU  - Rantner, B.
AU  - Kronenberg, M.F.
AU  - König, P.
AU  - Thiery, J.
AU  - Koch, M.
AU  - von Eckardstein, A.
AU  - Dieplinger, H.
C1  - 1059
C2  - 22049
SP  - 348-354
TI  - Lipoprotein(a)- and low-density lipoprotein-derived cholesterol in nephrotic syndrome: Impact on lipid-lowering therapy?
JO  - Kidney Int.
VL  - 66
PY  - 2004
SN  - 0085-2538
ER  - 

TY  - JOUR
AU  - Kronenberg, F.
AU  - Lingenhel, A.*
AU  - Lhotta, K.*
AU  - Rantner, B.*
AU  - Kronenberg, M.F.*
AU  - König, P.*
AU  - Thiery, J.*
AU  - Koch, M.*
AU  - von Eckardstein, A.*
AU  - Dieplinger, H.*
C1  - 2443
C2  - 22059
SP  - 606-612
TI  - The apolipoprotein(a) size polymorphism is associated with nephrotic syndrome.
JO  - Kidney Int.
VL  - 65
PY  - 2004
SN  - 0085-2538
ER  - 

TY  - JOUR
AU  - Kronenberg, F.
AU  - Lingenhel, A.
AU  - Neyer, U.*
AU  - Lhotta, K.*
AU  - König, P.*
AU  - Auinger, M.*
AU  - Wiesholzer, M.*
AU  - Andersson, H.*
AU  - Dieplinger, H.*
C1  - 10017
C2  - 21719
SP  - 113-116
TI  - Prevalence of dyslipidemic risk factors in hemodialysis and CAPD patients. 
JO  - Kidney Int.
VL  - 63
PY  - 2003
SN  - 0085-2538
ER  - 

TY  - JOUR
AU  - White, K.E.*
AU  - Carn, G.*
AU  - Lorenz-Depriereux, B.*
AU  - Benet-Pagès, A.*
AU  - Strom, T.M.
AU  - Econs, M.J.*
C1  - 10018
C2  - 20550
SP  - 2079-2086
TI  - Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23.
JO  - Kidney Int.
VL  - 60
PY  - 2001
SN  - 0085-2538
ER  -