Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children

Ažukaitis, Karolis; Ju, Wenjun; Kirchner, Marietta; Nair, Viji; Smith, Michelle R.; Fang, Zhiyin; Thurn‐Valsassina, Daniela; Bayazıt, Aysun Karabay; Niemirska, Anna; Canpolat, Nur; Bulut, İpek Kaplan; Yalçınkaya, Fatoş; Paripović, Dušan; Harambat, Jérôme; Çakar, Nilgün; Alpay, Harika; Lugani, Francesca; Mencarelli, Francesca; Çivilibal, Mahmut; Erdoğan, Hakan; Gellermann, Jutta; Vidal, Enrico; Tabel, Yılmaz; Gimpel, Charlotte; Ertan, Pelin; Yavaşcan, Önder; Melk, Anette; Querfeld, Uwe; Wühl, Elke; Kretzler, Matthias; Schaefer, Franz; Arbeiter, Klaus; Rosales, Alejandra; Dušek, Jiří; Zaloszyc, Ariane; Liebau, Max C.; Weber, Lutz T.; Muschiol, Evelin; Büscher, Rainer; Oh, Jun; Thurn-Valassina, Daniela; Haffner, Dieter; John, U; Wygoda, Simone; Jeck, Nikola; Wigger, Marianne; Testa, Sara; Murer, Luisa; Matteucci, Maria Chiara; Jankauskienė, Augustina; Drożdż, Dorota; Zurowska, Aleksandra; Zaniew, Marcin; Litwin, Mieczysław; Nimierska, Anna; Teixeira, Ana; Peco-Antić, Amira; Laube, Guido F.; Anarat, Ali; Düzova, Ali; Bilginer, Yelda; Çalışkan, Salim; Mır, Sevgı; Sözeri, Betül; Kranz, Brigitta; Dorn, Brigitte; Baskın, Esra; Söylemezoğlu, Oğuz; Emre, Sevinç; Candan, Cengiz; Kıyak, Aysel; Özçelik, Gül; Shroff, Rukshana; Rachin, Bruno; Szczepańska, Maria; Dönmez, Osman; Balat, Ayşe; Aksu, Nejat; Yılmaz, Ebru; Bakkaloğlu, Ayşı̇n; Özaltın, Fatih; Sartipy, Peter; Bonzel, Klaus-Eugen; Wingen, Anna-Margrete; Zurowska, Aleksandra; Bałasz, I; Trivelli, Antonella; Perfumo, Francesco; Müller-Wiefel, Dirk-Erhard; Möller, Kerstin; Offner, G.; Enke, Barbara; Hadtstein, Charlotte; Mehls, Otto; Hohbach-Hohenfellner, Katharina; Jeck, N; Klaus, Günter; Ardissino, Gianluigi; Montini, Giovanni; Charbit, Marina; Niaudet, Patrick; Afonso, Alberto Caldas; Fernandes-Teixeira, Ana; Picca, Stefano; Berg, Ulla; Celsi, G.; Fischbach, Michel; Terzic, J.; Fydryk, J; Urasiński, Tomasz; Coppo, Rosanna; Peruzzi, Licia; Grenda, Ryszard; Neuhaus, Thomas J.

doi:10.1016/j.kint.2019.01.035

Cited by 52 publications

(33 citation statements)

References 29 publications

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“…However, as our population-based studies were cross-sectional and also included a substantial amount of healthy individuals, it would be interesting to study any protective effects of cubilin deficiency on the progression of specific glomerular diseases in a longitudinal manner. Moreover, given that the observed effects on eGFR were mild and that eGFR itself reflected creatinine clearance with a margin of error, future studies could benefit from more specific tubular damage markers, such as urinary EGF (49).…”

Section: Discussionmentioning

confidence: 99%

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

Bedin¹,

Boyer²,

Servais³

et al. 2019

Journal of Clinical Investigation

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BACKGROUND. Proteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding. METHODS. We used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods. RESULTS. We identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts. CONCLUSION. Collectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.

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Section: Discussionmentioning

confidence: 99%

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

Bedin¹,

Boyer²,

Servais³

et al. 2019

Journal of Clinical Investigation

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“…EGF and its receptor are involved in several processes within kidney tissue, mainly related to tubular cell proliferation [13] and pathways of cell survival [10,11], making EGF a critical component in promoting kidney recovery from acute injury [11]. Therefore, its dysregulation is involved in key pathogenic pathways that drive kidney disease progression independent of etiology, e.g., chronic inflammation [24], extracellular matrix modulation and tubular cell dedifferentiation [15].…”

Section: Discussionmentioning

confidence: 99%

Urinary Epidermal Growth Factor/Creatinine Ratio and Graft Failure in Renal Transplant Recipients: A Prospective Cohort Study

Yepes-Calderón

Sotomayor

Kretzler

et al. 2019

JCM

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Graft failure (GF) remains a significant limitation to improve long-term outcomes in renal transplant recipients (RTR). Urinary epidermal growth factor (uEGF) is involved in kidney tissue integrity, with a reduction of its urinary excretion being associated with fibrotic processes and a wide range of renal pathologies. We aimed to investigate whether, in RTR, uEGF is prospectively associated with GF. In this prospective cohort study, RTR with a functioning allograft ≥1-year were recruited and followed-up for three years. uEGF was measured in 24-hours urine samples and normalized by urinary creatinine (Cr). Its association with risk of GF was assessed by Cox-regression analyses and its predictive ability by C-statistic. In 706 patients, uEGF/Cr at enrollment was 6.43 [IQR 4.07–10.77] ng/mg. During follow-up, 41(6%) RTR developed GF. uEGF/Cr was inversely associated with the risk of GF (HR 0.68 [95% CI 0.59–0.78]; P < 0.001), which remained significant after adjustment for immunosuppressive therapy, estimated Glomerular Filtration Rate, and proteinuria. C-statistic of uEGF/Cr for GF was 0.81 (P < 0.001). We concluded that uEGF/Cr is independently and inversely associated with the risk of GF and depicts strong prediction ability for this outcome. Further studies seem warranted to elucidate whether uEGF might be a promising marker for use in clinical practice.

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“…The primary endpoint was renal survival defined as time from baseline to the composite event of either eGFR of <10ml/min or 50% loss in eGFR or start of RRT, whatever occurred first, as described previously [ 14 , 15 ]; if eGFR<10 or 50% loss in eGFR occurred between two visits, linear interpolation was used to determine the “exact” point in time. As sensitivity analyses, two procedures were applied to prove consistency of our results because of not having observed the precise date of the event.…”

Section: Methodsmentioning

confidence: 99%

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

et al. 2020

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The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3–0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD.

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Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children

Cited by 52 publications

References 29 publications

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

Urinary Epidermal Growth Factor/Creatinine Ratio and Graft Failure in Renal Transplant Recipients: A Prospective Cohort Study

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

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