Serum Uromodulin in Children and Adolescents with Type 1 Diabetes Mellitus and Controls: Its Potential Role in Kidney Health

Abstract

Introduction Uromodulin is a kidney-specific tubular protein, and its assessment in serum (sUMOD) reveals the potential as a novel marker for function and the integrity of renal parenchymal cells and does not directly depend on the glomerular filtration rate. Early diabetic nephropathy parallels glomerular hyperfiltration, often leading to diagnostic misinterpretation. Moreover, traditional kidney function markers are not able to diagnose structural lesions. Recent data show that sUMOD is linked to glucose intolerance in adults. Thus, we launched to assess the hypothesis that sUMOD is also associated with kidney function, biometric data, and quality of metabolic control in children/adolescents with type 1 diabetes.

Patients and methods Patients with type 1 diabetes (n=135) and healthy controls (n=69) were recruited to participate in the trial. Clinical, biometrical data, sUMOD, and other laboratory parameters were assessed.

Results The mean concentrations of sUMOD in diabetic patients and controls were comparable (201.19±103.22 vs. 198.32±84.27 ng/mL, p=0.832). However, in contrast to healthy controls, sUMOD levels in patients with diabetes were associated with serum-creatinine (r=−0.368, p<0.0001), age (r=−0.350, p<0.0001), height (r=−0.379, p<0.0001), body weight (r=−0.394, p<0.0001), Body mass index (r=−0.292, p=0.001), daily insulin dosage (r=−0.300, p<0.0001), HbA1c (%) (r=−0.190, p=0.027), standardized HbA1c/IFCC (mmol/mol) (r=−0.189, p=0.028), and systolic (r=−0.299, p<0.0001) and diastolic (r=−0.235, p=0.006) arterial blood pressure.

Conclusions Our study shows that children/adolescents with type 1 diabetes disclose similar sUMOD concentrations as healthy controls. Serum UMOD appears to indicate higher risks for kidney tissue remodeling and possibly subsequent cardiovascular alterations. However, further studies are mandatory to settle these findings.

Key words

Serum uromodulin - ELISA - kidney biomarker - juvenile type 1 diabetes - risk assessment

Publikationsverlauf

Eingereicht: 08. April 2021
Eingereicht: 05. August 2022

Angenommen: 14. September 2022

Accepted Manuscript online:
14. September 2022

Artikel online veröffentlicht:
13. Dezember 2022

• References

• 1 Jepson C, Hsu JY, Fischer MJ. et al. Incident type 2 diabetes among individuals with CKD: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study. Am J Kidney Dis 2019; 73: 72-81
• 2 Thomas MC, Cooper ME, Zimmet P.. Changing epidemiology of type 2 diabetes mellitus and associated kidney disease. Nat Rev Nephrol 2016; 12: 73-81
• 3 Koye DN, Magliano DJ, Nelson RG. et al. The global epidemiology of diabetes and kidney disease. Adv Chronic Kidney Dis 2018; 25: 121-132
• 4 Frei U, Schober-Halstenberg HJ.. Nierenersatztherapie in Deutschland. Bericht über dialysebehandlung und nierentransplantation in Deutschland 2006/2007. Berlin: QuaSi-Niere; 2008
• 5 Merker M, Bautsch BW, Ebert T. et al. Nephropathie bei diabetes. Diabetologie 2019; 14: S235-S239
• 6 Umanath K, Lewis JB.. Update on diabetic nephropathy: Core Curriculum 2018. Am Kidney Dis 2018; 71: 884-895
• 7 Magagnotti C, Zerbini G, Fermo I. et al. Identification of nephropathy predictors in urine from children with a recent diagnosis of type 1 diabetes. J Proteomics 2019; 193: 205-216
• 8 Raja P, Maxwell AP, Brazil DP.. The potential of albuminuria as a biomarker of diabetic complications. Cardiovasc Drugs Ther 2020;
• 9 Kaplan B, Schold J, Meier-Krische H-L.. Poor predictive value of serum creatinine for renal allograft loss. Am J Transplant 2003; 3: 1560-1566
• 10 Delanaye P, Cavalier E, Pottel H.. Serum creatinine: Not so simple!. Nephron 2017; 136: 302-308
• 11 Knight EL, Verhave JC, Spiegelman D. et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004; 65: 1416-1421
• 12 Brezis M, Rosen S.. Hypoxia of the renal medulla – its implications for disease. N Engl J Med 1995; 332: 647-655
• 13 Heyman SN, Rosenberger C, Rosen S.. Experimental ischemia–reperfusion: Biases and myths – the proximal vs. distal hypoxic tubular injury debate revisited. Kidney Int 2010; 77: 9-16
• 14 Devuyst O, Olinger E, Rampoldi L.. Uromodulin: From physiology to rare and complex kidney disorders. Nat Rev Nephrol 2017; 13: 525-544
• 15 Schaeffer C, Devuyst O, Rampoldi L.. Uromodulin: Roles in health and disease. Ann Rev Physiol 2021; 83: 477-501
• 16 Alesutan I, Luong TTD, Schelski N. et al. Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signaling. Cardiovasc Res 2021; 117: 930-941
• 17 Mo L, Huang HY, Zhu XH. et al. Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. Kidney Int 2004; 66: 1159-1166
• 18 Tokonami N, Takata T, Beyeler J. et al. Uromodulin is expressed in the distal convoluted tubule, where it is critical for regulation of the sodium chloride cotransporter NCC. Kidney Int 2018; 94: 701-715
• 19 Boder P, Mary S, Mark PB. et al. Mechanistic interactions of uromodulin with thick ascending limb: perspectives in physiology and hypertension. J Hypertens 2021; 39: 1490-1504
• 20 LaFavers KA, Macedo E, Garimella PS. et al. Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel. Sci Transl Med 2019; 11: eaaw3639
• 21 Scherberich JE, Gruber R, Nockher WA. et al. Serum uromodulin – A marker of kidney function and renal parenchymal integrity. Nephrol Dial Transplant 2018; 33: 284-295
• 22 Steubl D, Block M, Herbst V. et al. Urinary uromodulin independently predicts end-stage renal disease and rapid kindney function decline in a cohort of chronic kidney disease patients. Medicine 2019; 98: 21 (e15808)
• 23 Leiherer A, Muendlein A, Saely CH. et al. The value of uromodulin as a new serum marker to predict decline in renal function. J Hypertens 2018; 36: 110-118
• 24 Scherberich JE, Wolf G, Albers C. et al. Glomerular and tubular membrane antigens reflecting cellular adaptation in human renal failure. Kidney Int 1989; 36: S18-S51
• 25 Risch L, Lhotta K, Meier D. et al. The serum uromodulin level is associated with kidney function. Clin Chem Lab Med 2014; 52: 1755-1761
• 26 Then C, Then HL, Lechner A. et al. Serum uromodulin and decline of kidney function in older participants of the population-based KORA F4/FF4 study. Clin Kidney J 2021; 14: 205-211
• 27 Scheurlen KM, Billeter AT, Kopf S. et al. Serum uromodulin and Roux-en-Y gastric bypass: Improvement of a marker reflecting nephron mass. Surg Obes Relat Dis 2019; 15: 1319-1325
• 28 Cosentino F, Grant PJ, Aboyans V. et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020; 41: 255-323
• 29 Arbeitsgemeinschaft Adipositas im Kindes- und Jugendalter (AGA). Leitlinien. Verabschiedet auf der Konsensus-Konferenz der AGA am 10.09.04. HYPERLINK "http://www.a-g-a.de/" \t "_parent" http://www.a-g-a.de, 04.04.2013
• 30 Williams B, Mancia G, Spiering W. et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018; 39: 3021-3104
• 31 Meixner K, Glattacker M, Gerdes N. et al. Effects of treatment in mother-child rehabilitation centres. Rehabilitation (Stuttgart) 2001; 40: 280-288
• 32 The Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S. et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977-986
• 33 International Society of Nephrology 2012. International Society of Nephrology. KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013; 3. http://www.kidney-international.org, 03.04.2020
• 34 Enko D, Meinitzer A, Scherberich JE. et al. Individual uromodulin serum concentration is independent of glomerular filtration rate in healthy kidney donors. Clin Chem Lab Med 2020; 59: 563-570
• 35 El-Achkar TM, McCracken R, Rauchman M. et al. Tamm-Horsfall protein-deficient thick ascending limbs promote injury to neighboring S3 segments in an MIP-2-dependent mechanism. Am J Physiol Renal Physiol 2011; 300: F999-F1007
• 36 Tan RJ, Li Y, Rush BM. et al. Tubular injury triggers podocyte dysfunction by ß-catenin-driven release of MMP-7. JCI Insight 2019; 4: e122399
• 37 Wiromrat P, Bjornstad P, Roncal C. et al. Serum uromodulin inversely associates with aortic stiffness in youth with type 1 diabetes: A brief report from EMERALD study. J Diabetes Complications 2019; 33: 434-436
• 38 Van JAD, Clotet-Freixas S, Zhou J. et al. Peptidomic analysis of urine from youths with early type 1 diabetes reveals novel bioactivity of uromodulin peptides in vitro. Mol Cell Proteomics 2020; 19: 501-517
• 39 Then C, Then H, Meisingerr C. et al. Serum uromodulin is associated with but does not predict type 2 diabetes in elderly KORA F4/FF4 study participants. J Clin Endocrinol Metab 2019; jc.2018-02557
• 40 Youhanna S, Weber J, Beaujean V. et al. Determination of uromodulin in human urine: Influence of storage and processing. Nephrol Dial Transplant 2014; 29: 136-145