Background: Chronic kidney disease (CKD) and low serum total testosterone (TT) concentrations are independent predictors of mortality risk in the general population, but their combined potential for improved mortality risk stratification is unknown. Methods: We used data of 1,822 men from the population-based Study of Health in Pomerania followed- up for 9.9 years (median). The direct effects of kidney dysfunction (estimated glomerular filtration rate <60 ml/min/ 1.73 m2), albuminuria (urinary albumin-creatinine ratio ≧2.5 mg/mmol) and their combination (CKD) on all-cause and cardiovascular mortality were analyzed using multivariable Cox regression models. Serum TT concentrations below the age-specific 10th percentile (by decades) were considered low and were used for further risk stratification. Results: Kidney dysfunction (hazard ratio, HR, 1.40; 95% confidence interval, CI, 1.02–1.92), albuminuria (HR, 1.38; 95% CI, 1.06–1.79), and CKD (HR, 1.42; 95% CI, 1.09–1.84) were associated with increased all-cause mortality risk, while only kidney dysfunction (HR, 2.01; 95% CI, 1.21–3.34) was associated with increased cardiovascular mortality risk after multivariable adjustment. Men with kidney dysfunction and low TT concentrations were identified as high-risk individuals showing a more than 2-fold increased all-cause mortality risk (HR, 2.52; 95% CI, 1.08–5.85). Added to multivariable models, nonsignificant interaction terms suggest that kidney dysfunction and low TT are primarily additive rather than synergistic mortality risk factors. Conclusion: In the case of early loss of kidney function, measured TT concentrations might help to detect high-risk individuals for potential therapeutic interventions and to improve mortality risk assessment and outcome.

Keywords:
Kidney disease, Total testosterone, Estimated glomerular filtration rate, Albuminuria, The Study of Health in Pomerania
1.
Weiner DE: Public health consequences of chronic kidney disease. Clin Pharmacol Ther 2009;86:566–569.
2.
Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, Garg AX: Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol 2006;17:2034–2047.
3.
Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT: Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010;375:2073–2081.
4.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. New Engl J Med 2004;351:1296–1305.
5.
Handelsman DJ: Hypothalamic-pituitary gonadal dysfunction in renal failure, dialysis and renal transplantation. Endocr Rev 1985;6:151–182.
6.
Albaaj F, Sivalingham M, Haynes P, McKinnon G, Foley RN, Waldek S, O’Donoghue DJ, Kalra PA: Prevalence of hypogonadism in male patients with renal failure. Postgrad Med J 2006;82:693–696.
7.
Handelsman DJ, Dong Q: Hypothalamo-pituitary gonadal axis in chronic renal failure. Endocrinol Metab Clin North Am 1993;22:145–161.
8.
Haring R, Volzke H, Steveling A, Krebs A, Felix SB, Schofl C, Dorr M, Nauck M, Wallaschofski H: Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20–79. Eur Heart J 2010;31:1494–1501.
9.
Carrero JJ, Qureshi AR, Nakashima A, Arver S, Parini P, Lindholm B, Barany P, Heimburger O, Stenvinkel P: Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease. Nephrol Dial Transplant 2011;26:184–190.
10.
Carrero JJ, Qureshi AR, Parini P, Arver S, Lindholm B, Barany P, Heimburger O, Stenvinkel P: Low serum testosterone increases mortality risk among male dialysis patients. J Am Soc Nephrol 2009;20:613–620.
11.
Dörr M, Wallaschofski H, Friedrich N: Association of low total testosterone levels and prevalent carotid plaques: result of the Study of Health in Pomerania. Eur J Epidemiol 2009;24:389–391.
12.
Haring R, Volzke H, Felix SB, Schipf S, Dorr M, Rosskopf D, Nauck M, Schofl C, Wallaschofski H: Prediction of metabolic syndrome by low serum testosterone levels in men: results from the Study of Health in Pomerania. Diabetes 2009;58:2027–2031.
13.
Maggio M, Basaria S: Welcoming low testosterone as a cardiovascular risk factor. Int J Impot Res 2009;21:261–264.
14.
Volzke H, Alte D, Schmidt CO, Radke D, Lorbeer R, Friedrich N, Aumann N, Lau K, Piontek M, Born G, Havemann C, Ittermann T, Schipf S, Haring R, Baumeister SE, Wallaschofski H, Nauck M, Frick S, Arnold A, Junger M, Mayerle J, Kraft M, Lerch MM, Dorr M, Reffelmann T, Empen K, Felix SB, Obst A, Koch B, Glaser S, Ewert R, Fietze I, Penzel T, Doren M, Rathmann W, Haerting J, Hannemann M, Ropcke J, Schminke U, Jurgens C, Tost F, Rettig R, Kors JA, Ungerer S, Hegenscheid K, Kuhn JP, Kuhn J, Hosten N, Puls R, Henke J, Gloger O, Teumer A, Homuth G, Volker U, Schwahn C, Holtfreter B, Polzer I, Kohlmann T, Grabe HJ, Rosskopf D, Kroemer HK, Kocher T, Biffar R, John U, Hoffmann W: Cohort Profile: The Study of Health in Pomerania. Int J Epidemiol, Epub ahead of print.
15.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461–470.
16.
de Jong PE, Curhan GC: Screening, monitoring, and treatment of albuminuria: public health perspectives. J Am Soc Nephrol 2006;17:2120–2126.
17.
K/DOQI clinical practice guidelines for chronic kidney disease evaluation, classification and stratification. Am J Kidney Dis 2002;39:S1–S266.
18.
Friedrich N, Volzke H, Rosskopf D, Steveling A, Krebs A, Nauck M, Wallaschofski H: Reference ranges for serum dehydroepiandrosterone sulfate and testosterone in adult men. J Androl 2008;29:610–617.
19.
Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Bacquer D, Ducimetiere P, Jousilahti P, Keil U, Njolstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H, Tverdal A, Wedel H, Whincup P, Wilhelmsen L, Graham IM: Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003;24:987–1003.
20.
Afifi AA, Kotlerman JB, Ettner SL, Cowan M: Methods for improving regression analysis for skewed continuous or counted responses. Annu Rev Public Health 2007;28:95–111.
21.
Solling K, Christensen CK, Solling J, Christiansen JS, Mogensen CE: Effect on renal haemodynamics, glomerular filtration rate and albumin excretion of high oral protein load. Scand J Clin Lab Invest 1986;46:351–357.
22.
Corona G, Boddi V, Balercia G, Rastrelli G, De Vita G, Sforza A, Forti G, Mannucci E, Maggi M: The effect of statin therapy on testosterone levels in subjects consulting for erectile dysfunction. J Sex Med 2010;7:1547–1556.
23.
Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS: Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27:157–172.
24.
Hallan S, Astor B, Romundstad S, Aasarod K, Kvenild K, Coresh J: Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: The HUNT II Study. Arch Intern Med 2007;167:2490–2496.
25.
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM: Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536–2559.
26.
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR: Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724–731.
27.
McLachlan RI: Certainly more guidelines than rules. J Clin Endocrinol Metab 2010;95:2610–2613.
28.
Haring R, Ittermann T, Volzke H, Krebs A, Zygmunt M, Felix SB, Grabe HJ, Nauck M, Wallaschofski H: Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the Study of Health in Pomerania. Aging Male 2010;13:247–257.
29.
Haring R, Baumeister SE, Völzke H, Dorr M, Felix SB, Kroemer HK, Nauck M, Wallaschofski H: Prospective association of low total testosterone concentrations with an adverse lipid profile and increased incident dyslipidemia. Eur J Cardiovasc Prev Rehabil 2010, Epub ahead of print.
30.
Haring R, Baumeister SE, Volzke H, Kohlmann T, Marschall P, Flessa S, Nauck M, Wallaschofski H: Prospective association of low serum total testosterone levels with health care utilization and costs in a population-based cohort of men. Int J Androl 2010;33:800–809.
31.
Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N: Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 2007;116:2694–2701.
32.
Laughlin GA, Barrett-Connor E, Bergstrom J: Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008;93:68–75.
33.
Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellstrom D, Ohlsson C: Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab 2009;94:2482–2488.
34.
Yi S, Selvin E, Rohrmann S, Basaria S, Menke A, Rifai N, Guallar E, Platz EA, Astor B: Endogenous sex steroid hormones and measures of chronic kidney disease (CKD) in a nationally representative sample of men. Clin Endocrinol (Oxf) 2009;71:246–252.
35.
Fortepiani LA, Yanes L, Zhang H, Racusen LC, Reckelhoff JF: Role of androgens in mediating renal injury in aging SHR. Hypertension 2003;42:952–955.
36.
Reckelhoff JF, Yanes LL, Iliescu R, Fortepiani LA, Granger JP: Testosterone supplementation in aging men and women: possible impact on cardiovascular-renal disease. Am J Physiol Renal Physiol 2005;289:F941–F948.
37.
Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S: Adverse events associated with testosterone administration. New Engl J Med 2010;363:109–122.
38.
Fernandez-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos-Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM: Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010;95:2560–2575.
39.
Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, De Zeeuw D, Hostetter TH, Lameire N, Eknoyan G: Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2005;67:2089–2100.
40.
Weiner DE, Krassilnikova M, Tighiouart H, Salem DN, Levey AS, Sarnak MJ: CKD classification based on estimated GFR over three years and subsequent cardiac and mortality outcomes: a cohort study. BMC Nephrol 2009;10:26.
41.
Liu PY, Death AK, Handelsman DJ: Androgens and cardiovascular disease. Endocr Rev 2003;24:313–340.
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