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Doi:10.1016/j.semnephrol.2005.09.009Diabetes mellitus (DM) is becoming more common in the United States affecting anestimated 18.2 million Americans. Not only is the number of American’s with DM stagger-ing, but so are the medical and economic costs of DM. DM accounts for nearly 15% of allhealth care costs in the United The chronic hyperglycemia of DM is associatedwith long-term damage, dysfunction and failure of multiple organ systems, including thegenitourinary system. Genitourinary complications are common among diabetics. Of indi-viduals diagnosed with DM, 80% have lower urinary tract complications, while 50%develop nephropathy and 35-75% develop sexual dysfunction. In order to decrease thenumber and severity of diabetic urologic complications, early recognition and a morecomprehensive understanding of how diabetes impacts the genitourinary tract isimperative.
Semin Nephrol 26:182-185 2006 Elsevier Inc. All rights reserved.
KEYWORDS Diabetes mellitus, genitourinary complications, nephropathy, cystopathy, sexual
Diabetes mellitus (DM) is becoming more common in complicationsarecommonamongdiabeticpatients.Ofindi- the United States. From 1980 to 2003, the number of viduals diagnosed with DM, 80% have lower urinary tract Americans with diabetes more than doubled (from 5.8 complications, 50% develop nephropathy, and 35% to 75% million to 13.8 million). The Center for Disease Control develop sexual dysfunction. In this article the urologic com- estimates that 18.2 million Americans, 6.3% of the popu- lation, have DM. Of the 18.2 million, 5.2 million are un-diagnosed. Not only is the number of Americans with DMstaggering, but so are the medical and economic costs of Diabetic Cystopathy
DM. DM accounts for nearly 15% of all health care costs in More than 50% of diabetic patients have bladder dysfunc- the United The National Institutes of Health-Na- Classically, diabetic bladder dysfunction had been tional Institute for Diabetes and Digestive and Kidney Dis- called diabetic cystopathy, a constellation of clinical and uro- eases Bladder Research Progress Review Group’s August dynamic findings associated with long-term DM. Diabetic 2002 report noted that “because diabetes significantly al- cystopathy is characterized by decreased bladder sensation, ters the urinary tract, a large portion of people who have increased bladder capacity, impaired detrusor contractility, this disease will develop costly and debilitating urologic and increased residual However, more recent re- complications. . .Unfortunately, the mechanisms involved search suggests that diabetic bladder dysfunction is a pro- are poorly understood. The paucity of knowledge has been gressive condition with a spectrum of clinical findings and a barrier to developing the best methods of prevention and Some studies support the classic findings of diabetic cys- The chronic hyperglycemia of DM is associated with long- topathy whereas others do not. Ueda et and Frimodt- term damage, dysfunction, and failure of multiple organ sys- Moller et consistently found increased bladder volume at tems, including the genitourinary system. Genitourinary first sensation to void and a decrease in detrusor contractility,resulting in increased residual urine, in diabetic patients. Incontrast, a number of clinical studies have reported bladder From the Center for Female Pelvic Medicine and Reconstructive Surgery, instability as the most common finding among diabetic pa- Glickman Urological Institute, The Cleveland Clinic Foundation, Cleve- tients. In a study of 182 diabetic patients, Kaplan et found 55% to have detrusor instability whereas only 23% had im- Address reprint requests to Firouz Daneshgari, Glickman Urological Insti- tute/A100, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleve- paired contractility. A study by Starer and elderly diabetic patients showed similar results with 76% of diabetic 0270-9295/06/$-see front matter 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.semnephrol.2005.09.009 Diabetic uropathy
patients showing involuntary bladder contractions. These hyperglycemia results in increased polyol pathway flux, in- studies suggest that diabetes causes different types of bladder creased hexoamine pathway flux, activation of the cytokine dysfunction with diabetic cystopathy being only one of the transcription factor nuclear factor B, increased advanced conditions found along the spectrum of diabetic bladder dys- glycation end-product formation, stimulation of angiotensin function. Therefore, the International Continence Society II synthesis, and activation of the protein kinase C recommended the term diabetic bladder dysfunction to de- All of these pathways cause an overproduction of reactive scribe the problems of storage, voiding, or both that occur in The clinical and histopathologic changes associated with Diabetic bladder dysfunction has been attributed to several type I diabetic nephropathy are classified into 5 causes including autonomic axonopathy, diuresis-induced These changes are present in variable degrees in patients with myopathy, metabolic alterations in adrenergic and cholin- type 2 Stage I is characterized by an increase in ergic receptors in detrusor smooth muscle, and oxidative glomerular filtration rate and renal hypertrophy. In stage II stress leading to smooth muscle damage and there is an increase in glomerular basement membrane thick- Diabetic bladder dysfunction can lead to secondary com- ness and mesangial matrix volume Stage III is plications including recurrent or atypical urinary tract infec- characterized by microalbuminuria and an increase in blood tions that are assumed to originate from increased postvoid pressure. Stage IV is overt diabetic nephropathy. Stage V is residuals. Other complications include pyelonephritis, ESRD, characterized by minimal residual renal function re- nephrolithiasis, urinary retention, hydrourteronephrosis, Diabetic nephropathy, although present in 50% of diabetic patients, does not occur in all diabetic patients. Therefore, Diabetic Nephropathy
the identification of modifiable risk factors is important inpreventing disease progression. These modifiable risk factors Diabetic nephropathy is the most common single cause of include hypertension, poor glycemic control, smoking, dys- renal insufficiency in the United States, Japan, and lipidemia, dietary factors, and proteinuria and has been defined classically by proteinuria of more than0.5 g/24 Between 1994 and 1999, 43.7% of US Sexual Dysfunction
patients receiving treatment for end-stage renal disease(ESRD) had renal failure as a result of diabetic The incidence of erectile dysfunction (ED) among diabetic In 2000, the Medicare and non-Medicare expenditures for men ranges from 27% to 75%, depending on the patient’s age the treatment of renal failure totaled $19.35 billion; half of and duration of In a cohort study of more than which was used for the treatment of patients with 31,000 men aged 53 to 90 years, the age-adjusted relative ESRD is a significant cause of morbidity and mortality among risk for ED among diabetic men compared with men without diabetic patients. Diabetic patients on dialysis have signifi- diabetes was Among diabetic men the relative risk cantly lower survival rates compared with patients with for ED increases with poor glycemic control, duration of ESRD from hypertension, glomerulonephritis, and other diabetes, and the number of nonurologic complications such Diabetic nephropathy is more prevalent among African Risk factors associated with an increased risk for ED in- Americans, Mexican Americans, Native Americans, and clude hypertension, dyslipidemia, coronary artery disease, Asians than Epidemiologic and familial stud- smoking, older age, higher body mass index, and lower uri- ies of patients with both type I and II DM have shown a genetic susceptibility to the development of diabetic ne- The etiology of diabetic ED is multifactorial. Neuropathic, vascular, psychogenic, and pharmacologic factors all play a Diabetic nephropathy causes unique structural changes of the glomeruli, tubules, extraglomerular blood vessels, and Erections occur as a result of cavernosal smooth muscle the The earliest histologic change is thick- relaxation with resultant increased blood flow into the sinu- ening of the glomerular basement This occurs soids. Nitric oxide released from nonadrenergic noncholin- early in the disease, 1 year after the onset of diabetes, and is ergic nerves and endothelial cells is required to induce cav- As the disease progresses, there is expansion of ernosal smooth muscle relaxation. In diabetic men, the mesangial This is caused by an accumulation of neurogenic and endothelial-mediated smooth muscle relax- extracellular matrix deposition and mesangial cell hypertro- ation is impaired secondary to abnormal levels of nitric oxide Several studies have shown an inverse relationship synthase, nitric oxide, cyclic guanosine monophosphate, and between the glomerular filtration rate and mesangial expan- protein Several animal studies have shown dimin- Tubular and interstitial changes follow as a result of ished nitric oxide and nitric oxide synthase in cells grown in Despite its frequency and importance, the pathophysiol- Treatment options for diabetic men with ED are similar to ogy underlying diabetic nephropathy is incompletely under- those for nondiabetic men. Vacuum-constriction devices of- stood. On a molecular level, at least 5 pathways have been fer a noninvasive option effective in 70% of patients with implicated in histologic changes induced by DM. Chronic DM.Complications such as petechiae, ecchymoses, and F. Daneshgari and C. Moore
hematomas can be seen if the device is used for more than 30 Several recent large-scale studies showed that diabetes was Along with control of hyperglycemia, oral agents associated with a 30% to 80% increased risk for urinary in- are the first line of therapy for ED in patients with DM. Oral with the risk for urge incontinence (storage agents such as Viagra (Pfizer, Inc., New York) have been problem) increased by 40% to 80% in a multivariate analysis shown to be efficacious in diabetic patients. The first study to that controlled for stroke and other chronic medical condi- look at the effect of Viagra in diabetic patients found 50% and 52% of diabetic patients treated with 25 and 50 mg, respec-tively, had improvement in In a subsequent mul- Conclusions
ticenter, randomized, double-blind, placebo-controlledstudy, 56% of patients taking sildenafil reported improved Diabetes mellitus is a growing health problem worldwide.
The efficacy of sildenafil was not affected by pa- With more than 18 million people affected, the cost to the tient age, the duration of ED, or the duration of The health care system and patients quality of life is overwhelm- newer phosphodiesterase 5 inhibitors, vardenafil and ing. Urologic complications such as bladder dysfunction, ne- tadalafil, have shown equal efficacy in diabetic phropathy, and sexual dysfunction are common among dia- Intraurethral suppositories and intracavernous injections betic patients, both male and female. To decrease the number also have been proven to be effective in diabetic pa- and severity of diabetic urologic complications, early recog- The rate-limiting factor for both therapies are nition and a more comprehensive understanding of how di- side effects. Intraurethral suppositories are associated with abetes impacts the genitourinary tract is imperative.
penile pain and urethral bleeding, whereas injection therapyhas been associated with painful penile sensation, fibroticchanges in the corporeal body, and priapism.
Surgical therapy including penile implants and revascular- 1. Krishnamurthi V, Hijaz AH, Daneshgari F: Urological manifestations of ization typically are reserved for patients who fail all previous 2. Brown JS, Wessells H, Chancellor MB, et al: Urologic complications of Similar to male sexual dysfunction, female sexual dysfunc- diabetes. Diabetes Care 28(1):177-185, 2005 3. Kaplan SA, Te AE, Blaivas JG: Urodynamic findings in patients with tion (FSD) is highly prevalent among female diabetic pa- diabetic cystopathy. J Urol 153(2):342-344, 1995 tients. Eighteen percent to 27% of women with type I and 4. Sasaki K, Yoshimura N, Chancellor MB: Implications of diabetes mel- 42% of women with type II diabetes report Female litus in urology. Urol Clin North Am 30(1):1-12, 2003 diabetic patients have a 2-fold greater prevalence of FSD 5. Ueda T, Yoshimura N, Yoshida O: Diabetic cystopathy: Relationship to compared with nondiabetic Yet unlike diabetic autonomic neuropathy detected by sympathetic skin response. J Urol157(2):580-584, 1997 male sexual dysfunction, little is known about the patho- 6. Frimodt-Moller C: Diabetic cytopathy. A review of the urodynamic and physiology or treatment of FSD in diabetic patients. Recent clinical features of neurogenic bladder dysfunction in diabetes mellitus.
animal studies have shown that similar to male ED, diabetic women with FSD had impaired relaxant responses of vaginal 7. Starer P, Libow L: Cystometric evaluation of bladder dysfunction in elderly diabetic patients. Arch Intern Med 150(4):810-813, 1990 8. Abrams P, Cardozo L, Fall M, et al: The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub- Urinary Incontinence in Women
committee of the International Continence Society. Neurourol Urodyn21(2):167-178, 2002 Several reports indicated that women with either type I or II 9. Beshay E, Carrier S: Oxidative stress plays a role in diabetes-induced DM have a higher prevalence of lower urinary tract compli- bladder dysfunction in a rat model. Urology 64(5):1062, 2004 10. Wolf G: New insights into the pathophysiology of diabetic nephropa- cations, including urinary incontinence. In several large ob- thy: From haemodynamics to molecular pathology. Eur J Clin Invest servational studies, DM was identified as an independent risk factor for urinary incontinence. In 2,763 postmenopausal 11. Gross JL, de Azevedo MJ, Silveiro SP, et al: Diabetic nephropathy: women the prevalence of stress, urge, and mixed urinary Diagnosis, prevention, and treatment. Diabetes Care 28(1):164, 2005 incontinence was significantly higher in diabetic women 12. Knowler WC, Coresh J, Elston RC, et al: The Family Investigation of Nephropathy and Diabetes (FIND): Design and methods. J Diabetes In a recent cross-sectional analysis of a population-based 13. Canani LH, Gerchman F, Gross JL: Familial clustering of diabetic ne- study of 1,017 postmenopausal women aged 55 to 75 years, phropathy in Brazilian type 2 diabetic patients. Diabetes 48(4):909, 60% of all women reported incontinence in the past month, with 8% having severe Women with diabetes 14. Bacon CG, Hu FB, Giovannucci E, et al: Association of type and dura- tion of diabetes with erectile dysfunction in a large cohort of men.
reported disproportionately more severe incontinence, diffi- culty controlling urination, mixed incontinence, use of pads, 15. Brown JS, Luft J: Women & diabetes. Urinary incontinence. Diabetes inability to empty the bladder completely, being unaware of leakage, and discomfort with urination (P ϭ Diabetes 16. Price DE, Cooksey G, Jehu D, et al: The management of impotence in duration, treatment type, peripheral neuropathy, and reti- diabetic men by vacuum tumescence therapy. Diabet Med 8:964, 1991 17. Price DE, Gingell JC, Gepi-Attee S, et al: Sildenafil: Study of a novel oral nopathy were associated significantly with severe inconti- treatment for erectile dysfunction in diabetic men. Diabet Med 15(10): nence in a multiple regression model adjusting for age, edu- cation, and history of urinary tract infection (P ϭ 18. Rendell MS, Rajfer J, Wicker PA, et al: Sildenafil for treatment of erectile Diabetic uropathy
dysfunction in men with diabetes: A randomized controlled trial.
24. Giraldi A, Persson K, Werkstrom V, et al: Effects of diabetes on neuro- Sildenafil Diabetes Study Group. JAMA 281(5):421-426, 1999 transmission in rat vaginal smooth muscle. Int J Impot Res 13(2):58- 19. Pryor J. Vardenafil: Update on clinical experience. Int J Impot Res 25. Brown JS, Grady D, Ouslander JG, et al: Prevalence of urinary inconti- 20. Saenz de Tejada I, Angulo J, Cuevas P, et al: The phosphodiesterase nence and associated risk factors in postmenopausal women. Heart & inhibitory selectivity and the in vitro and in vivo potency of the new Estrogen/Progestin Replacement Study (HERS) Research Group. Ob-stet Gynecol 94(1):66-70, 1999 PDE5 inhibitor vardenafil. Int J Impot Res 13(5):282-290, 2001 26. Jackson SL, Scholes D, Boyko EJ, et al: Urinary incontinence and dia- 21. Hakim LS, Goldstein I: Diabetic sexual dysfunction. Endocrinol Metab betes in postmenopausal women. Diabetes Care 28(7):1730-1738, 22. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al: Treatment of men 27. Diokno AC, Brock BM, Herzog AR, et al: Medical correlates of urinary with erectile dysfunction with transurethral alprostadil. Medicated incontinence in the elderly. Urology 36(2):129-138, 1990 Urethral System for Erection (MUSE) Study Group. N Engl J Med 28. Hunter KF, Moore KN: Diabetes-associated bladder dysfunction in the older adult (CE). Geriatr Nurs 24(3):138-145, 2003 23. Valdevenito R, Melman A: Intracavernous self-injection pharmacother- 29. Wetle T, Scherr P, Branch LG, et al: Difficulty with holding urine apy program: Analysis of results and complications. Int J Impot Res among older persons in a geographically defined community: Preva- lence and correlates. J Am Geriatr Soc 43(4):349-355, 1995
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