hroughout the industrialized world, diabetes mellitus is the the prevalence of ESRD caused by diabetes have risen each year over …
Diabetic Nephropathy: Impact of Comorbidity
Eli A Friedman
T
hroughout the industrialized world, diabetes mellitus is the leading cause of end-stage renal disease ESRD, surpassing glomerulonephritis and hypertension Both the incidence and the prevalence of ESRD caused by diabetes have risen each year over the past decade, according to reports from European, Japanese, and North American registries of patients with renal failure Illustrating the dominance of diabetes in ESRD is the 1997 report of the United States Renal Data System USRDS, which noted that of 257,266 patients receiving either dialytic therapy or a kidney transplant in 1995 in the United States, 80,667 had diabetes [1], a prevalence rate of 314 Also, during 1995 the most recent year for which summative data are available, of 71,875 new incident cases of ESRD, 28,740 40 patients were listed as having diabetes In America, Europe, and Japan, the form of diabetes is predominantly type II; fewer than 8 of diabetic Americans are insulinopenic, C-peptide-negative persons with type I disease It follows that ESRD in diabetic persons reflects the demographics of diabetes per se [2]: 1 The incidence is higher in women [3],
blacks [4], Hispanics [5], and native Americans [6] 2 The peak incidence of ESRD occurs from the fifth to the seventh decade Consistent with these attack rates is the fact that blacks older than the age of 65 face a seven times greater risk of diabetes-related renal failure than do whites Within our Brooklyn and New York state hospital ambulatory hemodialysis units in October 1997, 97 of patients had type II diabetes Despite widespread thinking to the contrary, vasculopathic complications of diabetes, including hypertension, are at least as severe in type II as in type I diabetes [7,8] When carefully followed over a decade or longer, cohorts of type I and type II diabetic individuals have equivalent rates of proteinuria, azotemia, and ultimately ESRD Both types of diabetes show strong similarities in their rate of renal functional deterioration [9] and onset of comorbid complications Initial nephromegaly as well as both glomerular hyperfiltration and microalbuminuria previously thought to be limited to type I is now recognized as equally in type II [10]
CHAPTER
1
12
Systemic Diseases and the Kidney
Overview and Prevalence
DIABETIC NEPHROPATHY
Epidemiology IDDM vs NIDDM Natural
history Intervention measures ESRD options Promising strategies
FIGURE 1-1 Diabetic neuropathy topics People with diabetes and progressive kidney disease are more difficult to manage than age- and gender-matched nondiabetic persons because of extensive, often life-threatening extrarenal comorbid disease Diabetic patients manifesting end-stage renal disease ESRD suffer a higher death rate than do nondiabetic patients with ESRD owing to greater incidence rates for cardiac decompensation, stroke, sepsis, and pulmonary disease Concurrent extrarenal disease–especially blindness, limb amputations, and cardiac disease–limits and may preempt their rehabilitation For most diabetic patients with ESRD, the difference between rehabilitation and heartbreaking invalidism hinges on attaining a renal transplant as well as comprehensive attention to comorbid conditions Gradually, over a quarter century, understanding of the impact of diabetes on the kidney has followed elucidation of the epidemiology, clinical course, and options in therapy available for diabetic individuals who progress to ESRD For each of the discussion points listed, improvement in patient outcome has been contingent on a
simple counting point prevalence of the number of individuals under consideration For example, previously the large number of diabetic patients with ESRD were excluded from therapy owing to the belief that no benefit would result A reexamination of exactly why dialytic therapy or kidney transplantation failed in diabetes, however, was stimulated IDDM–insulin dependent diabetes mellitus; NIDDM–noninsulin-dependent diabetes mellitus FIGURE 1-2 Maintenance hemodialysis In the United States, the large majority more than 80 of diabetic persons who develop end-stage renal disease ESRD will be treated with maintenance hemodialysis Approximately 12 of diabetic persons with ESRD will be treated with peritoneal dialysis, while the remaining 8 will receive a kidney transplant A typical hemodialysis regimen requires three weekly treatments lasting 4 to 5 hours each, during which extracorporeal blood flow must be maintained at 300 to 500 mL/min Motivated patients trained to perform self-hemodialysis at home gain the longest survival and best rehabilitation afforded by any dialytic therapy for diabetic ESRD When given hemodialysis at a facility, however, diabetic patients fare less well,
receiving significantly less dialysis than nondiabetic patients, owing in part to hypotension and reduced blood flow [11] Maintenance hemodialysis does not restore vigor to diabetic patients, as documented by Lowder and colleagues [12] In 1986, they reported that of 232 diabetics on maintenance hemodialysis, only seven were employed, while 649 were unable to conduct routine daily activities without assistance 
[12] Approximately 50 of diabetic patients begun on maintenance hemodialysis die within 2 years of their first dialysis session Diabetic hemodialysis patients sustained more total, cardiac, septic, and cerebrovascular deaths than did nondiabetic patients When initially applied to diabetic patients with ESRD in the 1970s, maintenance hemodialysis was associated with a first-year mortality in excess of 75, with inexorable loss of vision in survivors Until the at-first-unappreciated major contribution of type II diabetes to ESRD became evident, kidney failure was incorrectly viewed as predominantly limited to the last stages of type I juvenile, insulin-dependent diabetes Illustrated here is a blind 30-year-old man undergoing maintenance hemodialysis after experiencing 20 years of
type I diabetes A diabetic renal-retinal syndrome of blindness and renal failure was thought to be inevitable until the salutary effect of reducing hypertensive blood pressure became evident Without question, reduction of hypertensive blood pressure levels was the key step that permitted improvement in survival and reduction in morbidity
Diabetic Nephropathy: Impact of Cormorbidity
13
28,740
Diabetes 40
43,135 All other 60
FIGURE 1-3 Statistical increase in diabetes In the past 20 years, since the diabetic patient with endstage renal disease ESRD is no longer excluded from dialytic therapy or kidney transplantation, there has been a steady increase in the proportion of all patients with ESRD who have diabetes In the United States, according to the 1997 report of the United States Renal Data System USRDS for the year 1995, more than 40 of all newly treated incident patients with ESRD have diabetes For perspective, the USRDS does not list the actual incidence of a renal disease but rather tabulates those individuals who have been enrolled in federally reimbursed renal programs The distinction may be important in that a relaxation in policy for referral of diabetic kidney
patients would be indistinguishable from a true increase in incidence
25 Prevalence of diabetes, 20 15 10 5 0 4 9
Country of origin United States
23 18 15 10 7 8 15 16 19
PERCENTAGE OF PATIENTS WITH END-STAGE RENAL DISEASE WITH TYPE II DIABETES
Country
Japan Germany United States Pima Indians
18 14
Percentage
99 90 95
5
Black Mexican Puerto Rican
Japanese Filipinos Chinese
Koreans
FIGURE 1-4 Prevalence of diabetes mellitus in minority populations Attack rates incidence for diabetes are higher in nonwhite populations than in whites Type II diabetes accounts for more than 90 of all patients with end-stage renal disease ESRD with diabetes As studied by Carter and colleagues [13], the effect of improved nutrition on expression of diabetes is remarkable The American diet not only induces an increase in body mass but also may more than double the expressed rate of diabetes, especially in Asians From Carter and coworkers [13]; with permission
FIGURE 1-5 Percent of diabetic ESRD Noted first in United States inner-city dialysis programs, type II diabetes is the predominant variety noted in those individuals undergoing maintenance hemodialysis Our recent survey of hemodialysis
units in Brooklyn, New York, found that 97 of the mainly African-American patients had type II diabetes Thus, there has been a reversal of the previously held impression that uremia was primarily a late manifestation of type I diabetes From Ritz and Stefanski [14] and Nelson and coworkers [15]; with permission
Infrequent feeding
Overfeeding
Insulin resistance
Obesity
Fat in muscle NIDDM
FIGURE 1-6 Thrifty gene In addition to the artificial increase in incident patients with end-stage renal disease ESRD and diabetes that followed relaxation of acceptance criteria, industrialized nations have experienced a real increase in type II diabetes that correlates with an increase in body mass attributed to overfeeding Formerly
termed noninsulin-dependent diabetes mellitus NIDDM or maturity-onset diabetes, the variety of diabetes observed in industrialized overfed populations is now classified as type II disease According to the Thrifty Gene hypothesis, the ability to survive extended fasts in prehistoric populations that hunted to survive selected genes that in time of excess caloric intake are expressed as hyperglycemia, insulin resistance, and hyperlipidemia type II diabetes A study
by Ravussin and colleagues of American and Mexican Pima Indian tribes illustrates the effect of overfeeding on a genetic predisposition to type II diabetes Separated about 200 years ago, Indians with the same genetic makeup began living in different areas with different lifestyles and diets In the Arizona branch of the Pimas, who were fed surplus food and restrained to a reservation that restricted hunting and other activities, the prevalence of type II diabetes progressively increased to 37 in women and 54 in men In contrast, Pimas living in Mexico with shorter stature, lower body mass, and lower cholesterol had a lower prevalence of type II diabetes 11 in women and 6 in men From Shafrir [16] and Schalin-Jantti [17]; with permission
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