Diabetic Nephropathy: Impact of Comorbidity

Eli A. Friedman

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 31.4%. 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

1.2

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 diseaseespecially blindness, limb amputations, and cardiac diseaselimits 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. IDDMinsulin dependent diabetes mellitus; NIDDMnoninsulin-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 64.9% 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

1.3

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

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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Systemic Diseases and the Kidney

Type I and Type II Classified

IGT Type II Type I Proportion on insulin, %

C-PEPTIDE CRITERIA
70 60 50 40 30 20 10 0 05 510 1015 Years of NIDDM
13 33 60

Insulin requiring Type II decreased insulin secretion/sensitvity Type I -cell destruction

Type I (90% concordence between clinical criteria and C-peptide testing) Basal C-peptide <0.17 pmol/mL Increment above basal at 6 min <0.07 pmol/mL

FIGURE 1-7 Type I and type II compared. Differentiating type I from type II diabetes may be difficult, especially in young nonobese adults with minimal insulin secretion. Furthermore, with increasing duration of type II diabetes, beta cells may decrease their insulin secretion, sometimes to the range diagnostic of type I diabetes. Shown here is a modification of the schema devised by Kuzuya and Matsuda [18] that suggests a continuum of diabetes classification based on amount of insulin secreted. Lacking in this construction is the realization of the genetic determination of type I diabetes (all?) and the clear hereditary predisposition (despite inconstant genetic analyses) of many individuals with type II diabetes. At present, classification of diabetes is pragmatic and will likely change with larger-population screening studies. IGTimpaired glucose tolerance. (From Kuzuya and Matsuda [18]; with permission.)

FIGURE 1-8 Increasing insulin treatment in noninsulindependent diabetes mellitus (NIDDM). A decision to treat diabetes with insulin does not necessarily equate with establishing a diagnosis of type I diabetes. Terms such as insulin-requiring do not help because the need for insulin is physician-determined and will vary from clinician to clinician. After 10 to 15 years of metabolic regulation of type II diabetes, treatment with insulin has been initiated in more than half of individuals with this disorder. Even in patients with type II diabetes treated with insulin, measured secretion of insulin may fall in the normal range. (From Clauson and coworkers [19]; with permission.)

FIGURE 1-9 C-peptide criteria. Multiple strategies have been proposed to distinguish type I from type II diabetes. Each has limitations. Service and colleagues [20] employed baseline and stimulated C-peptide levels to differentiate between the two. They found satisfactory differentiation of type I from type II diabetes with minimal overlap using the screening levels shown. (From Service and coworkers [20]; with permission.)

TERMINOLOGY IN DIABETIC NEPHROPATHY

Hyperfiltration A supernormal glomerular filtration rate associated with hyperglycemia during the early years of diabetes Microalbuminuria Urinary albumin excretion of 30 to 300 mg/day or 20 to 200 g/mina predictor of nephropathy Mesangial expansion An increase in mesangial matrix often but not always associated with basement membrane thickening

FIGURE 1-10 Terminology. Clarification of the course of both types of diabetes was made possible by recognizing two functional perturbations: microalbuminuria and glomerular hyperfiltration. Additionally, early glomerular mesangial expansion was noted to be a constant finding in diabetic nephropathy.

Diabetic Nephropathy: Impact of Cormorbidity

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Clinical Features of Diabetic Kidney

FIGURE 1-11 Diabetic kidney characteristics. The diabetic kidney is about 140% greater in length, width, and weight. Morphologic findings on histologic examination of the kidney in diabetes include increased size of glomeruli and tubules. Physiologic assessment of renal function is supernormal in diabetes, as shown by increases of about 150% in renal plasma flow and glomerular filtration rate in initial phases of diabetic nephropathy. In the induced-diabetic rat and in limited observations of type I diabetes, establishing euglycemia will return enlarged kidneys and abnormal renal function test results to normal, suggesting that hyperglycemia is the cause of nephromegaly.

B
FIGURE 1-12 Mesangial expansion. Expansion of the mesangium is depicted in light and electron microscopic views of a kidney biopsy specimen from a patient with type I diabetes with a urinary albumin concentration of 500 mg/dL. A, Electron microscopic view of a greatly expanded mesangium in a glomerulus is shown. B, Less advanced changes are seen on a silver stain. C, Progression to nodular intercapillary glomerulosclerosis is shown.

1.6

Systemic Diseases and the Kidney

C
FIGURE 1-13 Glomerular basement membrane thickening. B and D, Glomerular basement membrane thickening is a constant abnormality in diabetic nephropathy, as seen in these photomicrographs from a biopsy specimen in type I diabetes. Note the loss of epithelial foot processes in

D
panel B. In panel D, a mesangial nodule (MN) is present. A and C, Electron photomicrographs from a normal kidney. BMbasement membrane; Ccapillary; Eepithelial cell; MNmesangial nodule; Mmesangial cell.

FIGURE 1-14 Diabetic nephropathy is a microvasculopathy. Microaneurysms are visible in the retina and occasionally in glomerular capillaries. A microaneurysm in a biopsy specimen from a 42-year-old woman with type I diabetes is shown.

FIGURE 1-15 Key pathologic findings. Nondiabetic renal disorders (eg, amyloidosis, cryoglobulinemia, nephrosclerosis) may simulate the nodular and diffuse intercapillary glomerulosclerosis of diabetes (both type I and type II). When associated with afferent and efferent arteriolosclerosis, nodular and diffuse intercapillary glomerulosclerosis is pathognomonic for diabetic nephropathy. Aafferent artery arteriosclerosis; Ddiffuse intercapillary glomerulosclerosis; Eefferent artery arteriosclerosis; Nnodular intercapillary glomerulosclerosis.

Diabetic Nephropathy: Impact of Cormorbidity

1.7

FIGURE 1-16 Diabetic nodules. Diabetic nodules are characterized by clear centers with cells along the periphery of the nodule, as shown here in a kidney biopsy specimen from a 44-year-old man with type II diabetes (hematoxylin and eosin stain).

FIGURE 1-17 Nodular size variability. Great variability in nodular size in diabetic nodular glomerulosclerosis is usual, as illustrated in this totally obliterated glomerulus obtained by biopsy from a 65-year-old woman with type II diabetes (periodic acidSchiff stain).

>4 4.0 3.5 Urinary albumin, g/d 3.0 2.5 2.0 1.5 1.0 0.5 0 0 3 6 9 12 15 18 Hyperglycemia, y 21 24 27
Clinical nephropathy

B
Typically, proteinuria increases to the nephrotic range, leading to edema of the extremities and subsequent anasarca, which are often the presenting complaints in diabetic nephropathy.

FIGURE 1-18 A and B, Progression of nephropathy. Microalbuminuria, the excretion of minute quantities of albumin in the urine (more than 20 mg/day), is a marker of subsequent renal deterioration in diabetic nephropathy.

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Systemic Diseases and the Kidney

180 160 140 120 GFR, mL/min 100 80 60 40 20 0 0 3 6 9 12 15 18 21 24 27 Hyperglycemia, y

10
Clinical nephropathy

Type 2 diabetes Type 1 diabetes (13)

(12)

Cumulative incidence chronic renal failure, %

(69)

(205)

(447) (1,832) (1,377) (112) (812) (75) (49) (30)

(136)

10

15

20

25

30

35

Years from diagnosis of diabetes

FIGURE 1-19 Hyperfiltration. Almost immediately after the onset of hyperglycemia (signaling the onset of diabetes), glomerular filtration rate (GFR) increases to the limit of renal reserve function (hyperfiltration). Over subsequent years of hyperglycemia, a steady decline in glomerular filtration rate ensues in the 20% to 40% of diabetic individuals destined to manifest diabetic nephropathy. There is great variability in the rate of decline of GFR, from as rapid as 20 mL/min/year to 1 to 2 mL/min/year (usually seen in aging). Projection of future loss of GFR on the basis of the slope of the curve of prior decline in function contains errors as high as 37%. The importance of an inconstant and thus unpredictable decline in GFR lies in interpretation of interventive studies designed to protect kidney function. Careful attention to both selection of sufficient untreated controls and a run-in period is vital.

FIGURE 1-20 Renal failure cumulative incidence. Before careful studies of the natural history of type II diabetes were reported, it was not appreciated that diabetic nephropathy was a real endpoint risk. Older diabetic individuals with a touch of sugar are now known to be subject to the same microvascular and macrovascular complications that afflict individuals with type I disease. Population studies indicate that the rate of loss of glomerular filtration is superimposable in type I and type II diabetes. Humphrey and colleagues [21] documented the development of end-stage renal disease in diabetic subjects in Rochester, Minnesota. They showed that chronic renal failure was as likely to develop at a superimposable rate in both diabetic subsets. Numbers in parentheses indicate number of patients for each line. (From Humphrey and coworkers [21]; with permission.)

130 120 110 100 90 80 70 60 50 40 30 20 10 0 1 2

Type I diabetic patients

130 120 110 100 90 80 70 60 50 40 30 20 10 0 1 2

Creatinine clearance, mL/min

Creatinine clearance, mL/min

Type II diabetic patients

5 6 Time, y

10

11

5 6 Time, y

10

11

FIGURE 1-21 Creatinine clearance. Further evidence of the similarity in course of diabetic nephropathy in type I (A) and type II (B) diabetes was presented in Ritz and Stefanskys study [22] of equivalent deterioration

in creatinine clearance over the course of a decade in subjects with either type of diabetes in Heidelberg, Germany. (From Ritz and Stefanski [22]; with permission.)

Diabetic Nephropathy: Impact of Cormorbidity

1.9

14 >4 4.0 3.5 GFR, mL/min 3.0 2.5 2.0 1.5 1.0 0.5 0 0 3 6 9
Microalbuminuria Clinical nephropathy Clinical nephropathy Hyperfiltration

>4 Serum creatinine, mg/dL 4.0 3.5 Urinary albumin, g/d 3.0 2.5 2.0 1.5 1.0 0.5 0 21 24 27 12 15 18 Hyperglycemia, y

12 10 8 6 4 2 0 0 15 30 45 60 75 90 105 120 135 150 165 Creatinine clearance, mL/min

Window for conservative management

FIGURE 1-22 Diabetic nephropathy in types I and II. Whereas microalbuminuria and glomerular hyperfiltration are subtle pathophysiologic manifestations of early diabetic nephropathy, transformation to overt clinical diabetic nephropathy takes place over months to many years. In this figure, the curve for loss of glomerular filtration rate is plotted together with the curve for transition from microalbuminuria to gross proteinuria, affording a perspective of the course of diabetic nephropathy in both types of diabetes. While not all microalbuminuric individuals progress to proteinuria and azotemia, the majority are at risk for end-stage renal disease due to diabetic nephropathy. GFRglomerular filtration rate.

FIGURE 1-23 Clinical recognition of diabetic nephropathy. The timing of renoprotective therapy in diabetes is a subject of current inquiry. Certainly, hypertension, poor metabolic regulation, and hyperlipidemia should be addressed in every diabetic individual at discovery. Discovery of microalbuminuria is by consensus reason to start treatment with an angiotensin-converting enzyme inhibitor in either type of diabetes, regardless of blood pressure elevation. As is true for other kidney disorders, however, nearly the entire course of renal injury in diabetes is clinically silent. Medical intervention during this silent phase, however (comprising blood pressure regulation, metabolic control, dietary protein restriction, and administration of angiotensin-converting enzyme inhibitors), is renoprotective, as judged by slowed loss of glomerular filtration. FIGURE 1-24 Renoprotection with enzyme inhibitors. Streptozotocin-induced diabetic rats manifest slower progression to proteinuria and azotemia when treated with angiotensin-converting enzyme inhibitors than with other antihypertensive drugs. The consensus supports the view that angiotensin-converting enzyme inhibitors afford a greater level of renoprotection in diabetes than do other classes of antihypertensive drugs. Large long-term direct comparisons of antihypertensive drug regimens in type II diabetes are now in progress. In the study shown here by Lewis and colleagues [23], treatment with captopril delayed the doubling of serum creatinine concentration in proteinuric type I diabetic patients. Trials of different angiotensin-converting enzyme inhibitors in both types of diabetes confirm their effectiveness but not their unique renoprotective properties in humans. For patients who cannot tolerate angiotensin-converting enzyme inhibitors because of cough, hyperkalemia, azotemia, or other side effects, substitution of an angiotensin-converting enzyme receptor blocker (losartan) may be renoprotective, although clinical trials of its use in diabetes are uncompleted. (From Lewis and coworkers [23]; with permission.)

50 Doubling of base-line creatinine, % 45 40 35 30 25 20 15 10 5 0 0.0 Placebo 202 Captopril 207 0.5 184 199 1.0 173 190 1.5 161 180 2.0 2.5 Follow-up, y 142 167 99 120 3.0 75 82 3.5 45 50 4.0 22 24
Captopril

Placebo P=0.007

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Systemic Diseases and the Kidney

FIGURE 1-25 Albumin excretion rate. In the recently completed Italian Euclid multicenter study, both microalbuminuric and normalbuminuric type I diabetic patients showed benefit from treatment with lisinopril, an angiotensin-converting enzyme inhibitor. Although microalbuminuria, with or without hypertension, is now sufficient reason to start treatment with an angiotensin-converting enzyme inhibitor, the question of whether normalbuminuric, normotensive diabetic individuals should be started on drug therapy is unanswered. AERalbumin excretion rate. (From Euclid study [24]; with permission.)

10 8 AER, g/min 6 4 2 0 0 n n

Normoalbuminuric

Microalbuminuric

70 60 AER, g/min 50 40 30 20

Lisinopril Placebo

10 0 18 25 32 24 32 37

12 18 24 0 6 12 Time from randomization, m 193 34 191 45 33 37 29 34

227 202 201 179 213 196 179 170

120 100 Glomerular filtration rate, mL/min/1.73 m2 80 60 40 20 0 0 10

Normal diet

FIGURE 1-26 Restricting protein. Dietary protein restriction in limited trials in small patient cohorts has slowed renal functional decline in type I diabetes. Because long-term compliance is difficult to attain, the place of restricted protein intake as a component of management is not defined. A, Normal diet. B, Protein-restricted diet. Dashed line indicates trend line slope. (From Zeller and colleagues [25]; with permission.)

20

30 Time, mo

40

50

A
120 100 Glomerular filtration rate, mL/min/1.73 m2 80 60 40 20 0 0 10 20

Protein-restricted diet

30 Time, mo

40

50

Diabetic Nephropathy: Impact of Cormorbidity

1.11

125

80

100 Rate of change in AER, % /year Rate of change in AER, % /year 0 10 Mean Hb A1, % 12 14 60

75

40

50

25

20

0 6 8 10 Mean Hb A1, % 12 14

FIGURE 1-27 Metabolic regulation studies. Multiple studies of the strict metabolic regulation of type I and type II diabetes all indicate that reduction of hyperglycemic levels to near normal slows the rate of renal functional deterioration. In this study, the albumin excretion rate (AER) another way of expressing albuminuriacorrelates directly with

hyperglycemia, as indicated by hemoglobin A1 (Hb A1) levels in both type I (A) and type II (B) diabetes. As for other studies using different markers, the courses of both types of diabetes over time were found to be equivalent. (From Gilbert and coworkers [26]; with permission.) FIGURE 1-28 Stages of nephropathy. The interrelationships between functional and morphologic markers of the stages of diabetic nephropathy are shown. Additional pathologic studies are needed to time with precision exactly when glomerular basement membrane (GBM) thickening and glomerular mesangial expansion take place. ESRDendstage renal disease.

Function Hyperfiltration

Pathology Mesangial expansion

Microalbuminuria GBM thickening

Proteinuria

Glomerulosclerosis

ESRD

DIABETIC NEPHROPATHY: COMPLICATIONS

Rate of GFR Loss Course of proteinuria Nephropathology Comorbidity Progression to ESRD

FIGURE 1-29 Type I and II nephropathic equivalence. A summation about the equivalence of type I and type II diabetes in terms of nephropathy is listed. Both types have similar complications. ESRDendstage renal disease; GFRglomerular filtration rate.

Hyperglycemia
Normotension Euglycemia Protein restriction

Glomerulosclerosis

FIGURE 1-30 Major therapeutic maneuvers to slow loss of glomerular filtration rate are shown. Recent recognition of the adverse effect of hyperlipidemia is reason to include dietary and, if necessary, drug treatment for elevated blood lipid levels.

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Systemic Diseases and the Kidney

PROGRESSION OF COMORBIDITY IN TYPE II DIABETES*

Complication
Retinopathy Cardiovascular Cerebrovascular Peripheral vascular

COMORBIDITY INDEX
Persistent angina or myocardial infarction Other cardiovascular problems Respiratory disease Autonomic neuropathy Musculoskeletal disorders Infections including AIDS Liver and pancreatic disease Hematologic problems Spinal abnormalities Vision impairment Limb amputation Mental or emotional illness Score 0 to 3: 0 = absent; 1 = mild; 2 = moderate; 3 = severe. Total = Index.

HEART DISEASE
Hyperlipidemia Hypertension Volume overload ACE inhibitor Erythropoietin

Initial, %
50 45 30 15

Subsequent, %
100 90 70 50

*Creatinine clearance declined from 81 mL/min over 74 (40119) mo. Endpoint: dialysis or death.

FIGURE 1-31 Comorbidity in type II. In both type I and type II diabetes, comorbidity, meaning extrarenal disease, makes every stage of progressive nephropathy more difficult to manage. In the long-term observational study in type II diabetes done by Bisenbach and Zazgornik [27], the striking impact of eye, heart, and peripheral vascular disease was noted in a cohort over 74 months. (From Bisenbach and Zazgornik [27]; with permission.)

FIGURE 1-32 Comorbidity index. We devised a Comorbidity Index to facilitate initial and subsequent evaluations of patients over the course of interventive studies. Each of 12 areas is rated as having no disease (0) to severe disease (3). The total score represents overall illness and can be both reproduced by other observers and followed for years to document improvement or deterioration.

FIGURE 1-33 Heart disease. Heart disease is the leading cause of morbidity and death in both type I and type II diabetes. Throughout the course of diabetic nephropathy, periodic screening for cardiac integrity is appropriate. We have elicited symptomatic improvement in angina and work tolerance by using erythropoietin to increase anemic hemoglobin levels. ACEangiotensin-converting enzyme.

FIGURE 1-34 Heart disease and renal transplants. A, Pretransplantation. B, Five years after kidney transplation. Experienced clinicians managing renal failure in diabetes rapidly reach the conclusion that quality of life following successful kidney transplantation is far superior to that attained during any form of dialytic therapy. In the most favorable series, as illustrated by a singlecenter retrospective review of all kidney transplants performed between 1987 and 1993, there is no significant difference in actuarial 5-year patient or kidney graft survival between diabetic and nondiabetic recipients overall or when analyzed by donor source. It is equally encouraging that no difference in mean serum creatinine levels at 5 years was noted between diabetic and nondiabetic recipients [28]. Remarkably superior survival following kidney transplantation compared with survival after peritoneal dialysis and hemodialysis is documented in the 1997

report of the United States Renal Data System (USRDS) [1]. Fewer than five in 100 diabetic patients with end-stage renal disease (ESRD) treated with dialysis will survive 10 years, while cadaver donor and living donor kidney allograft recipients fare far better. Rehabilitation of diabetic patients with ESRD is incomparably better following renal transplantation compared with dialytic therapy. The enhanced quality of life permitted by a kidney transplant is the reason to prefer this option for newly evaluated diabetic persons with ESRD who are younger than the age of 60. More than half of diabetic recipients of a kidney transplant in most series live at least 3 years: many survivors return to occupational, school, and home responsibilities. Failure to continue monitoring of cardiac integrity may have disastrous results, as in this relatively young type I diabetic recipient of a cadaver renal allograft for diabetic nephropathy Although her allograft maintained good function, coronary artery disease progressed silently until a myocardial infarction occurred We now perform annual cardiac testing in all diabetic patients who have ESRD and are receiving any form of treatment.

Diabetic Nephropathy: Impact of Cormorbidity

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RETINOPATHY
Hyperglycemia Hypertension Volume overload Photocoagulation Erythropoietin

FIGURE 1-35 Retinopathy. Blindness due to the hemorrhagic and fibrotic changes of diabetic retinopathy is the most dreaded extrarenal complication feared by diabetic kidney patients. The pathogenesis of proliferative retinopathy reflects release by retinal and choroidal cells of growth (angiogenic) factors triggered by hypoxemia, which is caused by diminished blood flow. The interrelationship among hyperglycemia, hypertension, hypoxemia, and angiogenic factors is now being defined. There is reason to hope that specifically designed interdictive measures may halt progression of loss of sight.

FIGURE 1-36 Retinopathic changes. Proliferative retinopathy, microcapillary aneurysms, and dot plus blot hemorrhages are present in this funduscopic photograph taken at the time of initial renal evaluation of a nephrotic 37-year-old woman with type I diabetes. After prescription of a diuretic regimen, immediate consultation with a laser-skilled ophthalmologist was arranged.

A
FIGURE 1-37 Panretinal photocoagulation (PRP). A, PRP is the therapeutic technique performed for proliferative retinopathy using an argon laser to deliver approximately 1500 discrete retinal burns, avoiding the fovea and disk (IA<I). By reducing the amount of retina to be perfused by 35%, PRP somehow lessens the stimulus to release angiogenic factors, and proliferative retinopathy regresses. B, Disappearance of hemorrhages and nearly complete regression

B
of proliferative retinopathy were attained with PRP, as shown in this fundus, photographed 6 weeks after the one shown in panel A. Vision stabilized, and sight has been retained through the past 6 years of observation. If applied before retinal traction and detachment supervene, PRP is effective in preserving sight in more than 90% of diabetic patients undergoing dialytic therapy or kidney transplantation.

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Systemic Diseases and the Kidney

FIGURE 1-38 Amputation. After blindness, no comorbid complication limits rehabilitation in diabetic kidney patients more than lower limb amputation. A combination of macrovascular and microvascular disease in the limb, loss of pain perception due to sensory nephropathy, and impaired resistance to infection converts any minor insult to the foot into a major threat to the limb and life. Previously regarded as unavoidable in as many as 30% of patients with end-stage renal disease treated with dialysis or kidney transplantation, programs that emphasize prophylactic foot care as a component of preventive medicine have reduced the incidence of limb amputation to about 5% after 3 years.

AMPUTATION
Inspection Shoes Socks Nails Prompt treatment

B
FIGURE 1-39 Genesis of foot problems. The genesis of diabetic foot problems includes peripheral neuropathy, peripheral vascular disease, impaired vision (nail cutting), edema (heart and kidney), and slow wound healing. A, Note the demarcated hair line indicative of peripheral vascular insufficiency. B, The foot radiograph shows a Charcots joint. (From Shaw and Boulton [29]; with permission.)

FIGURE 1-40 Charcots joint. Diabetic neuropathy may involve the proprioceptive nerves, removing limitation of joint stretching and resulting in bone shifts and joint destruction, as seen in the Charcots joint shown here. An insensitive deformed foot with a compromised blood supply is at risk of ulceration, with slow or absent healing after minor trauma.

FIGURE 1-41 Ulcers. A collaborating podiatrist stationed within the renal clinic adds a level of protection for diabetic kidney patients. Common lesions, like this pressure ulcer overlying the head of the first metatarsal, are managed easily with shoe pads that shift weightbearing. The recent introduction of genetically engineered human skin holds promise for closing formerly unhealable diabetic foot ulcers.

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CLINICAL STRATEGY
Main Collaborators
Opththalmologist Podiatrist Cardiologist Nutritionist Nurse educator

AUTONOMIC NEUROPATHY
Cardiovascular (rate, QT, R-R) Orthostatic hypotension Gastroparesis Cystopathy Diarrhea, obstipation

GASTROPARESIS IN DIABETIC NEPHROPATHY

Prevalent in majority, often silent Correlates with autonomic neuropathy Symptoms not linked to delayed emptying Management includes Prokinetic agents: cisapride, erythromycin, metoclopramide, domperidone Serotoninergic (5-HT-3) antagonists

Consultants
Neurologist Vascular surgeon Endocrinologist Gastroenterologist Urologist

FIGURE 1-42 Team management of neuropathy. Proper management of diabetic kidney patients requires a skilled team including collaborating specialists. Depending on the qualifications of the patients primary physician, other professionals are recruited as needed. A nurse educator can ease the interface between otherwise independent specialists. Without such a team mentality, the diabetic patient is often set adrift, forced to cope with conflicting instructions and unneeded repetition of tests. Especially helpful as renal function declines toward end-stage renal disease, patient education facilitates the choice of uremia therapy and, if appropriate, interaction with the renal transplant service.

FIGURE 1-43 Autonomic neuropathy. Autonomic neuropathy accompanies advanced diabetic nephropathy. While an unvarying R-R interval may have minimal clinical importance, diabetic cystopathy and reduced bowel motility, including gastroparesis, may seriously impede quality of life. Questioning to discern the presence of travel-limiting diarrhea, obstipation, and gastroparesis should be included in each initial evaluation of a diabetic kidney patient. (From Spallone and Menzinger [30]; with permission.)

FIGURE 1-44 Gastroparesis. Incomplete and inconstant gastric emptying due to diabetic autonomic neuropathy (gastroparesis) may preempt good glucose regulation because of an inability to match insulin dosing with food ingestion. The diagnosis can be established by having the patient ingest a test meal with a radioisotope tracer. Satisfactory drug treatment for gastroparesis is usually able to minimize the problem. (From Enck and Frieling [31] and Savkan and coworkers [32]; with permission.)

NEPHROTIC SYNDROME
Precedes renal failure May arrest or revert (15%) Confused with cardiac failure Intensifies risk to feet Management: ACEi + metolazone + furosemide

FIGURE 1-45 Nephrotic syndrome. Proteinuria in diabetic nephropathy typically progresses more than 3.5 g/day (nephrotic range), leading to hypoproteinemia, hyperlipidemia, and extracellular fluid accumulation (nephrotic syndrome). Management of a nephrotic diabetic patient includes minimizing protein loss using an angiotensin-converting enzyme inhibitor (ACEi) and promoting diuresis with a combination of loop diuretics (furosemide) and thiazide diuretics (metolazone). Distinction between congestive heart failure and nephrotic edema requires assessment of cardiac function. (From Herbert et at. [33] and Gault and Fernandez [34]; with permission.)

ANASARCA
Hypoproteinemia (renal loss, liver disease) Glycated albumin (more permeable) Heart failure (coronary disease) Management includes Daily weight Metolazone + furosemide Cardiac compensation

FIGURE 1-46 Anasarca. Anasarca is a long-term management problem in diabetic nephropathy. As renal reserve decreases, the balance between volume overload and excessive diuresis may be difficult to maintain. Having the patient measure and record weight daily as a guide for each days dose of diuretics (metolazone plus furosemide) is a workable strategy. Once the creatinine clearance falls below 10 mL/min, ambulatory dialysis may be the only means of continuing life outside the hospital.

1.16

Systemic Diseases and the Kidney

peritoneal dialysis (CAPD) affords the advantages of freedom from a machine, ability to be performed at home, rapid training, minimal cardiovascular stress, and avoidance of heparin [35]. Some enthusiasts believe CAPD to be a first choice treatment for diabetic patients with ESRD [36]. Consistent with the authors view, however, is the report of Rubin and colleagues [37]. They found that in a largely black diabetic population, only 34% of patients continued CAPD after 2 years, and at 3 years, only 18% remained on CAPD. In fairness, comparisons of either mortality or comorbidity in patients receiving hemodialysis versus peritoneal dialysis suffer from the limitations of starting with unequal cohorts reflecting selection bias. Data subsets from the United States Renal Data System (USRDS) report for 1997 [1] show that in diabetic patients, all cohorts have a higher risk of death with CAPD than with hemodialysis. Furthermore, patients receiving peritoneal dialysis in the United States have a 14% greater risk of hospitalization than do patients undergoing hemodialysis [38]. Benefits of peritoneal dialysis, including freedom from a machine and electrical outlets and ease of travel, stand against the disadvantages of unremitting attention to fluid exchange, constant risk of peritonitis, and disappearing exchange surface. There are no absolute criteria for abandoning conservative management in favor of initiating maintenance hemodialysis or peritoneal dialysis. As a generalization, diabetic individuals with progressive renal disease decompensate with uremic symptoms earlier than nondiabetic individuals. A decision to start dialysis is usually the culmination of unsuccessful efforts to regain compensation after episodic dyspnea due to volume overload or nausea and a reversed sleep pattern characteristic of renal failure. Sometimes, both physician and patient appreciate that lassitude and decreasing activity in a catabolic patient signal the need to begin dialysis. FIGURE 1-48 Treatment for end-stage renal disease (ESRD). Ideally, treatment for ESRD should be selected without stress or urgency on the basis of prior thought and planning. Discussions with representatives of patient self-help groups, such as the American Association of Kidney Patients, and institutional transplant coordinators aid in communicating the information required by patients to enable them to select from available options for uremia therapy.

0
5 10

s tic be D ia
Creatinine clearance, mL/min 60 Nondiabetic 51.5% Center hemo Transplant 36.3%

30

15

90

FIGURE 1-47 Uremia therapy, conservative management. Although enthusiastically favored in Canada and Mexico, in the United States peritoneal dialysis sustains the life of only about 12% of diabetic patients with end-stage renal disease (ESRD) [1]. Continuous ambulatory

PLANNING FOR ESRD

Expose patient to treatment options Establish vascular or peritoneal access Encourage intrafamilial kidney donation Schedule visit with transplant surgeon Monitor creatinine, general well being Err on side of early dialysis start

75

45

Diabetic 4064 y 71.5% Center hemo Transplant 13.0%

FIGURE 1-49 Management with dialysis. As tabulated in the 1997 report of the United States Renal Data System [1], diabetic patients with end-stage renal disease (ESRD) are less likely than nondiabetic patients with ESRD to receive a kidney transplant and are most often managed with maintenance hemodialysis (center hemo). A greater proportion of diabetic patients with ESRD are managed with continuous ambulatory peritoneal dialysis (CAPD) or machine-based continuous cyclic peritoneal dialysis (CCPD) than are nondiabetic patients with ESRD.

Center hemo Home hemo CAPD CCPD Transplant

Diabetic Nephropathy: Impact of Cormorbidity

1.17

26.2 24.1

Nondiabetic transplant Nondiabetic dialysis

Diabetic transplant Diabetic dialysis

100 80 Surviving, % 60 40 20

100 94.9 91.2 76.3

90.3 84.3 75.3 57.9 64.7

205.4 279.9 0 50 100 150 200 250 300

36.9 26.5 20.1 3.9

0 0 1 2 5 Time after initiatling treatment, y

Deaths per 1000 Patient Years

10

FIGURE 1-50 Survival rates of diabetics and nondiabetics. As tabulated in the 1997 report of the United States Renal Data System [1], there are sharp differences in survival between diabetic and nondiabetic patients with end-stage renal disease (ESRD) as well as between treatment by dialysis versus kidney transplantation. The highest death rate is suffered by diabetic dialysis patients (combined peritoneal dialysis and hemodialysis), while the best survival is experienced by nondiabetic renal transplant recipients. Selection bias in choosing more fit ESRD patients for kidney transplantation while leaving a residual pool of sicker patients for dialysis accounts for some of the difference in mortality. Other variables, especially extrarenal comorbidity, are probably more important in defining the less favorable course in diabetes.

FIGURE 1-51 Survival rates of diabetic ESRD patients. After a decade of treatment, the remarkable superiority of renal transplantation over dialysis (combined peritoneal dialysis and hemodialysis, lower curve) is starkly evident in these survival curves drawn from the 1997 report of the United States Renal Data System [1]. Fewer than 1 in 20 diabetic patients with end-stage renal disease (ESRD) treated with any form of dialysis will live a decade. In contrast, kidney transplantation from a living donor (upper curve) or a cadaver donor (middle curve) permits substantive cohorts to survive.

42.4 40 Deaths per 1000 Patient Years 30.9 30 21.5 14.5 7.5 7.5 1.4 0 MI Nondiab MI Diab CVA Nondiab CVA Diab Cancer Nondiab Cancer Diab 2.0 1.8 8.7 6.8 3.7 0.4 1.6 0.1
+]

Transplant Hemodialysis Peritoneal dialysis

USRDS 1996 Ages 4564

20 15.1 10

19

6.3 2.4

4.5 3.0 1.6 0.1 [K Nondiab

4.0

[K+] Diab

FIGURE 1-52 Comorbidity in ESRD. Death of diabetic patients with end-stage renal disease (ESRD) relates to comorbidity, as shown in this table abstracted from the 1997 report of the United States Renal Data System (USRDS) [1]. Representative subsets of patients with ESRD with and without diabetes treated by peritoneal dialysis, hemodialysis, or renal transplantation are shown. Note that for each comorbid

cause of death, rates are higher in patients receiving peritoneal dialysis than in those receiving hemodialysis and are lowest in renal transplant recipients. For undetermined reasons, deaths due to cancer are less frequent in diabetic than in nondiabetic patients with ESRD. CVAcerebrovascular accident; Diabdiabetes; K+potassium; MImyocardial infarction.

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Systemic Diseases and the Kidney

COMPLICATIONS IN PATIENTS RECEIVING HEMODIALYSIS

Inadequate vascular access Steal, thrombosis/infection Interdialytic hypotension Progressive eye disease Progressive vascular disease Minimal rehabilitation

COMPLICATIONS IN PATIENTS RECEIVING PERITONEAL DIALYSIS

Peritonitis Tunnel infection Abdominal/back pain Retinopathy Progressive vascular disease Minimal rehabilitation

COMPLICATIONS IN PATIENTS UNDERGOING KIDNEY TRANSPLANTATION

Infections: bacterial (AFB), fungal viral (CMV); genitourinary, lung, skin, wound Cancer: skin, lymphoma, solid organ Drug induced: gout, cataracts Allograft rejection: acute/chronic Recurrent diabetic nephropathy Progressive eye, vascular disease

FIGURE 1-53 Complications prevalent in diabetic hemodialysis patients.

FIGURE 1-54 Complications prevalent in diabetic peritoneal dialysis patients.

FIGURE 1-55 Frequent complications reported in diabetic kidney transplant recipients. AFBacid fast bacteria; CMVcytomegalovirus.

OPTIONS IN DIABETES WITH ESRD

CAPD/CCPD
First-year survival Survival >10 y Diabetic complications Rehabilitation Patient acceptance 75% <5% Progress Poor Fair

Rehabilitation 100

Hemodialysis
75% <5% Progress Poor Fair

Transplantation
Karnofsky score >90% >25% Slow progression Fair to excellent Good to excellent

Kidney transplant

Hemodialysis 50 Peritoneal dialysis

FIGURE 1-56 Options in diabetes with ESRD. Comparing outcomes of various options for uremia therapy in diabetic patients with end-stage renal disease (ESRD) is flawed by the differing criteria for selection for each treatment. Thus, if younger, healthier subjects are offered kidney transplantation, then subsequent relative survival analysis will be adversely affected for the residual pool treated by peritoneal dialysis or hemodialysis. Allowing for this caveat, the table depicts usual outcomes and relative rehabilitation results for continuous ambulatory peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), hemodialysis, and transplantation.

Withdrawal 0 Death

FIGURE 1-57 Karnofsky scores in rehabilitation. Graphic depiction of rehabilitation in diabetic patients with end-stage renal disease (ESRD) as judged by Karnofsky scores. Few diabetic patients receiving hemodialysis or peritoneal dialysis muster the strength to resume fulltime employment or other gainful activities. Originally devised for use by oncologists, the Karnofsky score is a reproducible, simple means of evaluating chronic illness from any cause. A score below 60 indicates marginal function and failed rehabilitation.

Diabetic Nephropathy: Impact of Cormorbidity

1.19

FIGURE 1-58 Complications of the hemodialysis regimen are more frequent in diabetic than in nondiabetic patients. A, Axillary vein occlusion proximal to an arteriovenous graft used for dialysis access is shown. B, Balloon angioplasty proffers only temporary respite owing to a high rate (70% in 6 months) of restenosis in diabetic patients. The value of an intraluminal stent prosthesis is being studied.

76.2 75
USRDS 1996 PD + Hemo

74 72.6 Surviving, % 70.9 70 68.9 67.7 65.9 65 1983 1984 1985 1986 1987 1988 1989 1990 1991 66.2 66.4 73.1

74.4

LIFE PLAN FOR DIABETIC NEPHROPATHY

Explore and endorse treatment goals Enlist patient as key team member Prepare patient for probable course Prioritize ESRD options

1992

1993

FIGURE 1-59 Improving one year survival with dialysis. The summative effect of multiple incremental improvements in management of diabetic patients with end-stage renal disease (ESRD) is reflected in a continuing increase in survival. Shown here, abstracted from the 1977 report of the United States Renal Data System (USRDS), is the increasing first-year survival rates for hemodialysis (hemo) plus peritoneal dialysis (PD) patients with diabetes.

FIGURE 1-60 Life plan. Given the concurrent involvement of multiple consultants in the care of diabetic individuals with end-stage renal disease (ESRD), there is a need for a defined strategy, here termed a Life Plan. Switching from hemodialysis to peritoneal dialysis (or the reverse) and deciding on a midcourse kidney transplant are common occurrences that ought not to provoke anxiety or stress. Reappraisal and reconstruction of the Life Plan should be performed by patient and physician at least annually.

1.20

Systemic Diseases and the Kidney

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