Diabetic Nephropathy: Impact of Comorbidity · 1 Diabetic Nephropathy: Impact of Comorbidity T hroughout the industrialized world, diabetes mellitus is the leading cause of end-stage

1

Diabetic Nephropathy:Impact of Comorbidity

Throughout the industrialized world, diabetes mellitus is theleading cause of end-stage renal disease (ESRD), surpassingglomerulonephritis and hypertension. Both the incidence and

the prevalence of ESRD caused by diabetes have risen each year overthe past decade, according to reports from European, Japanese, andNorth American registries of patients with renal failure. Illustratingthe dominance of diabetes in ESRD is the 1997 report of the UnitedStates Renal Data System (USRDS), which noted that of 257,266patients receiving either dialytic therapy or a kidney transplant in1995 in the United States, 80,667 had diabetes [1], a prevalence rateof 31.4%. Also, during 1995 (the most recent year for which summa-tive 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 predomi-nantly type II; fewer than 8% of diabetic Americans are insulinopenic,C-peptide-negative persons with type I disease. It follows that ESRDin diabetic persons reflects the demographics of diabetes per se [2]: 1)The incidence is higher in women [3], blacks [4], Hispanics [5], andnative Americans [6]. 2) The peak incidence of ESRD occurs from thefifth to the seventh decade. Consistent with these attack rates is thefact that blacks older than the age of 65 face a seven times greater riskof diabetes-related renal failure than do whites. Within our Brooklynand New York state hospital ambulatory hemodialysis units inOctober 1997, 97% of patients had type II diabetes. Despite wide-spread thinking to the contrary, vasculopathic complications of dia-betes, including hypertension, are at least as severe in type II as in typeI diabetes [7,8]. When carefully followed over a decade or longer,cohorts of type I and type II diabetic individuals have equivalent ratesof proteinuria, azotemia, and ultimately ESRD. Both types of diabetesshow strong similarities in their rate of renal functional deterioration[9] and onset of comorbid complications. Initial nephromegaly as wellas both glomerular hyperfiltration and microalbuminuria (previouslythought to be limited to type I) is now recognized as equally in type II [10].

Eli A. Friedman

C H A P T E R

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 moredifficult to manage than age- and gender-matched nondiabetic persons because of extensive,often life-threatening extrarenal (comorbid) disease. Diabetic patients manifesting end-stagerenal disease (ESRD) suffer a higher death rate than do nondiabetic patients with ESRDowing to greater incidence rates for cardiac decompensation, stroke, sepsis, and pulmonarydisease. Concurrent extrarenal disease—especially blindness, limb amputations, and cardiacdisease—limits and may preempt their rehabilitation. For most diabetic patients with ESRD,the difference between rehabilitation and heartbreaking invalidism hinges on attaining arenal transplant as well as comprehensive attention to comorbid conditions.

Gradually, over a quarter century, understanding of the impact of diabetes on the kidneyhas followed elucidation of the epidemiology, clinical course, and options in therapy avail-able 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 preva-lence) of the number of individuals under consideration. For example, previously the largenumber of diabetic patients with ESRD were excluded from therapy owing to the belief thatno benefit would result. A reexamination of exactly why dialytic therapy or kidney trans-plantation failed in diabetes, however, was stimulated. IDDM—insulin dependent diabetesmellitus; NIDDM—non–insulin-dependent diabetes mellitus.

FIGURE 1-2

Maintenance hemodialysis. In the United States, the large majority (more than 80%) ofdiabetic persons who develop end-stage renal disease (ESRD) will be treated with mainte-nance hemodialysis. Approximately 12% of diabetic persons with ESRD will be treatedwith peritoneal dialysis, while the remaining 8% will receive a kidney transplant. A typicalhemodialysis regimen requires three weekly treatments lasting 4 to 5 hours each, duringwhich extracorporeal blood flow must be maintained at 300 to 500 mL/min. Motivatedpatients trained to perform self-hemodialysis at home gain the longest survival and bestrehabilitation afforded by any dialytic therapy for diabetic ESRD. When given hemodialy-sis at a facility, however, diabetic patients fare less well, receiving significantly less dialysisthan nondiabetic patients, owing in part to hypotension and reduced blood flow [11].Maintenance hemodialysis does not restore vigor to diabetic patients, as documented byLowder and colleagues [12]. In 1986, they reported that of 232 diabetics on maintenancehemodialysis, only seven were employed, while 64.9% were unable to conduct routinedaily activities without assistance [12]. Approximately 50% of diabetic patients begun onmaintenance hemodialysis die within 2 years of their first dialysis session. Diabetichemodialysis patients sustained more total, cardiac, septic, and cerebrovascular deathsthan did nondiabetic patients.

When initially applied to diabetic patients with ESRD in the 1970s, maintenancehemodialysis was associated with a first-year mortality in excess of 75%, with inexorableloss of vision in survivors. Until the at-first-unappreciated major contribution of type IIdiabetes to ESRD became evident, kidney failure was incorrectly viewed as predominantlylimited to the last stages of type I (juvenile, insulin-dependent) diabetes. Illustrated here isa blind 30-year-old man undergoing maintenance hemodialysis after experiencing 20 yearsof type I diabetes. A diabetic renal-retinal syndrome of blindness and renal failure wasthought to be inevitable until the salutary effect of reducing hypertensive blood pressurebecame evident. Without question, reduction of hypertensive blood pressure levels was thekey step that permitted improvement in survival and reduction in morbidity.

1.3Diabetic Nephropathy: Impact of Cormorbidity

All other60%

Diabetes40%28,740

43,135

FIGURE 1-3

Statistical increase in diabetes. In the past 20 years, since the diabetic patient with end-stage renal disease (ESRD) is no longer excluded from dialytic therapy or kidney trans-plantation, there has been a steady increase in the proportion of all patients with ESRDwho have diabetes. In the United States, according to the 1997 report of the United StatesRenal 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 havebeen 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 indistin-guishable from a true increase in incidence.

5

15

20

25

10

0

4

9

14

18

5

18

7

15

108

16

19

15

23

Pre

vale

nce

of d

iab

etes

, %

Black Mexican PuertoRican

Japanese Filipinos Chinese

Country of originUnited States

Koreans

FIGURE 1-4

Prevalence of diabetes mellitus in minority populations. Attackrates (incidence) for diabetes are higher in nonwhite populationsthan in whites. Type II diabetes accounts for more than 90% of allpatients with end-stage renal disease (ESRD) with diabetes. Asstudied by Carter and colleagues [13], the effect of improved nutri-tion on expression of diabetes is remarkable. The American dietnot only induces an increase in body mass but also may more thandouble the expressed rate of diabetes, especially in Asians. (FromCarter and coworkers [13]; with permission.)

PERCENTAGE OF PATIENTS WITH END-STAGE RENAL DISEASE WITH TYPE II DIABETES

Country

Japan

Germany

United States Pima Indians

Percentage

99

90

95

FIGURE 1-5

Percent of diabetic ESRD. Noted first in United States inner-citydialysis programs, type II diabetes is the predominant variety notedin those individuals undergoing maintenance hemodialysis. Ourrecent survey of hemodialysis units in Brooklyn, New York, foundthat 97% of the mainly African-American patients had type II dia-betes. Thus, there has been a reversal of the previously heldimpression that uremia was primarily a late manifestation of type Idiabetes. (From Ritz and Stefanski [14] and Nelson and coworkers[15]; with permission.)

Insulin resistance

Fat in muscle

Overfeeding

Obesity

NIDDM

Infrequent feeding

termed non–insulin-dependent diabetes mellitus (NIDDM) ormaturity-onset diabetes, the variety of diabetes observed in indus-trialized overfed populations is now classified as type II disease.According to the Thrifty Gene hypothesis, the ability to surviveextended fasts in prehistoric populations that hunted to surviveselected genes that in time of excess caloric intake are expressed ashyperglycemia, insulin resistance, and hyperlipidemia (type II dia-betes). A study by Ravussin and colleagues of American andMexican Pima Indian tribes illustrates the effect of overfeeding ona genetic predisposition to type II diabetes. Separated about 200years ago, Indians with the same genetic makeup began living indifferent areas with different lifestyles and diets. In the Arizonabranch of the Pimas, who were fed surplus food and restrained to areservation that restricted hunting and other activities, the preva-lence of type II diabetes progressively increased to 37% in womenand 54% in men. In contrast, Pimas living in Mexico with shorterstature, lower body mass, and lower cholesterol had a lower preva-lence of type II diabetes (11% in women and 6% in men). (FromShafrir [16] and Schalin-Jantti [17]; with permission.)

FIGURE 1-6

Thrifty gene. In addition to the artificial increase in incidentpatients with end-stage renal disease (ESRD) and diabetes that fol-lowed relaxation of acceptance criteria, industrialized nations haveexperienced a real increase in type II diabetes that correlates withan increase in body mass attributed to overfeeding. Formerly


Insulin requiring

Type IIdecreased insulin

secretion/sensitvity

Type Iβ-cell destruction

IGT Type II Type I

10

30

40

50

60

70

20

0

Pro

po

rtio

n o

n in

sulin

, %

0–5

13

33

60

5–10

Years of NIDDM

10–15FIGURE 1-7

Type I and type II compared. Differentiatingtype I from type II diabetes may be difficult,especially in young nonobese adults withminimal insulin secretion. Furthermore,with increasing duration of type II diabetes,beta cells may decrease their insulin secre-tion, sometimes to the range diagnostic oftype I diabetes. Shown here is a modifica-tion of the schema devised by Kuzuya andMatsuda [18] that suggests a continuum ofdiabetes classification based on amount ofinsulin secreted. Lacking in this constructionis the realization of the genetic determina-tion of type I diabetes (all?) and the clearhereditary predisposition (despite inconstantgenetic analyses) of many individuals withtype II diabetes. At present, classification ofdiabetes is pragmatic and will likely changewith larger-population screening studies.IGT—impaired glucose tolerance. (FromKuzuya and Matsuda [18]; with permission.)

Type I and Type II Classified

FIGURE 1-8

Increasing insulin treatment in non–insulin-dependent diabetes mellitus (NIDDM). Adecision to treat diabetes with insulin doesnot necessarily equate with establishing adiagnosis of type I diabetes. Terms such as“insulin-requiring” do not help because theneed for insulin is physician-determined andwill vary from clinician to clinician. After10 to 15 years of metabolic regulation oftype II diabetes, treatment with insulin hasbeen initiated in more than half of individu-als with this disorder. Even in patients withtype II diabetes treated with insulin, mea-sured secretion of insulin may fall in thenormal range. (From Clauson and cowork-ers [19]; with permission.)

C-PEPTIDE CRITERIA

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 1-9

C-peptide criteria. Multiple strategies havebeen proposed to distinguish type I fromtype II diabetes. Each has limitations. Serviceand colleagues [20] employed baseline andstimulated C-peptide levels to differentiatebetween the two. They found satisfactorydifferentiation of type I from type II diabeteswith minimal overlap using the screeninglevels shown. (From Service and coworkers[20]; with permission.)

TERMINOLOGY IN DIABETIC NEPHROPATHY

Hyperfiltration

A supernormal glomerular filtration rate associated with hyperglycemia during theearly years of diabetes

Microalbuminuria

Urinary albumin excretion of 30 to 300 mg/day or 20 to 200 �g/min—a predictor ofnephropathy

Mesangial expansion

An increase in mesangial matrix often but not always associated with basementmembrane thickening

FIGURE 1-10

Terminology. Clarification of the course of both types of diabeteswas made possible by recognizing two functional perturbations:microalbuminuria and glomerular hyperfiltration. Additionally,early glomerular mesangial expansion was noted to be a constantfinding in diabetic nephropathy.


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 his-tologic examination of the kidney in diabetes include increased sizeof glomeruli and tubules. Physiologic assessment of renal functionis supernormal in diabetes, as shown by increases of about 150%in renal plasma flow and glomerular filtration rate in initial phasesof diabetic nephropathy. In the induced-diabetic rat and in limitedobservations of type I diabetes, establishing euglycemia will returnenlarged kidneys and abnormal renal function test results to nor-mal, suggesting that hyperglycemia is the cause of nephromegaly.

A

C

B

FIGURE 1-12

Mesangial expansion. Expansion of the mesangium is depicted inlight and electron microscopic views of a kidney biopsy specimenfrom a patient with type I diabetes with a urinary albumin concen-tration of 500 mg/dL. A, Electron microscopic view of a greatlyexpanded mesangium in a glomerulus is shown. B, Less advancedchanges are seen on a silver stain. C, Progression to nodular inter-capillary glomerulosclerosis is shown.


A B

C D

FIGURE 1-13

Glomerular basement membrane thickening. B and D, Glomerularbasement membrane thickening is a constant abnormality in diabeticnephropathy, as seen in these photomicrographs from a biopsy speci-men in type I diabetes. Note the loss of epithelial foot processes in

panel B. In panel D, a mesangial nodule (MN) is present. A and C,Electron photomicrographs from a normal kidney. BM—basementmembrane; C—capillary; E—epithelial cell; MN—mesangial nodule;M—mesangial cell.

FIGURE 1-14

Diabetic nephropathy is a microvasculopathy. Microaneurysms arevisible in the retina and occasionally in glomerular capillaries. Amicroaneurysm in a biopsy specimen from a 42-year-old womanwith type I diabetes is shown.

FIGURE 1-15

Key pathologic findings. Nondiabetic renal disorders (eg, amyloido-sis, cryoglobulinemia, nephrosclerosis) may simulate the nodular anddiffuse intercapillary glomerulosclerosis of diabetes (both type I andtype II). When associated with afferent and efferent arteriolosclero-sis, nodular and diffuse intercapillary glomerulosclerosis is pathogno-monic for diabetic nephropathy. A—afferent artery arteriosclerosis;D—diffuse intercapillary glomerulosclerosis; E—efferent artery arte-riosclerosis; N—nodular intercapillary glomerulosclerosis.


FIGURE 1-16

Diabetic nodules. Diabetic nodules are characterized by clear cen-ters with cells along the periphery of the nodule, as shown here ina kidney biopsy specimen from a 44-year-old man with type II dia-betes (hematoxylin and eosin stain).

FIGURE 1-17

Nodular size variability. Great variability in nodular size in diabeticnodular glomerulosclerosis is usual, as illustrated in this totallyobliterated glomerulus obtained by biopsy from a 65-year-oldwoman with type II diabetes (periodic acid–Schiff stain).

B

0.5

1.5

2.0

2.5

1.0

3.5

4.0

>4

3.0

0

Uri

nar

y al

bu

min

, g/d

0

A

3 6 9 12 15

Hyperglycemia, y

18

Clinicalnephropathy

21 24 27

FIGURE 1-18

A and B, Progression of nephropathy. Microalbuminuria, the excretionof minute quantities of albumin in the urine (more than 20 mg/day), isa marker of subsequent renal deterioration in diabetic nephropathy.

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


20

60

80

100

40

140

160

180

120

0

GFR

, mL/

min

0 3 6 9 12 15

Hyperglycemia, y

18

Clinicalnephropathy

21 24 27

0

5

10

Cu

mu

lati

ve in

cid

ence

ch

ron

ic r

enal

failu

re, %

0 5 10 15

Years from diagnosis of diabetes

20

(136) (112) (75) (49)

(30)

(1,832)(1,377)

(812)

(447)

(205)

(69)

(13)

(12)

25 30 35

Type 2 diabetes

Type 1 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). Oversubsequent years of hyperglycemia, a steady decline in glomerular fil-tration rate ensues in the 20% to 40% of diabetic individuals destinedto manifest diabetic nephropathy. There is great variability in the rateof decline of GFR, from as rapid as 20 mL/min/year to 1 to 2mL/min/year (usually seen in aging). Projection of future loss of GFRon the basis of the slope of the curve of prior decline in function con-tains errors as high as 37%. The importance of an inconstant and thusunpredictable decline in GFR lies in interpretation of interventive stud-ies designed to protect kidney function. Careful attention to both selec-tion of sufficient untreated controls and a “run-in” period is vital.

FIGURE 1-20

Renal failure cumulative incidence. Before careful studies of the nat-ural history of type II diabetes were reported, it was not appreciatedthat diabetic nephropathy was a real endpoint risk. Older diabeticindividuals with a “touch of sugar” are now known to be subject tothe same microvascular and macrovascular complications thatafflict individuals with type I disease. Population studies indicatethat the rate of loss of glomerular filtration is superimposable intype I and type II diabetes. Humphrey and colleagues [21] document-ed the development of end-stage renal disease in diabetic subjects inRochester, Minnesota. They showed that chronic renal failure was aslikely 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.)

20

405060

30

8090

100110120130

70

10

0

A

1 2 3 4 5

Time, y

6

Type I diabetic patients

7 8 9 10 11

Cre

atin

ine

clea

ran

ce, m

L/m

in

20

405060

30

8090

100110120130

70

10

Cre

atin

ine

clea

ran

ce, m

L/m

in

0

B

1 2 3 4 5

Time, y

6

Type II diabetic patients

7 8 9 10 11

FIGURE 1-21

Creatinine clearance. Further evidence of the similarity in course ofdiabetic nephropathy in type I (A) and type II (B) diabetes was pre-sented in Ritz and Stefansky’s study [22] of equivalent deterioration

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


0.5

1.5

2.0

2.5

1.0

3.5

4.0

>4

3.0

0

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1.5

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>4

3.0

0

GFR

, mL/

min

Uri

nar

y al

bu

min

, g/d

0 3 6 9 12 15

Hyperglycemia, y

18

Clinicalnephropathy

Microalbuminuria

Hyperfiltration

Clinicalnephropathy

21 24 27

5

15

20

25

10

35

30

45

50

40

0

Do

ub

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of b

ase-

line

crea

tin

ine,

%

0.0

PlaceboCaptopril

202207

184199

173190

161180

142167

99120

7582

4550

2224

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0Follow-up, y

Placebo

Captopril

P=0.007

2

6

8

10

4

14

12

0

Seru

m c

reat

inin

e, m

g/dL

0 15 30 45 60 75

Creatinine clearance, mL/min

90

Window forconservative management

105 120 135 150 165

FIGURE 1-22

Diabetic nephropathy in types I and II. Whereas microalbuminuriaand glomerular hyperfiltration are subtle pathophysiologic manifes-tations of early diabetic nephropathy, transformation to overt clini-cal diabetic nephropathy takes place over months to many years. Inthis figure, the curve for loss of glomerular filtration rate is plottedtogether with the curve for transition from microalbuminuria togross proteinuria, affording a perspective of the course of diabeticnephropathy in both types of diabetes. While not all microalbumin-uric individuals progress to proteinuria and azotemia, the majorityare at risk for end-stage renal disease due to diabetic nephropathy.GFR—glomerular filtration rate.

FIGURE 1-23

Clinical recognition of diabetic nephropathy. The timing of reno-protective therapy in diabetes is a subject of current inquiry.Certainly, hypertension, poor metabolic regulation, and hyperlipi-demia should be addressed in every diabetic individual at discovery.Discovery of microalbuminuria is by consensus reason to starttreatment with an angiotensin-converting enzyme inhibitor ineither type of diabetes, regardless of blood pressure elevation. As istrue for other kidney disorders, however, nearly the entire course ofrenal injury in diabetes is clinically silent. Medical interventionduring this “silent phase,” however (comprising blood pressureregulation, metabolic control, dietary protein restriction, andadministration of angiotensin-converting enzyme inhibitors), isrenoprotective, as judged by slowed loss of glomerular filtration.

FIGURE 1-24

Renoprotection with enzyme inhibitors. Streptozotocin-induced dia-betic rats manifest slower progression to proteinuria and azotemiawhen treated with angiotensin-converting enzyme inhibitors thanwith other antihypertensive drugs. The consensus supports the viewthat angiotensin-converting enzyme inhibitors afford a greater level ofrenoprotection in diabetes than do other classes of antihypertensivedrugs. Large long-term direct comparisons of antihypertensive drugregimens in type II diabetes are now in progress. In the study shownhere by Lewis and colleagues [23], treatment with captopril delayedthe doubling of serum creatinine concentration in proteinuric type Idiabetic patients. Trials of different angiotensin-converting enzymeinhibitors in both types of diabetes confirm their effectiveness but nottheir unique renoprotective properties in humans. For patients whocannot tolerate angiotensin-converting enzyme inhibitors because ofcough, hyperkalemia, azotemia, or other side effects, substitution ofan angiotensin-converting enzyme receptor blocker (losartan) may berenoprotective, although clinical trials of its use in diabetes areuncompleted. (From Lewis and coworkers [23]; with permission.)


0 6 12 18

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8

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24 0 6 12 18 24

0

20

10

30

40

50

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70Normoalbuminuric Microalbuminuric

Lisinopril

Placebo

Time from randomization, m

nn

227213

202196

201179

179170

193191

3445

3337

2934

2532

3237

AER

,µg/

min

AER

,µg/

min

FIGURE 1-25

Albumin excretion rate. In the recently completed Italian Euclid mul-ticenter study, both microalbuminuric and normalbuminuric type Idiabetic patients showed benefit from treatment with lisinopril, anangiotensin-converting enzyme inhibitor. Although microalbumin-uria, with or without hypertension, is now sufficient reason to starttreatment with an angiotensin-converting enzyme inhibitor, the ques-tion of whether normalbuminuric, normotensive diabetic individualsshould be started on drug therapy is unanswered. AER—albuminexcretion rate. (From Euclid study [24]; with permission.)

0 10 20 30 400

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40

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80

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120

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0 10 20

Normal diet

30 400

A

Protein-restricted diet

B

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50

Glo

mer

ula

r fi

ltra

tio

n r

ate,

mL/

min

/1.7

3 m

2G

lom

eru

lar

filt

rati

on

rat

e,m

L/m

in/1

.73

m2

Time, mo

Time, mo

FIGURE 1-26

Restricting protein. Dietary protein restriction in limited trials insmall patient cohorts has slowed renal functional decline in type Idiabetes. Because long-term compliance is difficult to attain, theplace of restricted protein intake as a component of managementis not defined. A, Normal diet. B, Protein-restricted diet. Dashedline indicates trend line slope. (From Zeller and colleagues [25];with permission.)


0 10 120

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25

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Rat

e o

f ch

ange

in A

ER, %

/ye

ar

Mean Hb A1, %A

6 8 10 120

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40

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14

Rat

e o

f ch

ange

in A

ER, %

/ye

ar

Mean Hb A1, %B

FIGURE 1-27

Metabolic regulation studies. Multiple studies of the strict metabolicregulation of type I and type II diabetes all indicate that reduction ofhyperglycemic levels to near normal slows the rate of renal function-al deterioration. In this study, the albumin excretion rate (AER)—another way of expressing albuminuria—correlates directly with

hyperglycemia, as indicated by hemoglobin A1 (Hb A1) levels inboth type I (A) and type II (B) diabetes. As for other studies usingdifferent markers, the courses of both types of diabetes over timewere found to be equivalent. (From Gilbert and coworkers [26];with permission.)

Hyperfiltration

Function

Microalbuminuria

Proteinuria

Mesangial expansion

Pathology

GBM thickening

Glomerulosclerosis

ESRD

FIGURE 1-28

Stages of nephropathy. The interrelationships between functionaland morphologic markers of the stages of diabetic nephropathy areshown. Additional pathologic studies are needed to time with pre-cision exactly when glomerular basement membrane (GBM) thick-ening and glomerular mesangial expansion take place. ESRD—end-stage renal disease.

DIABETIC NEPHROPATHY:COMPLICATIONS

Rate of GFR Loss

Course of proteinuria

Nephropathology

Comorbidity

Progression to ESRD

FIGURE 1-29

Type I and II nephro-pathic equivalence. Asummation about theequivalence of type Iand type II diabetes interms of nephropathyis listed. Both typeshave similar compli-cations. ESRD—end-stage renal disease;GFR—glomerular filtration rate.

Normotension

Euglycemia

Protein restriction

Hyperglycemia

Glomerulosclerosis

FIGURE 1-30

Major therapeuticmaneuvers to slowloss of glomerularfiltration rate areshown. Recentrecognition of theadverse effect ofhyperlipidemia isreason to includedietary and, if nec-essary, drug treat-ment for elevatedblood lipid levels.


PROGRESSION OF COMORBIDITYIN TYPE II DIABETES*

Complication

Retinopathy

Cardiovascular

Cerebrovascular

Peripheral vascular

Initial, %

50

45

30

15

Subsequent, %

100

90

70

50

*Creatinine clearance declined from 81 mL/min over 74(40—119) mo.

Endpoint: dialysis or death.

FIGURE 1-31

Comorbidity in type II. In both type I andtype II diabetes, comorbidity, meaningextrarenal disease, makes every stage ofprogressive nephropathy more difficult tomanage. In the long-term observationalstudy in type II diabetes done by Bisenbachand Zazgornik [27], the striking impact ofeye, heart, and peripheral vascular diseasewas noted in a cohort over 74 months.(From Bisenbach and Zazgornik [27]; with permission.)

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.

FIGURE 1-32

Comorbidity index. We devised a Comor-bidity Index to facilitate initial and subse-quent evaluations of patients over thecourse of interventive studies. Each of 12areas is rated as having no disease (0) tosevere disease (3). The total score representsoverall illness and can be both reproducedby other observers and followed for yearsto document improvement or deterioration.

HEART DISEASE

Hyperlipidemia

Hypertension

Volume overload

ACE inhibitor

Erythropoietin

FIGURE 1-33

Heart disease. Heart disease is the leadingcause of morbidity and death in both type Iand type II diabetes. Throughout the courseof diabetic nephropathy, periodic screeningfor cardiac integrity is appropriate. We haveelicited symptomatic improvement in anginaand work tolerance by using erythropoietinto increase anemic hemoglobin levels.ACE—angiotensin-converting enzyme.

A B

report of the United States Renal Data System(USRDS) [1]. Fewer than five in 100 diabet-ic patients with end-stage renal disease(ESRD) treated with dialysis will survive 10years, while cadaver donor and livingdonor kidney allograft recipients fare farbetter. Rehabilitation of diabetic patientswith ESRD is incomparably better follow-ing renal transplantation compared withdialytic therapy. The enhanced quality oflife permitted by a kidney transplant is thereason to prefer this option for newly eval-uated diabetic persons with ESRD who areyounger than the age of 60. More than halfof diabetic recipients of a kidney transplantin most series live at least 3 years: manysurvivors return to occupational, school,and home responsibilities.

Failure to continue monitoring of car-diac integrity may have disastrous results,as in this relatively young type I diabeticrecipient of a cadaver renal allograft fordiabetic nephropathy Although her allo-graft maintained good function, coronaryartery disease progressed silently until amyocardial infarction occurred We nowperform annual cardiac testing in all dia-betic patients who have ESRD and arereceiving any form of treatment.

FIGURE 1-34

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


RETINOPATHY

Hyperglycemia

Hypertension

Volume overload

Photocoagulation

Erythropoietin

FIGURE 1-35

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

FIGURE 1-36

Retinopathic changes. Proliferative retinopathy, microcapillaryaneurysms, and dot plus blot hemorrhages are present in this fun-duscopic photograph taken at the time of initial renal evaluation ofa nephrotic 37-year-old woman with type I diabetes. After pre-scription of a diuretic regimen, immediate consultation with alaser-skilled ophthalmologist was arranged.

A B

FIGURE 1-37

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

of proliferative retinopathy were attained with PRP, as shown inthis fundus, photographed 6 weeks after the one shown in panelA. Vision stabilized, and sight has been retained through the past6 years of observation. If applied before retinal traction anddetachment supervene, PRP is effective in preserving sight inmore than 90% of diabetic patients undergoing dialytic therapyor kidney transplantation.


AMPUTATION

Inspection

Shoes

Socks

Nails

Prompt treatment

FIGURE 1-38

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

B

A

FIGURE 1-39

Genesis of foot problems. The genesis of diabetic foot problemsincludes peripheral neuropathy, peripheral vascular disease, impairedvision (nail cutting), edema (heart and kidney), and slow woundhealing. A, Note the demarcated hair line indicative of peripheralvascular insufficiency. B, The foot radiograph shows a Charcot’sjoint. (From Shaw and Boulton [29]; with permission.)

FIGURE 1-40

Charcot’s joint. Diabetic neuropathy may involve the propriocep-tive nerves, removing limitation of joint stretching and resulting inbone shifts and joint destruction, as seen in the Charcot’s jointshown here. An insensitive deformed foot with a compromisedblood supply is at risk of ulceration, with slow or absent healingafter minor trauma.

FIGURE 1-41

Ulcers. A collaborating podiatrist stationed within the renal clinicadds a level of protection for diabetic kidney patients. Commonlesions, like this pressure ulcer overlying the head of the firstmetatarsal, are managed easily with shoe pads that shift weightbear-ing. The recent introduction of genetically engineered human skinholds promise for closing formerly unhealable diabetic foot ulcers.


CLINICAL STRATEGY

Main Collaborators

Opththalmologist

Podiatrist

Cardiologist

Nutritionist

Nurse educator

Consultants

Neurologist

Vascular surgeon

Endocrinologist

Gastroenterologist

Urologist

FIGURE 1-42

Team management of neuropathy. Propermanagement of diabetic kidney patientsrequires a skilled team including collaborat-ing specialists. Depending on the qualifica-tions of the patient’s primary physician,other professionals are recruited as needed.A nurse educator can ease the interfacebetween otherwise independent specialists.Without such a team mentality, the diabeticpatient is often set adrift, forced to copewith conflicting instructions and unneededrepetition of tests. Especially helpful as renalfunction declines toward end-stage renal dis-ease, patient education facilitates the choiceof uremia therapy and, if appropriate, inter-action with the renal transplant service.

AUTONOMIC NEUROPATHY

Cardiovascular (rate, QT, R-R)

Orthostatic hypotension

Gastroparesis

Cystopathy

Diarrhea, obstipation

FIGURE 1-43

Autonomic neuropathy. Autonomic neu-ropathy accompanies advanced diabeticnephropathy. While an unvarying R-Rinterval may have minimal clinical impor-tance, diabetic cystopathy and reducedbowel motility, including gastroparesis, mayseriously impede quality of life. Questioningto discern the presence of travel-limitingdiarrhea, obstipation, and gastroparesisshould be included in each initial evaluationof a diabetic kidney patient. (From Spalloneand Menzinger [30]; with permission.)

GASTROPARESIS IN DIABETICNEPHROPATHY

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

FIGURE 1-44

Gastroparesis. Incomplete and inconstantgastric emptying due to diabetic autonomicneuropathy (gastroparesis) may preemptgood glucose regulation because of aninability to match insulin dosing with foodingestion. The diagnosis can be establishedby having the patient ingest a test mealwith a radioisotope tracer. Satisfactory drugtreatment for gastroparesis is usually ableto minimize the problem. (From Enck andFrieling [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

ANASARCA

Hypoproteinemia (renal loss, liver disease)

Glycated albumin (more permeable)

Heart failure (coronary disease)

Management includes

Daily weight

Metolazone + furosemide

Cardiac compensation

FIGURE 1-45

Nephrotic syndrome. Proteinuria in diabetic nephropathy typically progresses more than3.5 g/day (nephrotic range), leading to hypoproteinemia, hyperlipidemia, and extracellularfluid accumulation (nephrotic syndrome). Management of a nephrotic diabetic patientincludes minimizing protein loss using an angiotensin-converting enzyme inhibitor (ACEi)and promoting diuresis with a combination of loop diuretics (furosemide) and thiazidediuretics (metolazone). Distinction between congestive heart failure and nephrotic edemarequires assessment of cardiac function. (From Herbert et at. [33] and Gault andFernandez [34]; with permission.)

FIGURE 1-46

Anasarca. Anasarca is a long-term management problem in diabetic nephropathy. As renalreserve decreases, the balance between volume overload and excessive diuresis may be dif-ficult to maintain. Having the patient measure and record weight daily as a guide for eachday’s dose of diuretics (metolazone plus furosemide) is a workable strategy. Once the crea-tinine clearance falls below 10 mL/min, ambulatory dialysis may be the only means ofcontinuing life outside the hospital.


60

0

7545

30

15

5

90

105

Diabetics

Creatinineclearance,mL/min

peritoneal dialysis (CAPD) affords the advantages of freedom from a machine, ability to beperformed at home, rapid training, minimal cardiovascular stress, and avoidance of heparin[35]. Some enthusiasts believe CAPD to be “a first choice treatment” for diabetic patientswith ESRD [36]. Consistent with the author’s view, however, is the report of Rubin and col-leagues [37]. They found that in a largely black diabetic population, only 34% of patientscontinued CAPD after 2 years, and at 3 years, only 18% remained on CAPD.

In fairness, comparisons of either mortality or comorbidity in patients receivinghemodialysis versus peritoneal dialysis suffer from the limitations of starting with unequalcohorts 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 riskof death with CAPD than with hemodialysis. Furthermore, patients receiving peritonealdialysis in the United States have a 14% greater risk of hospitalization than do patientsundergoing hemodialysis [38]. Benefits of peritoneal dialysis, including freedom from amachine and electrical outlets and ease of travel, stand against the disadvantages ofunremitting attention to fluid exchange, constant risk of peritonitis, and disappearingexchange surface.

There are no absolute criteria for abandoning conservative management in favor of initi-ating maintenance hemodialysis or peritoneal dialysis. As a generalization, diabetic indi-viduals with progressive renal disease decompensate with uremic symptoms earlier thannondiabetic individuals. A decision to start dialysis is usually the culmination of unsuccess-ful efforts to regain compensation after episodic dyspnea due to volume overload or nau-sea and a reversed sleep pattern characteristic of renal failure. Sometimes, both physicianand patient appreciate that lassitude and decreasing activity in a catabolic patient signalthe need to begin dialysis.

FIGURE 1-47

Uremia therapy, conservative management.Although enthusiastically favored in Canadaand Mexico, in the United States peritonealdialysis sustains the life of only about 12%of diabetic patients with end-stage renal dis-ease (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

FIGURE 1-48

Treatment for end-stage renal disease (ESRD). Ideally, treatment for ESRD should be select-ed without stress or urgency on the basis of prior thought and planning. Discussions withrepresentatives of patient self-help groups, such as the American Association of KidneyPatients, and institutional transplant coordinators aid in communicating the informationrequired by patients to enable them to select from available options for uremia therapy.

Center hemoHome hemoCAPDCCPDTransplant

Nondiabetic Diabetic

40–64 y

51.5%Center hemo

71.5%Center hemo

Transplant36.3%

Transplant13.0%

FIGURE 1-49

Management with dialysis. As tabulated in the 1997 report of theUnited States Renal Data System [1], diabetic patients with end-stagerenal disease (ESRD) are less likely than nondiabetic patients withESRD to receive a kidney transplant and are most often managedwith maintenance hemodialysis (center hemo). A greater proportionof diabetic patients with ESRD are managed with continuous ambu-latory peritoneal dialysis (CAPD) or machine-based continuous cyclicperitoneal dialysis (CCPD) than are nondiabetic patients with ESRD.


0 50 100 150 200 250 300

Deaths per 1000 Patient Years

26.2

24.1

205.4

279.9

Nondiabetic transplant

Nondiabetic dialysis

Diabetic transplant

Diabetic dialysis

0 1 2 50

100

80

60

40

20

10

Time after initiatling treatment, y

Surv

ivin

g, %

76.3

91.294.9

57.9

84.390.3

20.1

64.7

75.3

3.9

26.5

36.9

100

FIGURE 1-50

Survival rates of diabetics and nondiabetics. As tabulated in the1997 report of the United States Renal Data System [1], there aresharp differences in survival between diabetic and nondiabeticpatients with end-stage renal disease (ESRD) as well as betweentreatment by dialysis versus kidney transplantation. The highestdeath rate is suffered by diabetic dialysis patients (combined peri-toneal dialysis and hemodialysis), while the best survival is experi-enced by nondiabetic renal transplant recipients. Selection bias inchoosing more fit ESRD patients for kidney transplantation whileleaving a residual pool of sicker patients for dialysis accounts forsome of the difference in mortality. Other variables, especiallyextrarenal comorbidity, are probably more important in definingthe 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) isstarkly evident in these survival curves drawn from the 1997 reportof the United States Renal Data System [1]. Fewer than 1 in 20diabetic patients with end-stage renal disease (ESRD) treated withany form of dialysis will live a decade. In contrast, kidney trans-plantation from a living donor (upper curve) or a cadaver donor(middle curve) permits substantive cohorts to survive.

0

40

30

20

10

Dea

ths

per

100

0 Pa

tien

t Ye

ars

2.4

15.1

19

6.3

30.9

42.4

1.4

7.5 7.5

2.0

14.5

21.5

1.8

8.7

6.8

0.4

3.71.6

0.1

3.01.6 0.1

4.5 4.0

USRDS 1996Ages 45–64

MI Nondiab MI Diab CVA Nondiab Cancer Nondiab [K+] Nondiab [K+] DiabCancer DiabCVA Diab

Transplant

Hemodialysis

Peritoneal dialysis

FIGURE 1-52

Comorbidity in ESRD. Death of diabetic patients with end-stagerenal disease (ESRD) relates to comorbidity, as shown in this tableabstracted from the 1997 report of the United States Renal DataSystem (USRDS) [1]. Representative subsets of patients with ESRDwith and without diabetes treated by peritoneal dialysis, hemodialy-sis, or renal transplantation are shown. Note that for each comorbid

cause of death, rates are higher in patients receiving peritoneal dialy-sis than in those receiving hemodialysis and are lowest in renal trans-plant recipients. For undetermined reasons, deaths due to cancer areless frequent in diabetic than in nondiabetic patients with ESRD.CVA—cerebrovascular accident; Diab—diabetes; K+—potassium;MI—myocardial infarction.


COMPLICATIONS IN PATIENTSRECEIVING HEMODIALYSIS

Inadequate vascular access

“Steal,” thrombosis/infection

Interdialytic hypotension

Progressive eye disease

Progressive vascular disease

Minimal rehabilitation

COMPLICATIONS IN PATIENTSRECEIVING PERITONEAL DIALYSIS

Peritonitis

“Tunnel” infection

Abdominal/back pain

Retinopathy

Progressive vascular disease

Minimal rehabilitation

COMPLICATIONS IN PATIENTSUNDERGOING KIDNEYTRANSPLANTATION

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 diabetichemodialysis patients.

FIGURE 1-54

Complications prevalent in diabetic peri-toneal dialysis patients. FIGURE 1-55

Frequent complications reported in diabetickidney transplant recipients. AFB—acid fastbacteria; CMV—cytomegalovirus.

Rehabilitation

Death

Kidney transplant

Hemodialysis

Peritoneal dialysis

Withdrawal

Kar

no

fsky

sco

re50

100

0

OPTIONS IN DIABETES WITH ESRD

First-year survival

Survival >10 y

Diabetic complications

Rehabilitation

Patient acceptance

CAPD/CCPD

75%

<5%

Progress

Poor

Fair

Hemodialysis

75%

<5%

Progress

Poor

Fair

Transplantation

>90%

>25%

Slow progression

Fair to excellent

Good to excellent

FIGURE 1-56

Options in diabetes with ESRD. Comparing outcomes of various options for uremia thera-py in diabetic patients with end-stage renal disease (ESRD) is flawed by the differing crite-ria for selection for each treatment. Thus, if younger, healthier subjects are offered kidneytransplantation, then subsequent relative survival analysis will be adversely affected for theresidual pool treated by peritoneal dialysis or hemodialysis. Allowing for this caveat, thetable depicts usual outcomes and relative rehabilitation results for continuous ambulatoryperitoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), hemodialysis,and transplantation.

FIGURE 1-57

Karnofsky scores in rehabilitation. Graphicdepiction of rehabilitation in diabeticpatients with end-stage renal disease (ESRD)as judged by Karnofsky scores. Few diabeticpatients receiving hemodialysis or peritonealdialysis muster the strength to resume full-time employment or other gainful activities.Originally devised for use by oncologists,the Karnofsky score is a reproducible, sim-ple means of evaluating chronic illness fromany cause. A score below 60 indicates mar-ginal function and failed rehabilitation.


A B

FIGURE 1-58

Complications of the hemodialysis regimenare more frequent in diabetic than in nondia-betic patients. A, Axillary vein occlusionproximal to an arteriovenous graft used fordialysis access is shown. B, Balloon angio-plasty proffers only temporary respite owingto a high rate (70% in 6 months) of resteno-sis in diabetic patients. The value of an intra-luminal stent prosthesis is being studied.

1983 1984 1985 1986 1987 1988 1989 1990 1991 199265

75

70

1993

65.966.2 66.4

67.7

68.9

70.9

72.673.1

7474.4

76.2

USRDS 1996

PD + Hemo

Surv

ivin

g, %

FIGURE 1-59

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

LIFE PLAN FOR DIABETICNEPHROPATHY

Explore and endorse treatment goals

Enlist patient as key team member

Prepare patient for probable course

Prioritize ESRD options

FIGURE 1-60

Life plan. Given the concurrent involvementof multiple consultants in the care of dia-betic individuals with end-stage renal dis-ease (ESRD), there is a need for a definedstrategy, here termed a “Life Plan.”Switching from hemodialysis to peritonealdialysis (or the reverse) and deciding on amidcourse kidney transplant are commonoccurrences that ought not to provoke anx-iety or stress. Reappraisal and reconstruc-tion of the Life Plan should be performedby patient and physician at least annually.


References

1. United States Renal Data System: USRDS 1997 Annual Data Report.Bethesda, MD: The National Institutes of Health, National Instituteof Diabetes and Digestive and Kidney Diseases; April, 1997.

2. Zimmet PZ: Challenges in diabetes epidemiology—from West to therest (Kelly West Lecture 1991). Diabetes Care 1992, 15:232–252.

3. Harris M, Hadden WC, Knowles WC, and colleagues: Prevalence ofdiabetes and impaired glucose tolerance and plasma glucose levels inU.S. population aged 20-74 yr. Diabetes 1987, 36:523–534.

4. Stephens GW, Gillaspy JA, Clyne D, and colleagues: Racial differencesin the incidence of end-stage renal disease in types I and II diabetesmellitus. Am J Kidney Dis 1990, 15:562–567.

5. Haffner SM, Hazuda HP, Stern MP, and colleagues: Effects of socioe-conomic status on hyperglycemia and retinopathy levels in MexicanAmericans with NIDDM. Diabetes Care 1989, 12:128–134.

6. National Diabetes Data Group: Diabetes in America. Bethesda, MD:NIH Publication No. 85-1468; August, 1985.

7. Mauer SM, Chavers BM: A comparison of kidney disease in type Iand type II diabetes. Adv Exp Med Biol 1985, 189:299–303.

8. Melton LJ, Palumbo PJ, Chu CP: Incidence of diabetes mellitus byclinical type. Diabetes Care 1983, 6:75–86.

9. Biesenback G, Janko O, Zazgornik J: Similar rate of progression inthe predialysis phase in type I and type II diabetes mellitus. NephrolDial Transplant 1994, 9:1097–1102.

10. Wirta O, Pasternack A, Laippala P, Turjanmaa V: Glomerular filtra-tion rate and kidney size after six years disease duration in non-insulin-dependent diabetic subjects. Clin Nephrol 1996, 45:10–17.

11. Cheigh J, Raghavan J, Sullivan J, and colleagues: Is insufficient dialysisa cause for high morbidity in diabetic patients [abstract]? J Am SocNephrol 1991, 317.

12. Lowder GM, Perri NA, Friedman EA: Demographics, diabetes type,and degree of rehabilitation in diabetic patients on maintenancehemodialysis in Brooklyn. J Diabet Complications 1988, 2:218–226.

13. Carter JS, et al.: Non-insulin-dependent diabetes mellitus in minoritiesin the United States. Ann Intern Med 1996, 125:221–232.

14. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am JKidney Dis 1996, 27:167–194.

15. Nelson RG, Pettitt DJ, Carraher MJ, et al.: Effect of proteinuria onmortality in NIDDM. Diabetes 1988, 37:1499–1504.

16. Shafrir E: Development and consequences of insulin resistance: lessonsfrom animals with hyperinsulinemia. Diabetes Metab 1996, 22:122–131.

17. Schalin-Jantii C, et al.: Polymorphism of the glycogen synthase gene inhypertensive and normotensive subjects. Hypertension 1996, 27:67–71.

18. Kuzuya T, Matsuda A: Classification of diabetes on the basis of etiologiesversus degree of insulin deficiency. Diabetes Care 1997, 20:219–220.

19. Clausson P, Linnarsson R, Gottsater A, et al.: Relationships betweendiabetes duration, metabolic control and beta-cell function in a repre-sentative population of type 2 diabetic patients in Sweden. DiabetMed 1994, 11:794–801.

20. Service FJ, Rizza RA, Zimmerman BR, et al.: The classification of diabetes by clinical and C-peptide criteria: a prospective population-based study. Diabetes Care 1997, 20:198–201.

21. Humphrey LL, et al.: Chronic renal failure in non-insulin-dependentdiabetes mellitus: a population-based study in Rochester, Minnesota.Ann Intern Med 1989, 111:788–796.

22. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am JKidney Dis 1996, 27:167–194.

23. Lewis EJ, et al.: The effect of angiotensin-converting-enzyme inhibitionon diabetic nephropathy: the Collaborative Study Group. N Engl JMed 1993, 329:1456–1462.

24. The Euclid Study Group: Randomised placebo-controlled trial of lisino-pril in normotensive patients with insulin-dependent diabetes and nor-moalbuminuria or microalbuminuria. Lancet 1997, 349:1787–1792.

25. Zeller K, et al.: Effect of restricting dietary protein on the progressionof renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 1991, 324:78–84.

26. Gilbert RE, Tsalamandris C, Bach LA, et al.: Long-term glycemic controland the rate of progression of early diabetic kidney disease. Kidney Int1993, 44:855–859.

27. Biesenbach G, Zazgornik J: High mortality and poor quality of lifeduring predialysis period in type II diabetic patients with diabeticnephropathy. Ren Fail 1994, 16:263–272.

28. Shaffer D, Simpson MA, Madras PN, et al.: Kidney transplantation indiabetic patients using cyclosporine. Five-year follow-up. Arch Surg1995, 130:287–288.

29. Shaw JE, Boulton AJ: The pathogenesis of diabetic foot problems: anoverview. Diabetes 1997, 46 (suppl 2): S58–S61.

30 Spallone V, Menzinger G: Diagnosis of cardiovascular autonomic neuropathy in diabetes. Diabetes 1997, 46 (suppl 2):S67–S76.

31. Enck P, Frieling T: Pathophysiology of diabetic gastroparesis. Diabetes1997, 46 (suppl 2):S77–S81.

32. Soykan I, et al.: The effect of chronic oral domperidone therapy ongastrointestinal symptoms, gastric emptying, and quality of life inpatients with gastroparesis. Am J Gastroenterol 1997, 92:976–980.

33. Hebert LA, Bain RP, Verme D, Cattran Det al.: Remission of nephroticrange proteinuria in type I diabetes: Collaborative Study Group.Kidney Int 1994, 46:1688–1693.

34. Gault MH, Fernandez D: Stable renal function in insulin-dependentdiabetes mellitus 10 years after nephrotic range proteinuria. Nephron1996, 72:86–92.

35. Lindblad AS, Nolph KD, Novak JW, Friedman EA: A survey of theNIH CAPD Registry population with end-stage renal disease attributedto diabetic nephropathy. J Diabet Complications 1988, 2:227-232.

36. Legrain M, Rottembourg J, Bentchikou A, et al.: Dialysis treatment ofinsulin dependent diabetic patients: ten years experience. Clin Nephrol1984, 21:72-81

37. Rubin J, Hsu H: Continuous anbulatory peritoneal dialysis: ten yearsat one facility. Am J Kidney Dis 1991, 17: 165-169.

38. Habach G, Bloembergen WE, Mauger EA, et al.: Hospitalizationamong United States dialysis patients: hemodialysis versus peritonealdialysis. J Am Soc Nephrol 1995, 11:1940-1948.

Documents

Diabetic Nephropathy: Impact of Comorbidity · 1 Diabetic Nephropathy: Impact of Comorbidity T hroughout the industrialized world, diabetes mellitus is the leading cause of end-stage