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1

Diabetic Nephropathy:Impact of Comorbidity

Throughout the industrialized world, diabetes mellitus is the

leading cause of end-stage renal disease (ESRD), surpassing

glomerulonephritis and hypertension. Both the incidence and

the pr evalence of ESRD cau sed by diabetes have r isen 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, dur ing 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 tha n 8% of diabetic Americans are insulinopenic,

C-peptide-negative persons with type I disease. It follows that ESRD

in diabetic persons r eflects the demograp hics 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 o ccurs from th e

fifth to the seventh decade. Consistent with these attack rates is the

fact that b lacks older than t he 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 199 7, 97% of patients had type II diabetes. Despite wide-

spread thinking to the contrary, vasculopathic complications of dia-

betes, including hypertension, are a t least as severe in type II as in t ype

I diabetes [7,8]. When carefully followed over a decade or longer,

cohor ts of type I and t ype II diabetic individuals have equivalent ratesof pro teinuria, azotemia, and ultimately ESRD. Both types of diabetes

show strong similarities in their rate of renal functional deterioration

[9] and onset of comorb id complications. Initial nephro megaly 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].

Eli A. Friedman

C H A P T E R

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1.2 Systemic Diseases and the Kidney

Overview and Prevalence

DIABETIC NEPHROPATHY

Epidemiology

IDDM vs. NIDDM

Natural history

Intervention measures

ESRD opt ions

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-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 a s well as comprehensive attention to comorbid conditions.

Gradually, over a quarter century, understanding of the impact of diabetes on the k idney

has 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 large

number of diabetic patients with ESRD were excluded from therapy owing to the belief that

no benefit would result. A r eexamination of exactly why dialytic therapy or k idney trans-plantation 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 tr eated with mainte-

nance hemodialysis. Approximately 12% of diabetic persons with ESRD will be treated

with peritoneal dialysis, while the remaining 8% will receive a kidney tran splant. A typical

hemodialysis regimen requires thr ee weekly treatments lasting 4 t o 5 hours each, du ring

which extracorporeal blood flow must be maintained at 300 to 500 mL/min. Motivated

patients tra ined to p erform self-hemodialysis at home gain the longest survival and best

rehabilitation afforded by any dialytic therapy for d iabetic ESRD. When given hemod ialy-

sis 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 withou t assistance [12]. Approximately 50% of diabetic patients begun on

maintenance hemodialysis die within 2 years of their first dialysis session. Diabetic

hemodialysis patients sustained mor e total, card iac, 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 contr ibution of type II

diabetes to ESRD b ecame evident, kidney failure wa s incorrectly viewed as predominant ly

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 b lindness and renal failure was

thought to b e inevitable until the salutary effect of reducing hypertensive blood pressure

became evident. Withou t question, reduction of hypertensive blood pr essure levels was thekey step that permitted improvement in survival and reduction in morbidity.

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1.3Diabetic Nephropathy: Impact of Cormorbidity

All other

60%

Diabetes

40%28,740

43,135

FIGURE 1-3

Statistical increase in diabetes. In th e past 20 years, since the diabetic patient with end-

stage renal disease (ESRD) is no longer excluded from dialytic therapy o r k idney trans-

plantation, 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 tha n 40% of all newly treated

(incident) patients with ESRD have diabetes. For perspective, the USRDS does not listthe actual incidence of a renal disease but rather tabulates those individuals who have

been enrolled in federally reimbursed renal programs. The distinction may be import ant

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

Prevalenceofdiabetes,%

Black Mexican PuertoRican

Japanese Filipinos Chinese

Country of originUnited States

Koreans

FIGURE 1-4

Prevalence of diabetes mellitus in minor ity popu lations. Attack

rates (incidence) for d iabetes are higher in nonwhite populat ions

than in whites. Type II diabetes accounts for more than 9 0% of all

patients with end-stage renal disease (ESRD) with diabetes. As

studied by Cart er and colleagues [13], the effect of impro ved nutri-

tion 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.)

PERCENTAGE OF PATIENTSWITH END-STAGERENAL DISEASE WITH TYPE II DIABETES

Country

JapanGermany

United States Pima Indians

Percentage

9990

95

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 sur vey of hemodialysis units in Brooklyn, N ew York, found

that 97% of the mainly African-American patients had type II dia-

betes. 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.)

Insulin resistance

Fat in muscle

Overfeeding

Obesity

NIDDM

Infrequent feeding

termed noninsulin-dependent diabetes mellitus (NIDDM ) or

matur ity-onset diabetes, the variety of diabetes observed in indus-

trialized overfed populations is now classified as type II disease.

According to the Thr ifty Gene hypothesis, the ab ility 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 dia-

betes). A study by Ravussin and colleagues of American a nd

Mexican Pima Indian tribes illustrates the effect of overfeeding on

a genetic predisposition to type II diabetes. Separat ed abou t 200years 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 preva-

lence of type II diabetes progressively increased to 3 7% in wom en

and 54% in men. In contrast, Pimas living in Mexico with shorter

stature, lower body mass, and lower cholesterol had a lower preva-

lence of type II diabetes (11% in women and 6% in men). (From

Shafrir [16] and Schalin-Jantt i [17]; with permission.)

FIGURE 1-6

Thrifty gene. In addition to the art ificial increase in incident

patients with end-stage renal disease (ESRD) and diabetes that fol-

lowed relaxation of acceptance criteria, industrialized na tions have

experienced a r eal increase in type II diabetes tha t corr elates with

an increase in body mass at tributed to overfeeding. Formerly

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Insulin requiring

Type II

decreased insulin

secretion/sensit vity

Type I

-cell destruction

IGT Type II Type I

10

30

40

50

60

70

20

0

Proportiononinsulin,%

05

13

33

60

510

Years of NIDDM

1015FIGURE 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 secre-

tion, sometimes to the range diagnostic of

type I diabetes. Shown here is a modifica-

tion 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 determina-

tion 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.)

Type I and Type II Classified

FIGURE 1-8

Increasing insulin treatment in noninsulin-

dependent diabetes mellitus (NIDDM). A

decision to treat diabetes with insulin does

not necessarily equate w ith 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 individu-

als with th is disorder. Even in patients with

type II diabetes treated with insulin, mea-

sured secretion of insulin may fall in the

normal range. (From Clauson and cowork-ers [19]; with permission.)

C-PEPTIDE CRITERIA

Type I (90%concordence between clinical criteriaand C-peptide testing)

Basal C-peptide

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Clinical Features of Diabetic Kidney

FIGURE 1-11

Diabetic kidney characteristics. The diabetic kidney is about 14 0%greater in length, width, and weight. Morphologic findings on his-

tologic examination of the k idney in diabetes include increased size

of glomeruli and tubu les. 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 nephropa thy. 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 nor-

mal, suggesting that hyperglycemia is the cause of nephromegaly.

A

C

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 concen-

tration 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 inter-

capillary glomerulosclerosis is shown.

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A B

C D

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 speci-

men in type I diabetes. Note the loss of epithelial foot processes in

panelB. 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 arevisible in the retina and occasionally in glomerular capillaries. Amicroaneurysm in a biopsy specimen from a 4 2-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 and

type II). When associated with afferent and efferent ar teriolosclero-sis, nodular and diffuse intercapillary glomerulosclerosis is pathogno-monic for diabetic nephropathy. Aafferent artery arteriosclerosis;Ddiffuse intercapillary glomerulosclerosis; Eefferent a rtery arte-riosclerosis; Nnodular intercapillary glomerulosclerosis.

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FIGURE 1-16

Diabetic nodu les. Diabetic nodules are chara cterized by clear cen-

ters with cells along the periphery of the nod ule, as shown here in

a 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 diabetic

nodu lar glomerulosclerosis is usual, as illustrated in this totally

obliterated glomerulus obta ined by biopsy from a 65-year-old

woman with type II diabetes (periodic acidSchiff stain).

B

0.5

1.5

2.0

2.5

1.0

3.5

4.0

>4

3.0

0

Urinarya

lbum

in,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 excretion

of minute quant ities of albumin in the urine (more than 20 mg/day), is

a marker of subsequent renal deterioration in diabetic nephropa thy.

Typically, proteinuria increases to the nephrotic range, leading to

edema of the extremities and subsequent anasarca, which are often

the pr esenting complaints in diabetic nephropathy.

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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

Cumu

lative

inc

idence

chron

icrena

lfailure,%

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). Over

subsequent years of hyperglycemia, a steady decline in glomerular fil-

tration 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 con-

tains errors as high as 37%. The importance of an inconstant and thus

unpredictable 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 wa s not appreciatedthat diabetic nephropa thy was a real endpoint r isk. Older diabetic

individuals with a touch of sugar are now known to be subject to

the same microvascular a nd 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] document-

ed 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.

N um bers in parent heses indicate number of patients for each line.

(From Humphrey and cowork ers [21]; with permission.)

20

4050

60

30

8090

100110120130

70

10

0

A

1 2 3 4 5

Time,y

6

Type I diabetic patients

7 8 9 10 11

Crea

tin

inec

learance,mL/min

20

4050

60

30

8090

100110120130

70

10

Crea

tin

inec

learance,mL/min

0

B

1 2 3 4 5

Time,y

6

Type II diabetic patients

7 8 9 10 11

FIGURE 1-21Creatinine clearance. Further evidence of the similarity in course of

diabetic nephropa thy in type I (A) and type II (B) diabetes was pre-

sented 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.)

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0.5

1.5

2.0

2.5

1.0

3.5

4.0

>4

3.0

0

0.5

1.5

2.0

2.5

1.0

3.5

4.0

>4

3.0

0

GFR

,mL/min

Urinarya

lbum

in,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

Dou

blingo

fbase-l

inecrea

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

Serum

crea

tin

ine

,mg/dL

0 15 30 45 60 75

Creatinine clearance,mL/min

90

Window forconservativemanagement

105 120 135 150 165

FIGURE 1-22

Diabetic nephropathy in types I and II. Whereas microalbuminuriaand glomerular hyperfiltration are subt le pathophysiologic manifes-

tations of early diabetic nephropathy, transformation to overt clini-

cal diabetic nephropat hy takes place over mon ths 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 microalbumin-

uric individuals progress to prot einuria 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 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 start

treatment with an angiotensin-converting enzyme inhibitor in

either type of diabetes, regardless of blood pressure elevation. As is

true for other k idney 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

renoprot ective, 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 azotemia

when treated with angiotensin-converting enzyme inhibitors than

with o ther ant ihypertensive 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.)

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0 6 12 18

0

2

4

6

8

10

24 0 6 12 18 24

0

20

10

30

40

50

60

70Normoalbuminuric Microalbuminuric

Lisinopril

Placebo

Time from randomization, m

nn

227213

202196

201179

179170

193191

3445

3337

2934

2532

3237

AER

,g/m

in

AER

,g/m

in

FIGURE 1-25

Albumin excretion rate. In the recently completed Italian Euclid mul-

ticenter study, both microalbuminuric and normalbuminuric type I

diabetic patients showed benefit from treatment with lisinopril, an

angiotensin-converting enzyme inhibitor. Although microalbumin-

uria, with or without hypertension, is now sufficient reason to start

treatment with an angiotensin-converting enzyme inhibitor, the ques-tion of whether normalbuminuric, normotensive diabetic individuals

should be started on drug therapy is unanswered. AERalbumin

excretion rate. (From Euclid study [24]; with permission.)

0 10 20 30 40

0

20

40

60

80

100

120

50

0 10 20

Normal diet

30 400

A

Protein-restricted diet

B

20

40

60

80

100

120

50

Glomeru

lar

filtra

tionra

te,

mL/min/1

.73m

2

Glomeru

lar

filtra

tionra

te,

mL/min/1

.73m

2

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 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.)

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0 10 120

125

100

75

50

25

14

Ra

teo

fc

hange

inAER

,%/year

Mean Hb A1, %A

6 8 10 120

20

40

60

80

14

Ra

teo

fc

hange

inAER

,%/year

Mean Hb A1, %B

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 function-

al 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 cowor kers [26];

with permission.)

Hyperfiltration

Function

Microalbuminuria

Proteinuria

Mesangial expansion

Pathology

GBM thickening

Glomerulosclerosis

ESRD

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 pre-

cision exactly when glomerular basement membrane (GBM) thick-

ening and glomerular mesangial expansion take place. ESRDend-

stage renal disease.

DIABETIC NEPHROPATHY:COMPLICATIONS

Rate of GFRLoss

Course of proteinuria

Nephropathology

Comorbidity

Progression to ESRD

FIGURE 1-29

Type I and II nephro-

pathic equivalence. A

summation about the

equivalence of type I

and type II diabetes in

terms of nephropathy

is listed. Both types

have similar compli-

cations. ESRDend-

stage renal disease;

GFRglomerular

filtration rate.

Normotension

Euglycemia

Protein restriction

Hyperglycemia

Glomerulosclerosis

FIGURE 1-30

Major therapeutic

maneuvers to slow

loss of glomerular

filtration rate are

shown. R ecentrecognition of the

adverse effect of

hyperlipidemia is

reason to include

dietary and, if nec-

essary, drug treat-

ment for elevated

blood lipid levels.

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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(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 nephropat hy more difficult tomanage. 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 a nd Z azgornik [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

Comorb idity index. We devised a Comor-

bidity Index to facilitate initial and subse-

quent evaluations of patients over the

course of interventive studies. Each of 12

areas is rated as ha ving no disease (0) to

severe disease (3). The total score represents

overall illness and can be bo th r eproduced

by other observers and followed for years

to document improvement or deterioration.

HEART DISEASE

Hyperlipidemia

Hypertension

Volume overload

ACEinhibitor

Erythropoietin

FIGURE 1-33

Heart disease. Heart disease is the leading

cause of morbidity and death in both type I

and type II diabetes. Throughou t 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.

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 an d living

donor kidney allograft recipients fare far

better. Rehabilitation o f diabetic patients

with ESRD is incomparably better follow-

ing 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 eval-

uated diabetic persons with ESRD who are

younger than the age of 60. More than half

of diabetic recipients of a kidn ey transplant

in most series live at least 3 years: many

survivors return to occupational, school,

and home r esponsibilities.

Failure to continue monitoring of car-diac integrity may have disastrous results,

as in this relatively young type I diabetic

recipient of a cadaver renal allograft for

diabetic nephrop athy Although her allo-

graft maintained good function, coronary

artery disease progressed silently until a

myocardial infarction occurred We now

perform annua l cardiac testing in all dia-

betic patients who ha ve ESRD an d are

receiving any form of treatment.

FIGURE 1-34Heart disease and renal transplants. A, Pretransplantation. B, Five years after kidney transpla-

tion. 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 single-

center 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

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RETINOPATHY

Hyperglycemia

Hypertension

Volume overload

Photocoagulation

Erythropoietin

FIGURE 1-35

Retinopathy. Blindness due to t he hemorrha gic and fibrotic changes of diabetic retinopathy

is 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. The

interrelationship among hyperglycemia, hypertension, hypoxemia, and angiogenic factors is

now being defined. There is reason to hope that specifically designed interdictive measuresmay halt progression of loss of sight.

FIGURE 1-36

Retinopath ic changes. Proliferative retinopathy, microcapillary

aneurysms, and dot plus blot hemorrhages are present in this fun-

duscopic photograph taken at the time of initial renal evaluation of

a nephr otic 37-year-old woman with type I diabetes. After pre-

scription of a d iuretic regimen, immediate consultation with a

laser-skilled opht halmologist was arranged.

A B

FIGURE 1-37

Panretinal phot ocoagulation (PRP). A, PRP is the therapeutic

technique performed for proliferative retinopathy using an argon

laser t o d eliver ap proximately 1500 discrete retinal burns, avoid-

ing the fovea and disk (IA

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AMPUTATION

Inspection

Shoes

Socks

Nails

Prompt treatment

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 thatemphasize prophylactic foot care as a component of preventive medicine have reduced the

incidence of limb amputation to about 5% after 3 years.

B

A

FIGURE 1-39

Genesis of foot problems. The genesis of diabetic foot problems

includes peripheral neuropa thy, 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 neuropat hy may involve the propr iocep-

tive nerves, removing limitation of joint stretching and resulting in

bone shifts and joint destruction, a s seen in the Charcot s joint

shown h ere. 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 collaborat ing podiatrist stat ioned within the renal clinic

adds a level of protection for d iabetic kidney patients. Common

lesions, like this pressure ulcer overlying the head of the first

metatarsal, are managed easily with shoe pads that shift weightbear-

ing. 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

OpththalmologistPodiatrist

Cardiologist

Nutritionist

Nurse educator

Consultants

NeurologistVascular surgeon

Endocrinologist

Gastroenterologist

Urologist

FIGURE 1-42

Team management of neuropathy. Proper

management of diabetic kidney patients

requires a skilled team including collaborat-

ing specialists. Depending on the qualifica-

tions of the patients primary physician,

other professionals are recruited as needed.

A nurse educator can ease the interfacebetween otherwise independent specialists.

Without such a t eam mentality, the d iabetic

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 dis-

ease, patient education facilitates the choice

of uremia therapy and, if appropr iate, inter-

action with the renal tr ansplant service.

AUTONOMIC NEUROPATHY

Cardiovascular (rate, QT, R-R)

Orthostatic hypotension

Gastroparesis

Cystopathy

Diarrhea, obstipation

FIGURE 1-43

Autonomic neuropathy. Autonomic neu-

ropathy accompanies advanced diabetic

nephropa thy. While an unvarying R-R

interval may ha ve minimal clinical impor -

tance, diabetic cystopathy and reduced

bowel mo tility, including gastroparesis, may

seriously impede quality of life. Questioning

to discern the presence of travel-limitingdiarrhea, obstipation, and gastroparesis

should be included in each initial evaluation

of a diabetic kidney patient. (From Spallone

and M enzinger [30]; with permission.)

GASTROPARESISIN 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 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 t racer. Satisfactory drug

treatment for gastropar esis 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

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 than

3.5 g/day (nephrotic range), leading to hypoproteinemia, hyperlipidemia, and extracellular

fluid accumulation (nephrotic syndrome). Management of a nephrotic diabetic patientincludes minimizing pro tein loss u sing 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 nephrot ic edema

requires assessment of cardiac function. (From Herbert et at. [33] and Gault and

Fernandez [34]; with permission.)

FIGURE 1-46

Anasarca. Anasarca is a long-term management problem in diabetic nephropa thy. As renal

reserve 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 each

days dose of diuretics (metolazone plus furosemide) is a workable strategy. Once the crea-

tinine clearance falls below 10 mL/min, ambu latory dialysis may be the only means of

continuing life outside the hospital.

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60

0

7545

30

15

5

90

105

Diab

etics

Creatinine

clearance,mL/min

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 col-

leagues [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 mor tality or comorbidity in pat ients receivinghemodialysis versus peritoneal dialysis suffer from the limitations o f starting with un equal

cohorts r eflecting 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 w ith CAPD tha n with hemodialysis. Furthermore, pat ients receiving peritoneal

dialysis in the United States have a 14% greater risk of hospitalization than do pa tients

undergoing hemodialysis [38]. Benefits of peritoneal dialysis, including freedom from a

machine and electrical outlets and ease of travel, stand against the disadvanta ges 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 initi-

ating maintenance hemodialysis or peritoneal dialysis. As a generalization, d iabetic indi-

viduals with pr ogressive renal disease decompensate with u remic symptoms earlier t han

nondiabetic 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 r eversed sleep pattern characteristic of renal failure. Sometimes, both physicianand patient appreciate that lassitude and decreasing activity in a catabolic patient signal

the need to begin dialysis.

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 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 with

representatives of patient self-help groups, such as the American Association of Kidney

Patients, and institutional t ransplant coordinato rs aid in communicating the information

required by patients to enable them to select from available options for uremia therapy.

Center hemoHome hemoCAPDCCPDTransplant

Nondiabetic Diabetic

4064 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 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 ambu-

latory peritoneal dialysis (CAPD) or machine-based continuous cyclic

peritoneal dialysis (CCPD) than are nondiabetic patients with ESRD.

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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

Surviv

ing,%

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 tabulat ed in the

1997 report of the United States Renal Data System [1], there are

sharp differences in survival between diabetic and nond iabetic

patients with end-stage renal disease (ESRD) as well as between

treatment b y dialysis versus kidney transplan tation. The highest

death rate is suffered by diabetic dialysis patients (combined peri-

toneal dialysis and hemodialysis), while the best survival is experi-enced by nond iabetic renal transplant recipients. Selection bias in

choosing more fit ESRD patients for kidney transplantation while

leaving a r esidual pool of sicker pa tients for dialysis account s 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 w ith end-stage renal disease (ESRD) tr eated 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 t o survive.

0

40

30

20

10Dea

thsper

1000Pa

tien

tYears

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

USRDS1996

Ages 4564

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-stage

renal disease (ESRD) relates to comorbidity, as shown in this tab leabstracted 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, hemodialy-

sis, or renal transplantation are shown. N ote 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 are

less frequent in diabetic than in nondiabetic patients with ESRD.

CVAcerebrovascular accident; Diabdiabetes; K+potassium;

MImyocardial infarction.

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COMPLICATIONSIN PATIENTSRECEIVING HEMODIALYSIS

Inadequate vascular access

Steal, thrombosis/infection

Interdialytic hypotension

Progressive eye disease

Progressive vascular disease

Minimal rehabilitation

COMPLICATIONSIN PATIENTSRECEIVING PERITONEAL DIALYSIS

Peritonitis

Tunnel infection

Abdominal/back pain

Retinopathy

Progressive vascular disease

Minimal rehabilitation

COMPLICATIONSIN 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 diabetic

hemodialysis p atients.

FIGURE 1-54

Complications prevalent in d iabetic peri-

toneal d ialysis patients. FIGURE 1-55

Frequent complications reported in diabetic

kidney transplant recipients. AFBacid fast

bacteria; CMVcytomegalovirus.

Rehabilitation

Death

Kidney transplant

Hemodialysis

Peritoneal dialysis

Withdrawal

Karno

fskyscore

50

100

0

OPTIONSIN DIABETESWITH ESRD

First-year survival

Survival >10 y

Diabetic complications

Rehabilitation

Patient acceptance

CAPD/ CCPD

75%

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 tr eatment. Thus, if younger, healthier subjects are offered kidney

transplantation, then subsequent relative survival analysis will be adversely affected for the

residual pool t reated 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.

FIGURE 1-57

Karnofsky scores in r ehabilitation. Graphic

depiction o f rehabilitation in d iabetic

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 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 from

any cause. A score below 60 indicates mar-

ginal function and failed rehabilitation.

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A B

FIGURE 1-58

Complications of the hemodialysis regimen

are more frequent in diabetic than in nondia-

betic patients. A, Axillary vein occlusion

proximal to an art eriovenous graft used for

dialysis access is shown. B, Balloon angio-

plasty proffers only temporary respite owingto a h igh 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

74 74.4

76.2

USRDS1996

PD + Hemo

Surv

iving,%

FIGURE 1-59Improving one year survival with dialysis. The summative effect of multiple incremen-

tal improvements in man agement o f diabetic patients with end-stage renal disease

(ESRD) is reflected in a continuing increase in survival. Shown here, abstracted from

the 19 77 report of the United States Renal Data System (USRDS), is the increasing

first-year survival rates for hemodialysis (hemo) plus p eritoneal dialysis (PD) pa tients

with diabetes.

LIFE PLAN FOR DIABETICNEPHROPATHY

Explore and endorse treatment goals

Enlist patient as key team member

Prepare patient for probable course

Priorit ize ESRD opt ions

FIGURE 1-60

Life plan. Given the concurrent involvement

of multiple consultants in the care of dia-

betic individuals with end-stage renal dis-

ease (ESRD), there is a need for a defined

strategy, here termed a Life Plan.

Switching from hemodialysis to peritonealdialysis (or the reverse) and deciding on a

midcourse kidney transplant are common

occurrences that ought not to provoke anx-

iety or stress. Reappraisal and r econstruc-

tion o f the Life Plan should be performed

by patient and physician at least annually.

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