Review

E arly Diabetic Nephropathy: Assessment and

Potential Therapeutic Interventions
JULIO ROSENSTOCK, MD AND PHILIP RASKIN, MD
End-stage renal failure secondary to diabetes has increasingly become a health and socioeconomic issue.
Diabetic nephropathy is the major cause of death in type I insulin-dependent diabetic patients and
accounts for —25% of all patients beginning hemodialysis in the United States. Once diabetic nephrop-
athy is well established, attempts to modify the relentless downward progression of the disease have
been essentially unsuccessful. We focus on the early structural and functional changes that occur as a
consequence of diabetic renal disease and examine the evidence for microalbuminuria as an early marker
and predictor for future overt diabetic nephropathy. The rationale for different therapeutic interventions
to alter the course of early diabetic nephropathy are discussed, DIABETES CARE 1986; 9:529-45.

E
nd-stage renal failure secondary to diabetes mellitus
has become an important health and socioeconomic
issue in the United States. Diabetic nephropathy is
the major cause of renal failure in twenty-five per-
cent of all patients beginning therapy for end-stage renal
disease in this country.1 By the end of this decade, the cost
of care for the uremic diabetic patient is estimated to approach
$2 billion a year.2
Once diabetic renal disease is well established, attempts to
modify the relentless progression of the disease have been
essentially unsuccessful. Apparently, when diabetic nephrop-
athy reaches a certain level of severity, the process becomes
self-perpetuating. Improved glycemic control has not been
shown to have obvious beneficial effects.3 Treatment of hy-
pertension has retarded the progression of the kidney disease,
however.4"6
Considerable interest has emerged with recent reports that
have characterized a much earlier stage of diabetic nephrop-
athy. A growing body of evidence suggests that a persistent
elevation of urinary albumin excretion in diabetic patients
without clinical proteinuria predicts future development of
overt diabetic nephropathy.7 This review addresses the issue
of diabetic nephropathy from the different and much more
promising perspective of early identification and early inter-
vention. We discuss the rationale for different therapeutic
approaches on the progression of early diabetic nephropathy.
OVERT DIABETIC NEPHROPATHY
Magnitude of the nephropathy problem in diabetes mellitus.
Diabetic nephropathy is the major cause of death in pa-
tients with type I diabetes mellitus.8 Deckert et al.9 reported
that of 306 diabetic patients whose illness was diagnosed
before age 31 yr and analyzed after at least 40 yr of diabetes,
proteinuria was present in 38% and uremia in 22% of the
patients. In 31% of the deceased patients, uremia was the
cause of death. The excess mortality in patients exhibiting
persistent proteinuria with <40 yr of diabetes was three to
four times higher than in patients who, after 40 yr of diabetes,
were free of proteinuria.
The Pittsburgh insulin-dependent diabetes mellitus (IDDM)
morbidity and mortality study analyzed 1894 patients with
IDDM diagnosed between 1950 and 1981.10 Overall, IDDM
patients had a 7-fold excess in mortality risk compared with
the United States' population of the same age. The average
age of death in 8.7% of this population was 23 yr. The mag-
nitude of the increased mortality was particularly striking in
patients 25-40 yr old. More than 2% of these patients died
each year, which is ~20-fold greater mortality compared with
the United States' population. In this age group (25—40 yr),
renal disease accounted for >50% of the deaths.
Important information has emerged from the elegant epi-
demiological studies carried out at Steno Memorial Hospital.
These workers have been able to analyze ~ 2 3 % of all IDDM
patients diagnosed in Denmark between 1923 and 1953. n In
1303 patients, who were followed until death or for at least
25 yr after the onset of diabetes, they were able to obtain
sufficient information on proteinuria. Diabetic nephropathy,
defined by persistent proteinuria (protein excretion >0.5 g/
24 h in at least four consecutive 24-h samples), was found
in 41% of the patients. Fifty-seven percent did not develop
persistent proteinuria during the follow-up period. The max-

DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986 529

 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
imal prevalence of nephropathy in relation to duration of
diabetes was 21% after 20-25 yr of diabetes. It declined
(probably by a process of self-selection) to —10% in patients
who had suffered from diabetes for >40 yr. The cumulative
incidence data from the study indicate that ~45% of all
IDDM patients will develop nephropathy after 40 yr of the
disease.
Patients with nephropathy had a much poorer survival rate
than those without proteinuria. After 40 yr of diabetes, only
10% of the patients who developed nephropathy were alive,
whereas >70% of patients who did not develop nephropathy
survived. Uremia was the cause of death in 66% of the pa-
tients with nephropathy. Mortality was ~49% in patients
with persistent proteinuria for ^ 7 yr."
Diagnosis of overt diabetic nephropathy. There are clear struc-
tural and functional abnormalities in the kidney in IDDM
patients. The hallmark for the classic clinical diagnosis of
diabetic nephropathy is the appearance of persistent dipstick-
positive proteinuria that usually represents a urinary protein
excretion >0.5 g/24 h . n Arterial blood pressure then usually
begins to rise, and the glomerular filtration rate (GFR) starts
its apparent inexorable decline with the subsequent progres-
sive elevation of serum creatinine levels.13 The advanced
pathologic lesions of diabetic nephropathy are highly specific
and separate chronic renal failure due to diabetes from other
causes of end-stage renal disease. Glomerular basement mem-
brane (GBM) thickening and mesangial expansion, as well
as afferent and efferent arterial hyalinosis, are commonly seen.
In addition, there is an increased renal linear extracellular-
membrane staining for albumin and immunoglobulin G (IgG)
that are quite specific for diabetic nephropathy.14
GBM thickening and expansion of the glomerular mes-
angium, primarily due to the enlargement of the mesangial
matrix, is a constant finding in most patients with diabetic
nephropathy.15 It seems that initially the pattern is of a pro-
gressive GBM thickening, and then most of the basement
membrane-like material eventually accumulates in the mes-
angial region.16 The end result of the basement membrane
accumulation within an individual glomerulus is glomerular
occlusion. This event occurs after ~15 yr of diabetes, and it
may be related to mesangial expansion encroaching on the
subendothelial space, eventually compromising the glomer-
ular capillary lumen and blood flow.H The number of occluded
glomeruli appears to increase as the duration of diabetes in-
creases. In autopsy studies of patients with long-standing IDDM,
Gunderson and Osterby17 found a relationship between the
number of glomeruli with capillary occlusions and both du-
ration of the disease and degree of renal failure.
However, an intriguing dissociation occurs when structural
and morphological changes in the kidney are related to renal
function in IDDM patients. Whereas 30-40% of all IDDM
patients will develop overt clinical diabetic nephropathy, 60-
70% of patients never develop clinical renal disease, despite
histological evidence of glomerulosclerosis in nearly all IDDM
patients after only a few years of the disease.18
To elucidate the relationship between clinical diabetic renal
disease and renal pathology, the Steno group studied autopsy
530 DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
material from 34 long-term IDDM patients. Half of these
patients had no clinical evidence of nephropathy, and the
other 17 matched patients had severe clinical nephrop-
athy. 19>2° Patients who had clinical renal disease had signifi-
cantly more interstitial tissue and glomerular mesangium ex-
pansion and less open glomerular capillaries than the diabetic
subjects without clinical nephropathy. However, severe glom-
erulosclerosis was also seen in patients without clinical evi-
dence of nephropathy. Serum creatinine levels were best cor-
related with the mesangial area, and a significant negative
correlation existed between the relative areas of open capil-
laries and amount of mesangium present. Remarkable mes-
angial expansion was seen in most of the patients with clinical
renal disease, but it was also present in several diabetic sub-
jects who did not have clinical nephropathy. The area of
open capillaries appeared to be a good light-microscopic in-
dicator of clinical nephropathy.
Mauer et al.21 have reported elegant studies of renal biopsies
from 45 patients with IDDM. These specimens were exam-
ined by semiquantitative light-microscopic and quantitative
electron-microscopic stereologic morphometry. These pa-
tients had IDDM for 2.5-29 yr, but only 16 patients had
clinical evidence of nephropathy. The renal biopsies were
performed as part of their evaluation as potential pancreas-
transplant recipients. Surprisingly, no relationship was found
between either GBM thickening or mesangial expansion and
the duration of the diabetes. A relatively weak but statistically
significant relationship was found between the thickness of
the GBM and the expansion of the mesangium, suggesting a
different production and turnover rate for GBM and mes-
angial matrix constituents. The total mesangium volume had
a strong inverse correlation with the capillary-filtration sur-
face area. Finally, there was no significant relationship be-
tween creatinine clearance and GBM thickness. The mes-
angial expansion had a strong inverse correlation with creatinine
clearance, however. This meticulous study demonstrates that
clinical diabetic nephropathy does not become manifest until
renal lesions become far advanced. Patients with the earliest
findings of overt clinical nephropathy uniformly had severe
glomerular lesions. It was hypothesized that progressive mes-
angial expansion could ultimately contribute to glomerular
functional deterioration by restriction of the glomerular cap-
illary vasculature and the surface area available for filtration.
Natural course of diabetic nephropathy. Once clinical pro-
teinuria develops in diabetic patients, glomerular function
progressively and relentlessly declines. The mean duration of
diabetes at onset of proteinuria and the subsequent clinical
course was reported in a retrospective study by the Joslin
Clinic (Table I). 22 Similar results were found by the Steno
Memorial Hospital in 157 IDDM patients with diabetic ne-
phropathy.23 Persistent proteinuria appeared after an average
of 19 yr, and death ensued 5-6 yr later.
The rate of deterioration of glomerular function in diabetic
nephropathy varies considerably among patients. However,
the decline is linear over time and is characteristic for the
individual patient.24'25 Once the serum creatinine concentra-
tion rises above 2 mg/dl, the progression of the renal failure
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
TABLE 1
Duration of diabetes and degree of renal dysfunction at various stages of nephropathy
Onset of proteinuria
(N = 112)
Duration of diabetes (yr) 17.3 ± 6.0
Blood urea nitrogen level (mg/100 ml) 18.2 ± 6.0
Creatinine level (mg/100 ml) 1.2 ± 0.3
From Kussman et al. 22
in each patient is constant and predictable. The relationship
between the inverse of the serum creatinine concentration
and time in months is used to show this straight-line corre-
lation (Fig. 1).
Prospective studies in IDDM patients with clinical pro-
teinuria have also shown that the decline in GFR has a striking
linear relationship with time.26'27 Mogensen26 found that GFR
fell at a rate of 0.9 ml • min" 1 • mo" 1 during 34 mo of ob-
servation. Recently, Viberti et al.27 reported a similar linear
decline in GFR. In this study the rate of fall of the GFR
ranged between 0.63 and 2.4 ml • min" 1 -mo" 1 with a mean
of 1.2 ml • min" 1 • mo" 1 . Furthermore, a positive correlation
was found between the rate of change of GFR and the recip-
rocal of the serum creatinine level. When the reciprocal of
the plasma 32-microglobulin concentration was used, there
was an even stronger correlation with GFR. The plasma fi2-
microglobulin concentration rises to levels above normal as
the GFR falls below 80 ml • min" 1 • 1.73 m" 2 . This is in
clear contrast with the plasma creatinine concentration, which
is still within the normal range at a similar level of glomerular
filtration.28 Although Parving et al.29 found a similar strong
correlation between the reciprocal of the plasma (32-micro-
globulin concentration and the rate of decline of GFR, the
cutoff point when the serum p2-microglobulin concentration
exceeded the upper limit of normal was at a GFR of <60
ml • min" 1 • 1.73 m~2.
FIG. 1. Progression of renal failure in 9 di-
abetic patients. Inverse of serum creatinine
(jjunol/L) plotted against time.25
DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
Renal failure
Early Late Death
(N = 70) (N = 62) (N = 61)
19.4 ± 5.4 21.6 ± 6.3 22.1 ± 6.4
41.2 ± 13.5 98.5 ± 45.5 151.0 ± 53.6
2.8 ± 0.9 8.5 ± 3.9 12.4 ± 6.4
EARLY DIABETIC NEPHROPATHY
Important functional and structural events occur in the kid-
ney of diabetic patients during the 10-20 yr before the onset
of overt clinical proteinuria. There is now overwhelming evi-
dence of a silent period in the course of diabetic nephropathy
with demonstrable pathological glomerular changes but with-
out clinical manifestations. This silent period is followed by
a stage of early diabetic nephropathy. The only clinical man-
ifestation of this stage of early diabetic nephropathy is an
increased urinary albumin excretion rate (UAER).30 Unger
and Foster31 have summarized the clinical course of diabetic
nephropathy beginning with the diagnosis of diabetes (Table
2). Mogensen's original classification of the different stages
of diabetic renal disease, however, clearly separated the silent
period from the microalbuminuric stage. Mogensen et al.32
called the period of increased urinary albumin excretion (UAE)
incipient or early diabetic nephropathy.
Microalbuminuria. In addition to developing the first uri-
nary albumin radioimmunoassay (RIA),33 Keen and Chlou-
verakis conceived the idea in the Bedford study that subclin-
ical elevations of UAE in nonproteinuric subjects may indicate
an earlier stage of diabetic nephropathy.34
Microalbuminuria can be defined as an increased UAE
above the upper limit of normal but not detectable by standard
clinical tests. The albumin excretion rate (AER) measured
10 20 30
Time (months)
531
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
TABLE 2
Typical clinical course of diabetic nephropathy
Years after onset
of diabetes
0 Enlarged kidneys, supernormal function,
microalbuminuria reversed by meticulous insulin
treatment
—2 Thickening of glomerular basement membrane and
increase in mesangial matrix
—10—15 "Silent period," no overt proteinuria, micro-
albuminuria may be present, especially after
exercise (>30 |xg/min indicative of future
proteinuria)
— 10-20 "Proteinuric period," intermittent at first, then
persistent (>0.5 g/24 h); a relentless decline in
glomerular function has begun
>15 "Azotemic period" begins —17 yr after onset
—20 "Uremic period," diabetic retinopathy, hypertension,
and nephrotic syndrome may be present
From Unger and Foster."
by a sensitive RIA in healthy subjects varies between 2.5 and
25 mg/24 h with a mean —9.5 mg/24 h.35 By use of part-day,
timed collections, the normal values of AER can be more
narrowly defined with a mean of 4.3 ± 1.3 (xg/min, with a
range of 2.3-8.3 |xg/min.7 In normal subjects, albumin rep-
resents up to 11% of the total urinary protein excretion. In
patients with increased AER, the proportion of albumin rises
to 22%. Diabetic patients with dipstick-positive urine have
a total urinary protein excretion >0.5 g/24 h, of which 50%
is albumin.36 The glomerular origin of the microalbuminuria
found in IDDM patients is supported by the concommitant
finding of a normal excretion of 32'microglobulin, a sensitive
indicator of tubular reabsorptive capacity.37
In January 1985, researchers from the three major diabetes
centers in Denmark met at "The Gentofte Convention on
Microalbuminuria and Incipient Diabetic Nephropathy. "38 A
consensus was reached to define microalbuminuria as an UAER
>20 (xg/min but ^200 (xg/min (Table 3). The diagnosis of
early or incipient diabetic nephropathy is made only when
microalbuminuria is found in two of three urine samples col-
lected within 6 mo.
Note that collections of sequential urine samples are re-
quired. Diabetic subjects with and without microalbuminuria
can have a daily variation in albumin excretion as high as
47%.39 The reason for this high coefficient of variation among
multiple samples remains largely unknown, but several factors
such as incomplete urine collections, physical activity, and
differences in metabolic control might influence the AER.
Before a patient is categorized as having microalbuminuria,
other causes of transient or reversible elevation of albumin
excretion must be excluded. Such transient or reversible causes
include poor diabetic control, urinary tract infection, physical
exercise, essential hypertension, cardiac insufficiency, and
water loading.
532 DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
At diagnosis, Mogensen found slight elevations of AER
that promptly reverted to normal with insulin therapy.40 Even
short periods of poor glycemic control would elevate the AER,
as shown by Parving et al. ,41 when insulin therapy was de-
liberately withdrawn in type I diabetic patients. It has been
estimated that with conventional diabetes management ~ 3 0 -
45% of dipstick-negative IDDM patients will be found to
have an elevated AER.42 The prevalence of real and persistent
microalbuminuria, however, remains to be established.
Enthusiastic attention was initially given to exercise-in-
duced albuminuria in an attempt to establish a provocative
test that might identify an even earlier stage of diabetic
nephropathy.43"47 Under conventional glycemic control, di-
abetic patients with normal resting AER show marked albu-
minuric response to physical exercise compared with matched
nondiabetic controls. In most studies, patients with microal-
buminuria responded with an even greater potentiation of
AER. However, exercise-induced albuminuria may have no
predictive value and adds no additional information to that
obtained with timed urine collections (under basal condi-
tions) that measure AER.48
The AER can be transiently increased by an acute increase
in urine flow during water loading (as with GFR studies).
The peak albumin excretion is reached 30—60 min after water
loading and then falls by 90 min to remain constant thereafter
with a steady state of water diuresis.49
Predictive value of microalbuminuria. Substantial evidence
is available to suggest that an elevation of UAE without
clinical proteinuria, strongly predicts a later progression of
diabetic renal disease.50"55 Table 4 summarizes the long-term
longitudinal studies that have examined the predictive value
of microalbuminuria.
Parving et al.50 were probably the first to attempt to identify
patients at high risk of developing diabetic nephropathy. After
6 yr, 5 of the 8 patients with an elevated AER (mean 115 ±
24 mg/24 h) had subsequently developed persistent overt
proteinuria, elevated serum creatinine, and raised blood pres-
sure. One patient developed intermittent proteinuria. In
contrast, only 2 of 15 patients with normal AER developed
proteinuria. Viberti et al.51 reported a cohort study of 63
insulin-treated diabetic subjects screened in 1966—1967 and
reassessed 14 yr later. Persistent dipstick-positive proteinuria
developed in 7 of the 8 patients (88%) with an overnight
AER >30 |xg/min and in only 2 of the remaining 55 (4%)
TABLE 3
Early diabetic nephropathy
Albumin excretion rates
Normoalbuminuria (dipstick-negative) <20 n-g/min (<30 mg/24 h)
Microalbuminuria (dipstick-negative) 20-200 pug/min
(30-300 mg/24 h)
Overt proteinuria (dipstick-positive) >200 (xg/min (>300 mg/24 h)
Diagnosis
Persistent microalbuminaria levels found in at least two of three urine
samples collected within 6 mo
From Mogensen.38
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN

TABLE 4
Predictive value of microalbuminuria

Type of No. of Initial age Follow-up No. patients at AER Patients with
Study diabetes patients (yr) (yr) follow-up (ng/min) progression

Parving et al.50 Age 16-40 yr 25 29 6 23 (92%) 28 >28 = 6/8 (75%)

Onset >31 yr
Duration 10-25 yr <28 = 2/15 (13%)
Viberti et al.51 Insulin treated 84 40 14 63 (75%) 30 >30 = 7/8 (88%)
Age <60 yr <30 = 2/55 (4%)'
Mogensen and Onset <20 yr 44 25 10 43 (98%) 15 >15 = 12/14(86%)
Christiansen52 Duration 7-19 yr < 15 = 0/29 (0%)
Mathiesen et al.53 Age < 50 yr 71 30 6 71 (100%) 70 >70 = 7/7 (100%)
Onset <35 yr <70 = 3/64 (5%)

AER, albumin excretion rate cutoff point. Modified from Mogensen.7

patients that had an AER below that level. Therefore, the values <10 |xg/min, whereas 6 of 17 deceased patients had
risk of the microalbuminuric group developing diabetic ne- an AER >30 (xg/min. The mortality risk for subjects with an
phropathy was 22 times higher than patients without elevated AER >30|xg/min was 3.3.
AERs. Natural course of early diabetic nephropathy. The role of blood
Recently Mogensen and Christensen52 showed that 86% of pressure and renal hemodynamics on the progression rate of
IDDM patients with AERs >15 |xg/min will develop clinical early diabetic nephropathy was recently examined in 46
nephropathy over the next 10 yr. Of the 14 patients with an matched IDDM subjects with and without microalbumin-
initial AER ^15 jxg/min, 12 patients had clinically detect- uria.56 Both systolic and diastolic blood pressure levels as well
able proteinuria (>0.5 g/24 h) or an AER >150 |xg/min at as GFRs were higher in patients with microalbuminuria com-
the subsequent examination. Of the 29 patients who initially pared with normal subjects and normoalbuminuric diabetic
had an AER <15 (xg/min, none had subsequent clinically patients. A small subgroup of 10 patients with microalbu-
detectable proteinuria, although 4 subjects later developed minuria were followed for 5 yr in an uncontrolled longitudinal
microalbuminuria. Patients whose conditions progressed to fashion. These patients showed an average yearly AER in-
clinically overt proteinuria had elevated GFRs and higher crease of 20%; furthermore, the increased AER correlated
blood pressures at the initial examination than patients in significantly with the increase in diastolic blood pressure. A
whom proteinuria did not develop. Of note was the finding hypothetical model of the natural course of diabetic nephrop-
that the GFR and UAE increased concommitantly until the athy as suggested by Mogensen30 is shown in Fig. 2.
GFR was >150 ml/min. Thereafter, the values for the GFR
declined and, at the same time, the AER increased. A pre-
10,000
dictive index was suggested by the authors because all patients
fulfilling the criteria of a UAER >15 jtg/min, a GFR >150
ml/min, and a diastolic blood pressure ^90 mmHg did prog-
ress to overt nephropathy. Mathiesen et al. ,53 from the Steno
Memorial Hospital, reported findings similar to the above
studies, but the levels of AER that predicted nephropathy
were considerably higher (70 (xg/min).
Mogensen54 has also clearly shown that microalbuminuria
predicts clinical proteinuria and increased mortality in pa-
tients with type II diabetes mellitus. Clinical proteinuria de-
veloped in 22% of patients with microalbuminuria but in only
5% of the patients with AERs <30 fxg/min. After 10 yr,
22% of the group with an AER between 30 and 140 n-g/min
were still alive compared with 57% of the patients with an
AER <15 u,g/min. The survival rate of patients with a long 10
duration of diabetes (>11 yr) was 4.5% in the group with an Diabetes duration (yrs)
AER 30-140 u.g/min compared with a 57% survival rate in
FIG. 2. Hypothetical model of development of renal changes in
patients with an AER <15 |xg/min and same duration of diabetes mellitus. In incipient or early nephropathy, yearly per-
disease. A substantially increased mortality risk in non-in- centage increase is ~20% with wide range of variations. In overt
sulin-dependent diabetics with an elevated AER was also renal disease, rate of progression occurs at accelerated rate but
found by Jarret et al.55 Note that of 25 survivors, 24 had AER varies widely among patients.30

DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986 533

 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
PATHOGENESIS OF MICROALBUMINURIA
Much controversy exists regarding the mechanisms that affect
the glomerular filtration barrier in microalbuminuric patients
with early diabetic nephropathy. The transglomerular passage
of plasma proteins depends on several factors, including 1)
structural changes in the glomerular membrane, 2) renal
hemodynamics such as renal plasma flow and the transcap-
illary hydraulic pressure, and 3) filtration surface area ab-
normalities at the pore-size or pore-charge level. Mechanisms
that explain the increased albumin clearance across the glo-
merular filter can therefore be found at different sites.
Renal structure abnormalities. Mogensen and Andersen57 first
reported a 22% increase in radiological size of the kidney
associated with an elevated GFR in 12 short-term IDDM
patients. Subsequently, they obtained similar findings in 6
newly diagnosed IDDM patients that showed a significant
reduction in kidney size and GFR after 3 mo of strict insulin
treatment.58 It has been consistently shown that GFR has a
significant positive correlation with kidney size, measured
either by radiological57 or ultrasound techniques.59 However,
the initial report of the reduction of kidney size that occurs
with insulin therapy has not yet been confirmed. Christiansen
et al.60 studied newly diagnosed IDDM patients who achieved
near-normoglycemic control for 8 days with either an artificial
pancreas device or multiple daily insulin injections. Although
GFR was reduced by 17%, it still remained >20% of the
normal value. In this study, the kidney size was unchanged
by insulin therapy. Recently, Wiseman and colleagues61 dem-
onstrated no change in kidney volume despite a significant
reduction of GFR in 6 IDDM patients treated with continuous
subcutaneous insulin infusion (CSII) for 1 yr. The conven-
tionally treated control group showed no change in any of
the above parameters.
Morphometric studies that use stereological electron-mi-
croscopic methods of renal biopsies from short-term IDDM
patients have shown an increase in glomerular size62 and glo-
merular filtration surface area.63 After 4 days of streptozocin-
induced diabetes in rats, a significant glomerular enlargement
is demonstrable by light microscopy.64 An increased volume
of the glomerular peripheral basement membrane was also
found after 4 days of diabetes in the streptozocin rats.65 Kidney
weight increased 15-20% 3 days after streptozocin and 70-
90% after 6 wk. The water concentration of the kidneys is
constant, and the protein content rises in parallel to the
weight.66
The diabetic kidney enlarges because of cellular hypertro-
phy and hyperplasia. The first sign of growth is an increase
in RNA content that is measurable 24 h after the onset of
glycosuria. Shortly thereafter, an increase in the protein/
DNA ratio can be measured, indicating hypertrophy of the
cells.67 There is a close correlation between the blood glucose
level and the rate of kidney growth.68 Plasma glucagon levels
are elevated in diabetic rats, and orotate incorporation into
glomerular DNA correlates with the plasma glucagon con-
centration.69 Furthermore, orotate incorporation is inhibited
by infusion of insulin in doses so small that plasma glucose
534 DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
levels remain unchanged, but glucagon levels are lowered.
The addition of glucagon to the infusion mixture increases
orotate incorporation. The role of the growth hormone in
this process is controversial. The effect of growth hormone
increases in GFR in clinical studies will be discussed below.
However, when growth hormone is administered for 4 days,
no increase in kidney weight or content of nucleic acids is
found in normal or diabetic rats.70 The mechanism for the
renal hypertrophy and hyperplasia in diabetes is unknown.71
Interestingly, insulin treatment for 8 days prevents changes
in both kidney weight and cell growth (protein/DNA ratio).66
Six months of insulin treatment prevents all renal morpho-
logic changes.72"74
The implications of all the observed early, structural, renal
changes on the development of diabetic kidney disease re-
mains to be established. Diabetic nephropathy should be re-
garded as a continuum that evolves from early renal hyper-
trophy through the late changes of advanced structural distortion
of glomeruli, renal vasculature, and interstitium.14 Sophisti-
cated morphometric studies performed on kidney biopsies
showed that GBM and mesangial basement membrane-like
material are normal at diagnosis of type I diabetes.75 However,
within 1.5-2.5 yr the GBM width increases 10-15%. After
5 yr of diabetes the GBM width is 30% greater than it is in
controls.
The gradual progression of GBM thickening with time may
not explain the alteration in glomerular permselectivity man-
ifested by increased albumin excretion. A gradual increase in
albuminuria would be expected as GBM thickening increases;
however, the structural-functional studies by Mauer et al.21
mentioned above indicate that GBM thickening is compatible
with intact permselectivity, whereas minimal GBM thick-
ening can be associated with massive proteinuria. Note, how-
ever, that this study21 was not designed to evaluate patients
with microalbuminuria and early diabetic nephropathy. Mi-
croalbuminuria levels were found in 6 of 24 patients without
overt diabetic nephropathy, but the assay of urinary albumin
used had a low sensitivity, and the number of urine collections
was not specified. No structural glomerular parameter pre-
cisely predicted UAE. However, all patients whose kidneys
showed a total mesangial volume >37% and a reduced pe-
ripheral capillary surface had >400 mg/24 h UAE (overt
proteinuria). A UAER between 40 and 400 mg/24 h was not
necessarily associated with more advanced glomerular changes.
Conversely, patients with severe glomerulopathy, regularly
seen in patients with clinical nephropathy, had normal UAE.
There was a trend of a relationship between the GBM thick-
ness and the UAE, but it did not reach statistical significance.
Note the finding, not commented on by the authors, of hy-
alinized glomeruli in 5 of the 24 patients without overt ne-
phropathy, and 4 of these 5 patients had microalbuminuria.
Osterby et al.76 recently reported that patients with early
diabetic nephropathy, defined as a UAER between 20 and
600 |xg/ml and a GFR >100 ml/min, appeared to have more
advanced renal structural changes than patients without this
condition. They also had less glomerular destruction than
patients with advanced diabetic nephropathy. Contrary to
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
the previous study,21 significant correlations were found be-
tween the duration of diabetes and the thickness of the GBM.
Mesangial expansion as well as the volume of mesangial base-
ment membrane-like material relative to tuft volume were
also increased with increasing duration of diabetes in this
study.76 Finally, at the Steno Hospital, analysis of the amount
of mesangial tissue and the area of open capillaries in human
diabetic kidney biopsies failed to disclose significant differ-
ences when diabetic patients with no evidence of clinical
nephropathy were compared with patients with early diabetic
nephropathy.77
In summary, it appears that morphological changes them-
selves cannot be the chief cause of the increased UAER seen
in early diabetic nephropathy. Although it is generally ac-
cepted that kidney biopsy is not a screening procedure for all
patients, structure-function studies are viewed as increasingly
important by some researchers. However, we cannot now
accept the view of the Minnesota group who recommend
kidney biopsy as a baseline procedure in diabetic patients after
~10 yr of disease to decide the degree of intensive diabetes
management.78 Their main argument is: "There is no other
progressive, primarily glomerular disorder with such a high
risk of renal failure in which there is such reluctance to per-
form renal biopsies as in patients with IDDM. If the onset of
clinical nephropathy represents the beginning of the end of
useful function of the kidneys in diabetes, it may only make
sense to perform renal biopsies before renal disease is clinically
detectable."79 If there*was some proven therapeutic interven-
tion at this time, there would be more merit to this suggestion.
Renal hemodynamic disturbances. Elevated GRFs in IDDM
patients at different stages of their disease have been reported
in several studies.80"84 GFR is increased by 40% in newly
diagnosed patients and by 25% in young short-term IDDM
patients with <15 yr of the disease.82 This increase in GFR,
characteristic of almost all IDDM patients, persists for many
years. In patients who apparently escape overt clinical ne-
phropathy, it is probably unremitting.85
The mechanisms for this hyperfiltration are not entirely
clear. The elevated GFR associated with poor metabolic con-
trol can be reduced substantially with effective insulin treat-
ment, as shown by Mogensen et al.86 Furthermore, even 3
days of insulin treatment will reduce the GFR from 160 ± 9
to 141 ± 6 ml • min" 1 • 173 m~2 in newly diagnosed IDDM.
After 8 days of treatment, a 17% reduction in GFR is seen.60
It appears that GFR is related to the degree of glycemic con-
trol. Studies performed in normal subjects and short-term
IDDM patients have revealed that oral glucose loading does
not cause an increase in GFR,87 whereas intravenous glucose
administration induces a significant 5% elevation in GFR.88
Insulin per se does not seem to induce alterations in GFR,
as shown by studies that use insulin and glucose infusions
that maintain the blood glucose levels constant.89'90 Glucagon
infusions administered to normal subjects and IDDM patients
in doses low enough to achieve plasma concentrations similar
to those observed in poorly controlled diabetes have been
shown to induce significant elevations in GFR.91'92 The mag-
nitude of increase in GFR was ~ 6 % and probably was not
DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
due to glycemic changes. Glucagon, however, may be only
one of several factors affecting glomerular hemodynamics be-
cause well-controlled IDDM patients with normoglucagone-
mia still have high GFRs.92 The influence of human growth
hormone (HGH) has also been studied because uncontrolled
diabetes is associated with high HGH levels,93 and acrome-
galic patients also have an elevated GFR.94 Daily subcuta-
neous administration of 6 IU of HGH for a week increased
the GFR by 9% in normal subjects95 and by 7% in IDDM
patients.96
The acute changes seen in GFR after increments in plasma
concentrations of glucose, glucagon, and HGH to levels sim-
ilar to those seen in IDDM were 5%, 6%, and 7%, respec-
tively. Unless an additive effect is postulated, these changes
cannot fully explain the hyperfiltration state seen in IDDM.97
The main mechanism involved in the high GFR in IDDM
may be related to the structural changes seen very early in
the course of the disease.86 Increased kidney size and GFR
are positively correlated,57'58 and the glomerular volume and
glomerular capillary surface show marked enlargements very
early.62'63 Opponents97 of the above morphological hypothesis
argue that the rapid fall in GFR obtained with insulin therapy60
cannot be explained by changes in the enlarged glomerular
size and filtration surface area because these abnormalities
remain unchanged after >1 mo of insulin treatment.63
There is experimental evidence to suggest that the lesions
of diabetic nephropathy may develop as a consequence of
glomerular hyperfiltration.98" This argument is based on
Brenner's "remnant-kidney" model. This experimental model
is produced by surgical ablation and infarction of —90% of
the renal mass in normal rats. 10° Compensatory hemodynamic
mechanisms to the reduced number of nephrons result in the
establishment of hyperfiltration and hyperperfusion in the
remnant kidney that leads to pathologic changes similar to
those seen in diabetic nephropathy. An increase in the single-
nephron glomerular flow and transcapillary hydraulic pressure
in the nephrons of the remaining kidney may cause changes
in the permselective properties of the glomeruli. This then
results in albuminuria.101 Hostetter et al.102 have proposed
that the renal hemodynamic alterations manifested as glo-
merular hyperfiltration associated with "less than optimal
metabolic control" could initiate and determine the progress
of diabetic nephropathy (Fig. 3).
Additional experimental evidence suggests that hemody-
namic factors play a major role and can influence the rate of
progression of the diabetic nephropathy lesions.1O3"105 Uni-
lateral nephrectomy in streptozocin-induced diabetic rats
clearly accelerates the progression of mesangial expansion,
with lesions developing more rapidly and severely than in
intact diabetic animals.103 Similar findings are obtained with
uninephrectomy in the diabetic dog model.104 By use of the
classic two-kidney Goldblatt model, both streptozocin dia-
betic rats and normal animals became hypertensive.105 The
undipped kidneys that were exposed to the elevated systemic
arterial pressure showed more severe glomerular lesions that
kidneys from normotensive diabetic rats. Moreover, the clipped
kidneys (i.e., kidneys protected from the hypertension) in
535
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
ECFV VASOREGULATORY
EXPANSION HORMONES
COMPENSATORY
HYPERFILTRATION MESANGIAL
EXPANSION
IN SURVIVING
GLOMERULI
HGLOMERULOSCLEROSIs)
FIG. 3. Hypothetical model of glomerular hyperfiltration in ini-
tiation and progression of diabetic nephropathy.102
the diabetic rats tended to show a lesser degree of glomeru-
lopathy than the normotensive rats. In one of the most widely
quoted case reports in medical literature, Berkman and Rifkin106
described autopsy findings in a patient with long-standing
diabetes and unilateral renal artery stenosis. Classic diabetic
lesions were confined to the kidney on the side of the normal
renal artery. The contralateral kidney that was protected by
the stenotic renal artery showed only mild ischemic changes
and no pathological changes of diabetes.
It has been hypothesized that the "remnant-kidney" model
can be extended to diabetes when the capillary luminal space
and the peripheral capillary filtering surface of the glomeruli
are diminished as a consequence of marked mesangial expan-
sion. 79 This hypothesis implies that glomerular hyperfiltration
develops in patients with established glomerular lesions and
that the compensatory hemodynamic changes will accelerate
the progress of diabetic nephropathy. However, as discussed
above, it is puzzling that almost all IDDM patients have an
elevated GFR86 and also increased GBM thickness with mes-
angial expansion20'21 after several years of disease, but still
only 30-40% go on to develop clinical diabetic nephropa-
thy.11 Furthermore, the removal of a single kidney in normal
rats produces identical hemodynamic changes as seen in ex-
perimental diabetes in the intact rat. Yet, despite similar
hemodynamic changes, these nondiabetic animals fail to de-
velop lesions similar to diabetic nephropathy even after pro-
longed observation.103
Recently, 52 renal allograft normal donors were assessed
>10 yr after uninephrectomy.10? A higher incidence of mild
proteinuria and hypertension were found in male donors com-
pared with their values before nephrectomy and compared
with age- and sex-matched inpatient and outpatient control
536 DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
subjects. Female donors had increased proteinuria compared
with prenephrectomized and age-matched inpatient potential
donors. However, the extent of the proteinuria and hyper-
tension was not significantly different from outpatient age-
matched females with two kidneys. There was no significant
deterioration in renal function as determined by serum cre-
atinine levels or creatinine clearance. In a separate study by
Bertolatus et al.,108 uninephrectomized donors did not have
abnormalities in glomerular permselectivity as demonstrated
by the finding of normal UAER for up to 3 yr after surgical
ablation.
In summary, it appears that in the absence of diabetes,
clinically important glomerulopathy does not develop with
removal of a single kidney either in animal models or humans,
despite the fact that the uninephrectomy causes glomerular
hyperfiltration. Compensatory hemodynamic changes might
contribute substantially to the progression of diabetic ne-
phropathy, but sufficient evidence is not yet available to
implicate this as the primary pathogenic mechanism.
Alterations in filtration permselectivity. It has been postulated
that the primary event responsible for albuminuria is a qual-
itative change affecting the permselective properties of the
glomerular barrier and that this change is independent of
basement membrane thickening, mesangial expansion, and
glomerular hyperfiltration.77
The glomerular filtrate passes through the endothelial fe-
nestrae, permeates the basement membrane (composed of
lamina rara interna, lamina densa, lamina rara externa) and
then passes through the filtration slits of the epithelial cells.109
The glomerular capillary filter can be regarded functionally
as a membrane with pores of an average size of 55 A that is
uniformly coated by negative electrical charges.110111 The
glomerular barrier has properties of size selectivity and charge
selectivity in relation to the transcapillary passage of plasma
proteins.110
The pore-size selectivity of the glomerular barrier appears
to be intact in diabetic patients with microalbuminuria as
shown by studies that use the clearance of uncharged neutral
dextran of several molecular weights.112 Normal dextran clear-
ances are also found in experimental diabetes of rats.113 Pa-
tients with advanced diabetic nephropathy and marked pro-
teinuria have clear evidence of increased glomerular porosity
size, however.114 The glomerular charge-selective property is
conferred by fixed negative charges on the basement mem-
brane that generate electrostatic interactions with the plasma
proteins.110 Negatively charged proteins like albumin are fil-
tered in smaller amounts than neutral molecules of a com-
parable size, whereas filtration of positively charged molecules
is facilitated.115
In early diabetic nephropathy with AERs >30 |xg/min,
the clearance of albumin is greater than the IgG clearance.116
Because albumin is highly anionic (pi 4-8, stokes radius 36
A) and IgG is a larger but essentially neutral molecule (pi
7.6, stokes radius 55 A), these findings suggest a defect in
the charge-selectivity properties of the glomerular filter in
patients with microalbuminuria.
Sialic acid appears to contribute <5% of the total anionic
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
content of the GBM.117 Nevertheless, decreased concentra-
tions of sialic acid in GBM have been found in diabetic
patients.118 The anionic net charge of the glomerular barrier
is primarily determined by glycosaminoglycans rich in heparan
sulfate.119'120 The congenital nephrotic syndrome may result
from failure to develop the sulfate-rich anionic sites in the
lamina rara externa of the GBM as shown by quantitative
cytochemical methods from kidney biopsies examined by elec-
tron microscopy.121
Removal of heparan sulfate and other glycosaminoglycans
by the perfusion of rat kidneys with heparinase greatly in-
creases the passage of native anionic ferritin across the GBM.122
Similar results are found in the heparinase-perfused kidney
by use of 125I-labeled albumin as a marker.123 Neutralization
of heparan sulfate by infusion of the polycation protamine
sulfate clearly increases UAE.124 Both systemic and unilateral
kidney perfusions in rats with protamine sulfate reduce the
glomerular staining for polyanions and markedly increase al-
bumin excretion. Similar results are found with polyethyle-
neimine as the polycation and with native or cationic ferritins
as glomerular permeability markers.125
Experimental evidence strongly suggests that the diabetic
state influences the synthesis of glycosaminoglycans rich in
heparan sulfate. 126~128 A decreased de novo synthesis of sul-
fated proteoglycans was demonstrated by a 30-40% less in
vitro [35S]sulfate incorporation into glomerular extracellular
matrices of diabetic rats compared with normal rats.128 In vivo
studies with the injection of [35S]sulfate into normal and strep-
tozocin-diabetic rats showed a diminished sulfation and/or
production but a normal turnover of glycosaminoglycans in
the GBM in experimental diabetes.128 Finally, the glycosa-
minoglycan (heparan sulfate) component of GBMs from hu-
man diabetic kidneys has been found to be significantly de-
creased compared with nondiabetic control subjects.129
Therefore, the hypothesis proposed by Deckert and
colleagues77 to explain the onset and progression of early
diabetic nephropathy seems very attractive. Increased albu-
min excretion is probably associated with a depletion of he-
paran-sulfate concentrations. This depletion of heparan sul-
fate compromises the anionic barrier to albumin. The quality
of glycemic control as well as genetic differences might in-
fluence the rate of synthesis and turnover of glomerular sul-
fated proteoglycans. This may explain differences commonly
found in prevalence and severity of diabetic nephropathy.
Mesangial expansion with accumulation of albumin and ma-
cromolecules is probably due to both an impaired capacity to
clear macromolecules130 and a stimulated mesangium matrix
production. These changes will eventually restrict glomerular
capillary filtration surface and other glomerular hemody-
namics.79 Figure 4 summarizes the potential pathogenic mech-
anisms that result in microalbuminuria.
THERAPEUTIC INTERVENTIONS ON MICROALBUMINURIA
If microalbuminuria is indeed a powerful predictor for the
development of late diabetic renal disease, then various ther-
apeutic interventions can be evaluated at an early stage of
DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
„ Hyperglycemia •
Genetic Differences \
(GAGMetab.) \
tGFK I Altered Charge Permselectivity
I
\
\
\
\
• Albumin Excretion
f SNGFR • BP
t Mesangial Deposition.
f Basement Membrane Thickness
FIG. 4. Hypothetical summary of potential pathogenic media-
nisms that result in microalbuminuria.
the kidney disease in an attempt to interfere with the natural
course of the disease.
Improved glycemic control. Experimental evidence strongly
suggests that an abnormal metabolic environment plays a
major role in the genesis of diabetic nephropathy. Studies by
the Minnesota group have become classic in support of the
effect of glycemic control on diabetic renal lesions. Diabetic
glomerulopathy develops in normal kidneys when they are
transplanted into diabetic rats.131 Islet-cell transplantation
in highly inbred diabetic Lewis rats results in marked reduc-
tion of immunofluorescence staining and mesangial vol-
ume.132-133 Note the finding that the increased UAE seen in
intact and uninephrectomized diabetic rats is completely re-
verted by islet-cell transplantation.134 Similarly, institution
of meticulous glycemic control with insulin on streptozocin-
induced diabetes in rats early in the course of the disease
prevents the development of diabetes glomerular lesions72"74
and also prevents the increase in UAE.135
Furthermore, normal kidneys transplanted into human di-
abetic recipients develop hyaline arteriolar lesions in all renal
biopsies in <4 yr.136 Mesangial expansion was also noted in
several cases. The report of the transplantation of kidneys
with clinical diabetic nephropathy into nondiabetic recipients
caused much controversy. Renal biopsies taken 7 mo after
the transplants showed that the mesangial expansion and
GBM thickness were almost completely reversed.I37
Long-term improvement in diabetes control with CSII in
six patients with overt diabetic nephropathy proved to be of
little value in slowing either the rate of decline in GFR or
the plasma creatinine rise seen during the 24 mo of intensive
therapy.3 The degree of glycemic control achieved (HbAj
9.5%) might not have been close enough to normal to show
an effect; however, near-normoglycemia is very difficult to
achieve in patients with diabetic nephropathy.138 The main
issue appears to be that it is probably too late to attempt to
achieve near-normoglycemia when the diabetic nephropathy
is clinically established. Advanced renal lesions are already
present, and the process may have become self-perpetuating.
Glycemic control, as assessed by glycosylated hemoglobin
537
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
levels, closely correlates with the AER in early diabetic
nephropathy.42'53 Short- and relatively long-term near-nor-
moglycemic control achieved with CSII has been shown to
reduce and even normalize the microalbuminuria of
diabetes,139"142 but the impact on the progression of estab-
lished diabetic nephropathy still remains to be established.
CSII for 1-3 days was shown to significantly reduce the UAE
in 7 IDDM patients with microalbuminuria.139 The Steno
Memorial Hospital initially reported the effect of 6 mo of
strict metabolic control on kidney function in 32 IDDM pa-
tients randomized either to unchanged conventional treat-
ment (UCT) or to CSII. HbA lc was unchanged in the UCT,
around 8%, but fell significantly to 6.7% in the CSII-treated
group. UAE fell by 12% with CSII and rose by 56% with
UCT. GFR was significantly reduced by 9% in the CSII and
practically unchanged in the UCT.140 Subsequently, the same
study group reported results of the 2-yr follow-up study on
the effect of near-normoglycemia on kidney function.141 GFR
decreased from 132 ± 19 to 111 ± 16 ml • min" 1 -1.73 m~2
in the CSII group and was unchanged in the UCT. UAER
remained unchanged during CSII in 12 of 13 patients with
initial UAERs <70 |xg/min. Only 1 of the 3 microalbumin-
uric patients (>70 |xg/min) in the CSII group progressed to
overt proteinuria, whereas all 5 microalbuminuric patients in
the UCT group progressed to persistent proteinuria. In the
remaining 8 UCT patients, UAE remained constant.
The Kroc multicenter study also found a beneficial effect
of near-normoglycemia on microalbuminuria.142 Complete
24-h urine collections were obtained throughout the 8-mo
study in 59 of the 68 IDDM patients. At baseline, the UAER
was normal (<12 (xg/min) in 39 patients, 20 receiving con-
ventional insulin treatment and 19 on CSII, and above nor-
mal in the other 20 patients (10 patients in each group). In
the patients with normoalbuminuria, AER was relatively con-
stant regardless of the type of treatment. However, patients
on CSII with an elevated AER had a progressive decline in
albumin excretion from 48 ± 18 |xg/min at entry to 19 ± 6
at 4 mo and to 16 ± 5 (xg/min at 8 mo. In contrast, the
elevated AER in the conventional treatment group remained
unchanged (Fig. 5). The main objection to this study is that
baseline urinary albumin consisted of only a single sample
that could have reflected the poor glycemic control before
the CSII treatment. Several urine samples are usually required
to define persistent microalbuminuria characteristic of early
diabetic nephropathy. The importance of this is best illus-
trated by the recent study from the Steno Memorial Hospital
that was specifically designed to assess the impact of strict
glycemic control on kidney function in IDDM patients with
persistent microalbuminuria.143 Patients selected for the study
had two of three 24-h dipstick-negative urine collections with
an AER between 30 and 300 mg/24 h (20-200 (xg/min).
Thirty-six patients were matched in pairs according to the
level of AER, sex, and HbA lc before random assignment to
either UCT or CSII. Despite a significant reduction in HbA lc
(from 9.5 to 7.3%) in the CSII group, the AER remained
constant in both groups. GFR was unchanged, and kidney
size was significantly reduced in the CSII group. These find-
538 DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
CIT CSII
1000
AER AER
(pg/min)
Months Months
FIG. 5. Effect of treatment on albumin excretion in patients with
microalbuminuria in KROC study. CIT, conventional therapy;
CSII, continuous subcutaneous insulin infusion.142
ings are in direct opposition with the report by Wiseman et
al. ,61 who showed that prolonged (1 yr) correction of hyper-
glycemia with CSII can reduce the GFR in IDDM patients
with persistent glomerular hyperfiltration. In the Wiseman
study,61 the GFR was reduced well into the normal range in
most cases. A return to conventional insulin treatment in the
pump group resulted in both metabolic deterioration and a
significant rise in the mean GFR toward baseline values. No
change in kidney volume was noted, and the UAER was
normal in all the patients on CSII, whereas in the conven-
tional group, 3 patients had elevated AER. No significant
changes in AER was detected in either group during the study.
In terms of developing diabetic kidney disease, more pro-
longed observation will be required to properly assess whether
near-normoglycemia can prevent further progression of dia-
betic nephropathy. Hopefully after several years the two ther-
apeutic groups will separate, assuming that the AER continues
to rise in the UCT group and at least remains stable in the
CSII group.
Early antihypertensive therapy. Hypertension superimposed
on diabetes in an individual patient seems to produce an added
mortality risk factor in IDDM patients.144 Experimental and
clinical evidence, as discussed above, strongly suggests that
arterial hypertension accelerates the glomerular lesions of di-
abetic nephropathy.103"106 Moreover, mesangial expansion to
an extent >37% of the glomerular volume is strongly pre-
dictive of hypertension.21
Increased arterial blood pressure is an early feature of overt
diabetic nephropathy, as shown by Parving et al.145 They
found a higher mean blood pressure level (146/96 mmHg)
in IDDM patients with persistent proteinuria and normal
serum creatinine than in patients without proteinuria (123/
75 mmHg). A diastolic blood pressure >95 mmHg was found
in 51% of the proteinuric patients.145 A prospective study of
14 IDDM patients with persistent proteinuria but normal GFR
and blood pressure levels showed clear worsening of all the
parameters after 26 mo of observation.146 GFR decreased from
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
TABLE 5
Renal function decline in diabetic nephropathy: effect of antihypertensive therapy
Duration of
Patients Age diabetes
Study (N) (yr) (yr)
Mogensen5 6 30 18
Before therapy
With therapy
Parving et al.6 10 29 16
Before therapy
With therapy
GFR, glomerular filtration rate. Modified from Mogensen.30
107 to 87 ml • min 1 • 173 m 2; proteinuria increased from
1.8 to 3.3 g/day; and blood pressure rose from 132/88 to
153/101 mmHg. GFR decreased linearly with time with a
mean decline of 0.75 ml • min" 1 • mo" 1 , similar to previous
and subsequent reports.2627
Effective antihypertensive therapy has proven to have a
clear beneficial effect on slowing the progression rate of di-
abetic nephropathy (Fig. 5).5'6 A summary of the data from
the two available studies in overt diabetic nephropathy is
shown in Table 5. Both studies found ~60% reduction in
the decline of GFR and a substantial decrease in proteinuria
after antihypertensive therapy.
Slightly but significantly elevated blood pressure levels have
consistently been reported in microalbuminuric patients with
early diabetic nephropathy.53>56147 Wiseman et al.147 divided
28 IDDM patients into a low-microalbuminuria (12-29 |xg/
min) and a high-microalbuminuria group (>30 (xg/min). A
significant correlation was found between AER and blood
pressure; the latter was significantly higher in the high-mi-
croalbuminuria group. An association between AER and es-
sential hypertension was previously reported.148 Antihyper-
tensive therapy has been shown to reduce AER.149 The reason
for this mild elevation in blood pressure associated with mi-
croalbuminuria is unclear. Microalbuminuria may indicate
renal dysfunction and mesangial expansion sufficient to raise
the blood pressure. Alternatively, the conventionally ac-
cepted normal blood pressure level may be too high for a
diabetic subject and may account for the increased albumin
excretion.
Of interest is the study by Christiansen and Mogensen150
that demonstrates the effect of early antihypertensive therapy
in six microalbuminuric diabetic patients with minimally el-
evated blood pressure levels. Treatment with 100 mg meto-
prolol twice daily for a mean of 2.6 yr reduced blood pressure
from 135 ± 8/93 ± 9 to 124 ± 6/84 ± 3 mmHg and the
mean blood pressure from 107 ± 7 to 97 ± 3 mmHg. AER
decreased from 131 ± 2 to 56 ± 3 |xg/min. GFR was elevated
and remained so despite treatment.
It is tempting to speculate that the initiation of antihy-
pertensive treatment at an early stage of microalbuminuria
may prove to have a more effective long-term beneficial im-
pact on the progression of diabetic nephropathy than when
DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
GFR Blood
Observation before therapy pressure Decrease in GFR
(mo) (ml/min) (mmHg) (ml • min"1 • mo"1)
86
28 162/103 1.23
73 144/95 0.49
80
29 144/99 0.91
39 128/84 0.34
treatment is started in the overt stage of diabetic nephropathy.
The 1984 report of the "Joint National Committee on De-
tection, Evaluation, and Treatment of High Blood Pressure"151
defines the diagnosis of hypertension in adults as confirmed
when the average of two or more diastolic blood pressures on
at least two subsequent visits is ^90 mmHg or when the
average of multiple systolic blood pressures on two or more
subsequent visits is consistently >140 mmHg. It is also stated:
"The benefits of drug therapy seem to outweigh any known
risks from such therapy for those with a diastolic blood pres-
sure persistently elevated above 95 mmHg and for those with
a lesser elevation who are at high risk, i.e., patients with
target organ damage, diabetes mellitus, or other major risk
factors for coronary heart disease."
The presence of diabetes mellitus and the coexistence of
microalbuminuria as a marker of initial and progressive target
organ damage may justify an aggressive approach to treat
blood pressure, perhaps in the levels of > 140/85, in an at-
tempt to stop or retard the progression of the renal disease.
It remains an open question whether conventional levels of
hypertension are set too high for potentially reversible dia-
betic nephropathy or whether some lower level of blood pres-
sure should be chosen to initiate antihypertensive treatment
in patients with diabetes.152 Well-designed controlled studies
are needed to show whether antihypertensive treatment given
for minimal hypertension has any impact on the course of
diabetic nephropathy and also on the morbidity and mortality
associated with other cardiovascular conditions.153
Low-protein diets. Dietary intervention with low-protein diets
has long been recommended in patients with chronic renal
failure.154 Several studies have shown that protein-restricted
diets slow the progressive decline of renal function and pro-
long life in patients with moderate to severe renal
disease. 154~157 The rationale for this dietary approach is based
on early experimental evidence that high-protein diets ac-
celerate the glomerular lesions in intact and uninephrectom-
ized rabbits or rats.158-161 Conversely, low-protein diets appear
to retard the progression of nephrotoxic serum nephritis in
rats.162 Graded reductions in dietary protein intake have been
shown to induce stepwise increases in the life span of rats
subjected to extensive renal ablation.163 Protein restriction is
clearly effective in preventing the hyperfiltration and renal
539
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
pathologic changes occurring in the remnant glomeruli of rats
with reduced renal mass. A reduction of dietary protein con-
tent from 24 to 6% in rats after the ablation of 90% of their
renal mass blunts the hemodynamic changes and prevents the
development of glomerular lesions and proteinuria. 10°
Brenner and colleagues,164165 and Jamison166 have recon-
ciled the hyperfiltration model of the "remnant kidney" with
the chronic effects of excess protein intake on the progression
of renal disease. This theory proposes that an increase in
protein intake causes renal vasodilation and glomerular hy-
perperfusion. The elevated transcapillary flux of ultrafiltrate
eventually disrupts the glomerular permselectivity and causes
albuminuria with subsequent mesangial expansion. As dis-
cussed above, the same model of glomerular hyperfiltration
has been proposed by those authors to explain the genesis of
diabetic nephropathy.98102
Note the report by Neugarten et al.167 that streptozocin
diabetic rats fed with high protein diets (50%) have an ac-
celeration of the diabetic nephropathy as evidenced by greater
mesangial expansion and GBM thickening as well as higher
proteinuria than diabetic rats fed with 20% protein chow. To
date there is only one clinical study available assessing the
effect of low-protein diets on an homogenous population of
patients with advanced diabetic nephropathy.168 Preliminary
data suggests that dietary protein restriction significantly re-
duces proteinuria, but more prolonged observation is needed
to determine whether the course of diabetic nephropathy is
indeed retarded. No studies are available on the potential
beneficial effect of low-protein diets on microalbuminuria in
patients with early diabetic nephropathy. Short- and long-
term prospective and controlled studies are required to explore
this attractive "noninvasive" intervention.
Aldose reductase inhibitors. Much experimental evidence
reviewed by Cogan et al.169 and in unpublished data of Raskin
and Rosenstock suggests that the enhanced polyol pathway
activity may provide a common biochemical vinculum in the
pathogenesis of late diabetic complications. The intracellular
accumulation of sorbitol and fructose occurs as a consequence
of the increased activity of aldose reductase, the rate-limiting
and key enzyme in this pathway. An osmotic effect was orig-
inally thought to be the main pathogenic mechanism that
results from the increased polyol concentration in tissues.170
Recently, more attention has been given to the concomitant
reduction of tissue-myoinositol levels seen in diabetes.171 Acute
reversible nerve-conduction abnormalities found in experi-
mental diabetes are apparently due to a myoinositol-related
defect in Na + -K ATP+-ase activity.172
Administration of an aldose-reductase inhibitor amelio-
rated the diabetes-related changes in nerve sorbitol and myo-
inositol and improved nerve-conduction velocities in rats173
and humans174 with an apparent beneficial effect in painful
diabetic neuropathy.175-176 In addition, experimental evidence
has also shown that aldose-reductase inhibitors prevent cat-
aract formation169 and, more importantly, prevent galactose-
induced retinopathy with striking reduction in retinal capil-
lary basement membrane thickness.177
The presence of aldose-reductase activity has been clearly
540 DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
documented in retina, lens, Schwann's cell, aorta, and also
in glomerular tissue.169 Beyer-Mears et al.178 measured polyols
in glomeruli isolated from control and streptozocin-diabetic
rats and assessed whether changes in diabetic glomeruli could
be prevented by oral treatment with the aldose-reductase in-
hibitor drug, sorbinil. Compared with controls, the polyol
content of glomeruli isolated from diabetic rats was increased
10-fold and 4-fold at 6 and 9 wk, respectively, after induction
of diabetes. It was unchanged in glomeruli from rats treated
with sorbinil. In contrast, glomeruli myoinositol content was
reduced in diabetic animals, and this fall was completely
prevented by the drug. Note that the glomerular accumula-
tion of protein in diabetic rats was also prevented with aldose-
reductase inhibition, suggesting a role for this pathway in the
genesis of diabetic nephropathy. Treatment of streptozocin-
diabetic rats with sorbinil reduces proteinuria and restores the
urine electrophoresis pattern towards normal.179 To date no
human studies have been reported on the potential beneficial
effects of aldose-reductase inhibitors on either overt protein-
uria or on the microalbuminuria of early diabetic nephropa-
thy.
CONCLUSION
T
he problem of diabetic nephropathy is so great that
the classic passive spectator approach can no longer
be justified. Although the natural history of early
diabetic nephropathy remains to be further eluci-
dated, microalbuminuria seems to be a reliable early marker
of self-perpetuating, slowly progressive diabetic kidney dis-
ease. The last annual report of the National Diabetes Ad-
visory Board2 has acknowledged that "elevated urinary al-
bumin excretion predicts with a high degree of accuracy the
ultimate development of overt clinical diabetic nephropa-
thy." Moreover, one of their recommendations is: "Further
tests must be designed to unmask early glomerular injury so
the treatment of hyperglycemia and hypertension can be in-
stituted at an optimum time." In accordance with the spirit
of that recommendation and the evidence presented, we sug-
gest the following protocol: I) Type I patients with >5 yr
duration of IDDM need to have UAER (overnight collec-
tions) assessed regularly (every 12 mo). NIDDM diabetics
may have overnight UAER measured every 2 yr. 2) If AER
is elevated, a series of three determinations over 3-6 mo is
required to define persistent microalbuminuria. 3) If microal-
buminuria is found, efforts should be directed toward im-
proving glycemic control and early intervention to maintain
normal blood pressure.
Long-term prospective studies are required to evaluate the
role of glycemic and blood pressure control as well as the
potential role of low-protein diets and aldose reductase in-
hibitors on the progression of early diabetic nephropathy.
ACKNOWLEDGMENTS: We appreciate the invaluable help of Suz-
anne Strowig, RN, MSN; Susan Mullen, RN; Laura Schnurr,
RN; and Susan Cercone, RDMS. We thank Rueben Dickter,
Lisa Gagliano, Katie Hammon, Arthur Ojirika, and Kevin
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
Sullivan for technical assistance and Betty Newton and Char-
lene Davis-Williams for assistance in preparing the manu-
script.
From the Department of Internal Medicine, The University of
Texas Health Science Center, Dallas, Texas.
Address reprint requests to Julio Rosenstock, MD, Department
of Medicine, University of Texas Health Science Center at Dallas,
5323 Harry Hines Blvd., Dallas, TX 75235.
REFERENCES
1 Diabetologia 1984; 26:361-65.
Friedman, E. A.: Diabetic nephropathy. Strategies in preven-
tion and management. Kidney Int. 1982; 21:780-91.
2 D. E. R., Brown, D. M., and Goetz, F. O : Structural-functional
Sixth Annual Report of the National Diabetes Advisory Board.
Bethesda, MD, U.S. Dept. of Health and Human Services, NIH
Publ. No. 84-1587, May 1984:1-59.
3 Kussman, M. J., Goldstein, H. H., and Gleason, R. E.: The
Viberti, G. C , Bilous, R. W., Mackintoch, B., Bending, J. J.,
and Keen, H.: Long-term correction of hyperglycemia and progres-
sion of renal failure in insulin-dependent diabetes. Br. Med. J. 1983;
286:598-602.
4 failing renal function. Acta Med. Scand. 1978; 203:131-34.
Mogensen, C. E.: Progression of nephropathy in long-term di-
abetics with proteinuria and effect of initial anti-hypertensive treat-
ment. Scand. J. Clin. Lab. Invest. 1976; 36:383-88.
5 change of serum creatinine concentration. Kidney Int. 1977; 11:62—
Mogensen, C. E.: Long-term antihypertensive treatment inhib-
iting progression of diabetic nephropathy. Br. Med. J. 1982; 285:685-
88.
6 Watkins, P. J.: Progression of diabetic nephropathy. Lancet 1979;
Parving, H.-H., Andersen, A. R., Smidt, U. M., andSvendsen,
P. Aa.: Early aggressive antihypertensive treatment in kidney func-
tion in diabetic nephropathy. Lancet 1983; 1:1175-78.
7 abetics with proteinuria and effect of initial anti-hypertensive treat-
Mogensen, C. E.: Microalbuminuria and incipient diabetic ne-
phropathy. Diabetic Nephrop. 1984; 3:75-78.
8
Knowles, H. C., Jr.: Magnitude of the renal failure problem in
diabetes. Kidney Int. 1974; 6:2-7.
9 Med. 1983; 74:256-64.
Deckert, T., Poulsen, J. E., and Larsen, M.: Prognosis of dia-
betics with diabetes onset before the age of thirty-one. Diabetologia
1978; 14:363-70.
10
Dorman, J. S., LaPorte, R. E., Kuller, L. H., Cruickshanks,
K. J., Orchard, J. J., Wagener, D. K., Becker, D. J., Cavender D.
E., and Drash, A. L.: The Pittsburgh insulin-dependent diabetes
mellitus (IDDM) morbidity and mortality study: mortality results.
Diabetes 1984; 33:271-76.
11
Andersen, A. R., Sandahl-Christiansen, J., Andersen, J. K.,
Kreiner, S., and Deckert, T.: Diabetic nephropathy in type I insulin-
dependent diabetes: an epidemiological study. Diabetologia 1983;
25:496-501.
12
Abuelo, J. G.: Proteinuria: diagnostic principles and proce-
dures. Ann. Intern. Med. 1983; 98:186-91.
13
Viberti, G. C., and Wiseman, M. J.: The natural history of
proteinuria in insulin-dependent diabetes mellitus. Diabetic Ne-
phrop. 1983; 2:22-25.
14
Mauer, S. M., Steffes, M. W., and Brown, D. M.: The kidney
in diabetes. Am. J. Med. 1981; 70:603-12.
15
Osterby, R.: Morphometric studies of the peripheral glomerular
basement membrane. Diabetologia 1973; 9:108-14.
16
Osterby, R.: Basement membrane morphology in diabetes mel-
litus. In Diabetes Mellitus, Theory and Practice, 3rd ed. Ellemberg,
M., and Rifkin, H., Eds. New Hyde Park, NY, Med. Exam., 1983:
323-41.
17
Gundersen, H. J. G., and Osterby, R.: Glomerular size and
structure in diabetes mellitus. II. Late abnormalities. Diabetologia
1977; 13:43-48.
DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
18
Deckert, T., and Poulsen, J. E.: Diabetic nephropathy: fault or
destiny? Diabetologia 1981; 21:178-183.
19
Deckert, T., Parving H.-H., Andersen, A. R., Christiansen,
J. S., Oxenboll, B., Svendesen, P. Aa., Telmer, S., Christy, M.,
Lauritzen, T., Thomas, O. F., Kreiner, S., Andersen, J. R., Binder,
C , and Nerup, J.: Diabetic nephropathy. A clinical and morpho-
metric study. In Advances in Diabetes Epidemiology. Eschwege, E.,
Ed. Amsterdam, Elsevier, 1982:235-243.
20
Thomsen, O. F, Andersen, A. R., Sandahl-Christiansen, J.,
and Deckert, T.: Renal changes in long-term type I (insulin-de-
pendent) diabetic patients with and without clinical nephropathy:
a light microscopic, morphometric study of an autopsy material.
21
Mauer, S. M., Steffes, M. W., Ellis, F. N., Sutherland,
relationships in diabetes nephropathy. J. Clin. Invest. 1984; 74:1143—
55.
22
clinical course of diabetes nephropathy. JAMA 1976; 236:1861-63.
23
Andersen, A. R., Andersen, J. K., Christiansen, J. S., and
Deckert, T.: Prognosis for juvenile diabetes with nephropathy and
24
Rutherford, W. E., Blondin, J., Miller, J. P., Greenwalt,
A. S., and Varra, J. D.: Chronic progressive renal disease. Rate of
70.
25
Jones, R. H., Mackay, J. D., Hayakawa, H., Parsons, V., and
1:1105-106.
26
Mogensen, C. E.: Progression of nephropathy in long-term di-
ment. Scand. J. Clin. Lab. Invest. 1976; 36:383-88.
27
Viberti, G. C , Bilous, R. W., Mackintosh, D., and Keen, H.:
Monitoring glomerular function in diabetic nephropathy. Am. J.
28
Viberti, G. C , Keen, H., and Mackintosh, D.: Beta2-micro-
globulinemia: a sensitive index of diminishing renal function in
diabetics. Br. Med. J. 1981; 282:95-98.
29
Parving, H.-H., Andersen, A. R.( and Smidt, V. M.: Moni-
toring kidney function in insulin-dependent diabetics with diabetic
nephropathy. Diabetic Nephrop. 1984; 3:130-33.
30
Mogensen, C . E.: Clinical and renal functional studies of dia-
betic nephropathy in humans. In Nephrology. Proc. IX Int. Congr.
Nephrol. Robinson, R. R., Ed., N e w York, Springer-Verlag,
1984:1053-73.
31
Unger, R. H., and Foster, D. W.: Diabetes mellitus. In Williams
Textbook of Endocrinology. Wilson, J. D. and Foster, D. W., Eds.
Philadelphia, PA, Saunders, 1985:1018-80.
32
Mogensen, C. E., Christiansen, C, K., and Vittinghus, E.: The
stages in diabetic renal disease: with emphasis on the stage of incip-
ient diabetic nephropathy. Diabetes 1983; 32 (Suppl. 2):64—78.
33
Keen, H . , and Chlouverakis, C : A n immunoassay method for
urinary albumin at low concentrations. Lancet 1963; 2 : 9 1 3 - 1 6 .
34
Keen, H . , Chlouverakis, C , Fuller, J. H . , and Jarrett, R. J.:
T h e concomitants of raised blood sugar: studies in newly detected
hyperglycemia. II. Urinary albumin excretion, blood pressure and
their relation to blood sugar levels. Guy's Hosp. Rep. 1963; 118:247—
52.
35
Viberti, G. C , Wiseman, M., and Redmond, S.: Microalbu-
minuria: its history and potential for prevention of clinical nephrop-
athy in diabetes mellitus. Diabetic Nephrop. 1984; 3:79-82.
36
Viberti, G. C , Mackintosh, D., and Keen, H.: Determinants
541
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
of the penetration of proteins through the glomerular barrier in
insulin-dependent diabetes mellitus. Diabetes 1983; 32 (Suppl.):92-
95.
37
Viberti, G . , a n d Keen, H . : T h e patterns of proteinuria in
diabetes mellitus: relevance to pathogenesis and prevention of di-
abetic nephropathy. Diabetes 1984; 3 3 : 6 8 6 - 9 2 .
38
Mogensen, C . E.: Microalbuminuria as a predictor of diabetic
nephropathy. Kidney Int. In press.
39
Rasmussen, B. F., and Mathiesen, E. R.: Variability of urinary
albumin excretion in incipient diabetic nephropathy. Diabetic Ne-
phrop. 1984; 3:101-103.
40
Mogensen, C. E.: Urinary albumin excretion in early and long-
term juvenile diabetes. Scand. J. Clin. Lab. Invest. 1971; 28:183—
93.
41
Parving, H.-H., Noer, I., Deckert, T., Errin, P. E., Nielsen,
S. L , Lyngsoe, J., Mogensen, C. E., Rorth, M., Svendsen, P. Aa.,
Jensen, J. T., andLarssen, N. A.: The effect of metabolic regulation
on microvascular permeability to small and large molecules in short-
term juvenile diabetics. Diabetologia 1976; 12:161-66.
42
Viberti, G. C , Mackintosh, D., Bilous, R. W., Pickup, J. C ,
and Keen, H.: Proteinuria in diabetes mellitus: role of spontaneous
and experimental variation of glycemia. Kidney Int. 1982; 21:714—
20.
43
Mogensen, C. E., and Vittinghus, E.: Urinary albumin excre-
tion during exercise in juvenile diabetes: a provocation test for early
abnormalities. Scand. J. Clin. Lab. Invest. 1975; 35:295-300.
44
Viberti, G. C , Jarrett, R. J., McCartney, M., and Keen, H.:
Increased glomerular permeability to albumin induced by exercise
in diabetic subjects. Diabetologia 1978; 14:293-300.
45
Mogensen, C. E., Vittinghus, E., and Soiling, K.: Abnormal
albumin excretion after two provocative renal tests in diabetes.
Physical exercise and lysine injection. Kidney Int. 1979; 16:385—
93.
46
Vittinghus, E., and Mogensen, C. E.: Albumin excretion and
renal hemodynamic response to physical exercise in normal and
diabetic man. Scand. J. Clin. Lab. Invest. 1981; 41:627-32.
47
Vittinghus, E., and Mogensen, C. E.: Graded exercise and
protein excretion in diabetic man and the effect of insulin treatment.
Kidney Int. 1982; 21:725-29.
48
Mogensen, C. E., Feldt-Rasmussen, B., Baker, L., and Deckert,
T.: Exercise as a provocative test in early renal disease in type I
(insulin-dependent) diabetes: albuminuric, systemic and renal
hemodynamic response. Diabetologia 1985; 28:389-96.
49
Viberti, G. C , Mogensen, C. E., Keen, H., Jacobsen, E K.,
Jarrett, R. J., and Christiansen, C. K.: Urinary excretion of albumin
in normal man: the effect of water loading. Scand. J. Clin. Lab.
Invest. 1982; 42:147-51.
50
Parving, H.-H., Oxenboll, B., Svendsen, P. Aa., Sandahl-
Christiansen, J., and Anderson, A. R.: Early detection of patients
at risk of developing diabetic nephropathy. A longitudinal study of
urinary albumin excretion. Acta Endocrinol. 1982; 100:550-55.
51
Viberti, G. C , Jarrett, R. J., Mahmud, U., Hill, R. D., Ar-
gyropoulos, A., and Keen H.: Microalbuminuria as a predictor of
clinical nephropathy in insulin-dependent diabetes mellitus. Lancet
1982; 1:1430-32.
52
Mogensen, C. E., and Christiansen, C. K.: Predicting diabetic
nephropathy in insulin-dependent patients. N. Engl. J. Med. 1984;
311:89-93.
53
Mathiesen, E. R., Oxenboll, B., Johansen, K., Svendsen,
P. Aa., and Deckert, T.: Incipient nephropathy in type I (insulin-
dependent) diabetes. Diabetologia 1984; 26:406-410.
54
Mogensen, C. E.: Microalbuminuria predicts clinical protein-
542 DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
uria and early mortality in maturity-onset diabetes. N. Engl. J. Med.
1984; 310:356-60.
"Jarrett, R. J., Viberti, G. C , Argyropoulos, A., Hill, R. D.,
Mahmud, U., and Murrells, T. J.: Microalbuminuria predicts mor-
tality in non-insulin-dependent diabetes. Diabetic Med. 1984; 1:17—
19.
56
Christiansen, C . K., a n d Mogensen, C . E.: T h e course of in-
cipient diabetic nephropathy: studies on albumin excretion and blood
pressure. Diabetic Med. 1985; 2:97-102.
57
Mogensen, C. E., and Andersen, M. J. E: Increased kidney
size and glomerular filtration rate in early juvenile diabetes. Diabetes
1973; 22:706-12.
58
Mogensen, C. E., and Andersen, M. J. E: Increased kidney
size and glomerular filtration rate in untreated juvenile diabetes:
normalization by insulin treatment. Diabetologia 1977; 13:207-10.
59
S a n d a h l - C h r i s t i a n s e n , J., G a m m e l g a a r d , J., Frandsen, M . , a n d
Parving, H.-H.: Increased kidney size, glomerular filtration rate,
and renal plasma flow in short-term insulin-dependent diabetics.
Diabetologia 1981; 20:451-56.
60
Christiansen, J. S., Gammelgaard, T., Tronier, B., and Svend-
sen, P. Aa., Parving, H.-H.: Kidney function and size in diabetics
before and during initial insulin treatment. Kidney Int. 1982; 21:683—
88.
61
Wiseman, M. J., Saunders, A. J., Keen, H., and Viberti,
G. C : Effect of blood glucose control on increased glomerular fil-
tration rate and kidney size in insulin-dependent diabetes. N. Engl.
J. Med. 1985; 312:617-21.
62
Osterby, R., and Gundersen, H. J. G.: Glomerular size and
structure in diabetes mellitus. I. Early abnormalities. Diabetologia
1975; 11:225-29.
63
Kroustrup, J. P., Gundersen, H. J. G., and Osterby, R.: Glo-
merular size and structure in diabetes mellitus. Diabetologia 1977;
13:207-10.
64
Hansen, K. S., Hansen, J., and Gundersen, H. J. G.: Renal
hypertrophy in experimental diabetes. Diabetologia 1980; 18:501-
505.
65
Osterby, R., and Gundersen, H. J. G.: Fast accumulation of
basement membrane material and the rate of morphological changes
in acute experimental diabetic glomerular hypertrophy. Diabetologia
1980; 18:493-500.
66
Seyer-Hansen, K.: Renal hypertrophy in streptozotocin-diabetic
rats. Clin. Sci. Mol. Med. 1976; 51:551-55.
67
Cortes, P., Levin, N. W., Dumler, E, Rubenstein, A. H.,
Verghese, C. P., and Venkatachalam, K. K.: Uridine triphosphate
and RNA synthesis during diabetes-induced kidney growth. Am. J.
Physiol. 1980; 238:E349-57.
68
Seyer-Hansen, K.: Renal hypertrophy in experimental diabetes:
Relation to severity of diabetes. Diabetologia 1977; 13:171-73.
69
Cortes, P., Dumler, E, Venkatachalam, K. K., Goldman, J.,
Sastry, K. S. S., Venkatachalam, H., Bernstein, J., and Levin,
N. W.: Alterations in glomerular RNA in diabetic rats: roles of
glucagon and insulin. Kidney Int. 1981; 20:491-99.
70
Seyer-Hansen, K., Gundersen, H. J. G., and Osterby, R.: Acute
renal hypertrophy in experimental diabetes: lack of effect of growth
hormone administration. Diabetologia 1981; 21:373-75.
71
Seyer-Hansen, K., Gundersen, H. J. G., and Osterby, R.: Acute
renal hypertrophy in experimental diabetes mellitus. Kidney Int.
1983; 23:643-76.
72
Rasch, R.: Prevention of diabetic glomerulopathy in strepto-
zotocin diabetic rats by insulin treatment: kidney size and glomerular
volume. Diabetologia 1979; 16:125-28.
73
Rasch, R.: Prevention of diabetic glomerulopathy in strepto-
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
zotocin diabetic rats by insulin treatment: glomerular basement
membrane thickness. Diabetologia 1979; 16:319-24.
74
Rasch, R.: Prevention of diabetic glomerulopathy in strepto-
zotocin diabetic rats by insulin treatment: the mesangial regions.
Diabetologia 1979; 17:243-48.
75
Osterby, R.: Early phases in the development of diabetic glom-
erulopathy. A quantitative electron microscopic study. Acta Med.
Scand. Suppl. 1975; 574:3-82.
76
Osterby, R., Andersen, A. R., Gundersen, H. J., Jorgensen,
H. E., Mogensen, C. E., and Parving, H.-H.: Quantitative studies
of glomerular ultrastructure in type I diabetics with incipient ne-
phropathy. Diabetic Nephrop. 1984; 3:95-100.
77
Deckert, T., Rasmussen, B. F., Mathiesen, E. R., and Baker,
L.: Pathogenesis of incipient nephropathy: a hypothesis. Diabetic
Nephrop. 1984; 3:83-88.
78
Mauer, S. M., Steffes, M. W., Ellis, E. N., and Brown,
D. M.: Can the insulin-dependent diabetic patient be managed
without kidney biopsy. In Nephrology. Proc. IX Int. Congr. Ne-
phrol. Robinson, R. R., Ed. New York, Springer-Verlag, 1984:
1103-108.
79
Mauer, S. M., Steffes, M. W., Goetz, F. C , Sutherland,
D. E. R., and Brown, D. M.: Diabetic nephropathy: a perspective.
Diabetes 1983; 32 (Suppl. 2):52-55.
80
Ditzel, J., and Schwartz, M.: Abnormally increased glomerular
filtration rate in short-term insulin-treated diabetic subjects. Dia-
betes 1967; 16:264-67.
81
Ditzel, J., and Junker, K.: Abnormal glomerular filtration rate,
renal plasma flow, and renal protein excretion in recent and short-
term diabetics. Br. Med. J. 1972; 2:13-19.
82
Mogensen, C. E.: Glomerular filtration rate and renal plasma
flow in short-term and long-term juvenile diabetes mellitus. Scand.
J. Clin. Lab. Invest. 1971; 28:91-100.
83
Mogensen, C. E.: Glomerular filtration rate and renal plasma
flow in long-term juvenile diabetes without proteinuria. Br. Med.
J. 1984; 4:257-59.
84
Nyberg, G., Granerus, G., and Urrell, M.: Renal extraction
fraction for 51Cr-EDTA PAH and glucose in early insulin-dependent
diabetic patients. Kidney Int. 1982; 21:706-708.
85
Mogensen, C. E.: Diabetes mellitus and the kidney. Kidney
Int. 1982; 21:673-75.
86
Mogensen, C. E., Osterby, R., and Gundersen, H. J. G.: Early
functional and morphologic vascular renal consequences of the di-
abetic state. Diabetologia 1979; 17:71-76.
87
Mogensen, C. E.: Glomerular filtration rate and renal plasma
flow in short-term and long-term juvenile diabetes mellitus. Scand.
J. Clin. Lab. Invest. 1971; 28:91-100.
88
Christiansen, J. S., Frandsen, M., and Parving, H.-H.: Effect
of intravenous glucose infusion on renal function in normal man
and in insulin-dependent diabetics. Diabetologia 1981; 20:199—204-
89
DeFronzo, R. A., Cooke, C. R., Andres, R., Faloona, G. R.,
and Davis, P. J.: The effect of insulin on renal handling of sodium,
potassium, calcium, and phosphate in man. J. Clin. Invest. 1975;
55:845-55.
90
Christiansen, J. S., Frandsen, M., and Parving, H.-H.: The
effect of intravenous insulin infusion on kidney function in insulin-
dependent diabetes mellitus. Diabetologia 1981; 20:199-204.
91
Parving, H. -H., Noer, I., Kehlet, H., Mogensen, C. E., Svend-
sen, P. Aa., and Heding, L. G.: The effect of short-term glucagon
infusion on kidney function in normal man. Diabetologia 1977;
13:323-25.
92
Parving, H.-H., Christiansen, J. S., Noer, I., Tronier, B., and
Mogensen, C. E.: The effect of glucagon infusion on kidney function
DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
in short-term insulin-dependent juvenile diabetics. Diabetologia 1980;
19:350-54.
93
Hayford, J. T., Danney, M. M., Hendrix, J. A., and Thomp-
son, R. G.: Integrated concentration of growth hormone in juvenile-
onset diabetes. Diabetes 1980; 29:391-98.
94
Ikkos, D., Luft, R., and Gemzell, C. A.: The effect of human
growth hormone in man. Acta Endocrinol. 1954; 32:341-61.
95
Christiansen, J. S., Gammelgaard, J., Orskov, H., Andersen,
A. R., Telmer, S., and Parving, H.-H.: Kidney function and size
in normal subjects before and during growth hormone administration
for one week. Eur. J. Clin. Invest. 1981; 11:487-90.
96
C h r i s t i a n s e n , J. S . , G a m m e l g a a r d , J . , F r a n d s e n , M . , O r s k o v ,
H., and Parving, H.-H.: Kidney function and size in type I diabetic
patients before and during growth hormone administration for one
week. Diabetologia 1982; 22:333-37.
97
Christiansen, J. S.: On the Pathogenesis of the Increased Glo-
merular Filtration Rate in Short-Term Insulin-Dependent Diabetics.
PhD thesis. Univ. of Copenhagen, Copenhagen, 1984.
98
Hostetter, T. H., Troy, J. L., and Brenner, B. M.: Glomerular
hemodynamics in experimental diabetes. Kidney Int. 1981; 19:410-
15.
99
Jensen, P. K., Christiansen, J. S., Steven, K., and Parving,
H.-H.: Renal function in streptozotocin-diabetic rats. Diabetologia
1981; 21:409-14.
100
Hostetter, T. H., Olson, J. L , Rennke, H. G., Venkatach-
alam, M. A., and Brenner, B. M.: Hyperfiltration in remnant neph-
rons: a potentially adverse response to renal ablation. Am. J. Physiol.
1981; 241:F85-93.
101
Olson, J. L., Hostetter, T. H., Rennke, H. G., Brenner,
B. M., and Venkatachalam, M. A.: Altered glomerular permselec-
tivity and progressive sclerosis following extreme ablation of renal
mass. Kidney Int. 1982; 22:112-26.
102
Hostetter, T. H., Rennke, H. G., and Brenner, B. M.: The
case for intrarenal hypertension in the initiation and progression of
diabetic and other glomerulopathies. Am. J. Med. 1982; 72:375-
80.
103
Steffes, M. W., Brown, D. M., and Mauer, S. M.: Diabetic
glomerulopathy following unilateral nephrectomy in the rat. Dia-
betes 1978; 27:35-41.
104
Steffes, M. W., Buchwald, H., Wigness, B. D., Grappoli,
T. J., Rupp, W. M., Rodhe, T. D., Blackshear, P. J., and Mauer,
S. M.: Diabetic nephropathy in the uninephrectomized dog: micro-
scopic lesions after one year. Kidney Int. 1982; 21:721-24.
105
Mauer, S. M., Steffes, M. W., Azar, S., Sandberg, S. M.,
and Brown, D. M.: The effect of Goldblatt hypertension on the
development of glomerular lesions of diabetes mellitus in the rat.
Diabetes 1978; 27:738-44.
106
Berkman, J., and Rifkin, H.: Unilateral nodular diabetic
glomerulosclerosis (Kimmestiel-Wilson). Metabolism 1973; 22:715—
22.
107
Hakim, R. M., Goldzer, R. C , and Brenner, B. M.: Hyper-
tension and proteinuria: long-term sequelae of uninephrectomy in
humans. Kidney Int. 1984; 25:930-36.
108
Bertolatus, J. A., Friedlander, M. A., Scheidt, C , and Hur-
sicker, L. G.: Urinary albumin excretion after nephrectomy. Am.
J. Kid. Dis. 1985; 5:165-69.
109
Farquhar, M. G., Courtoy, P. J., Lemkin, M. A., and Kanwar,
Y. S.: Current knowledge of the functional architecture of the glo-
merular basement membrane. In New Trends in Basement Mem-
brane Research. Kuehn, K., Schoene, H., and Timple, R., Eds.
New York, Raven, 1982:9-29.
110
Brenner, B. M., Hostetter, T. M., and Humes, H. D.: Mo-
543
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
lecular basis of proteinuria of glomerular origin. N. Engl. J. Med.
1978; 298:826-33.
111
Deen, W. M., and Satvat, B.: Determinants of glomerular
filtration of proteins. Am. J. Physiol. 1981; 241:F162-70.
112
Mogensen, C. E.: Kidney function and glomerular permeability
to macromolecules in early juvenile diabetes. Scand. J. Clin. Invest.
1971; 28:79-90.
113
Pennell, J. P., Yanagawa, N., Hwang, K. J., Millard, M. M.,
and Bourgioignie, J. J.: Glomerular selective permeability to ma-
cromolecular neutral dextrans in experimental diabetes. Diabeto-
logia 1981; 20:223-27.
114
Meyer, B. D., Wiretz, J. A., Chui, R, and Michaels, A. S.:
Mechanisms of proteinuria in diabetic nephropathy. A study of
glomerular barrier function. Kidney Int. 1982; 21:633-41.
115
Ireland, J. T., Viberti, G. C., and Watkins, P. J.: The kidney
and renal tract. In Complications of Diabetes. Keen, H., andjarrett,
J., Eds. London, Arnold, 1982:166-72.
116
Viberti, G. C , Mackintosh, D., and Keen, H.: Determinants
of the penetration of proteins through the glomerular barrier in
insulin-dependent diabetes mellitus. Diabetes 1983; 32 (Suppl. 2):92—
95.
117
Spiro, G., and Parthasarathy, N.: Studies on the proteoglycan
of basement membrane. In New Trends in Basement Membrane
Research. Kuehn, K., Schoene, H., and Timple, R., Eds. New
York, Raven, 1982:87-98.
118
Wahl, P., Deppermann, D., and Hasslacher, C.: Biochemistry
of glomerular basement membrane of the normal and diabetic hu-
man. Kidney Int. 1982; 21:744-49.
119
Kanwar, Y. S., and Farquhar, M. G.: Presence of heparan
sulfate in the glomerular basement membrane. Proc. Natl. Acad.
Sci. USA 1974; 76:1303-1307.
120
Linker, A., Hovingh, P., Kanwar, Y. S., and Farquhar,
M. G.: Characterization of heparan sulfate isolated from dog glo-
merular basement membranes. Lab. Invest. 1981; 44:560-65.
121
Vernier, R. L , Klein, D. J., Sission, S. P., Mahan, J. D.,
Oegema, T. R., and Brown, D. M.: Heparan sulfate-rich anionic
sites in the human glomerular basement membrane. N. Engl. J.
Med. 1983; 309:1001-1009.
122
Kanwar, Y. S., Linker, A., and Farquhar, M. G.: Increased
permeability of the glomerular basement membrane to ferritin after
removal of glycosaminoglycans (heparan sulfate) by enzyme diges-
tion. J. Cell Biol. 1980; 86:688-93.
123
Rosenzweig, L. J., and Kanwar, Y. S.: Removal of sulfated
(heparan sulfate) or nonsulfated (hyaluronic acid) glycosaminogly-
cans results in increased permeability of the glomerular basement
membrane to 125I-BSA. Lab. Invest. 1982; 47:177-84.
124
Vehaskari, V. M., Root, E. R., Germuth, F. G., and Robson,
A. M.: Glomerular charge and urinary protein excretion: effects of
systemic and intrarenal polycation infusion in the rat. Kidney Int.
1982; 22:127-235.
125
Barnes, J. L , Radnik, R. A., Gilchrist, E. P., and Venka-
tachalam, M. A.: Size and charge selective permeability defects
induced in glomerular basement membrane by a polycation. Kidney
Int. 1984; 25:11-19.
126
Rohrback, D. H., Hassell, J. R., Kleinman, H. K., and Martin,
G. R.: Alterations in the basement membrane (heparan sulfate)
proteoglycan in diabetic mice. Diabetes 1982; 31:185-88.
127
Kanwar, Y. S., Rosenzweig, L. J., Linker, A., andjakubowski,
L.: Decreased de novo synthesis of glomerular proteoglycans in di-
abetes: biochemical and autoradiographic evidence. Proc. Natl. Acad.
Sci. USA 1983; 80:2272-75.
128
Cohen, M. P., and Surma, M. L.: Effect of diabetes on in vivo
544 DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
metabolism of [35S]-labeled glomerular basement membrane. Dia-
betes 1984; 33:8-12.
129
Parthasarathy, N., and Spiro, R. G.: Effect of diabetes on the
glycosaminoglycan component of the human glomerular basement
membrane. Diabetes 1982; 31:738-41.
130
Mauer, S. M., Steffes, M. W., Chern, M., and Brown,
D. M.: Mesangial uptake and processing of macromolecules in rats
with diabetes mellitus. Lab. Invest. 1979; 41:401-406.
131
Lee, C. S., Mauer, S. M., Brown, D. M., Sutherland,
D. E. R., Michael, A. F., and Najarian, J. S.: Renal transplan-
tation in diabetes mellitus in rats. J. Exp. Med. 1974; 139:793—
800.
132
Mauer, S. M., Steffes, M. W., Sutherland, D. E. R., Najarian,
J. S., Michael, A. F, and Brown, D. M.: Studies of the rate of
regression of the glomerular lesions in diabetic rats treated with
pancreatic islet transplantation. Diabetes 1975; 24:280-85.
133
Steffes, M. W., Brown, D. M., Basgen, J. M., and Mauer,
S. M.: Amelioration of mesangial volume and surface alterations
following islet transplantation in diabetic rats. Diabetes 1980; 29:509-
15.
134
Mauer, S. M., Brown, D. M., Matas, A. J., and Steffes,
M. W.: Effects of pancreatic islet transplantation on the increased
urinary albumin excretion rates in intact and uninephrectomized
rats with diabetes mellitus. Diabetes 1978; 27:959-64.
135
Rasch, R.: Prevention of diabetic glomerulopathy in strepto-
zotocin diabetic rats by insulin treatment: albumin excretion. Dia-
betologia 1980; 18:413-16.
136
Mauer, S. M., Barbosa, J., Vernier, R. L., Kjellsatrand,
C. M., Buselmeier, T. J., Simmons, R. L., Najarian, J. S., Goetz,
F. C.: Development of diabetic vascular lesions in normal kidney
transplanted into patient with diabetes mellitus. N. Engl. J. Med.
1976; 295:916-20.
137
Abouna, G. M., Kremer, G. D., Daddah, S. K., Al-Adnani,
M. S., Kunar, S. A., and Kusma, G.: Reversal of diabetic nephrop-
athy in human cadaveric kidneys after transplantation into non-
diabetic recipients. Lancet 1983; 2:1274-76.
138
Bending, J. J., Pickup, J. C , Viberti, G. C , and Keen, H.:
Glycaemic control in diabetic nephropathy. Br. Med. J. 1984;
288:1187-91.
139
Viberti, G. C , Pickup, J. C , Jarrett, R. J., and Keen, H.:
Effect of control of blood glucose on urinary excretion of albumin
and beta2-microglobulin in insulin-dependent diabetes. N. Engl. J.
Med. 1979; 300:638-41.
140
Lauritzen, T., Frost-Larsen, K., Svendsen, P. Aa., Larsen,
H.-W., Deckert, T., Christiansen, J. S., Parving, H.-H., Binder,
C., Nerup, J., Deckert, M., Larsen, A., Lorup, B., Bojsen, J., and
Bech-Jansen, L.: Effect of six months of strict metabolic control on
eye and kidney function in insulin-dependent diabetics with back-
ground retinopathy. Lancet 1982; 1:121-24.
141
Deckert, T., Lauritzen, T., Parving, H.-H., Christiansen,
J. S., and the Steno Study Group.: Effect of two years of strict
metabolic control on kidney function in long-term insulin-depend-
ent diabetes. Diabetic Nephrop. 1983; 2:6-10.
142
The Kroc Collaborative Study Group.: Blood glucose control
and the evolution of diabetic retinopathy and albuminuria. N. Engl.
J. Med. 1984; 311:365-72.
143
Feldt-Rasmussen, B., Mathiesen, E. R., Hegedus, L., and
Deckert, T.: Kidney function during 12 months of strict metabolic
control in insulin-dependent diabetic patients with incipient ne-
phropathy. N. Engl. J. Med. 1986; 314:665-70.
144
Christlieb, A. R., Warram, J. H., Kr6lewski, A. S., Busick,
E. J., Ganda, O. P., Asmal, A. C., Soeldner, J. S., and Bradley,
 EARLY DIABETIC NEPHROPATHY/J. ROSENSTOCK AND P. RASKIN
R. R: Hypertension: the major risk factor in juvenile-onset insulin-
dependent diabetics. Diabetes 1981; 30 (Suppl. 2):90-96.
145
Parving, H.-H., Andersen, A. R., Smidt, U. M., Oxenboll,
B., Edsbert, B., and Christiansen, J. S.: Diabetic nephropathy and
arterial hypertension. Diabetologia 1983; 24:10-12.
146
Parving, H.-H., Smidt, U. M., Friisberg, B., Bonnevie-Niel-
sen, V., and Andersen, A. R.: A prospective study of glomerular
filtration rate on arterial blood pressure in insulin-dependent
diabetics with diabetic nephropathy. Diabetologia 1981; 20:457—
61.
147
Wiseman, M. J., Viberti, G. C., Mackintosh, D., Jarrett,
R. J., and Keen, H.: Glycemia, arterial pressure, and microalbu-
minuria in type I (insulin-dependent) diabetes mellitus. Diabetologia
1984; 26:401-405.
148
Parving, H.-H., Jensen, H. A., Mogensen, C. E., and Evrin,
P. -E.: Increased urinary albumin excretion rate in benign essential
hypertension. Lancet 1974; 1:1190-92.
149
Pedersen, E. B., and Mogensen, C. E.: Effect of antihyperten-
sive treatment on urinary albumin excretion, glomerular filtration
rate, and renal plasma flow in patients with essential hypertension.
Scand. J. Clin. Lab. Invest. 1976; 36:231-37.
150
Christiansen, C. K., and Mogensen, C. E.: Effect of antihy-
pertensive treatment on progression of incipient diabetic nephrop-
athy. Hypertension 1985; 7 (Suppl.): 109-13.
151
The 1984 Report of the Joint National Committee on Detec-
tion, Evaluation and Treatment of High Blood Pressure. Arch. In-
tern. Med. 1984; 144:1045-57.
152
Viberti, G. C., and Wiseman, M. J.: Early markers of diabetic
nephropathy: a road to prevention. In Nephropathy. Proc. IX Int.
Congr. Nephrol. Robinson, R. R., Ed. New York, Springer-Verlag,
1984:1094-102.
153
Drury, P. L , and Tarn, A. C : Are the WHO criteria for
hypertension appropriate in young insulin-dependent diabetics? Di-
abetic Med. 1985; 2:79-82.
154
Giordano, C.: Protein restriction in chronic renal failure. Kid-
ney Int. 1982; 22:401-408.
155
Maschio, G., Oldrizzi, L., Tessitore, N., D'Angelo, A., Valvo,
E., Lupo, A., Loschiavo, C , Fabris, A., Gammaro, L., Rugio, C.,
and Punzetta, G.: Effects of dietary protein and phosphorus restric-
tion in the progression of early renal failure. Kidney Int. 1982;
22:371-76.
156
Mitch, W. E., Walser, M., Steinman, T. I., Hill, S., Zeger,
S., and Tungsanga, K.: The effect of a keto acid-amino acid sup-
plement to a restricted diet on the progression of chronic renal
failure. N. Engl. J. Med. 1984; 311:623-24.
157
Rosman, J. B., Meijer, S., Sluioter, W. J., Terwee, P. M.,
Pierts-Becht, T. P. M., and Dunker, A. M.: Prospective randomized
trial of early dietary protein restriction in chronic renal failure.
Lancet 1984; 2:1291-96.
158
Newburgh, L. H.: The production of Bright's disease by feeding
high-protein diets. Arch. Intern. Med. 1914; 24:354-77.
159
Newburgh, L. H., and Curtis, A. C : Production of renal injury
in the white rat by the protein of the diet. Arch. Intern. Med.
1928; 42:$01-21.
160
Blutherwick, N. R., and Medlon, E. M.: Chronic nephritis
in rats fed high-protein diets. Arch. Intern. Med. 1932; 59:582—
96.
161
Lalich, J. J., and Allen, J. R.: Protein overload nephropathy
in rats with unilateral nephrectomy. Arch. Pathol. 1971; 91:372-
82.
162
Farr, L. E., and Smardel, J. E.: The effect of dietary protein
DIABETES CARE, VOL. 9 NO. 5, SEPTEMBER-OCTOBER 1986
on the course of nephrotoxic nephritis in rats. J. Exp. Med. 1934,
70:615-27.
163
Kleinknecht, C , Salusky, I., Broyer, M., andGublen, M. C :
Effect of various protein diets on growth, renal function, and survival
of uremic rats. Kidney Int. 1974; 15:534-41.
164
Brenner, B. M., Meyer, T. W., and Hostetter, T. H.: Dietary
protein intake and the progressive nature of kidney disease. N. Engl.
J. Med. 1982; 307:652-59.
165
Meyer, T. W., Lawrence, W. E., and Brenner, B. M.: Dietary
protein and the progression of renal disease. Kidney Int. 1983; 24
(Suppl. ):243-47.
166
Jamison, R. L.: Dietary protein, glomerular hyperemia, and
progressive renal failure: Ann. Intern. Med. 1983; 99:849-51.
167
N e u g a r t e n , J., Liv, D . , Feiner, H . , Schacht, R., C h u b a , J.,
and Baldwin, D. S.: Aggravation of experimental diabetic nephrop-
athy by high dietary protein. Abstract. Clin. Res. 1983; 31:438A.
168
Zeller, K., Raskin, P., Rosenstock, J., and Jacobson. H.: The
effect of dietary protein restriction in diabetic nephropathy: reduc-
tion in proteinuria. Abstract. Clin. Res. 1985; 33:503A.
169
Cogan, D. G., Kinoshita, J. H., Kador, P. R, Robinson,
W. G., Datilis, M. B., Cobo, L. M., and Kupfer, C : Aldose re-
ductase and complications of diabetes. Ann. Intern. Med. 1984;
101:82-91.
170
Gabbay, K. H.: Hyperglycemia, polyol metabolism, and the
complications of diabetes mellitus. Annu. Rev. Med. 1978; 26:521—
36.
171
Gillon, K. R. W., Hawthorne, J. N., and Tomlinson, D. R.:
Myo-inositol and sorbitol metabolism in relation to peripheral nerve
function in experimental diabetes in the rat: the effect of aldose
reductase inhibition. Diabetologia 1983; 25:365-71.
172
Greene, D. A., and Lattimer, S. A.: Impaired rat sciatic nerve
sodium-potassium adenosine triphosphatase in acute streptozotocin
diabetes and its correction by dietary myo-inositol supplementation.
J. Clin. Invest. 1983; 72:1058-63.
173
Greene, D. A., and Lattimer, S. A.: Action of sorbinil in
diabetic peripheral nerve: relationship of polyol (sorbitol) pathway
inhibition to a nvyo-inositol-mediated defect in sodium-potassium
ATPase activity. Diabetes 1984; 33:712-16.
174
Judzewitsch, R. G., Jaspan, J. B., Polonsky, K. S., Weinberg,
C. R., Halter, J. B., Halar, E., Pfeifer, M. A., Vakadinovic, C ,
Bernstein, L., Schneider, M., Liang, K. Y., Gabbay, K. H., Ru-
benstein, A. H., and Porte, D., Jr.: Aldose reductase inhibition
improves nerve conduction velocity in diabetic patients. N. Engl.
J. Med. 1983; 308:119-25.
175
Jaspan, J., Maselli, R., Herold, K., and Bartkus, C : Treatment
of severely painful diabetic neuropathy with an aldose reductase
inhibitor: relief of pain and improved somatic and automatic nerve
function. Lancet 1983; 2:758-62.
176
Young, R. J., Ewing, D. J., and Clarke, B. R: A controlled
trial of sorbinil, an aldose reductase inhibitor in chronic painful
diabetic neuropathy. Diabetes 1983; 32:938-42.
177
Robinson, Jr., W. G., Kador, P. R, and Kinoshita, J. H.:
Retinal capillaries: basement membrane thickening by galactosemia
prevented with aldose reductase inhibitor. Science 1983; 221:1177—
79.
178
Beyer-Mears, A., Ku, L., and Cohen, M. P.: Glomerular polyol
accumulation in diabetes and its prevention by oral sorbinil. Diabetes
1984; 33:604-607.
179
Beyer-Mears, A., Varagiannis, E., and Cruz, E.: Effect of sor-
binil on reversal of proteinuria. Abstract 402. Diabetes 1985; 34
(Suppl. l):101A.
545