Kidney International, Vol. 59 (2001), pp.

702–709

Progression of diabetic nephropathy

PETER HOVIND, PETER ROSSING, LISE TARNOW, ULLA M. SMIDT, and HANS-HENRIK PARVING
Steno Diabetes Center, Gentofte, Denmark

Progression of diabetic nephropathy. Diabetic nephropathy is a clinical syndrome character-

Background. Diabetic nephropathy is a major cause of renal ized by persistent albuminuria, arterial blood pressure
failure. The decline in glomerular filtration rate (GFR) is highly elevation, a relentless decline in glomerular filtration
variable, ranging from 2 to 20, with a median of 12 mL/min/
year. The risk factors of losing filtration power (progression rate (GFR), and a high risk of cardiovascular morbidity
promoters) have not been clearly identified. Furthermore, in- and mortality [1]. This major life-threatening complica-
formation on optimal arterial blood pressure, glycemic control, tion develops in approximately 35% of type 1 diabetic
and cholesterol levels are lacking. patients [2, 3]. Diabetic nephropathy is a leading cause
Methods. We measured GFR with 51Cr-EDTA plasma clear- of end-stage renal disease. However, the decline in GFR
ance technique, blood pressure, albuminuria, glycosylated he- is highly variable, ranging from 2 to 20 mL/min/year
moglobin A1c, and serum cholesterol every year for seven years
(range 3 to 14 years) in 301 consecutive type 1 diabetic patients [4–6]. The risk factors for losing filtration power, that
with diabetic nephropathy recruited consecutively during 1983 is, the so-called progression promoters, have not been
through 1997. Diabetic nephropathy was diagnosed clinically studied extensively. Hypertension and proteinuria con-
if the following criteria were fulfilled: persistent albuminuria tribute to the progressive loss of renal function, while
⬎200 ␮g/min, presence of diabetic retinopathy, and no evi- other progression promoters, for example, glycemic con-
dence of other kidney or renal tract disease. In total, 271 pa- trol and lipids, are still debatable as reviewed by Rossing
tients received antihypertensive treatment at the end of the
observation period.
[7]. The identification of progression promoters is impor-
Results. Mean arterial blood pressure was 102 ⫾ 0.4 (SE) tant for the creation of new powerful treatment modal-
mm Hg. The average decline in GFR was 4.0 ⫾ 0.2 mL/min/year ities impeding the development of end-stage renal dis-
and even lower (1.9 ⫾ 0.5 mL/min/year) in the 30 persistently ease. The aim of our prospective observational study,
normotensive patients, none of whom had ever received antihy- started in 1983, was to evaluate the impact of several
pertensive treatment (P ⬍ 0.01). A multiple linear regression putative progression promoters in a consecutive cohort
analysis revealed a significant positive correlation between the
decline in GFR and mean arterial blood pressure, albuminuria,
of 301 type 1 diabetic patients with diabetic nephropathy,
glycosylated hemoglobin A1c, and serum cholesterol during who had serial measurements of glomerular filtration
follow-up (R2adj ⫽ 0.29, P ⱕ 0.001). No threshold level for blood performed and at least three years of follow-up. In addi-
pressure, glycosylated hemoglobin A1c, or serum cholesterol tion, we strived to obtain information on optimal arterial
was demonstrated. A two-hit model with mean arterial blood blood pressure, glycemic control, and cholesterol levels
pressure and glycosylated hemoglobin A1c below and above the in relationship to loss of kidney function.
median values (102 mm Hg and 9.2%, respectively) revealed a
rate of decline in GFR of only 1.5 mL/min/year in the lowest
stratum compared with 6.1 mL/min/year in the highest stratum METHODS
(P ⬍ 0.001).
Conclusions. The prognosis of diabetic nephropathy has Patients
improved during the past decades, predominantly because of Since 1983, at Steno Diabetes Center, all type 1 dia-
effective antihypertensive treatment. Genuine normotensive betic patients with nephropathy have had their kidney
patients have a slow progression of nephropathy. Several modi-
function monitored with one yearly determination of
fiable variables have been identified as progression promoters.
GFR. The data are kept in a diabetic nephropathy regis-
try, from which we included all type 1 diabetic patients
Key words: renal failure, proteinuria, glycemic control, type 1 diabetes
who had a minimum of three years of follow-up (N ⫽
mellitus, antihypertensive treatment, blood pressure control, glomeru- 301). The recruitment period for our prospective cohort
lar filtration rate, diabetic nephropathy. study ended in 1997. Diabetic nephropathy was diag-
Received for publication May 11, 2000
nosed clinically if the following criteria were fulfilled:
and in revised form August 29, 2000 persistent albuminuria ⬎200 ␮g/min in at least two out
Accepted for publication September 1, 2000 of three consecutive 24-hour urine collections, presence
 2001 by the International Society of Nephrology of diabetic retinopathy, and the absence of any clinical or

702
 Hovind et al: Progression of diabetic nephropathy 703

laboratory evidence of other kidney or renal tract disease munoassay (r ⫽ 0.99) [12] was documented before chang-
[8]. All patients took at least two daily injections of insulin ing the methods. The method used for measurement of
and had a diabetic diet containing 45 to 55% carbohy- glycosylated hemoglobin A1c from venous blood samples
drates, 30 to 35% fat, and 15 to 20% protein. No sodium has also changed over the years: From 1983 to 1988,
or protein restrictions were applied during the study. A high-performance liquid chromatography (HPLC) ion
total of 271 patients were treated with antihypertensive exchange [14] and isoelectric focusing [15] were used.
medication during the whole or the major part of the These methods have a normal range of 4.1 to 6.1% and
follow-up period, 179 patients predominantly with angio- 4.1 to 6.4%. Thereafter, glycosylated hemoglobin A1c
tensin-converting enzyme (ACE) inhibitors. Patients were was measured with HPLC (Bio-Rad Diamat, Richmond,
classified as taking a class of antihypertensive agent if CA, USA) with a normal range of 4.1 to 6.4%. The
the drug was prescribed for more than 50% of their correlations between this method and the two previous
follow-up time. Seventeen percent of the patients re- methods were r ⫽ 0.983 (N ⫽ 194) and r ⫽ 0.931 (N ⫽
ceived monotherapy. Forty-seven percent received two 119), respectively. Finally, from 1994, an HPLC-based
agents. Thirty percent received three agents, and 6% method was used (Bio-Rad Variant). The normal range
were treated with four or more antihypertensive drugs. remained unchanged (4.1 to 6.4%), and the coefficient
A stepped-care approach for antihypertensive treatment of correlation between the latter and present method
was applied. Before 1991, it included selective ␤ blockers, was r ⫽ 0.993 (N ⫽ 161). Serum cholesterol was mea-
diuretics, and vasodilators. After 1991, it included ACE sured with standard laboratory techniques, and the
inhibitors, diuretics, calcium channel blockers (mainly method was unchanged during the study. Arterial blood
dihydropyridines), and ␤ blockers. During the whole fol- pressure was measured at each visit with a standard mer-
low-up period, we strived to keep our patients’ blood cury sphygmomanometer and appropriate cuff size. The
pressure below 140/90 mm Hg. Thirty patients remained measurements were performed twice, on the right arm,
normotensive without antihypertensive treatment before after at least 10 minutes of rest in the supine position and
or during the observation period, that is, genuine normo- were averaged. Diastolic blood pressure was recorded
tensive patients. The local ethical committee approved at the disappearance of Korotkoff sounds (phase V).
the experimental design, and all patients gave their in- Arterial hypertension was diagnosed according to the
formed consent. World Health Organization’s criteria (ⱖ160/95 mm Hg)
until 1995 and thereafter according to the American Dia-
Procedures betes Associations criteria ⱖ140/90 mm Hg [16]. All
All investigations were made on the same day between patients visited the outpatient clinic every three to four
8 a.m. and 1 p.m. The patients had their normal breakfast months during the study. Blood glucose concentration,
and usual medication at least one hour before the proce- glycosylated hemoglobin A1c, albuminuria, blood pres-
dure, during which the patients rested in a supine posi- sure, and body weight were monitored, and the insulin
tion. During the investigation period, the patients drank dose and antihypertensive treatment were adjusted.
approximately 150 to 200 mL of tap water per hour. Retinopathy was assessed after pupillary dilation by
The GFR measurement was performed 3 to 24 times ophthalmoscopy and from 1991 by fundus photography
(median 8) in each patient during a follow-up period of and graded: nil, simplex, or proliferative diabetic retinop-
3 to 14 years (median 7). GFR was measured after a athy.
single intravenous injection of 3.7 MBq 51Cr-EDTA by
determination of the radioactivity in venous blood sam- Statistical analyses
ples taken 180, 200, 220, and 240 minutes after the injec- Results are expressed as means and SE, means and
tion [9]. The mean variability in GFR of each patient SD being used for descriptive information. Albuminuria
from day to day was 4%. Results are standardized for is given as median (range) and logarithmically trans-
1.73 m2 body surface, using the patient’s surface area at formed before analysis because of the positively skewed
the start of the study throughout. distribution. In each patient, all measurements per-
Albuminuria was measured in timed urine collections, formed during the entire follow-up period were used to
obtained during the four-hour clearance period. Before calculate the mean values. A linear regression analysis,
1984, the urinary albumin concentration was measured least-square method, was used to determine the rate of
by radial immunodiffusion [10], from 1984 to 1990 by decline in GFR for each patient.
radioimmunoassay [11], and from 1990 it was determined In normally distributed variables, a comparison be-
by enzyme immunoassay [12]. The assays had a sensitiv- tween groups was performed by an unpaired Student
ity of 2, 0.5, and 1.1 mg/L and a coefficient of variation t test. In non-normally distributed continuous variables,
of 8, 9, and 8%, respectively. A very close correlation a Mann–Whitney test was used for comparison between
between radial immunodiffusion and radioimmunoassay groups. A multiple linear regression analysis with back-
(r ⫽ 0.98) [13] and radioimmunoassay and enzyme im- ward selection was performed with decline in GFR as
704 Hovind et al: Progression of diabetic nephropathy

Table 1. Characteristics of type 1 diabetic patients suffering from diabetic nephropathy at baseline, and clinical and laboratory data during
the follow-up period
Total No antihypertensive therapy Antihypertensive therapya
N ⫽ 301 N ⫽ 30 N ⫽ 271
Baseline
Sex M/F 192/109 16/14 176/95
Age yearsb 36 ⫾ 11 35 ⫾ 10 36 ⫾ 11
Age at onset yearsb 14 ⫾ 9 13 ⫾ 9 14 ⫾ 9
Duration of diabetes yearsb 22 ⫾ 8 22 ⫾ 7 22 ⫾ 8
Height cmb 172 ⫾ 8 173 ⫾ 8 172 ⫾ 9
Retinopathy simplex/proliferative 99/202 15/15 84/187h
Smoking yes/no 164/137 20/10 144/127
Systolic blood pressure mm Hgb 140 ⫾ 19 129 ⫾ 14 141 ⫾ 19f
Diastolic blood pressure mm Hgb 85 ⫾ 9 79 ⫾ 9 86 ⫾ 9f
Mean arterial blood pressure mm Hgb 103 ⫾ 11 96 ⫾ 9 104 ⫾ 10f
Albuminuria lg/minc 629 (45–6177) 368 (204–1694) 691f (45–6177)
Glycosylated hemoglobin A1c %b 9.3 ⫾ 1.4 8.9 ⫾ 1.2 9.4 ⫾ 1.5
Glomerular filtration rate mL/min/1.73 m2 89 ⫾ 28 106 ⫾ 20 87 ⫾ 28f
During follow-up periodd
Rate of decline in glomerular filtration rate mL/min/yeare 4.0 (0.2) 1.9 (0.5) 4.3 (0.3)g
Systolic blood pressure mm Hge 140 (0.8) 131 (1.9) 141 (0.9)f
Diastolic blood pressure mm Hge 82 (0.5) 77 (1.0) 83 (0.4)f
Mean arterial blood pressure mm Hge 102 (0.4) 95 (1.1) 102 (0.5)f
Albuminuria lg/minc 557 (13–6939) 384 (124–2358) 585 (13–6939)h
Glycosylated hemoglobin A1c %e 9.3 (0.1) 8.9 (0.2) 9.3 (0.1)h
Serum cholesterol mmol/Le 5.7 (0.1) 5.0 (0.1) 5.8 (0.1)f
Observation time yearsc 6.7 (3.0–14.0) 7.0 (3.4–13.3) 6.6 (3.0–14.0)
Some patients with previously persistent albuminuria receiving antihypertensive treatment had baseline albuminuria below 200 ␮g/min.
a
These patients received antihypertensive treatment during the whole or the major part of the follow-up period
Data are: b means ⫾ SD, c median (range), e means (SE)
d
In each patient, all measurements performed during the entire follow-up period were used to calculate mean/median values
f
P ⬍ 0.001 as compared with patients receiving no antihypertensive therapy
g
P ⱕ 0.01 as compared with patients receiving no antihypertensive therapy
h
P ⬍ 0.05 as compared with patients receiving no antihypertensive therapy

dependent variable, including all variables with P ⬍ 0.10 3 to 14) years, the mean rate of decline in GFR was
in univariate analyses. A two-factor analysis of variance 4.0 ⫾ 0.2 mL/min/year. The 30 genuine normotensive
was used to evaluate the two hit models. The calculations patients had a significantly lower rate of decline in glo-
were performed with a commercially available program, merular filtration as compared with the hypertensive pa-
SPSS 8.0 (SPSS Inc., Chicago, IL, USA). tients (1.9 ⫾ 0.5 vs. 4.3 ⫾ 0.3 mL/min/year, respectively,
To evaluate whether there were nonlinear effects of P ⬍ 0.01). However, the mean arterial blood pressure
the variables on the decline in GFR, we extended the was also significantly lower in the normotensive group
linear regression model to a model with one change point compared with the patients receiving antihypertensive
for each variable at a time. By varying the change point, medication (95 ⫾ 1 vs. 102 ⫾ 0.5 mm Hg, P ⬍ 0.001).
we could estimate the position of the change point (thresh- In addition, albuminuria, glycosylated hemoglobin A1c,
old) and test whether inclusion of a change point improved and serum cholesterol were lower in the normotensive
the model [17]. These calculations were performed by patients (P ⬍ 0.05). When comparing the 30 genuine
the freely available software R (http://www.ci.tuwien. normotensive patients with previously hypertensive pa-
ac.at/R). tients, who on antihypertensive treatment obtained the
A P value ⬍0.05 (two-sided) was considered statisti- same level of blood pressure (N ⫽ 102), there was no
cally significant. difference in the decline in kidney function (1.9 ⫾ 0.5
vs. 2.5 ⫾ 0.3 mL/min/year, respectively, NS). The rate
of decline in GFR in patients predominantly treated with
RESULTS ACE inhibitors versus patients mainly treated with other
The characteristics of the patients at baseline are blood pressure-lowering agents did not differ signifi-
shown in Table 1. The demographic and clinical data of cantly (4.5 ⫾ 0.3 vs. 3.8 ⫾ 0.4 mL/min/year, respectively,
the patients in the genuine normotensive group and in NS). Furthermore, there was no difference in mean arte-
the group receiving antihypertensive treatment were rial blood pressure values between patients predomin-
alike. However, the latter group had higher arterial antly treated with ACE inhibitors as compared with pa-
blood pressure and albuminuria and lower GFR (P ⬍ tients mainly treated with other blood pressure-lowering
0.001). During the investigation period of seven (range agents (103 ⫾ 0.6 vs. 102 ⫾ 0.7 mm Hg, NS). No statistical
 Hovind et al: Progression of diabetic nephropathy 705

Table 2. Multiple linear regression analysis of progression promoters in type 1 diabetic patients suffering from diabetic nephropathy

Variable Slope (95% CI) P value

Dependent variable
Rate of decline in GFR mL/min/year
Independent variables
Mean arterial blood pressure per 10 mm Hg 1.18 (0.59–1.77) ⬍ 0.001
Albuminuria log10 2.04 (1.07–3.01) ⬍ 0.001
Hemoglobin A1c % 0.73 (0.36–1.10) ⬍ 0.001
Serum cholesterol mmol/L 0.66 (0.27–1.05) 0.001
R2 adj.: 0.29
Not included in the model are age, sex, height, grade of retinopathy, smoking, and class of antihypertensive treatment.

significant differences in any of the other progression mm Hg systolic and 90 mm Hg diastolic. Correspond-
promoters were demonstrated between these two groups ingly, 202 patients (75%; 69 to 80%) had a mean arterial
(data not shown). blood pressure below 107 mm Hg during follow-up.
A univariate analysis of demographic, clinical, and
laboratory parameters revealed a significant positive cor-
DISCUSSION
relation between the decline in GFR (dependent vari-
able) and systolic (r ⫽ 0.27, P ⬍ 0.001), diastolic (r ⫽ Our long-term prospective observational study in 301
0.37, P ⬍ 0.001) and mean arterial blood pressure (r ⫽ type 1 diabetic patients suffering from diabetic nephrop-
0.39, P ⬍ 0.001), albuminuria (r ⫽ 0.41, P ⬍ 0.001), athy revealed that the prognosis of diabetic nephropathy
glycosylated hemoglobin A1c (r ⫽ 0.30, P ⬍ 0.001), and has improved during the past decades. Genuine normo-
serum cholesterol (r ⫽ 0.32, P ⬍ 0.001) during the study. tensive patients have a slow rate of decline in GFR.
Men had a significantly higher rate of decline in GFR Furthermore, several modifiable variables—that is, arte-
than women (4.4 ⫾ 0.3 vs. 3.4 ⫾ 0.4 mL/min/year, P ⬍ rial blood pressure, albuminuria, glycemic control, and
0.04). After adjustment for other progression promoters, serum cholesterol—act as progression promoters. Fi-
the rate of decline in GFR was similar in men (4.1 ⫾ nally, except for albuminuria, no statistical threshold ef-
0.3 mL/min/year) and in women (4.0 ⫾ 0.4 mL/min/year, fect on the decline in GFR of any of the identified pro-
NS). Smoking, degree of retinopathy, height, age, class gression promoters was demonstrated.
of antihypertensive treatment, and baseline GFR had no To minimize selection bias and maximize generaliz-
predictive value. When these variables were examined in ability, all type 1 diabetic patients with diabetic nephrop-
combination by multiple linear regression analysis, the athy according to the well-defined criteria [8] who had
significant predictors of decline in GFR were high values a minimum of three years of follow-up on their kidney
of mean arterial blood pressure, albuminuria, glycosy- function were enrolled in our prospective cohort study.
lated hemoglobin A1c, and serum cholesterol (r ⫽ 0.54, To obtain a valid determination of the rate of decline in
r2adj ⫽ 0.29, P ⱕ 0.001; Table 2). GFR the following requirements should be fulfilled: The
The relationship between the rate of decline in GFR applied GFR method should have good accuracy and pre-
and each of the four previously mentioned progression cision, and repeated measurements of GFR (⬃every 6 to
promoters separated in quintiles is shown in Figure 1. 12 months) should be performed. The observation period
Except for albuminuria (threshold 436 ␮g/min, P ⬍ 0.01), should be extended to at least two years [18]. These
none of the other potentially modifiable progression pro- requirements were fulfilled in our study. A major strength
moters showed a significant threshold, suggesting that in prospective cohort studies (such as ours) is a long-term
the best fit of the data is linear or curve linear. follow-up period of an unselected, well-defined group
A two-hit model with mean arterial blood pressure of patients, which maximize the generalizability of the
(previously demonstrated to be a modifiable progression findings. The limitations are that the identified progres-
promoter) combined with each of the three previously- sion promoters can only be documented as modifiable
mentioned potentially modifiable risk factors for losing risk factors in randomized clinical intervention trials,
filtration power is shown in Figure 2. and interpretation of the impact of different treatment
Of the 271 patients treated with antihypertensive modalities is limited, since different categories of pa-
agents, 139 patients (51%; 95% CI, 45 to 57) achieved tients can receive different therapy.
a systolic blood pressure below 140 mm Hg during fol- The natural history of diabetic nephropathy is charac-
low-up. In 234 patients (86%; 82 to 90%), diastolic blood terized by arterial blood pressure elevation and a relent-
pressure was below 90 mm Hg, whereas 128 patients less decline in GFR of approximately 12 mL/min/year
(47%; 41 to 53%) achieved a blood pressure below 140 [4–6]. Data from studies evaluating the rate of decline
706 Hovind et al: Progression of diabetic nephropathy

Fig. 1. Impact of mean arterial blood pressure, glycosylated hemoglobin A1c, albuminuria, and serum cholesterol on the decline in GFR (P ⬍
0.001 for each factor).

in GFR are presented in Table 3. While the original the glomerular capillaries and therefore to glomerular
studies did not include patients on antihypertensive capillary hypertension. Studies in experimental diabetic
treatment, such treatment was applied in 90% of our animals [28, 29] and more recently in humans [30] have
patients, and we demonstrated a much slower rate of documented intrarenal hypertension, and have stressed
decline in GFR (4 mL/min/year). A retrospective analy- the importance of this hemodynamic phenomenon in the
sis of 158 type 1 diabetic patients with nephropathy has initiation and progression of diabetic and nondiabetic
revealed results nearly identical to the present findings glomerulopathies [31].
[19]. Several prospective antihypertensive treatment tri- Impaired autoregulation of glomerular pressure and
als have documented a beneficial effect on albuminuria, systemic blood pressure elevation induce distention–
rate of decline in GFR, progression to end-stage renal contraction of glomeruli. These alterations are associated
disease, and survival in type 1 diabetic patients suffering with mesangial cell stretch, that in turn stimulates the
from diabetic nephropathy [8, 20–25]. Thus, arterial blood synthesis and deposition of extracellular matrix material
pressure seems to have a rather complex relationship with leading to mesangial expansion and glomerulosclerosis
diabetic nephropathy: nephropathy raising blood pressure [32, 33]. In diabetic glomeruli, the mechanical stretch
and blood pressure accelerating the course of nephropa- effect on extracellular matrix material synthesis is mark-
thy. This acceleration may be at least partly due to im- edly aggravated by the presence of hyperglycemia [33].
paired/abolished autoregulation of GFR [26, 27], leading Proteinuria is usually considered a marker of the ex-
to enhanced transmission of systemic blood pressure to tent of glomerular damage, but studies in various experi-
 Hovind et al: Progression of diabetic nephropathy 707

sive treatment on the long-term decline in kidney func-

tion in diabetic and nondiabetic nephropathies [43–45].
Development of overt diabetic nephropathy has for
many years been regarded as “a point of no return” in
relationship to glycemic control as reviewed by Rossing
[7]. However, this statement is based on studies using
inappropriate methods for monitoring kidney function
(serum creatinine), long-term glycemic control (blood
glucose), and often, very few patients were studied.
Applying better research techniques and in some studies
a larger number of type 1 diabetic patients, a significant
impact of glycemic control on progression of nephropa-
thy has been found [19, 37, 46], as also documented in
our study. Furthermore, pancreas transplantation can
reverse the lesions of diabetic glomerulopathy, but rever-
sal requires more than five years of normoglycemia [47].
Our study demonstrated that elevated serum choles-
terol acts as an independent progression promoter in
diabetic nephropathy. This finding supports the concept
advocated by Moorhead et al [48] that hyperlipidemia
promotes progression in chronic renal diseases once an
initial event has damaged the glomerular capillary wall,
thereby allowing passage of lipids and lipoproteins into
the mesangium. Several short-term studies dealing with
a limited number of diabetic patients have failed to dem-
onstrate a beneficial effect of lipid lowering treatment
on the surrogate endpoint: albuminuria [7]. Long-term
trials applying a principal endpoint such as the decline
in GFR are still lacking.
A renoprotective effect of ACE inhibitors above and
beyond the effect of blood pressure lowering has been
demonstrated in some clinical trials [23, 24], while others
have failed to demonstrate an additional non-hemody-
namic effect of ACE inhibition [abstract; Tarnow et al,
Fig. 2. The decline in GFR divided according to median of mean arte- Diabetologia 42(Suppl 1):A275, 1999] [25]. In our long-
rial blood pressure combined with median albuminuria, glycosylated term prospective observational study, we could not dem-
hemoglobin A1c, and serum cholesterol. Within each combination of risk onstrate a renoprotective effect of treatment with ACE
factors, a comparison of the four different strata revealed a significant
difference (P ⬍ 0.001). inhibitors in comparison with other antihypertensive
treatment modalities. However, the present study was
not designed to evaluate this concept since ACE inhibi-
tors were not available until 1989. In addition, as our
mental animal models suggest that proteinuria per se study did not use a randomized design, different patient
may contribute to glomerular and tubulointerstitial le- categories could in fact receive different antihyperten-
sions [34]. Our study suggests that albuminuria is an sive treatment modalities.
independent risk factor for progression of diabetic ne- Previous studies have documented a relationship be-
phropathy, a finding that confirms and extends previous tween the degree of glomerular lesions and GFR and
results in normotensive and hypertensive type 1 and type 2 progression of diabetic nephropathy in type 1 and type 2
diabetic patients with nephropathy [19, 35–39]. Similarly, diabetic patients [49–51]. Furthermore, a progressive loss
proteinuria is a progression promoter in nondiabetic ne- of intrinsic ultrafiltration capacity has been shown to be
phropathies [40, 41]. Furthermore, intervention that has the predominant cause of the declining GFR in type 2
ameliorated the progression of diabetic nephropathy has diabetic patients with nephropathy [39]. The combined
always been associated with a reduction in proteinuria contribution from the previously identified renal struc-
as reviewed by Parving [42]. Finally, it should be recalled tural lesions and the present demonstrated progression
that initial reduction in albuminuria is the best clinical promoters explains the vast majority of progression in
guideline predicting a beneficial effect of antihyperten- diabetic nephropathy. Unfortunately, the role of genetic
708 Hovind et al: Progression of diabetic nephropathy

Table 3. Observational studies and clinical trials on progression of diabetic nephropathy in type 1 diabetic patients with and without
antihypertensive treatment (AHT)
⌬GFR Mean arterial blood pressure
mL/min/year mm Hg
Follow-up
Authors Study design N years No AHT NonACE-I ACE-I No AHT NonACE-I ACE-I
Mogensen et al [4] Observational, retrospective 10 2.8 10.9 — — 121a — —
Parving et al [5] Observational, prospective 14 2.2 9.0 — — 111 — —
Viberti et al [6] Observational, retrospective 13 2.5 14.4 — — 109b — —
Björck et al [23] Randomized trial 40 2.2 — 5.6 2.0 — 103 102
Lewis et al [24] Randomized trial 409 2.7 — 10.8c 8.0c — 100 96
Elving et al [25] Randomized trial 29 2.0 — 3.7 4.9 — 101d 100d
Tarnow et ale Randomized trial 48 4.0 — 5.5 6.5 103 100
Mulec et al [19] Observational, retrospective 158 8.0 — 3.8f — 102f
Present study Observational, prospective 301 6.7 1.9 3.8 4.5 95 102 103
Glomerular filtration rate (GFR) determination was based on renal or plasma clearance of filtration markers. Blood pressure measurements were based on mean
of values during follow-up.
a
MABP at end of the study
b
MABP at entry to the study
c
Creatinine clearance, GFR calculated from percentage decrease per year using the formula: y ⫽ y0 ⫻ exp(⫺kt), decline in GFR per year from baseline to mean
follow up of 2.7 years
d
MABP during last 6 months of follow up
e
Abstract [Tarnow et al., Diabetologia 42(Suppl 1): pA275, 1999]
f
Antihypertensive treatment varied throughout the follow-up period

factors cannot be evaluated in our study, since systemati- REFERENCES

cal collection of DNA first began in 1993. 1. Parving H, Østerby R, Ritz E: Diabetic nephropathy, in The
The available data suggest that multifactorial interven- Kidney, edited by Brenner BM, Levine S, Philadelphia, W.B.
Saunders, 2000, p 1731
tion targeting blood pressure, albuminuria, glycemic con- 2. Andersen AR, Christiansen JS, Andersen JK, et al: Diabetic
trol, and hyperlipidemia will diminish progression of ne- nephropathy in type 1 (insulin-dependent) diabetes: An epidemio-
phropathy and may even induce regression of diabetic logical study. Diabetologia 25:496–501, 1983
3. Rossing P, Rossing K, Jacobsen P, et al: Unchanged incidence
nephropathy, that is, a loss in GFR equal to the natural of diabetic nephropathy in IDDM patients. Diabetes 44:739–743,
aging process (⬃1 mL/min/year). Recently, the success 1995
4. Mogensen CE: Progression of nephropathy in long-term diabetics
of such a combined approach in delaying progression of with proteinuria and effect of initial antihypertensive treatment.
diabetic microangiopathy has been demonstrated in type Scand J Clin Lab Invest 36:383–388, 1976
2 diabetic patients with microalbuminuria [52]. It should 5. Parving H-H, Smidt UM, Friisberg B, et al: A prospective study
of glomerular filtration rate and arterial blood pressure in insulin-
be mentioned that there appear to be no substantial dependent diabetics with diabetic nephropathy. Diabetologia 20:
differences between patients with type 2 diabetes and 457–461, 1981
6. Viberti GC, Bilous RW, Mackintosh D, et al: Monitoring glomer-
those with type 1 diabetes with respect to initiation, ular function in diabetic nephropathy. Am J Med 74:256–264, 1983
progression, and treatment of diabetic nephropathy [53]. 7. Rossing P: Promotion, prediction, and prevention of progression
in diabetic nephropathy. Diabet Med 15:900–919, 1998
In summary, the prognosis of diabetic nephropathy 8. Parving H-H, Andersen AR, Smidt UM, et al: Early aggressive
has improved, probably because of effective antihyper- antihypertensive treatment reduces rate of decline in kidney func-
tensive treatment. Genuine normotensive patients have tion in diabetic nephropathy. Lancet 1:1175–1179, 1983
9. Bröchner-Mortensen J: A simple method for the determination
a very slow progression of nephropathy. Several modifi- of glomerular filtration rate. Scand J Clin Lab Invest 30:271–274,
able factors, that is, arterial blood pressure, albuminuria, 1972
10. Mancini G, Carbonara AO, Heremans JF: Immunochemical
glycemic control, and lipids, have been identified as pro- quantitation of antigens by single radial immunodiffusion. Immu-
gression promoters. Except for albuminuria, no thresh- nochemistry 2:235–254, 1965
11. Miles DW, Mogensen CE, Gundersen HJG: Radioimmunoassay
olds for the remaining risk factors were demonstrated. for urinary albumin using a single antibody. Scand J Clin Lab In-
vest 26:5–11, 1970
12. Feldt-Rasmussen B, Dinesen B, Deckert M: Enzyme immunoas-
ACKNOWLEDGMENTS say: An improved determination of urinary albumin in diabetics
The Paul and Erna Sehested Hansen Foundation, The Per S. Henrik- with incipient nephropathy. Scand J Clin Lab Invest 45:539–544,
sen Foundation, and the Danish Diabetes Association are gratefully 1985
13. Rossing P, Hommel E, Smidt UM, et al: Impact of arterial blood
thanked for financial support. We acknowledge the assistance of Berit
pressure and albuminuria on the progression of diabetic nephropa-
R. Jensen, Birgitte V. Hansen, and Inge-Lise Rossing.
thy in IDDM patients. Diabetes 42:715–719, 1993
14. Svendsen PA, Christiansen JS, Søegaard U, et al: Rapid changes
Reprint requests to Peter Hovind, M.D., Steno Diabetes Center, Niels in chromatographically determined haemoglobin A1c induced by
Steensens Vej 2 DK-2820 Gentofte, Denmark. short-term changes in glucose concentration. Diabetologia 19:130–
E-mail: [email protected] 136, 1980
 Hovind et al: Progression of diabetic nephropathy 709

15. Mortensen HB: Quantitative determination of hemoglobin A1c dent) diabetic patients with and without diabetic nephropathy.
by thin layer isoelectric focusing. J Chromatogr 182:325–333, 1980 Diabetologia 34:126–128, 1991
16. American Diabetes Association: Treatment of hypertension in 36. Breyer JA, Bain P, Evans JK, et al: Predictors of the progression
diabetes. Diabetes Care 16:1394–1401, 1993 of renal insufficiency in patients with insulin-dependent diabetes
17. Zoccali C, Postorino M, Martorano C, et al: The “breakpoint” and overt diabetic nephropathy. Kidney Int 50:1651–1658, 1996
test, a new statistical method for studying progression of chronic 37. Parving H-H, Smidt UM, Hommel E, et al: Effective antihyperten-
renal failure. Nephrol Dial Transplant 4:101–104, 1989 sive treatment postpones renal insufficiency in diabetic nephropa-
18. Levey AS, Gassman J, Hall PM, et al: Assessing the progression thy. Am J Kidney Dis 22:188–195, 1993
of renal disease in clinical studies: Effects of duration of follow- 38. Gall M-A, Nielsen FS, Smidt UM, et al: The course of kidney
up and regression to the mean. J Am Soc Nephrol 1:1087–1094, function in type 2 (non-insulin-dependent) diabetic patients with
1991 diabetic nephropathy. Diabetologia 36:1071–1078, 1993
19. Mulec H, Blohmé G, Grände B, Björck S: The effect of metabolic 39. Nelson RG, Bennett PH, Beck GJ, et al: Development and pro-
control on rate of decline in renal function in insulin-dependent gression of renal disease in Pima Indians with non-insulin-depen-
diabetes mellitus with overt diabetic nephropathy. Nephrol Dial dent diabetes mellitus. N Engl J Med 335:1636–1642, 1996
Transplant 13:651–655, 1998 40. Peterson JC, Adler S, Burkart JM, et al: Blood pressure control,
20. Mogensen CE: Long-term antihypertensive treatment inhibiting proteinuria, and the progression of renal disease: The modification
progression of diabetic nephropathy. Br Med J 285:685–688, 1982 of diet in renal disease study. Ann Intern Med 123:754–762, 1995
21. Parving H-H, Andersen AR, Smidt UM, et al: Effect of antihyper- 41. The Gisen Group: Randomised placebo-controlled trial of effect
tensive treatment on kidney function in diabetic nephropathy. Br of ramipril on decline in glomerular filtration rate and risk of
Med J 294:1443–1447, 1987 terminal renal failure in proteinuric, non-diabetic nephropathy.
22. Parving H-H, Hommel E: Prognosis in diabetic nephropathy. Br Lancet 349:1857–1863, 1997
Med J 299:230–233, 1989 42. Parving H-H: Renoprotection in diabetes: Genetic and non-
23. Björck S, Mulec H, Johnsen SA, et al: Renal protective effect genetic risk factors and treatment. Diabetologia 41:745–759, 1998
of enalapril in diabetic nephropathy. Br Med J 304:339–343, 1992 43. Rossing P, Hommel E, Smidt UM, et al: Reduction in albuminuria
24. Lewis E, Hunsicker L, Bain R, et al: The effect of angiotensin- predicts a beneficial effect on diminishing the progression of human
converting-enzyme inhibition on diabetic nephropathy. N Engl J diabetic nephropathy during antihypertensive treatment. Diabeto-
Med 329:1456–1462, 1993 logia 37:511–516, 1994
25. Elving LD, Wetzels JFM, Van Lier HJJ, et al: Captopril and 44. Rossing P, Hommel E, Smidt UM, et al: Reduction in albuminuria
atenolol are equally effective in retarding progression of diabetic predicts diminished progression in diabetic nephropathy. Kidney
nephropathy. Diabetologia 37:604–609, 1994 Int 45(Suppl 45):S145–S149, 1994
26. Parving H-H, Kastrup J, Smidt UM, et al: Impaired autoregulation 45. Apperloo AJ, De Zeeuw D, De Jong PE: Short-term antiprotein-
of glomerular filtration rate in type 1 (insulin-dependent) diabetic uric response to antihypertensive treatment predicts long-term
patients with nephropathy. Diabetologia 27:547–552, 1984 GFR decline in patients with non-diabetic renal disease. Kidney
27. Christensen PK, Hansen HP, Parving H-H: Impaired autoregula- Int 45(Suppl 45):S174–S178, 1994
tion of GFR in hypertensive non-insulin dependent diabetic pa- 46. Nyberg G, Blohmé G, Nordén G: Impact of metabolic control in
tients. Kidney Int 52:1369–1374, 1997 progression of clinical diabetic nephropathy. Diabetologia 30:82–86,
28. Hostetter TH, Troy JL, Brenner BM: Glomerular hemodynamics 1987
in experimental diabetes mellitus. Kidney Int 19:410–415, 1981 47. Fioretto P, Steffes MW, Sutherland DER, et al: Reversal of
29. Jensen PK, Steven K, Blæhr H, et al: The effects of indomethacin lesions of diabetic nephropathy after pancreas transplantation.
on glomerular hemodynamics in experimental diabetes. Kidney N Engl J Med 339:69–75, 1998
Int 29:490–495, 1986 48. Moorhead JF, El-Nahas M, Chan MK, et al: Lipid nephrotoxicity
30. Imanishi M, Yoshioka K, Konishi Y, et al: Glomerular hyperten- in chronic progressive glomerular and tubulo-interstitial disease.
sion as one cause of albuminuria in type II diabetic patients. Diabe- Lancet 2:1309–1311, 1982
tologia 42:999–1005, 1999 49. Mauer SM, Steffes MW, Ellis EN, et al: Structural-functional
31. Hostetter TH, Rennke HG, Brenner BM: The case for intrarenal relationships in diabetic nephropathy. J Clin Invest 74:1143–1155,
hypertension in the initiation and progression of diabetic and other 1984
glomerulopathies. Am J Med 72:375–380, 1982 50. Østerby R, Parving H-H, Hommel E, et al: Glomerular structure
32. Riser BL, Cortes P, Zhao X, et al: Intraglomerular pressure and and function in diabetic nephropathy -early to advanced stages.
mesangial stretching stimulate extracellular matrix formation in Diabetes 39:1057–1063, 1990
the rat. J Clin Invest 90:1932–1943, 1992 51. Østerby R, Gall M-A, Schmitz A, et al: Glomerular structure
33. Cortes P, Riser BL, Yee J, et al: Mechanical strain of glomerular and function in proteinuric type 2 (non-insulin-dependent) diabetic
mesangial cells in the pathogenesis of glomerulosclerosis: Clinical patients. Diabetologia 36:1064–1070, 1993
implications. Nephrol Dial Transplant 14:1351–1354, 1999 52. Gæde P, Vedel P, Parving H-H, et al: Intensified multifactorial
34. Remuzzi G, Bertani T: Is glomerulosclerosis a consequence of intervention in patients with type 2 diabetes mellitus and microal-
altered glomerular permeability to macromolecules? Kidney Int buminuria: The Steno type 2 randomised study. Lancet 353:617–
38:384–394, 1990 622, 1999
35. Elving LD, Wetzels JFM, De Nobel E, et al: Erythrocyte sodium- 53. Parving H-H: Initiation and progression of diabetic nephropathy.
lithium countertransport is not different in type 1 (insulin-depen- N Engl J Med 335:1682–1683, 1996