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Original Research
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 September 2014
Received in revised form
16 September 2015
Accepted 17 November 2015
Objectives: Estimation of the incidence of nephropathy as well as potential risk factors involved in its onset
in a cohort of patients with type 1 diabetes who were followed from diagnosis.
Methods: We studied 716 patients, who were followed for a mean (standard deviation [SD]) of 10.1 (SD:
5.3) years. We analyzed the inuence of demographic characteristics and levels of glycated hemoglobin
(A1C), lipids and blood pressure during the course of the disease by univariate and multivariate survival
methods.
Results: The cumulative incidence of nephropathy was 2.6%, 6.3% and 11.9% at 5, 10 and 15 years of evolution, respectively. The factors associated with increased risk for nephropathy were systolic blood pressure and A1C levels. An increment of 10 mm Hg in systolic blood pressure increases the risk by 36%, and
an increment of 1% in A1C levels raises the risk by 13% at 5 years since onset and 68% at 10 years, and it
doubles the risk at 15 years. Women have higher risk than men (hazard ratio 1.79; p=0.024).
Conclusions: Our study suggests that female gender and high levels of A1C and systolic blood pressure
throughout the course of the disease are the main factors associated with an increased risk for development of nephropathy in patients with type 1 diabetes mellitus.
2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.
Keywords:
glycated hemoglobin
low-density cholesterol
nephropathy
type 1 diabetes
r s u m
Mots cls :
hmoglobine glyque
cholestrol faible densit
nphropathie
le diabte de type 1
Objectifs : Estimation de lincidence de la nphropathie ainsi que les facteurs de risque potentiels impliqus
dans son apparition dans une cohorte de patients atteints de diabte de type 1 qui ont t suivis dun
diagnostic.
Mthodes : Nous avons tudi 716 patients, qui ont t suivis pendant une dure moyenne (cart type
[]) de 10,1 (SD: 5.3) ans. Nous avons analys linuence des caractristiques dmographiques et des niveaux
dhmoglobine glyque (A1C), les lipides et la pression artrielle au cours de lvolution de la maladie
par la survie univarie et multivarie mthodes.
Rsultats : Lincidence cumule de la nphropathie a t de 2,6%, 6,3% et de 11,9% 5, 10 et 15 annes
dvolution, respectivement. Les facteurs associs un risque accru de nphropathie taient la pression
artrielle systolique et les niveaux dA1C. Une augmentation de 10 mm Hg dans la pression artrielle
systolique augmente le risque de 36%, et une augmentation de 1% du taux dHbA1c augmente le risque
de 13% 5 ans depuis le dbut et 68% 10 ans, et il double le risque 15 ans. Les femmes ont un risque
plus lev que les hommes (hazard ratio 1,79; p=0,024).
Conclusions : Notre tude suggre que le sexe et des niveaux levs de femmes A1C et la pression artrielle
systolique pendant toute la dure de la maladie sont les principaux facteurs associs un risque accru
de dveloppement de la nphropathie chez les patients avec diabte de type 1.
2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.
* Address for correspondence: Maria Jos Goi, MD, PhD, Endocrinology Department, Complejo Hospitalario de Navarra, C/ Irunlarrea 3, Pamplona, Navarra 31008, Spain.
E-mail address: mariajosegoniiriarte@gmail.com
1499-2671 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jcjd.2015.11.008
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2
Introduction
Diabetic nephropathy is one of the most serious complications
in patients with type 1 diabetes. It includes several stages,
microalbuminuria being an early marker of structural renal disease.
The prevalence of microalbuminuria ranges from 12% to 25% at
10 years of evolution (1) and from 30% to 40% after 20 years (2,3).
Of patients with microalbuminuria, half evolve to more advanced
stages while 50% to 60% return to normal albuminuria values (4).
Although the incidence of this complication appears to be decreasing (5), it remains the most common cause of end stage renal disease
and increases cardiovascular risk for these patients (69).
Several risk factors have been associated with the onset of
nephropathy, apart from glycemic control (10), such as glycemic variability (11,12), duration of the diabetes, hypertension (13), smoking
(14), plasma lipid levels (1517), body mass indexes (BMIs) (18)
and genetic predisposition. Contradictory data have been published regarding factors, such as sex (19) or age at diagnosis (20),
with most of the studies referring to pediatric populations.
The objectives of this study were to estimate the risk for
nephropathy in its various phases and to assess the variables
related to its onset and progression in a cohort of patients who had
type 1 diabetes; no limits were placed on age at onset, and the
patients had been followed since diabetic onset in a longitudinal
study.
Methods
Statistical analysis
This was an observational, retrospective follow-up study. The subjects of the study were patients with onset of type 1 diabetes
between January 1990 and December 2008 who were treated in the
Navarra Hospital Complex between January 1990 and December
2010. The cohort included 716 patients. The regional Ethical Review
Board of Navarra approved this study.
Type 1 diabetes was diagnosed according to the clinical criteria recommended by the World Health Organization (21). The clinical diagnostic criteria were those previously validated by Molback
(22).
According to the medical protocol followed, all patients had at
least 1 scheduled outpatient appointment per year. The information for the study was obtained from the electronic health records
of the Navarre Health Service. We gathered information about age,
sex, GAD65 and IA2 autoantibodies at onset for all patients. At the
initial visit and for every visit through follow up, we included
weights; BMIs, systolic blood pressure (SBP) and diastolic blood pressure (DBP) (BP was obtained after patients rested for 5 minutes in
the sitting position); smoking status and analytic data, such as lipid
proles and A1C levels. When patients had more than 1 determination of these covariates in a year, we computed the arithmetic
mean in the case of continuous variables, whereas for the categoric variables, we chose the value that had lasted longest during
that year.
Urinary albumin excretion was measured in each patient at least
once a year by nephelometry (Beckman Coulter, Sharon Hill, Pennsylvania, US) between 1990 and 2006 and by immunoturbidimetry
(Roche Diagnostics, Risch-Rotkreuz, Switzerland) between 2006 and
2010. In line with current American Diabetes Association recommendations, microalbuminuria was dened as urinary albumin
excretion rates of 20 to 200 mg/g in the rst morning urine test in
at least 2 of 3 consecutive samples. The minimum time between
samples was 3 months. Macroalbuminuria was dened as albumin
excretion rates >200 mg/g. Kidney failure was dened by values of
creatinine 1.2 mg/dL or calculation of creatinine clearance <60 mL/
min/1.73 m2 using the Cockcroft-Gault formula at 2 consecutive study
visits. For total risk estimates, we considered nephropathy as pre-
The characteristics of the patients at disease onset were summarized using frequencies and percentages, means and standard
deviations (SDs). The cumulative incidence of nephropathy for the
global sample was estimated and graphed using Kaplan-Meier
curves, and condence intervals based on the cumulative hazard
were derived for 3 time points of the follow up: 5, 10 and 15 years
since onset. Data were right-censored when no nephropathy event
occurred throughout follow up or because of loss to follow up or
death.
The effects of demographic-, clinical- and analytic-related variables on nephropathy were assessed through a 2-step procedure.
First, univariate Cox-proportional regression models were tted using
the covariates as xed variables (characteristics at diabetes onset)
and as time-dependent variables (characteristics during followup). The proportional assumption implicit in the Cox-regression
modelling was assessed using weighted residuals and, when violated, an interaction term with time was included in the models.
The possible modifying effect of age group was also evaluated and,
when appropriate, models were adjusted or stratied by age group.
This step, which was complemented graphically with plots of the
stratied cumulative incidence curves obtained with the KaplanMeier method, provided the signication of the covariates and the
estimation of the hazard ratios. In the second step, a multivariate
regression model was tted with the variables that had turned out
to be signicant or marginally signicant (p<0.1) in the previous
step.
A p value of <0.05 was considered statistically signicant. All
analyses were performed using the R statistical package, v. 2.13
(R Foundation for Statistical Computing. Vienna, Austria).
Results
We followed 716 patients with type 1 diabetes from onset: 280
patients with onset younger than 15 years of age and 436 with onset
older than 15. The mean (SD) follow up was 10.1 (5.3) years, ranging
from 2 (those with onset in 2008) to 21 years (those with onset in
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M.J. Goi et al. / Can J Diabetes xxx (2016) 16
Table 1
Demographic and clinical characteristics at onset of patients with onset between
1990 and 2008 in the Navarra Hospital Complex
Variable
Categoric
variables
Sex
Age group
HTA
BMIqa
Smoking
GAD65
(<5 years)
IA2 (<5 years)
Continuous
variables
Years of
follow up
BMI (kg/m2)
SBP (mm Hg)
DBP (mm Hg)
LDL (mg/dL)
HDL (mg/dL)
Triglycerides
(mg/dL)
A1C (%)
Total
n (%)
Men
Women
09
1014
1529
3044
45
No
Yes
over q97a
q85-q97a
below q85a
No
Ex smoker
Yes
No
Yes
No
Yes
N
413
303
134
146
246
148
42
578
14
19
45
550
442
31
176
112
374
235
217
Mean
(58%)
(42%)
(19%)
(20%)
(34%)
(21%)
(6%)
(98%)
(2%)
(3%)
(8%)
(89%)
(68%)
(4%)
(27%)
(23%)
(77%)
(52%)
(48%)
(SD)
10.1 (5.3)
614
591
592
549
561
605
549
20.2
114.2
68.7
119.1
48.9
118.7
(4.2)
(14.5)
(10.9)
(39.9)
(15.1)
(141.4)
10.8 (2.6)
Patients
<15 years
Patients
15 years
n (%)
n (%)
154 (55%)
126 (45%)
134 (48%)
146 (52%)
200
2
4
4
236
254
0
1
56
128
71
109
Mean
(99%)
(1%)
(1.5%)
(1.5%)
(96.5%)
(100%)
(0%)
(0%)
(30%)
(70%)
(395%)
(61%)
(SD)
10.0 (5.6)
16.8
110.9
66.4
111.7
53.4
85.3
(2.8)
(12.9)
(11.4)
(32.2)
(14.0)
(55.4)
10.4 (2.2)
259 (59%)
177 (41%)
246 (56%)
148 (34%)
42 (10%)
378 (96%)
12 (3%)
15 (4%)
41 (11%)
314 (85%)
188 (48%)
31 (8%)
175 (44%)
56 (18%)
246 (82%)
164 (60%)
108 (40%)
Mean (SD)
10.3 (5.2)
22.4
116.0
69.9
124.2
45.8
140.7
(3.5)
(15.0)
(10.4)
(43.8)
(15.1)
(173.2)
11.1 (2.82)
A1C, glycated hemoglobin; BMI, body mass index; DBP, diastolic blood pressure; HTA,
Health Technology Assessment; LDL, low-density lipoprotein; SBP, systolic blood
pressure.
a
BMIq: Proportions calculated according to age-specic BMI quantiles.
Table 2
Cumulative incidence (95% CI) of total nephropathy by subtype and for age group
at onset, after 5, 10 and 15 years since onset
Time since onset
5 years (%)
Nephropathy
Microalbuminuria
Permanent
microalbuminuria
Macroalbuminuria
Kidney failure
Nephropathy by age
group at onset
09 years
1014 years
1529 years
3044 years
45 years
10 years (%)
2.6 (1.43.8)
2.5 (1.33.6)
1.1 (0.31.9)
6.3 (4.215.1)
6.1 (4.09.1)
2.2 (0.93.4)
0
0.1 (00.4)
0
0.1 (00.4)
2.5 (0.05.3)
5.0 (1.38.5)
2.1 (0.33.9)
0.7 (0.02.1)
4.8 (011.0)
9.1 (2.715.1)
10.0 (4.315.4)
4.7 (1.87.6)
1.8 (0.04.3)
9.8 (0.020.4)
15 years (%)
11.9 (8.515.1)
10.6 (7.413.6)
4.4 (2.26.5)
2.3 (0.54.2)
1.7 (0.13.2)
14.8 (5.723.1)
13.3 (6.120.1)
10.1 (5.314.8)
5.3 (0.012.2)
39.2 (1.662.5)
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Table 3
Association of covariates with risk of nephropathy using univariate Cox regression
models
Variable
Category/units
At onset of diabetes
HR (CI 95%)
Demographic characteristics
Sex
Males
Females
Age group
<10 years
1014 years
1530 years
3044 years
45 years
Positivity antibody levels at onset
GAD
No
Yes
IA2
No
Yes
Physical examination and laboratory
values as time-dependent variables
Tobacco (15 years)
Non/exsmoker
Smoker
<q85
BMIq
q85
SBP
per 10 mm Hga
DBP
per 10 mm Hga
TG
per 10 mg/dLa
HDL
per 10 mg/dLa
LDL 10 mg/dLa
LDLb
LDLa timea
A1C
A1Cb
A1Catime
Table 4
Multivariate Cox-proportional regression model results for nephropathy
Variable
Category
HR (CI 95%)
Sex
Males
Females
<10 years
1014 years
1529 years
3044 years
45 years
per 10 mm Hga
A1C tb
A1Ca tb
Reference
1.56 (0.862.83)
Reference
0.68 (0.291.61)
0.65 (0.301.40)
0.25 (0.080.77)
0.53 (0.151.81)
1.36 (1.111.67)
0.69 (0.451.06)
1.09 (1.041.13)
p
Age at onset
Reference
1.79 (1.082.99)
Reference
0.94 (0.461.94)
0.59 (0.301.19)
0.36 (0.131.00)
1.62 (0.624.23)
Reference
1.19 (0.48 - 2.92)
Reference
1.37 (0.642.92)
Reference
1.87 (0.883.94)
Reference
0.61 (0.301.23)
1.62 (1.051.52)
1.32 (0.971.79)
1.03 (1.011.05)
0.87 (0.721.05)
0.91 (0.741.11)
1.02 (1.001.04)
0.74 (0.491.11)
1.08 (1.041.13)
0.024
0.055
0.454
0.417
0.105
0.149
0.015
0.075
0.073
0.140
0.337
0.018
0.136
<0.001
A1C, glycated hemoglobin; BMI, body mass index; DBP, diastolic blood pressure; HDL,
high-density lipoprotein; HTA, Health Technology Assessment; LDL, low-density lipoprotein; SBP, systolic blood pressure; TG, triglycerides.
a
Hazard ratios for covariates SBP, DBP, HDL cholesterol, TG and LDL cholesterol
were estimated for 10-unit increments (HR per increments of 10 mm Hg in SBP and
DBP, and per increments of 10 mg/dL in HDL cholesterol and LDL cholesterol and
TGs).
b When interaction terms with time are signicant (for A1C and LDL cholesterol), HRs are time dependent: For A1C, HR(t)=0.74*1.08t; for LDL cholesterol:
HR(t)=0.91*1.02t.
SBP
A1C
p
0.144
0.149
0.004
0.078
<0.001
A1C, glycated hemoglobin; HR, hazard ratio; SBP, systolic blood pressure; t, time.
a The HR for SBP was evaluated according to increments of 10 mm Hg.
b The HR for A1C varies with time: the longer the follow up (t), the higher the
risk: HR(t)=0.69*1.09t (for t=5 years: HR=1.06; for t=10 years: HR=1.63; for t=15 years:
HR=2.51).
Discussion
In this study, we characterized the incidence of kidney disease
in patients of all ages with type 1 diabetes, children and adults, followed since they had been diagnosed. These characteristics make
this study original in respect to previously published studies. The
cumulative incidence at 5, 10 and 15 years since diabetes onset was
2.6%, 6.3% and 11.9%, respectively. Incidence studies published so
far have shown disparate data, to a great extent derived from differing characteristics of patients regarding age, risk factors and duration of diabetes but, overall, they point to a downward trend in the
incidence of late complications of diabetes compared to that
described in previous decades (15,2427). The relatively low incidence of nephropathy we found is in line with this downward trend,
which is likely to be the result of the implementation of better and
more successful control strategies for patients with diabetes.
With respect to the course of kidney disease, regression to
normoalbuminuria was the most common renal outcome, occurring in 35.8% of cases of microalbuminuria in the cohort. This
normoalbuminuric regression is similar to that found in the Epidemiology and Prevention of Diabetes (EURODIAB) study (18) and
that obtained by Perkins et al (28). Little is known about the
clinical signicance of these data. Progression to macroalbuminuria
in our patients (7.5%) was similar to the rate observed by Raile et al
(13) but less than that described by the EURODIAB group (14%) or
the Epidemiology of Diabetes Interventions and Complications (EDIC)
study (10) by de Boer et al (3) and by Hovind et al (5). The percentage of patients who develop more advanced renal disease
without having prior microalbuminuria (12%) is lower than that
reported by the DCCT/EDIC study (24%).
The increase in A1C levels is the most conrmed risk factor for
kidney disease in both pediatric and adult populations. The DCCT
demonstrated the benet of intensive treatment of hyperglycemia, which is maintained even in the long term (10). Thus, levels
below 8% are associated with regression of microalbuminuria to
normoalbuminuria and values less than 7% would be set as a target
for reducing the risk for glomerular ltration decrease (7). Glycemic variability could also be involved in the pathogenesis of this
complication (11,12). Our ndings support the importance of glycemic control in the prevention of kidney disease, with relatively
high HR estimates for A1C level variations, and the results suggest
that the increase in the risk for nephropathy associated with poor
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M.J. Goi et al. / Can J Diabetes xxx (2016) 16
Conclusions
In conclusion, our study suggests that several risk factors, primarily A1C levels and higher SBP throughout the course of the
disease, in addition to LDL cholesterol levels and female gender, point
to increased risks for developing nephropathy after diagnosis. The
identication of these factors may have therapeutic implications
in the follow up of these patients who have type 1 diabetes.
Acknowledgments
The authors thank the other members of the Type 1 Diabetes
Study Group of Navarra for their collaboration in this study: Marta
Garca-Mouriz, Ana Iriarte, Javier lata, Juan Pablo Martinez, Maria
Dolores Ollero, Rosa Rodriguez-Erdozain and Amaya Sainz de los
Terreros (Endocrinology, Navarra Hospital Complex, Pamplona,
Spain); Maria Chueca and Sara Berrade (Pediatric Endocrinology
Section, Navarra Hospital Complex, Pamplona, Spain); Javier Pineda
and Marta Toni (Endocrinology, Garca Orcoyen Hospital, Estella,
Spain); and Javier Basterra-Gortari and Patricia Munrriz (Endocrinology, Reina Sofa Hospital, Tudela, Spain).
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