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Saudi J Kidney Dis Transplant 2008;19(6):924-928

2008 Saudi Center for Organ Transplantation Saudi Journal
of Kidney Diseases
and Transplantation

Original Article

Association between Diabetic Nephropathy and Other Diabetic

Microvascular and Macrovascular Complications
Anila Chandy1, Basant Pawar2, Mary John1, Rajesh Isaac3

Departments of Internal Medicine1, Nephrology2 and Community Medicine3,

Christian Medical College and Hospital, Ludhiana, Punjab

ABSTRACT. Diabetic nephropathy is found to be significantly associated with diabetic retino-

pathy and coronary artery disease. Few studies have also shown an association between diabetic
nephropathy and neuropathy, and peripheral vascular disease. A cross sectional study was done
among consecutive type 2 diabetics presenting to Christian Medical College and Hospital,
Ludhiana from June 2004 to May 2005. Patients were subjected to the clinical and laboratory
investigations 174 patients were studied over a period of one year. Diabetic nephropathy was found
to be associated with proliferative diabetic retinopathy, neuropathy and cardiovascular disease by
univariate analysis. In multivariate analysis, diabetic nephropathy was again significantly asso-
ciated with proliferative diabetic retinopathy and coronary artery disease. We conclude that close
association between diabetic nephropathy and other micro and macrovascular complications
exists in our Indian patients also.

Keywords: Nephropathy, Retinopathy, Neuropathy, Peripheral vascular disease

Introduction plications, namely, nephropathy, retinopathy

Diabetes mellitus, due to its effect on small
and large blood vessels is known to cause
various microvascular and macrovascular com-
plications. The incidence of microvascular com-
Correspondence to:
Dr. Anila Chandy
Lecturer
Department of Internal medicine
Christian Medical College and Hospital
Brown Road, Ludhiana141008
Punjab, India
E-mail: chandyanila@gmail.com
and peripheral neuropathy increase with the
duration of diabetes.1 Macrovascular compli-
cations associated with diabetes, namely, coro-
nary artery disease, cerebrovascular disease
and peripheral vascular disease are mainly due
to accelerated atherosclerosis.
A close association between diabetic nephro-
pathy and retinopathy exits in majority of
patients, and one might entertain another cause
for nephropathy in the absence of retinopathy.
A similar association also exists between
coronary artery disease and diabetic nephro-
pathy.
This study was undertaken to document asso-
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Diabetic nephropathy and microvascular and macrovascular complications
ciation between diabetic nephropathy and other
microvascular and macrovascular complications
in type 2 diabetics presenting to our center.
Materials and Methods
Consecutive type 2 diabetic patients visiting
Christian Medical College and Hospital, Lud-
hiana were studied in a cross sectional design
from June 1, 2004 to May 31, 2005. Ethics co-
mmittee approval was obtained before starting
the study.
Patients with acute and chronic infections,
valvular heart disease, collagen vascular di-
sease and malignancies were excluded.
Patients were subjected to the following
clinical and laboratory tests: direct ophthal-
moscopy, clinical examination for pain, touch
and vibration, tendon reflexes, ankle brachial
index with hand held Doppler, ECG, Echocar-
diography when evidence of coronary artery
disease, serum creatinine, urinary protein (urine
albumin to creatinine ratio or 24 hour urine
protein) and fasting lipid profile.
Type 2 Diabetes mellitus was defined as Fas-
ting blood glucose of > 126 mg/dL or Random
Blood Sugar of > 200 mg/dL with symptoms
of diabetes.
Nephropathy was diagnosed by the presence
of microalbuminuria, macroalbuminuria or
Creatinine clearance of < 90 mL/min. Micro-
albuminuria was diagnosed by the presence of
30-300 mg albumin in a 24 hour urine sample
or 30-300 mg albumin per gm creatinine; albu-
min creatinine ratio (ACR). Macroalbuminuria
was diagnosed by the presence of more than
300 mg albumin in urine over 24 hours, or
more than 300 mg/gm urine ACR.1
Chronic Kidney Disease (CKD): K/DOQI
criteria for the definition of CKD were used to
estimate prevalence of chronic kidney disease
stages 1 to 5.2 GFR estimation was done by
Cockroft and Gault formula.3
Non-proliferative retinopathy was diagnosed
by the presence of cotton wool spots, micro
aneurysms and boat shaped hemorrhages on
direct ophthalmoscopic examination. Prolifera-
tive retinopathy was diagnosed by the presence
of neovascularization in the retina.
925
Peripheral sensory neuropathy was assessed
clinically by history of paresthesias in the peri-
pheries or decreased pain by pin-prick testing,
or decreased touch by fine cotton wisp or
decreased vibration sense by tuning fork of
frequency 256Hz or absent ankle reflexes.
Cerebrovascular disease was assessed by his-
tory of previous transient ischemic attack or
stroke.
Cardiovascular disease was assessed by his-
tory of angina or equivalents, verified by pre-
vious hospital record, or ECG changes of Q
waves, or poor progression of R waves in
anterior leads or Echocardiography showing
evidence of wall motion abnormalities, dilated
left ventricle or ejection fraction of < 40%.
Peripheral vascular disease (PVD) was asse-
ssed by ankle brachial index. Ankle brachial
index (ABI) was tested using Ultratec PD 1 v
hand held Doppler. ABI less than 0.9 was
considered as evidence of peripheral vascular
disease.4
Statistical Analysis
Chi square test, univariate and multivariate
logistic regression analysis was performed. P
value < 0.05 was taken as significant.
Results
174 patients were studied over a period of
one year, 107 were male. Mean age for males
was 57.6 11.78 years and 55.3 10.36 years
for females.
29 patients (16.6%) had normal renal function.
Microalbuminuria was found in 54 (31.03%)
patients, 29 (15%) patients had macroalbumi-
nuria with normal estimated GFR. Chronic Kid-
ney Disease (CKD) stage25 was present in 10
27, 11 and 20 respectively.
Distal symmetric polyneuropathy (DSPN) was
detected in 124 patients (72.5%). Ankle jerk
was absent in 109(63.3%) patients. Paresthe-
sias was the commonest, 85 patients (45.8%),
symptom of neuropathy.
Ophthalmoscopic examination was performed
in 144 patients, 49.3% had normal findings,
29.16% had non proliferative diabetic retino-
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926 Chandy A, Pawar B, John M, Isaac R

Table 1. Association between Diabetic nephropathy and other microvascular and macrovascular
complications: Univariate analysis
Nephropathy Present Nephropathy Absent P Value
Proliferative Retinopathy (33) 32 (23.6%) 1 (0.69%) 0.026
(n=144) (n=144)
Neuropathy (124) 109 (63.7%) 15 (8.7%) 0.006
(n=171) (n=171)
Cardiovascular Disease (81) 75((43.1%) 6 (3.4%) 0.001
(n=174) (n=174)
Cerebrovascular disease (22) 20 (11.49%) 2 (1.14%) 0.308
(n=174) (n=174)
Peripheral vascular disease (55) 47 (31.3%) 8 (5.3%) 0.748
(n=150) (n=150)

pathy (NPDR) and 21.5% had proliferative
retinopathy (PR).
Ankle brachial index was checked in 150
patients, 14% had evidence of peripheral vas-
cular disease. Eighty-one (46.5%) had evidence
of ischemic heart disease and 29 patients had
dilated cardiomyopathy on echocardiography.
Out of the 174 patients, 22 (12.6%) had evi-
dence of cerebrovascular disease, by history
and previous medical record.
Diabetic nephropathy was present in majority
of patients with other complications, Table 1.
Univariate analysis confirmed significant asso-
ciation of diabetic nephropathy with proli-
ferative diabetic retinopathy, neuropathy and
cardiovascular disease, but not with cerebro-
vascular disease or peripheral vascular disease,
Table 1. Similar association was observed even
with each stage of the CKD, Table 2.
Using multivariate analysis considering dura-
tion of diabetes, BMI, sex, smoking, alcohol
consumption of more than 10 years duration,
total cholesterol, triglycerides, HDL, LDL and
hypertension, diabetic nephropathy was signi-
ficantly associated with proliferative diabetic
retinopathy and coronary artery disease but not
significantly associated with neuropathy, ce-
rebrovascular or peripheral vascular disease.
With increasing stage of CKD a significant
increase in prevalence of proliferative retino-
pathy, neuropathy and coronary artery disease
was found. However, cerebrovascular disease
and peripheral vascular disease did not show
an association with the stage of CKD in dia-
betic nephropathy.
Discussion
Diabetic nephropathy was significantly asso-
ciated with proliferative diabetic retinopathy
and coronary artery disease in our patients. A
linear association between the stages of CKD

Table 2. Microvascular and Macrovascular disease with different stages of chronic kidney disease
Proliferative Neuropathy CAD* CVD* PVD*
Retinopathy (33) (114) (81) (22) (55)
No. Nephropathy 1 (3.03%) 15 (13.15%) 6 (7.4%) 2 (9%) 8 (14.5%)
CKD 1:
Microalbuminuria 2 (6.06%) 32 (28%) 17 (20.9%) 7 (31.8%) 8 (14.5%)
Macroalbuminuria 3 (9.09%) 24 (21%) 12 (14.8%) 4 (18.1%) 13 (23.6%)
CKD 2 1 (3.03%) 9 (7.8%) 8 (9.8%) 2 (9%) 4 (7.2%)
CKD 3 8 (24.24%) 20 (17.5%) 18 (22.2%) 5 (22.7%) 10 (18.1%)
CKD 4 5 (15.15%) 9 (7.8%) 8 (9.8%) 0 4 (7.2%)
CKD 5 13 (39.39%) 16 (14%) 13 (16%) 2 (9%) 6 (10.9%)
Chi square for 36.016 8.766 21.34 0.015 0.276
Linear trend
P value < 0.001 < 0.003 < 0.001 < 0.9 < 0.599
*CAD: Coronary Artery Disease, CVD: Cerebrovascular Disease, PVD: Peripheral Vascular Disease
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Diabetic nephropathy and microvascular and macrovascular complications
in diabetic nephropathy and retinopathy, coro-
nary artery disease was also observed. Corro-
borative data shows that in almost all diabetics
with End Stage Renal Disease (ESRD) who
are admitted into dialysis or transplant prog-
rammes, there is clinical evidence of diabetic
retinopathy on routine fundoscopic examina-
tion.5 As the renal disease advances, the prog-
ression of diabetic retinopathy accelerates.6
Parving and associates found that the inci-
dence of proliferative retinopathy rose from
12% in normoalbuminuric type1 diabetic pa-
tients to 28%, 58%, and > 90% in patients with
microalbuminuria, macroalbuminuria and ad-
vanced renal failure respectively.5
Microalbuminuria is proved to be not only a
harbinger of progressive kidney damage, but
its presence is associated with a higher risk for
coronary artery disease.6-9 Similar association
between microalbuminuria and coronary artery
disease(CAD) was also found in our patients
(p< 0.01).
Klein et al, also confirmed the association of
proliferative diabetic retinopathy with nephro-
pathy and coronary artery disease.10
Similarly Rius Riu et al, found a significant
relationship of CAD events with the new ap-
pearance or worsening of diabetic retinopathy
or nephropathy in Spanish patients.11
With progression from microalbuminuria to
macroalbuminuria, the proportion of individuals
with peripheral symmetric polyneuropathy in-
creased progressively in our patients (67-85%)
(p< 0.001). In fact majority of the patients
from CKD stages II to V (74-100%) had peri-
pheral symmetric polyneuropathy. However,
neuropathy was not found to be significantly
associated with diabetic nephropathy by multi-
variate analysis.
Fifty-five (34.8%) of the 158 patients checked
had evidence of PVD, more than half of these
patients had evidence of Nephropathy; how-
ever, no significant association was noted bet-
ween albuminuria and PVD.
Tzeng et al, to the contrary did find a signi-
ficant association with advanced nephropathy,
frequently in patients on dialysis.6 We did not
find an association between presence of neph-
ropathy and cerbrovascular disease contrary to
927
the studies reported by Mieltinen, Wada and
others.12,13 Studies done in South India on type
2 diabetics with peripheral vascular disease
(PVD) showed that there was a linear increase
in prevalence of PVD with increasing duration
of diabetes. Multiple logistic regression ana-
lyses showed that serum cholesterol, serum
creatinine, systolic BP, duration of diabetes
and ischemic heart disease are strong predic-
tive factors for PVD.14
In conclusion, the type II diabetic patients
presenting in our hospital had high frequency
of diabetic complications. Close association
between diabetic nephropathy and other micro
and macrrovascular complications exists in our
part of the Indian patients. A larger study is
further needed to explore the association of
nephropathy with PVD.
References
1. Keane WF, Eknoyan G. Proteinuria, albumi-
nuria, risk, assessment, detection, elimination
(PARADE): a position paper of the National
Kidney Foundation. Am J Kidney Dis 1999;
33(5):1004-10.
2. National Kidney Foundation. K/DOQI clinical
practice guidelines for chronic kidney disease:
evaluation, classification, and stratification.
Am J Kidney Dis 2002;39(2Suppl1):S1-266.
3. Coyne DW. Evaluation of the patient with
renal disease, Washington Manual of medical
therapeutics. In: Carey CF, Lee HH, Woeltje
KF, eds. 29th ed. 12:227.
4. Zheng ZJ, Rosamond WD, Chambless LE, et
al. Lower extremity arterial disease assessed
by ankle-brachial index in a middle-aged
population of African Americans and whites:
The Atherosclerosis Risk in Communities
(ARIC) Study. Am J Prev Med 2005;29(5
Suppl 1):42-9.
5. Zander E, Seidlein I, Herfurth S, et al. Increased
prevalence of proliferative retinopathy and car-
diovascular autonomic dysfunction in IDDM
patients with proteinuria. Exp Clin Endocr
1992;99(2):102-7.
6. Tzeng TF, Hsiao PJ, Hsieh MC, Shin SJ Asso-
ciation of nephropathy and retinopathy, blood
pressure, age in newly diagnosed type 2
diabetes mellitus. Kaohsiung J Med Sci 2001;
17(6):294-301.
7. Gall MA, Rossing P, Skott P, et al. Prevalence
[Downloaded free from http://www.sjkdt.org on Wednesday, August 25, 2010, IP: 110.138.139.94]
928
of micro- and macroalbuminuria, arterial hy-
pertension, retinopathy and large vessel disease
in European type 2 (non-insulin-dependent)
diabetic patients. Diabetologia 1991;34:655
61.
8. Messent JW, Elliott TG, Hill RD, Jarrett RJ,
Keen H, Viberti GC. Prognostic significance of
microalbuminuria in insulin-dependent dia-
betes mellitus: A twenty-three year follow-up
study. Kidney Int 1992;41:8369.
9. Mogensen CE. Microalbuminuria predicts
clinical proteinuria and early mortality in
maturity-onset diabetes. N Engl J Med 1984;
310:35660.
10. Klein R, Klein BE, Moss SE. Department of
Ophthalmology, University of Wisconsin,
Madison 53792-3220 Epidemiology of proli-
ferative diabetic retinopathy. Diabetes Care
1992;15(12):1875-91.
11. Rius Riu F, Salinas Vert I, Lucas Martin A,
Romero Gonzalez R, Sanmarti Sala A. Internal
Chandy A, Pawar B, John M, Isaac R
Medicine Service, Hospital Universitari Arnau
de Vilanova, Lleida, Spain: a prospective study
of cardiovascular disease in patients with Type
2 diabetes. 6.3 years of follow-up. J Diabetes
Compl 2003;17(5):235-42.
12. Miettinen H, Haffner SM, Lehto S, Rnnemaa
T, Pyrl K, Laakso M. Proteinuria predicts
stroke and other atherosclerotic vascular
disease events in nondiabetic and non-insulin-
dependent diabetic subjects. Stroke 1996;27:
2033-9.
13. Wada M, Nagasawa H, Kurita K, et al.
Microalbuminuria is a risk factor for cerebral
small vessel disease in community-based
elderly subjects, J Neurol Sci 2007;255(1-2):
27-34.
14. Mohan V, Premalatha G, Sastry NG. Peri-
pheral vascular disease in non-insulin-
dependent diabetes mellitus in south India.
Diabetes Res Clin Pract 1995;27(3):235-40.