Ministry of Health of the Republ ic of Moldova [601121]

1
Ministry of Health of the Republ ic of Moldova

Public Institution "N icolae Test emițanu"
State University of Medicine and Pharmacy of the Republic of Moldova

FACULTY OF MEDICINE II
Endocrinology department

DIPLOMA THESIS
DIABETIC NEPHROPATHY

Represented by:
Grifat Mohammad
VI year, 1641

Scientific advisor :
Vudu Lorina
PhD, associate professor
,
Chișinău 2015

2
CONTENTS
INTRODUCTION …………………………… ……………… ………………. …..3
CHAPTER I. LITERATURE REVIEW
Renal diseases …………… ……………………………………… ……………… ..6
1- the nature of the problem ……………………. …………………………………6
2- prevalence ……………………… ……………………. ………………………..6
3- Risk factors ……………………… …………………… ………… .…………… .7
4- progression and pathophisiology …… …………………… ………………… …8
4a-Insulinic insufficiency ……………… ………… …… ..……………… ..…… ..….8
4b-Insulinic resistance………………… …………………… ……… ……………… …15
5- mortality …………………………… ………………………. …………….…… 16
6- identifying patient with renal diseases …… …………………. ……………… 19
CKD Stages……………………………………… ……………. …………… ……19
7- current practices. (renal complication in DM) ……………………. ………. ….20
8- intervention to reduce renal complication of DM …………………… ………. .22
Antihypertensive drugs …………… ……. …………… ………………… ……….. 22
Improve blood glucose control ………………… ………………… ……… …….. .27
Reduce dietary protein and lipid reduction …… …………………. .…… …….. …28
9-multifactorial intervention ……….…………… …………….. …………… …..29
10-Cost …………………………………………… ……………. ……………. ….30
CONCLUSIONS ………………………………… ………….. ……………. …… 31
REFERENCE …………………………………………………………………… 32

3
INTRODUCTION:
Diabetes mellitus (DM) refers to a group of common metabolic disorders
that share the phenotype of hyperglycemia. Several distinct types of DM exist and
are caused by a complex interaction of genetics and environmental factors.
Depending on the etiology of the DM, factors contributing to hyperglycemia
include reduced insulin secretion, decreased glucose utilization, and increased
glucose production.
The metabolic dysregulation associated with DM causes seco ndary
pathophysiologic changes in multiple organ systems that impose a tremendous
burden on the individual with diabetes and on the health care system.
In the United States, DM is the leading cause of end -stage renal disease
(ESRD), nontraumatic lower extr emity amputations, and adult blindness. It also
predisposes to cardiovascular diseases. With an increasing incidence worldwide,
DM will be a leading cause of morbidity and mortality for the foreseeable
future. (120)
Classification
-DM is classified on the basis of the pathogenic process that leads to
hyperglycemia, as opposed to earlier criteria such as age of onset or type of
therapy.
-The two broad categories of DM are designated type 1 and type 2 .
-Both types of diabetes are preceded by a phase of abnor mal glucose
homeostasis as the pathogenic processes progresses.
-Type 1 diabetes is the result of complete or near -total insulin deficiency.
-Type 2 DM is a heterogeneous group of disorders characterized by variable
degrees of insulin resistance, impaired insulin secretion, and increased glucose
production.
-Distinct genetic and metabolic defects in insulin action and/or secretion
give rise to the common phenotype of hyperglycemia in type 2 DM and have
important potential therapeutic implications now that pharmacologic agents are
available to target specific metabolic derangements. Type 2 DM is preceded by a

4
period of abnormal glucose homeostas is classified as impaired fasting glucose
(IFG) or impaired glucose tolerance (IGT).
Other etiologies for DM include specific genetic defects in insulin secretion
or action, metabolic abnormalities that impair insulin secretion, mitochondrial
abnormalities , and a host of conditions that impair glucose tolerance (Table 338 -1).
Maturity onset diabetes of the young (MODY) is a subtype of DM characterized
by autosomal dominant inheritance, early onset of hyperglycemia (usually <25
years), and impairment in insu lin secretion (discussed below). Mutations in the
insulin receptor cause a group of rare disorders characterized by severe insulin
resistance. .(120)
Gestational Diabetes Mellitus (GDM)
Glucose intolerance may develop during pregnancy. Insulin resistance is
related to the metabolic changes of late pregnancy, and the increased insulin
requirements may lead to IGT. GDM occurs in ~4% of pregnancies in the United
States; most women revert to normal glucose tolerance post -partum but have a
substantial risk (30 –60%) of developing DM later in life. .(120)
Epidemiology
The worldwide prevalence of DM has risen dramatically over the past two
decades, from an estimated 30 million cases in 1985 to 177 million in 2000. Based
on current trends, > 360 million individuals will have diabetes by the year 2030.
Although the prevalence of both type 1 and type 2 DM is increasing worldwide,
the prevalence of type 2 DM is rising much more rapidly because of increasing
obesity and reduced activity levels as countries become more industrialized. This is
true in most countries, and 6 of the top 10 countries with the highest rates are in
Asia. In the United States, the Centers for Disease Control and Prevention (CDC)
estimated that 20.8 million persons, or 7% of the population, had diabetes in 2005
(~30% of individuals with diabetes were undiagnosed). Approximately 1.5 million
individuals (>20 years) were newly diagnosed with diabetes in 2005. DM increases
with aging. In 2005, the prevalence of DM in the United S ates was estimated to be
0.22% in those <20 years and 9.6% in those >20 years. In individuals >60 years,

5
the prevalence of DM was 20.9%. The prevalence is similar in men and women
throughout most age ranges (10.5% and 8.8% in individuals >20 years) but is
slightly greater in men >60 years. Worldwide estimates project that in 2030 the
greatest number of individuals with diabetes will be 45 –64 years of age.
There is considerable geographic variation in the incidence of both type 1
and type 2 DM.
Scandinavia has the highest incidence of type 1 DM (e.g., in Finland, the
incidence is 35/100,000 per year).
The Pacific Rim has a much lower rate (in Japan and China, the incidence is
1–3/100,000 per year) of type 1 DM;
Northern Europe and the United States have an intermediate rate (8 –
17/100,000 per year). Much of the increased risk of type 1 DM is believed to
reflect the frequency of high -risk HLA alleles among ethnic groups in different
geographic locations .(120)
Aim of the study
To determine different aspects of diabetic nephropathy: epidemiology ,risk
factors pathophisiology , classifications , screening & diagnosis and treatments.
Objectives :
 To determine and be familiar with : –
 Epidemiology .
 Risk factors .
 Pathophysiology .
 Stages of Diabetic nephropathy .
 Signs & symptoms .
 CKD stages .
 Screening for micro albuminuria .
 Treatment .

6
CHAPTER I. LITERATURE REVIEW
Renal disease: –
1 The nature of the problem
Elevated blood glucose – and related microvascular disease – is associated
with slow but progressive damage to the kidneys.
This damage becomes detectable when protein (primarily albumin) is
excreted in the urine in higher concentrations than normal. As the severity of
damage increases, the quantity of protein in the u rine also increases.
Eventually, the condition can lead to renal failure.2 When the level of
albumin in the urine is fairly low (although above normal), the condition is known
as microalbuminuria, or incipient nephropathy. Higher albumin excretion is
described as macroalbuminuria or proteinuria. A consensus definition of
microalbuminuria in Type 1 diabetes of 20 –200 l ug/min in urine collected in
patients at rest or 30 –300 mg/24hr in a 24 -hour sample was agreed in 1985.3 This
definition has been widely applied to Type 2 diabetes. From the patient’ s
perspective, the degree of kidney damage that produces microalbuminuria, or even
proteinuria, may not cause any detectable problems.
Symptoms may not become apparent until the kidneys are approaching the
point of failure.

2 Prevalence
Epidemiological studies of renal disease in people with Type 2 diabetes
report prevalence rates for microalbuminuria ranging from 8% to 32%; the
majority of estimates are around 25%.4 -15 This variation may be a product of the
range of criteria used to define the condition, the stage of disease and the methods
used to assess it. Prevalence estimates for \ proteinuria range from 5% to 19%, but
most studies give rates of around 15%. 5,6,9 11,15,16 UKPDS figures, based on a
sample o f 3,867 patients, suggest that about 12% have microalbuminuria (although
using a high threshold) and 1.9% have proteinuria at the time of diagnosis of
diabetes.17 A US study which followed 794 patients with Type 2 diabetes who

7
were initially free from pro teinuria (defined as >30 l ug protein per litre of urine)
found that 1.3% developed renal failure within 10 years.18 Studies of patients
treated in renal units in the UK show that a substantial proportion have diabetes.
Data from the UK Renal Registry, cov ering 43% of the UK adult population,
showed that in 1998 diabetic nephropathy was the most common single cause of
end-stage renal failure amongst adult patients starting on renal replacement therapy
(16% of the total). Diabetic renal disease was recorded in 9.5% of existing patients.
Of these, 6.8% were recorded as Type 1 and 2.7% were recorded as Type 2.19

3 Risk factors
The main identified risk factors for the development of diabetic renal disease
are hereditary susceptibility (including ethnic
origin), blood glucose levels, and blood pressure. Other suggested
relationships are between diabetic renal disease and smoking, blood lipids, body
mass index, age, sex and duration of diabetes.18,20 -30 People of Asian or African
ethnic origin seem to be p articularly susceptible both to Type 2 diabetes and to
diabetic renal disease. A study in Leicester of people whose families originated
from the Indian sub -continent found that the probability of their requiring renal
replacement therapy for diabetic nephropathy was 13.6 times higher than for white
Caucasians.31 Another survey, which included all 5,901 patients accepted for renal
replacement therapy by renal units in England, found that people of Asian or Afro –
Caribbean origin were both almost six time s as likely as white Caucasians to be
receiving treatment for end -stage renal failure associated with
diabetes.32 Close relatives of people with diabetic renal disease are much
more likely than others to develop the condition; odds ratios of 3.8 (95% CI, 1 .4 to
10.4)33 and 8.1 (95% CI, 2.2 to 29.6)34 have been reported. The majority of
studies have found that higher blood glucose is linked with a greater risk of renal
disease . 17, 18, 20, 21, 23, 35 Many studies (total participants >4,000) have
reported links between elevated blood pressure (either systolic or diastolic or both)
and diabetic renal disease.18,21,26 -28,35 Advancing renal disease can lead to

8
increased blood pressure, whilst increased blood pressure accelerates the course of
diabetic renal di sease.
People with diabetic retinopathy are significantly more likely to develop
signs of renal disease .

4 Disease progression and pathophisiology
Reported rates of progression of diabetic renal disease reflect the varied
definitions of the different stages of the condition; there are no clear -cut criteria to
define any specific point. Longitudinal studies suggest that whilst protein excretion
tends, in general, to increase over time, the rate and direction of change varies
between individuals.

4a -Diabetic nephropathy in INSULINIC INSUFFICIENCY: –
Is the main link in DM type 1 (insulinic dependent diabetess).
Result from autoimmune destruction of islet cells , caused by T -lymphocytes
reacting against these cells , with a consequence of reduced number of B -cell mass
The most important pathogenesis is insulitis – inflammation and autoimmune
alteration of langerhance islands with involvement of T -lymphocytes , cytokines ,
and autoantibodies .
As in many autoimmune diseases congenital (gene tic-whichdevelop and
progress with age) and acquired (invironmental) influnces play an important role in
the pathogenesis .
Insulin can cause serious metabolic disorders : –
1- Liver and muscle incapacity to synthesize glycogen from glucose –
(decrease glycogen ogenesis)
2- Adipose tissue incapacity to synthesize lipids from glucose –
(decrease lipogenesis)
3- Increase glycogenolytic and Increase lipolytic processes with
involvement of proteolysis to incorporate into glyconeogenesis .(120)

9
And these above mentioned processes result in : –
1- Hyperglycemia and reduce glucose intolerance : –
In lack of insulin , insulin dependent receptors (glut IV) in myocytes and
adipocytes remain in cytoplasm and are not exposed on cellular membrane , thus
glucose can not be assimilated by cells result in decrease glycogenogenesis
(glycogen not synthesized) and decrease also lipogenesis . .(120)
And these reduction of glucose tolerance ref lect the cell incapacity to
assimilate glucides , here the liver's glycogenosynthetase remain inactive , and
high amount of glucag on stimulate glycogenolysis from the liver and proteolysis
which result in hyperaminoacidemia , aminoaciduria , and icrease a mmonia and
urea in the blood .
.(120)
2- Hyper lipidemia : –
Adipocyte lipase remain inactive in lack of insulin and alimentary lipids are
not incorporated in adipocytes , increase glucose from liver by action of glucagon
stimulate lipolysis in adipose tissues and increase blood concentration of non –
estrified fatty acids . with their intense mobilization from adipose tissues ,
(transporting -hyperlipidemia) .
In intense beta -oxidation of fatty acids , there are abundant production of
acetyl coA , that in lack of insulin does not used for lipid synthesis , but for
synthesis of ketone bodies .
3- Renal syndrome : –
Glucosuria appear as compensatory mechanism for hype rglycemia that
outcomes the capacity of glucokinase from canalicular epithelium.
Glucosuria intensify polyuria and polydipsia (osmotic effect) .
4- Angiopathy (macrovascular &microvascular) : –
Result from :
a- protein glycozilation (glucose associate with protein non-
enzymatically from complexes in vascular wall ).
b- alteration of basal membrane of vessels .

10
c- degredation of intracellular matrix compounds (collagen , elastin , and
proteoglycans etc.) .

Tow forms of angiopathy are present : –
A- Macroangiopathy :
Best explained by atherosclerosis , with intimal affections observed in heart ,
brain , and large arteries of the abdomen including RENAL ARTERI ES – there are
activation of all 3 componenets above plus lipoprotein infiltration within the intima
and formation of atheromatotic plaque – result in HYPERTENSION (due to renin –
angiotensin -aldosterone system) .
Also glycolization and alteration of collagen and elastin from vascular wall –
can modify mechanical proprieties of the vessels result hya linization and
narrowing of the vessels affected – result in HYPERTENSION (due to the same
mechanism of RAA system activation) .
B- Microangiopathy :
Attack mainly GLOMERULAR CAPILLARIES with final resolution of
GLOMERULOSCLEROSIS .
Microvascular Changes :-
– Affects arterioles and capillaries, causes Nephropathy, Neuropathy, and
Retinopathy
-Underlying cause is thickened basement membranes .
3 ditinct metabolic pathway :-
a) Nonenzymatic Glycation
-this is th process by which the glucose chemically attached to amino groups
of protein without the aid of enzymes .
-the degree of the non -enzymatic glycosylation is directly related to blood
glucose level , indeed, the measurement of glycosylated hemoglobin level in blood
is useful in the management of di abetes mellitus , because it provides an index of
the average blood glucose level over the 120 day life span of erythrocytes.

11
-the early glycosylation product of collagen and other long lived prot eins in
interstitial tissues and blood vessel wall s undergo a smaal series of chemical
rearrangements to form irreversible to form advanced glycosylation end products
(AGEs) , which accumulate over the life time of the vessel wall .
– AGEs have a number of chemical and biological properties that are
pathogenic to extracellular matrix components and to the target cells of diabetic
complications :-
AGEs formation onproteins such as collagen causescross -links between
polypeptides, this in turn may trap nonglycosylated pl asma and interstitial proteins
In vessels , trapping low density lipoprotein , for example : retard its reflux
from vessels wall and enhances the depositin of cholesterol in the intima, thus
accelerating atherogenesis.
-In capillaries thus including renal glomeruli , plasma proteins such as
album in bind to the glycated basement membrane , accounting in part for basement
membrane thickening – characteristic of diab etic glomerulopathy circulating
plasma proteins modified by adding AGEs residues, these proteins in turn bind to
AGEs receptor on severa l cell types (endothelial, mesangial , macrophages).
The biologic effect AGEs receptorsignaling include : –
1-release of cytokines and growth factors from macrophages and mesangial
cells .
2-increase endothelial permeability .
3-increase procoagulant activity on endothelial cells and macrophages ,
4-enhanced proliferation and synthesis of extracellular matrix by fibroblasts
smooth muscle cells .
All these effects contribute to diabetic complications .

b) Alternate Glucose Pathways
– Certain tissues do not require insulin for glucose to enter the cell , (nerves,
kidneys, lens, blood vessels ): – hyperglycemia lead to increase intracellular glucose

12
that is metabolized by the enzyme aldose reductase to sorbitol, a polyol, and
eventually to fructose.
Accumulating fructose and sorbitol – implicating in causing cell injury via
increased intracellular osmolarity and water influx .

c) Protein Kinase C (PKC)
-activation of intracellular PKC by calcium ions and the second messenger
diacylglycerol is an important signal transduction pathway in many cellular
systems .
-intracellular hyperglycemia can stimulate the denovo synthesis of DAG
from glucolytic intermediates and hence cause activation of PKC .
The down -stream effect of PKC act ivation are numerous and include
production of pro-oncogenic molecules such as vascular endothelia l growth factor,
implicated in the neovascularization seen in diabetic retinopathy , and pro –
fibrogenic molecules like transforming growth factor B , leading to increased
deposition of extracellular matrix and basement membrane material . (120)

B.4b – Diabetic nephropathy in INSULINIC RESISTANCE :-
Type 2 DM characterized by 2 main pathological defects : –
1- Decrease ability of peripheral tissues to respond to insulin : –
-muscle & liver – decrease glycogenogenesis .
-Adipose tissues – decrease lipogenesis .
2- B-cell dysfunction that is manifested as inadequate insulin
Secretion in the face of insulin resista nce – result in hyper glycemia and
hyper lipidemia here there are resistance to : uptake , metabolism , and storage of
glucose
– Capturing of glucose is inhibited , lipolysis and endogenous
production of glucose get out of insulin's control .

13
– Glucidi c metabolism (carbohydrates) – is impaired in insulinic
resistance (glycogenosynthetase is inactive) . – hyperglycemia and Glycerol
(endogenous source of glucose) .
– Lipid metabolism – is impaired also (adipose lipase is inactive) –
decrease lipogenesis . and glucagon stimulate lipolysis – Hyperlipidemia and free
fatty acids .
– Free fatty acids deposits into hepatocytes and myocytes , icreasing of
triglycerides which a re also potent inhibitor for insulin – which intensify more the
resistance and become more worse . .(120)

– OBESITY : –
-hypertriglyceridemia – inhibit insulin release .
-adipocytokines in insulin resistance : – adipocytes hormones which are
released into cir culation are : –
a- Resistin : increased in obesity leading to increase insulin resistance .
b- Adiponectin : reduced in obesity and insulinic resistance , leading to
increase insulin sensitivity .
c- Leptin : reduce body weight via hypothalamic specific receptors.
.(120)

14

Fifure 1 -b.4

15

Figure 2 -b.4
AND , DM Type 2 hass the same pathology of : – Hyperglycemia and reduce
glucose tolerance , Hyperlipidemia , Re nal syndrome , and Angiopathy.

5 Mortality
Fewer than 5% of deaths among people with Type 2 diabetes are directly
attributed to renal disease. 37,38 The majority of deaths result from myocardial
infarction, heart failure or stroke. However, a meta -analysis of eight studies found
that the death rate among people with microalbuminuria was more than double the
rate in people with normal urinary albumin levels; risk ratios were 2.4 (95% CI, 1.8
to 3.1) and 2.0 (95% CI, 1.4 to 2.7) for overall and cardiovascular mortality,
respectively.39 A 12 -year study of 4,714 people with diabetes (both types)
reported that proteinuria was associated with an eight -fold increase in deaths
among women and a five -fold increase in risk among men, compared with those
who did not have proteinuria.40

16

Figure 3 -b.4

6 Identifying patients with renal disease
Since the defining feature of diabetic renal disease is the appearance of
protein in the urine, detection and monitoring of the condition depends on urine
tests. Some of these measure albumin alone; others allow an albumin/creatinine
ratio to be calculated. Some tests are suitable for near -patient testing (side -room
tests); others require more sophisticated laboratory equipment. The former group
are less accurate but quicker and easier to use. Seven such tests are available in the
UK but ev idence was found on the accuracy of Micral -Test II, Albustix and
Microbumintest only for measurement of albumin in urine, but not on any of the
other products.
No direct comparisons between near -patient tests were identified, and there
is no evidence to sh ow that any one is more accurate than others. Sensitivity
ranged from 51%41 to100%.42 -44 Specificity ranged from 27%45,46 to
97%.47,48 but different methods, reference standards, ranges and thresholds were

17
used to assess the tests. Any attempt to determine the most effective test is
hampered by the heterogeneity of the evidence. Laboratory tests include
radioimmunoassay, immunoturbidimetry, immunonephelometry, enzyme -linked
immunosorbent assay (ELISA), and the DCA 2000 microalbumin/ creatinine assay
system.
Studies assessing albumin concentration in urine produced sensitivity and
specificity levels above 90% in only two out of
eleven studies,7,49 -55 one using radioimmunoassay in an early
morning sample,49 and the other using immunonephelometry in a random
sample. Two studies of ELISA in early morning samples,7,50 and one using
immunoturbidimetry in overnight samples,51 reported sensitivity over 80% and
specificity over 90%. In three studies, sensitivity or specificity levels fell below
80%. 7,52,53 Studies as sessing the accuracy of measurement of
albumin/creatinine ratios reported both sensitivity and specificity levels
above 90% for every type of test.7,49 51,53,56 -59 The timing of the urine samples
used in these studies varied; accurate measurements were ach ieved with early
morning, overnight and 24 – hour samples, but the ELISA test on random urine
samples was less accurate, with 80% sensitivity and 81% specificity. These tests
differ in their nature and have been assessed by methods which may not be directly
comparable, so it is not clear which is the most effective or useful. Furthermore,
there is very marked day -to-day variation in urinary albumin excretion which other
illnesses may also increase and so a single test on a single day is not reliable.
Conside red as a whole, the evidence suggests that health
professionals should use these tests on several occasions each
year to assess whether patients show signs of renal disease. They
should not rely on a single nearpatient test.

Diagnosis and A1C Testing

Criteria for Diabetes Diagnosis: 4 options

18
1-A1C ≥6.5% Perform in lab using NGSP -certified method and
standardized to DCCT assay
2-FPG ≥126 mg/dL (7.0 mmol/L) Fasting defined as no caloric intake for
≥8 hrs
3-2-hr PG ≥200 mg/dL ( 11.1 mmol/L) during OGTT (7 5-g)
4-Random PG ≥200 mg/dL (11.1 mmol/L)
In persons with symptoms of hyperglycemia or hyperglycemic crisis
In the absence of unequivocal hyperglycemia results should be confirmed
using repeat testing

Frequency of A1C Testing
Perform A1C test
1-At least 2 times each year in patients who are meeting treatment targets
and have stable glycemic control
2-Quarterly in patients whose therapy has changed or who are not meeting
glycemic targets
Point -of-care A1C testing allows for more timely treatment changes

Nephropathy Screening and Treatment
Optimize glucose and BP control to reduce risk or slow progression of
nephropathy

Screening :
Annually measure urine albumin excretion in type 1 patients with ≥5 -yr
diabetes duration, and all type 2 patients starting at diagnosis

Treatment :
-Normal BP and albumin excretion <30 mg/24 h – ACEI or ARB for primary
prevention of kidney disease not recommended

19
-Nonpregnant with modest elevations (30-299 mg/24 h) or higher levels
(≥300 mg/24 h) of urinary albumin excretion – Use ACEI or ARB (but not in
combination)
-Diabetic kidney disease (albuminuria >30 mg/24 h) – Limiting protein
intake not recommended
-When using ACEI, ARB, diuretic – Monitor creatinine and potassium levels
-Monitor urine albumin excretion continually to assess therapeutic
response,disease progression
-If eGFR <60 mL/min/1.73 m2 – Evaluate, manage CKD complications
-Consider specialist referral – Uncertainty re: kidney disease etiology,
difficult management issues, advanced kidney disease

CKD stages
The stages of CKD (Chronic Kidney Disease) are mainly based on measured
or estimated GFR (Glomerular Filtration Rate). There are five stages but kidney
function is normal in Stage 1, and minimally reduced in Stage 2.
Table1 -1
Stage GFR* Description Treatment stage
1 90+ Normal kidney function
but urine findings or
structural abnormalities or
genetic trait point to
kidney disease Observation, control of blood
pressure. More on management of
Stages 1 and 2 CKD .
2 60-89 Mildly reduced kidney
function, and other
findings (as for stage 1)
point to kidney disease Observation, control of blood
pressure and risk factors. More on
management of Stages 1 and 2
CKD.
3A
3B 45-59
30-44 Moderately reduced
kidney function Observation, control of blood
pressure and risk factors. More on

20
management of Stage 3 CKD .
4 15-29 Severely reduced kidney
function Planning for endstage renal
failure. More on management of
Stages 4 and 5 CKD .
5 <15 or on
dialysis Very severe,
or endstage kidney
failure (sometimes
call established renal
failure ) Treatment choices. More on
management of Stages 4 and 5
CKD .
All GFR values are normalized to an average surface area (size) of 1.73m2

7 Current practice
Renal and other Complications of Diabetes Mellitus
Diabetic nephropathy is the leading cause of ESRD in the United States and
a leading cause of DM -related morbidity and mortality.
Both microalbuminuria and macroalbuminuria in individuals with DM are
associated with increased risk of cardiovascular disease .
Individuals with diabetic nephropathy commonly have diabetic retinopathy .
-Like other microvascular complications, the pathogenesis of diabetic
nephropathy is related to chronic hyperglycemia. The mechanisms by which
chronic hyperg lycemia leads to ESRD, though incompletely defined, involve the
effects of soluble factors (growth factors, angiotensin II, endothelin, AGEs),
hemodynamic alterations in the renal microcirculation (glomerular hyperfiltration
or hyperperfusion, increased gl omerular capillary pressure), and structural changes
in the glomerulus (increased extracellular matrix, basement membrane thickening,
mesangial expansion, fibrosis).
The natural history of diabetic nephropathy is characterized by a fairly
predictable sequ ence of events that was initially defined for individuals with type 1
DM but appears to be similar in type 2 DM . Glomerular hyperperfusion and renal

21
hypertrophy occur in the first years after the onset of DM and are associated with
an increase of the glom erular filtration rate (GFR).
During the first 5 years of DM, thickening of the glomerular basement
membrane, glomerular hypertrophy, and mesangial volume expansion occur as the
GFR returns to normal. After 5 –10 years of type 1 DM, ~40% of individuals beg in
to excrete small amounts of albumin in the urine.
Microalbuminuria is defined as 30 –300 mg/d in a 24 -h collection or 30 –300
mg/mg creatinine in a spot collection (preferred method). Although the appearance
of microalbuminuria in type 1 DM is an importa nt risk factor for progression to
overt proteinuria (>300 mg/d), only ~50% of individuals progress to
macroalbuminuria over the next 10 years. In some individuals with type 1 diabetes
and microalbuminuria of short duration, the microalbuminuria regresses. Once
macroalbuminuria is present, there is a steady decline in GFR, and ~50% of
individuals reach ESRD in 7 –10 years. Once macroalbuminuria develops, blood
pressure rises slightly and the pathologic changes are likely irreversible. Some
individuals with ty pe 1 or type 2 DM have a decline in GFR in the absence of
micro – or macroalbuminuria and this is the basis for assessing the GFR on an
annual basis using serum creatinine.
-The nephropathy that develops in type 2 DM differs from that of type 1 DM
in the following respects: (1) microalbuminuria or macroalbuminuria may be
present when type 2 DM is diagnosed, reflecting its long asymptomatic period,(2)
hypertension more commonly accompanies microalbuminuria or
macroalbuminuria in type 2 DM; and (3) microalb uminuria may be less predictive
of diabetic nephropathy and progression to macroalbuminuria in type 2 DM.
Finally, it should be noted that albuminuria in type 2 DM may be secondary to
factors unrelated to DM, such as hypertension, congestive heart failure (CHF),
prostate disease, or infection. Diabetic nephropathy and ESRD secondary to DM
develop more commonly in African Americans, Native Americans, and Hispanic
individuals than in Caucasians with type 2 DM.

22
– Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) :- may
occur in type 1 or 2 DM. These individuals develop a propensity to hyperkalemia,
which may be exacerbated by medications [especially angiotensin -converting
enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)].
– Patie nts with DM are predisposed to radiocontrast -induced nephrotoxicity .
Risk factors for radiocontrast -induced nephrotoxicity are preexisting nephropathy
and volume depletion. Individuals with DM undergoing radiographic procedures
with contrast dye should be well hydrated before and after dye exposure, and the
serum creatinine should be monitored for 24 h following the procedure.

8 Interventions to reduce renal complications of diabetes
The evidence discussed in this section comes from randomised controlled
trials (RCTs) which focus on : –
1- reducing blood pressure with antihypertensive drugs;
2-improving blood glucose control;
3-reducing dietary protein,
4-the use of lipid -reducing drugs
(1)-Antihypertensive treatment
Both diabetic renal disease and hypertension are associated with
increased cardiovascular mortality. Control of blood pressure could therefore
be a rational way of reducing mortality in hypertensive patients with diabetes. It
may also slow the progression of diabetic renal disease.
End-points related to renal disease were among a range of variables studied
in the UKPDS 38 trial of tight blood pressure control in Type 2 diabetes. This trial
was based in 20 hospital clinics in the UK; it recruited 1,148 hypertensive people,
randomised to tight or less tight blood pressure control, and followed them for a
median period of 8.4 years.
Mean blood pressures in the two groups were 144/82 and 154/87,
respectively. The tight control group had less microvascular disease, with a relative
risk (RR) for the aggregate endpoint (including retinopathy, vitreous haemorrhage

23
and renal failure) of 0.6 3 (95% CI, 0.44 to 0.89). The trend for reduced risk of fatal
and non -fatal renal disease was not significant (RR 0.35 (99% CI 0.03 to 3.66) and
0.58 (99% CI 0.15 to 2.21) respectively). However, five out of six surrogate
outcomes (microalbuminuria and pro teinuria each
measured at three 3 -yearly intervals) tended to favour tight blood pressure
control. Of these, only microalbuminuria at six years reached statistical
significance. 20.3% of the tight control group fell into this category, compared
with 28.5% with less tight control (RR 0.71 (99% CI 0.51 to 0.99)).

24

Figure 1 -8
ACE inhibitors
Particular attention has focused on one group of antihypertensive agents, the
angiotensin -converting enzyme (ACE) inhibitors. These drugs reduce constriction
of blood vessels, including small vessels (efferent arterioles) in the kidneys.
A large (n = 3,577) international study comparing an ACE inhibitor,
ramipril, with placebo in people with diabetes (98% Type 2, mean duration 11
years), reported that ramipril reduced b oth nephropathy and total mortality by 24%

25
after 4.5 years.62 All patients had at least one cardiovascular risk factor –
hypertension, high cholesterol, microalbuminuria, or smoking – in addition to
diabetes. Patients with proteinuria (>300 mg albumin/day or equivalent) at baseline
were excluded.
Many smaller studies have been pooled in a series of meta -analyses (Table
1). Most of these compare the effects of different antihypertensive drugs on renal
endpoints.
A meta -analysis which pooled trials lasting mo re than a week and comparing
ACE inhibitors with other antihypertensives, revealed that ACE inhibitors reduce
urinary protein levels significantly more than other antihypertensives.63 The mean
change in urine protein with ACE inhibition was -40% (95% CI, -43% to -37%),
compared with -17% (95% CI, -19% to -15%) for other drugs. Nifedipine had the
smallest effect: -8% (95% CI, -13% to -2%). There were no significant differences
between diabetic and non -diabetic groups of patients.
Another review, also designe d to determine whether specific types of
antihypertensive drugs have differing effects on renal disease, poo led trials with
follow -up times of at least six months. Two metaanalyses were carried out, one
using data from 84 trials of mixed designs, the secon d with data from 14 RCTs
only. The results of both showed that ACE inhibitors reduced urinary protein more
than other antihypertensives, in people with and without diabetes. Analy sis of data
from all the trials sugg ested that the anti -proteinuric effect of ACE in hibitors and
nondihydropyridine calcium channel blockers (verapamil, diltiazem) was greater
than could be explained by changes in blood pressure.
However, this enhanced benefit was not apparent from the metaanalysis of
RCTs only; this found that ef fects on urinary protein were proportional to changes
in blood pressure.
Two other meta -analyses, which have slightly different inclusion criteria and
include groups of trials which partially overlap with the studies above, reinforce
these results. One of these reported that ACE inhibitors reduced protein excretion
by 25% even when blood pressure remained constant,66 and also that kidney

26
function deteriorated significantly faster in people with diabetes and renal disease
treated with nifedipine than in peop le in the other treatment groups.
However, trials published since these meta -analyses have examined the
differences between drugs mainly in people who have microalbuminuria. Those
which included more than 100 patients are discussed below.
UKPDS 39 (n=758) found no differences in outcome between
atenolol (a beta -blocker) and captopril (an ACE inhibitor).67 Few patients
had renal disease. Also, for two -thirds of the study period, 60% were taking other
antihypertensives as well as (or instead of) the drug to w hich they were
randomised. 35% of patient s on atenolol discontinued treatment because of adverse
effects, compared with 22% on captopril (p<0.001).
A multi -centre trial in patients with Type 2 diabetes, hypertension and
microalbuminuria (n=314) found that lisinopril (an ACE inhibitor) reduced
albumin excretion significantly more than nifedipine. Similar results were found in
a study (n=103) comparing benazepril with nicardipine in both hypertensive and
normotensive patients. A study (n=162) which compared A CE inhibitors with
calcium channel blockers found little difference; however, as in UKPDS the
majority of patients did not have renal disease.
The most recently published metaanalysis of RCTs found that ACE
inhibitors also reduce albumin excretion in peopl e with diabetes with
microalbuminuria and normal blood pressure In the studies identified which were
not included in this metaanalysis and which compared ACE inhibitors (enalapril,
ramipril or perindopril) with placebo in patients with mild hypertension or normal
blood pressure and microalbuminuria, ACE inhibitors redu ced albumin
excretion.72 -74 The beneficial effects on risk of renal disease increased over five
years.73,74 Ravid et al found that albumin excretion increased less at six years in
the enalapri l group than in the placebo group and that renal function was
preserved.
Of these trials, only those carried out by UKPDS assessed renal failure or
death -rates, and none measured quality of life. There seems to be a general and

27
unquestioned assumption that reduction of urinary protein excretion would
inevitably beassociated with improvements in such end -points. Although this
assumption has face validity and no evidence is presented that suggests it is untrue,
neither does there appear to be any evidence dem onstrating that it is correct.
This is not a trivial academic point. Improvements in surrogate outcome
measures such as blood pressure can be associated with deterioration in crucial
end-points such as life -expectancy.75 It is important, therefore, that studies of
antihypertensive drugs in diabetic renal disease should be designed to detect effects
on longterm morbidity and mortality.

Summary of evidence on antihypertensive treatment
ACE inhibitors offer particular benefits for people with diabetic renal
disease or microalbuminuria, even when normotensive. These benefits may be
offered by other antihypertensive drugs when patients have high blood pressure but
show no signs of renal disease.119 Dihydropyridine calcium channel blockers have
a less favourabl e pattern of effects in people who have renal disease and diabetes.
(2)-Improved blood glucose control
More intensive control of blood glucose appears to delay the
development of renal disease. Using diabetes medication for type 2DM and
insulin injections for type 1 DM .
Treatments include ; –
(1) agents that increase the amount of insulin secreted by the
pancreas, (sulfonuria – tolbutamide , glipizide ,nonsulfonuria repaglinide )
(2) agents that increase the sensitivity of target organs to insulin, (
Biguani des and Thiazolidinediones)
(3) agents that decrease the rate at which glucose is absorbed from the
gastrointestinal tract. (acarbose )

UKPDS 33 (n=3,867) rep orted that the relative risk of microalbuminuria at
nine years was 0.76 (99% CI, 0.6 to 0.9) with tight control by sulphonylurea or

28
insulin (mean HbA1c, 7.0%), compared with less tight control by diet (mean
HbA1c , 7.9%).17 At 12 years, the relative risk fell to 0.67 (99% CI, 0.5 to 0.9). It
is too soon to know to what degree this may reduce the risk of renal failure.
A Japanese study reported that a mean HbA1c of 7.1 over a period of six
years achieved by multiple insulin injection therapy (MIT) reduced the risk of
worsening in nephr opathy by 70% (95% CI, 14% to 89%) relative to a mean
HbA1c of 9.4 achieved byconventional insulin injection therapy (CIT).76 This
result came from a combined cohort of patients with normal renal function at
baseline (defined as urinary albumin excretion ( UAE) <30 mg/24 hr) (the primary
prevention cohort) and patients with microalbuminuria (defined as UAE <300
mg/24hr) (the secondary prevention cohort). The cumulative percentages of the
development and progression in nephropathy after six years were 7.7% fo r the
group treated with MIT and 28% for the group treated wit h CIT in the primary
prevention cohort, (p = 0.032) and 11.5% and 32.0% respectively for the MIT and
CIT groups in the secondary intervention cohort (p = 0.044).
(3+4)-Lipid and protein control
Reduced dietary protein
A systematic review found that for people with Type 1 diabetes a diet
containing 0.3 –0.8 g/kg body weight of protein per day may slow progression to
renal failure. However, no reliable evidence was
found relating to Type 2 diabetes .
Lipid reduction
No conclusive evidence was found relating to the effect of statins or
gemfibrozil on renal function.78 -81 However, these drugs may be indicated
for reduction of cardiovascular morbidity and mortality in people with diabetes.
Management of Dyslipidemia
Screening :
1-Measure fasting lipids at least annually
2-Every 2 yrs for adults with low -risk lipid values: LDL -C <100 mg/dL

29
(2.6 mmol/L), HDL -C >50 mg/dL (1.3 mmol/L), TG <150 mg/dL (1.7
mmol/L)
Targets
• No overt CVD: LDL -C <100 mg/dL (2.6 mmol/L)
• Overt CVD: LDL -C <70 mg/dL (1.8 mmol/L), with high -dose statin*
• If targets not achieved on max statin therapy: ~30 -40% LDL -C
reduction from baseline

Treatment:
1-Lifestyle modification
• Reduce saturated fat, trans fat, cholesterol intake
• Increase omega -3 fatty acids, viscous fiber, plant stenols/sterols
intake
• Weight loss (if indicated)
• Increase physical activity
2-Statin therapy and lifestyle changes in patients with
• Overt CVD
• No CVD, aged >40 yrs, ≥1 CVD risk factor†
• Consider statins in lower -risk patients (no overt CVD, aged <40 yrs) if
LDL -C >100 mg/dL or if multiple CVD risk factors
**** Combination therapy not recommended

9 Multifactorial intervention
Four years of intensive multifactorial treatment of people with
microalbuminuria has been shown to produce significant reductions in the rate of
progression of renal disease, along with improvements in a range of other diabetes –
related end -points.83 The in tervention involved tight control of blood pressure,
glucose and lipids, ACE inhibitors for all patients in the intensive treatment group

30
regardless of blood pressure, specific advice on diet plus vitamin supplements,
exercise, and help with smoking cessat ion. 10% of patients in the intensively
treated group developed nephropathy during the study, compared with 24% in the
group which received standard treatment from GPs (odds ratio 0.27, 95% CI, 0.10
to 0.75). Blindness and autonomic neuropathy also develop ed significantly less
often in the intensively treated group.

10 Costs
Effective treatment of early renal complications of diabetes through tight
control of blood pressure is highly costeffective. Figures calculated from the
UKPDS trial comparing tight with less tight blood pressure control show that the
incremental cost per life year gained (using 1997 values) was £720 when costs and
effects were discounted at 6% per year. When costs were discounted at 6% per
year but effects were not discounted the cos t per life year gained fell to £291.84
This analysis was based on unit costs for all NHS resources used by all patients
over the entire period of the trial, adjusted to reflect standard clinical practice.
Tight blood pressure control reduced the rate of co mplications requiring
hospitalisation. Although this difference was not statistically significant, the
savings found offset the costs of antihypertensive drugs so that the net costs per
patient were very similar in the two groups. Tight control of blood pr essure
appears to be considerably more costeffective than either treatment to reduce
cholesterol levels, or lifestyle advice on reducing cardiovascular risk. A
hypothetical strategy of treating all middle aged people with diabetes (base case
50 years old) with ACE inhibitors was examined by the use of a model. This was
found to be more cost -effective than screening and treating for micro -albuminuria
or proteinuria. Analyses indicated a cost of $7,500 for each quality -adjusted life
year gained.85 However th is result was sensitive to a number of parameters such
as age and quality of life.

31
CONCLUSIONS
The urine of people with Type 2 diabetes should be tested regularly (at least
annually) for proteinuria, and if this is negative, for microalbuminuria. Two or
more measurements should be carried out.
Evidence for the effectiveness of individual near -patient tests is
inconclusive.
The blood pressure of people with diabetes should be checked at regular
intervals and treatment offered if it is found to be consisten tly higher than
140/90.86
In people with above -normal levels of protein in their urine, treatment with
ACE inhibitors is appropriate, even if blood pressure is within the normal range.
Treatment of other cardiovascular risk factors should also be considered.
Blood glucose levels should be kept as near to normal as is consistent with
an acceptable quality of life.
Further research is required with people with Type 2 diabetes to establish
what levels of dietary protein are effective for reducing the rate of progression of
renal complications, and are acceptable to people with diabetes.

32
REFERENCES
1. Calman K. On the state of the public health. The Annual Report of the
Chief Medical Officer of the Department of Health for the year 1997. London: The
Stationery Office, 1998.
2. Hutchinson A, McIntosh A, O’Keeffe C, et al. Type 2 Diabetes:
Systematic Review of Screening Methods and Interventions for Renal Disease.
RCGP (forthcoming) .
3. Mogensen CE, Chachati A, Christensen CK, et al. Microalbuminuria: A n
early marker of renal involvement in diabetes. Uremia Investigation 1985;9:85 -95.
4. Allawi J, Rao PV, Gilbert R, et al. Microalbuminuria in non -insulin
dependent diabetes: its prevalence in Indian compared with Europid patients.
British Medical Journal – Clinical Research Edition 1988;296:462 -4.
5. Bruno G, Cavallo -Perin P, Bargero G, et al. Prevalence and risk factors
for micro – and macroalbuminuria in an Italian populationbased cohort of NIDDM
subjects. Diabetes Care 1996;19:43 -7.
6. Gall MA, Rossing P, Skott P, et al. Prevalence of micro – and
macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in
European Type 2 (non insulin dependent) diabetic patients. Diabetologia
1991;34:655 -61.
7. Gatling W, Knight C, Mullee MA, et al. M icroalbuminuria in diabetes: a
population study of the prevalence and an assessment of three screening tests.
Diabetic Medicine 1988;5:343 -7.
8. Gupta DK, Verma LK, Khosla PK, et al. The prevalence of
microalbuminuria in diabetes: A study from North India. Diabetes Research and
Clinical Practice 1991;12:125 -8.
9. Klein R, Klein BEK, Moss SE. Prevalence of microalbuminuria in older –
onset diabetes. Diabetes Care 1993;16:1325 -30.
10. Lee KU, Park KY, Kim SW, et al. Prevalence and associated features of
albuminuria in Koreans with NIDDM. Diabetes Care 1995;18:793 -9.

33
11. Marshall SM, Alberti KG. Comparison of the prevalence and associated
features of abnormal albumin excretion in insulindependent and non -insulin –
dependent diabetes. Quarterly Journal of Med icine 1989;70:61 -71.
12. Mattock M, Morrish NJ, Viberti G, et al. Prospective study of
microalbuminuria as predictor of mortality in NIDDM. Diabetes 1992;41.
13. Mogensen CE. A complete screening of urinary albumin concentration
in an unselected diabetic o ut-patient clinic population. Diabetic Nephropathy
1983;2:11 -8.
14. Patrick AW, Leslie PJ, Clarke BF, et al. The natural history and
associations of microalbuminuria in type 2 diabetes during the first year after
diagnosis. Diabetic Medicine 1990;7:902 -8.
15. Standl E, Stiegler H. Microalbuminuria in a random cohort of recently
diagnosed type 2 (non-insulin dependent) diabetic patients living in the greater
Munich area. Diabetologia 1993;36:1017 -20.
16. Vijay V, Snehalatha C, Ramachandran A, et al. Prevalen ce of proteinuria
in non -insulin dependent diabetes. Journal of the Association of Physicians of
India 1994;42:792 -4.
17. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood –
glucose control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
The Lancet 1998;352:837 -53.
18. Klein R, Klein BEK, Moss SE, et al. Ten-year incidence of gross
proteinuria in people with diabetes. Diabetes 1995;44:916 -23.
19. Ansell D, Feest T, Will E, et al. The Second Annual report of The UK
Renal Registry . Bristol: The UK Renal Registry, 1999.
20. Mattock MB, Barnes DJ, Viberti G, et al. Microalbuminuria and
coronary heart disease in NIDDM: an incidence study. Diabetes 1998;47:1786 -92.
21. Niskanen LK, Penttila I, Parviainen M, et al. Evolution, risk factors, and
prognostic implications of albuminuria in NIDDM. Diabetes Care 1996;19:486 –
93.

34
22. Wirta OR, Pasternack AI, Mustonen JT, et al. Urinary albumin excretion
rate and its determinants after 6 years in non -insulindependent diabetic patients.
Nephrology, Dialysis,Transplantation 1996;11:449 -56.
23. Gall M, Hougaard P, Borch -Johnsen K, et al. Risk factors for
development of incipient and overt diabetic nephropathy in patients with non –
insulin dependent diabetes mellitus: prospective, observational study. British
Medical Journal 1997;314:783 -8.
24. Biesenbach G, Grafinger P, Janko O, et al. Influence of cigarette –
smoking on the progress ion of clinical diabetic nephropathy in type 2 diabetic
patients. Clinical Nephrology 1997;48:146 -50.
25. Sasaki A, Horiuchi N, Hasagawa K, et al. Persistent albuminuria as an
index of diabetic nephropathy in type 2 diabetic patients in Osaka, Japan –
incidence, risk factors, prognosis and causes of death. Diabetes Research &
Clinical Practice 1989;7:299 -306.
26. Nielsen S, Schmitz A, Poulsen PL, et al. Albuminuria and 24 -h
ambulatory blood pressure in normoalbuminuric and microalbuminuric NIDDM
patients. A longitudinal study. Diabetes Care 1995;18:1434 -41.
27. Ravid M, Brosh D, Ravid Safran D, et al. Main risk factors for
nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood
pressure, and hyperglycemia. Archives of Internal Medicine 1998;158:998 -1004.
28. Schmitz A, Vaeth M, Mogensen CE. Systolic blood pressure relates to
the rate of progression of albuminuria in NIDDM. Diabetologia 1994;37:1251 -8.
29. Davis TM, Stratton IM, Fox CJ, et al. U.K. prospective diabetes study
22. Effect of age a diagnosis on diabetic tissue damage during the first 6 years of
NIDDM. Diabetes Care 1997;20:1435 -41.
30. John L, Rao PS, Kanagasabapathy AS. Rate of Progression of
Albuminuria in Type II diabetes, five year prospective study from Sout h India.
Diabetes Care 1994;17:888 -90.

35
31. Burden AC, McNally PG, Feehally J, et al. Increased incidence of end
stage renal failure secondary to diabetes mellitus in Asian ethnic groups in the
United Kingdom. Diabetic Medicine 1992;9:641 -5.
32. Roderick PJ , Raleigh VS, Hallam L, et al. The need and demand for
renal replacement therapy in ethnic minorities in England. Journal of
Epidemiology and Community Health 1996;50:334 -9.
33. Canani LH, Gerchman F, Gross JL. Familial clustering of diabetic
nephropathy in Brazilian type 2 diabetic patients. Diabetes 1999;48:908 -13.
34. Freedman BI, Tuttle AB, Spray BJ. Familial predisposition to
nephropathy in African -Americans with non -insulin -dependent diabetes mellitus.
American Journal of Kidney Diseases 1995;25:710 -3.
35. Tanaka Y, Atsumi Y, Matsuoka K, et al. Role of glycemic control and
blood pressure in the development and progression of nephropathy in elderly
Japanese NIDDM patients. Diabetes Care 1998;21:116 -20.
36. Niskanen L, Voutilainen R, Terasvirta M, et al. A prospective study of
clinical and metabolic associates of proteinuria in patients with type 2 diabetes
mellitus. Diabetic Medicine 1993;10:543 -9.
37. Gall MA, Borch -Johnsen K, Hougaard P, et al. Albumin uria and poor
glycemic control predict mortality in NIDDM. Diabetes 1995;44:1303 -9.
38. Schmitz A, Vaeth M. Microalbuminuria: a major risk factor in non –
insulin -dependent diabetes. A 10 -year follow -up study of 503 patients. Diabetic
Medicine 1988;5:126 -34.
39. Dinneen SF, Gerstein HC. The association of microalbuminuria and
mortality in noninsulin -dependent diabetes mellitus: A systematic overview of the
literature. Archives of Internal Medicine 1997;157:1413 -8
40. Wang SL, Head J, Stevens L, et al. Excess mortality and its relation to
hypertension and proteinuria in diabetic patients: The World Health Organization
Multinational Study of Vascular Disease in Diabetes. Diabetes Care 1996;19:305 –
12.

36
41. Bashyam MM, O’Sullivan NJ, Baker HH, et al. Microalbuminuria in
NIDDM. Diabetes Care 1993;16:634 -5.
42. Williams BT, Ketchum CH, Robinson CA, et al. Screening for slight
albuminuria: a comparison of selected commercially available methods. Southern
Medical Journal 1990;83:1447 -9.
43. Tiu SC, Lee SS, Cheng MW. Comparison of six commercial techniques
in the measurement of microalbuminuria in diabetic patients. Diabetes Care
1993;16:616 -20.
44. Giampietro O, Penno G, Clerico A, et al. Which method for quan tifying
“microalbuminuria” in diabetics? Comparison of several immunological methods
(immunoturbidimeteric assay, immunonephelometric assay, radioimmunoassay
and two semi quantitative tests) for measurement of albumin in urine. Acta
Diabetologica 1992;28:2 39-45.
45. Leedman PJ, Nankervis A, Goodwin M, et al. Assessment of the
Albuscreen microalbuminuria kit in diabetic outpatients. Medical Journal of
Australia 1987;147:285 -6.
46. Colwell M, Halsey JF. High incidence of falsepositive albuminuria
results with the Micro -Bumintest. Clinical Chemistry 1989;35:1252 -4.
47. Al -Kassab AS. Evaluation of a simple method for the screening of
microalbuminuria in diabetic patients. Scandinavian Journal of Clinical
Laboratory Investigation 1990;50:913 -5.
48. Collins V, Zim met P, Dowse GK, et al. Performance of “Micro –
Bumintest” tablets for detection of microalbuminuria in Nauruans (West Pacific
Ocean). Diabetes Research and Clinical Practice 1989;6:271 -7.
49. Hutchison AS, O’Reilly DS, MacCuish AC. Albumin excretion rate,
albumin concentration, and albumin/creatinine ratio compared for screening
diabetics for slight albuminuria. Clinical Chemistry 1988;34:2019 -21.
50. Gatling W, Knight C, Hill RD. Screening for early diabetic nephropathy:
which sample to detect microalbuminuria? Diabetic Medicine 1985;2:451 -5.

37
51. Bakker AJ. Detection of microalbuminuria. Receiver operating
characteristic curve analysis favors albumin -to-creatinine ratio over albumin
concentration. Diabetes Care 1999;22:307 -13.
52. Kouri TT, Viikari JSA, Mattila KS, et al. Microalbuminuria: Invalidity
of simple concentration -based screening tests for early nephropathy due to urinary
volumes of diabetic patients. Diabetes Care 1991;14:591 -3.
53. Marbut K, Lane J. A new sensitive E LISA test for spot test of urinary
albumin. Clinical Chemistry 1992;36:1430 -1.
54. Sawicki PT, Heinemann L, Berger M. Comparison of methods for
determination of microalbuminuria in diabetic patients. Diabetic Medicine
1989;6:412 -5.
55. Bouhanick B, Berrut G, Chameau AM, et al. Predictive value of testing
random urine sample to detect microalbuminuria in diabetic subjects during
outpatient visit. Diabete et Metabolisme 1992;18:54 -8.
56. Nathan DM, Rosenbaum C, Protasowicki VD. Single -void urine samples
can b e used to estimate quantitative microalbuminuria. Diabetes Care
1987;10:414 -8.
57. Connell SJ, Hollis S, Tieszen KL, et al. Gender and the clinical
usefulness of the albumin: creatinine ratio. Diabetic Medicine 1994;11:32 -6.
58. Parsons M, Newman DJ, Pugia M, et al. Performance of a reagent strip
device for quantitation of the urine albumin: creatinine ratio in a point of care
setting. Clinical Nephrology 1999;51:220 -7.
59. Poulsen PL, Mogensen CE. Clinical evaluation of a test for immediate
and quantitative determination of urinary albumin -tocreatinine ratio. A brief report.
Diabetes Care 1998;21:97 -8.
60. British Diabetic Association. UKDIABS Study : (Unpublished Data).
61. UK Prospective Diabetes Study Group. Tight blood pressure control and
risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS
38. British Medical Journal 1998;317:703 -13.

38
62. Heart Outcomes Prevention Evaluation (HOPE) Study Inv estigators.
Effects of ramipril on cardiovascular and microvascular outcomes in people with
diabetes mellitus: results of the HOPE study and MICRO -HOPE substudy. The
Lancet 2000;355:253 -9.
63. Gansevoort RT, Sluiter WJ, Hemmelder MH, et al. Antiproteinuric effect
of blood -pressurelowering agents: a meta -analysis of comparative trials.
Nephrology, Dialysis,Transplantation 1995;10:1963 -74.
64. Maki DD, Ma JZ, Louis TA, et al. Long -term effects of antihypertensive
agents on proteinuria and renal function. Arch ives of Internal Medicine
1995;155:1073 -80.
65. Kasiske BL, Kalil RS, Ma JZ, et al. Effect of antihypertensive therapy on
the kidney in patients with diabetes: a meta -regression analysis. Annals of Internal
Medicine 1993;118:129 -38.
66. Weidmann P, Schneider M, Bohlen L. Therapeutic efficacy of different
antihypertensive drugs in human diabetic nephropathy: an updated meta -analysis.
Nephrology Dialysis and Transplantation 1995;10:39 -45.
67. UK Prospective Diabetes Study Group. Efficac y of atenolol and
captopril in reducing risk of macrovascular and microvascularn complications in
type 2 diabetes: UKPDS 39. British Medical Journal 1998;317:713 -20.
68. Agardh CD, Garcia Puig J, Charbonnel B, et al. Greater reduction of
urinary albumin excretion in hypertensive type II diabetic patients with incipient
nephropathy by lisinopril than by nifedipine. Journal of Human Hypertension
1996;10:185 -92.
69. De Cesaris R, Ranieri G, Andriani A, et al. Effects of benazepril and
nicardipine on microalbum inuria in normotensive and hypertensive patients with
diabetes. Clinical Pharmacology Therapeutics 1996;60:472 -8.
70. Crepaldi G, Carraro A, Brocco E, et al. Hypertension and non -insulin
dependent diabetes. Acta Diabetologica 1995;32:203 -8.

39
71. Lovell HG. Are angiotensin converting enzyme inhibitors useful for
normotensive diabetic patients with micro -albuminuria?(Cochrane Review). The
Cochrane Library . Oxford: Update Software, 1999.
72. Trevisan R, Tiengo A. Effect of low -dose ramipril on microalbuminuria
in normotensive or mild hypertensive non -insulin -dependent diabetic patients.
North -East Italy Microalbuminuria Study Group. American Journal of
Hypertension 1995;8:876 -83.
73. Ahmad J, Siddiqui MA, Ahmad H. Effective postponement of diabetic
nephropathy w ith enalapril in normotensive type 2 diabetic patients with
microalbuminuria. Diabetes Care 1997;20:1576 -81.
74. Ravid M, Brosh D, Levi Z, et al. Use of Enalapril to attenuate decline in
renal function in normotensive, normoalbuminuric patients with Type 2 Diabetes
Mellitus: A randomized, controlled trial. Annals of Internal Medicine
1998;128:982 -8.
75. Gøtzsche PC, Liberati A, Torri V. Beware of surrogate outcome
measures. International Journal of Technology Assessment in Health Care
1996;12:238 -46.
76. Oh kubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy
prevents the progression of diabetic microvascular complications in Japanese
patients with noninsulin – dependent diabetes mellitus: a randomized prospective 6 –
year study. Diabetes Research and Clinical Practice 1995;28:103 -17.
77. Waugh NR, Robertson AM. Protein restriction in diabetic renal disease
(Cochrane Review). In: The Cochrane Library . Oxford: Update Software, 1999.
78. Tonolo G, Ciccarese M, Brizzi P, et al. Reduction of albumin excretion
rate in normotensive microalbuminuric Type 2 diabetic patients during long -term
Simvastatin treatment. Diabetes Care 1997;20:1891 -5.
79. Smulders YM, Van Eeden AE, Stehouwer CDA, et al. Can reduction in
hypertriglyceridaemia slow progression of microalbuminuria in patients with non –
insulin dependent diabetes mellitus? European Journal of Clinical Investigation
1997;27:997 -1002.

40
80. Niel sen S, Schmitz O, Moller N, et al. Renal function and insulin
sensitivity during simvastatin treatment in type 2 (non -insulindependent) diabetic
patients with microalbuminuria. Diabetologia 1993;36:1079 -86.
81. Lam KSL, Cheng IKP, Janus ED, et al. Choleste rol-lowering therapy
may retard the progression of diabetic nephropathy. Diabetologia 1995;38:604 -9.
82. NHS Centre for Reviews and Dissemination, The University of York.
Cholesterol and coronary heart disease: screening and treatment. Effective Health
Care 1998;4:1 -16.
83. Gaede P, Vedel P, Parving HH, et al. Intensified multifactorial
intervention in patients with type 2 diabetes mellitus and microalbuminuria: the
Steno type 2 randomised study. The Lancet 1999;353:617 -22.
84. UK Prospective Diabetes Study Group. Cost effectiveness analysis of
improved blood pressure control in hypertensive patients with type 2 diabetes:
UKPDS 40. British Medical Journal 1998;317:720 -6.
85. Golan L, Birkmeyer JD, Welch G. The costeffectiveness of treating all
patients with Type 2 diabetes with angiotensin converting enzyme inhibitors.
Annals of Internal Medicine 1999;131:660 -7.
86. Ramsay LE, Williams B, Johnston GD, et al. British Hypertension
Society guidelines for hypertension management. British Medical Journal
1999;319: 630-5.
87. Coulter A. Partnerships with patients: the pros and cons of shared
clinical decision making. Journal of Health Services Research and Policy
1997;2:112 -21.
88. Bandura A. Social Learning Theory . N.J.: Prentice -Hall, 1977.
89. Mazzucca S, Moorman N, Wheelder M, et al. The Diabetes Education
Study: A controlled trial of the effects of diabetes patient education. Diabetes Care
1986;9:1 -10.
90. Vinicor F, Cohen SJ, Mazzuca SA, et al. DIABEDS: A randomized
controlled trial of the effects of physician and/or patient education on diabetes
patient outcomes. Journal ofChronic Diseases 1987;40:345 -56.

41
91. Hanefeld M, Fischer S, Schmechel H, et al. Diabetes intervention study:
multiintervention trial in newly diagnosed NIDDM. Diabetes Ca re 1991;14:308 –
17.
92. Rettig BA, Shrauger DG, Recker RR, et al. A randomised study of the
effects of a home diabetes education program. Diabetes Care 1986;9:173 -8.
93. Hawthorne K, Tomlinson S. One to one teaching with pictures –
flashcard health educatio n for British Asians with diabetes. British Journal of
General Practice 1997;47:301 -4.
94. Uusitupa M, Laitinen J, Siitonen O, et al. The maintenance of improved
metabolic control after intensified diet therapy in recent Type 2 diabetes. Diabetes
Research and Clinical Practice 1993;19:227 -38.
95. Kirkman SM, Weinberger M, Landsman PB, et al. A telephone -delivered
intervention for patients with NIDDM. Effect on coronary risk factors. Diabetes
Care 1994;17:840 -6.
96. Turnin MG, Beddok RH, Clottes JP, et al. Telematic expert system
diabeto. New tool for diet self -monitoring for diabetic patients. Diabetes Care
1992;15:204 -12.
97. Heller SR, Clarke P, Daly H, et al. Group education for obese patients
with Type 2 diabetes: Greater success at less cost. Diabetic Medicine 1988;5:552 –
6.
98. Mulrow C, Bailey S, Sonksen PH, et al. Evaluation of an audiovisual
diabetes education program: negative results of a randomised trial of patients with
non-insulin dependent diabetes. Journal of General Internal Medicine 1987;2:2 15-
9.
99. Wood ER. Evaluation of a hospital -based education program for patients
with diabetes. Journal of the American Dietetic Association 1989;89:354 -8.
100. Trento M, Passera P, Tomalino M, et al. Therapeutic group education in
the follow -up of patient s with non -insulin treated, noninsulin dependent diabetes
mellitus. Diabetes, Nutrition and Metabolism: Clinical and Experimental
1998;11:212 -6.

42
101. Campbell EM, Redman S, Moffitt PS, et al. The relative effectiveness
of educational and behavioral instruc tion programs for patients with NIDDM: A
randomised trial. Diabetes Educator 1996;22:379 -86.
102. Boehm S, Schlenk EA, Raleigh E, et al. Behavioral analysis and
behavioral strategies to improve self -management of Type II diabetes. Clinical
Nursing Research 1993;2:327 -44.
103. Glasgow RE, Toobert DJ, Hampson SE. A brief office -based
intervention to facilitate diabetes dietary self -management. Health Education
Research 1995;10:467 -78.
104. Glasgow RE, Toobert DJ, Hampson SE. Effects of a brief office -based
intervention to facilitate diabetes dietary self -management. Diabetes Care
1996;19:835 -42.
105. Glasgow RE, La Chance PA, Toobert DJ, et al. Long term effects and
costs of brief behav ioural dietary intervention for patients with diabetes delivered
from the medical office. Patient Education and Counselling 1997;32:175 -84.
106. Wing RR, Epstein LH, Nowalk MP, et al. Behavior change, weight
loss, and physiological improvements in Type II diabetic patients. Journal of
Consulting and Clinical Psychology 1985;53:111 -22.
107. Hartwell S, Kaplan R, Wallace J. Comparison of behavioral
interventions for control of Type II diabetes. Behavior Therapy 1986;17:447 -61.
108. Glasgow RE, Toobert DJ, Hampson SE, et al. Improving self -care
among older patients with Type II diabetes: The “sixty something …” study.
Patient Education and Counselling 1992;19:61 -74.
109. CA, Kaplan RM, Wilson DK, et al. Sex differences in weigh t loss
among adults with Type II diabetes mellitus. Journal of Behavioral Medicine
1987;10:197 -211.
110. Falkenberg MGK, Elwing BE, Goransson AM, et al. Problem oriented
participatory education in the guidance of adults with non -insulin treated Type II
diabetes mellitus. Scandinavian Journal of Primary Health Care 1986;4:157 -64.

43
111. Noel PH, Larme AC, Meyer J, et al. Patient choice in diabetes
education curriculum. Nutritional versus standard content for Type 2 diabetes.
Diabetes Care 1998;21:896 -901.
112. Brown SA. Effects of educational interventions in diabetes care: a
meta -analysis of findings. Nursing Research 1988;37:223 -30.
113. Brown SA. Studies of educational interventions and outcomes in
diabetic adults: a meta -analysis revisited. Patient Educatio n and Counselling
1990;16:189 -215.
114. Brown SA. Meta -analysis of diabetes patient education research:
variations in intervention effects across studies. Research in Nursing and Health
1992;15:409 -19.
115. Brown SA, Upchurch S, Anding R, et al. Promoting weight loss in
Type II diabetes. Diabetes Care 1996;19:613 -24.
116. Padgett D, Mumford E, Hynes M, et al. Metaanalysis of the effects of
educational and psychosocial interventions on management of diabetes mellitus.
Journal of Clinical Epidemiology 1988;41: 1007 -30.
117. Kleijnen J, Knipschild P, ter Riet G. Clinical trials of homeopathy.
British Medical Journal 1991;302:316 -23.
118. McIntosh A, Withers H, Hutchinson A, et al. Systematic review on the
effectiveness of patient education interventions in the ma nagement of Type 2
diabetes . RCGP (forthcoming).
119. National Prescribing Centre. What’s new in Type 2 diabetes. An
overview . February 2000.
120. Basic pathology , robin's 8th edition.

44
Declaration
I hereby declare that the license thesis titled “ DIABETIC
NEPHROPATHY ” is written by me under the guidance of Dr. Alexa Zinaida,
Department of Endocrinology .U.S.M.F. State University of Medicine and
Pharmacy “Nicolae Testemitanu” Of Republic of Moldova, and has never been
submitted to another university or institution of higher education in the country or
abroad. Also, that all sources used, including those on the Internet, are given in the
paper with the rules for avoiding plagiarism:
– All the fragments of text reproduced exactly, even in his own trans lation
from another language are written between quotation marks and have a detailed
reference source;
– Reformulation of the texts in own words written by other authors have
detailed refere
– Summarizing the ideas of other authors has detailed reference to the
original text.

Date
11/05/2015

Student: – Grifat Mohammad.
Group: -1641.
Signature : _______________