DIABETIC NEPHROPATHY

INTRODUCTION:

A chronic and
irreversible reduction in glomerular filtration (GFR), arterial hypertension,
and albuminuria (>300 mg/day or > 200 mcg/min) verified at least twice
within three to six months are the characteristics of diabetic nephropathy
(DN), a clinical syndrome.

Patients with
diabetes who have structural and functional problems in their kidneys are said
to have diabetic nephropathy.

The kidney's
enlargement, stronger glomerular basement membrane, tubular atrophy, widespread
and nodular glomerulosclerosis, and interstitial fibrosis are among the
structural abnormalities.

The functional alterations
include an early increase in GFR with intraglomerular hypertension,subsequent
proteinuria, systemic hypertension, and eventual loss of renal function.

EPIDEMIOLOGY:

Diabetic
nephropathy is a major cause of morbidity and mortality for persons with either
T1DM or T2DM.  Globally, diabetes is the
primary cause of end-stage renal disease.Diabetic kidney damage eventually
develops in 5% to 40% of patients with type 2 diabetes and 25% to 40% of
patients with type 1 diabetes.

Up to 20% of
T2DM patients are diagnosed with diabetic kidney disease, and another 30% to
40% go on to develop diabetic nephropathy, typically within ten years of their
diagnosis. Over 80% of diabetic patients receiving renal replacement treatment
have T2DM, despite the fact that nephropathy seems to be more common in T1DM
due to the huge and growing number of people with T2DM.

NATURAL HISTORY OF DN:

Diabetic
nephropathy is characterized clinically as a triad of hypertension, proteinuria,
and, renal impairment.

Even
though natural history of diabetic nephropathy has been better described in
Type 1 DM, the classification by Mogensen into five stages of nephropathy, can
be applied to both forms of diabetes.

Mogensen classification of diabetic nephropathy:

Stage
1:Hyperfiltration

Stage
2:Silent stage-normal albuminurias

Stage
3:Incipient stage-microalbuminuria

Stage
4:Overt stage-macroalbuminuria

Stage
5:End stage renal disease

·       
DN,diabetic nephropathy;ESRD,end
stage renal disease;GFR,glomerular filtration rate;UAE,urinary albumin
excretion.

·    Pugliese G Acta
Diabetol 2014;51:905-915

STAGE
1 HYPERFILTRATION:

When Type I DM is
diagnosed, this stage is observed. At this point, renal vasodilatation and
hyperfiltration take place. There is an increase in glomerular filtration rate
(GFR) in 41% of Type 2 DM and 90–95% of Type 1 DM. The primary reasons of
elevated GFR are decreased plasma oncotic pressure and elevated renal plasma
flow (RPF). But for any given RPF, GFR is higher. In diabetics, this is a sign
of elevated glomerular capillary hydrostatic pressure.

STAGE 2 SILENT STAGE:

Patients'
urine albumin excretion (UAE) is still between 15 and 20 micrograms per minute
at this stage. Exercise can lead to temporary microalbuminuria, which returns
to normal at rest.

Blood
pressure is either normal or slightly increased, and the glomerular filtration
rate is often high. Patients with type 2 diabetes who have microalbuminuria
exhibit elevated glomerular volume, indicating that microalbuminuria is a sign
of diabetic kidney damage regardless of GFR.

STAGE 3 INCIPIENT DIABETIC NEPHROPATHY MICROALBUMINURIA:

In
this stage, the UAE is between 20-200 mg/min or 30-300 mg/24 hr. Patients with
microalbuminuria have negative urine dipstick for protein and less than 300 mg
in 24 hours. This stage occurs usually 5 to 15 years after diagnosis of diabetes.

In
patients with Type 1 DM, microalbuminuria is a risk factor for progression to
nephropathy. In patients with Type 2 DM ,it is less predictive because of
comorbid conditions which are associated with microalbuminuria and death may occur
before development of nephropathy. Microalbuminuria is also associated with
increased risk of cardiovascular death in both forms of diabetes.

STAGE 4 OVERT DIABETIC NEPHROPATHY-MACROALBUMINURIA:

This
stage is defined by onset of clinical proteinuria, i.e. persistent dipstick positive
albuminuria (UAE > 300mg/ day or urinary protein excretion of more than 500mg/day).
It usually occurs 15-20 years after onset of Type 1 DM and after 10-12 years of
Type 2 DM.

In
association with this increase in proteinuria, more than two thirds of
patients have overt systemic hypertension. During this phase, if left
untreated, BP continues to rise, accelerating the decline in GFR, which
promotes a further rise in BP, creating a vicious cycle of progressive renal
impairment that
ultimately leads to ESRD.

STAGE 5 END STAGE RENAL DISEASE:

Very
low GFR and widespread glomerular sclerosis are characteristics of this stage.
Complications including edema and fluid retention are linked to the development
of uremia.

Since
kidney transplantation is linked to better results than continuing dialysis,
many people with diabetes and end-stage renal disease are now seen as potential
candidates.

RISK
FACTORS FOR DIABETIC NEPHROPATHY:

• Duration of diabetes
• Poor glycemic control
• Hypertension
• Genetic Predisposition
• Renal hypertrophy
• Race
• Smoking

SCREENING AND
DIAGNOSIS:

Screening for microalbuminuria is recommended for
type 2 diabetics from the day of diagnosis on annual basis, while in type 1
diabetics, annual screening should be done after 5 years of diagnosis of type 1
DM.

Screening can be
performed by measurement of albumin to creatinine ratio in the random spot
urine sample or 24 hour or timed urine collections which are more burdensome
and add little to prediction or accuracy.

Because of
variability in urine albumin excretion rate (UAE), two of the three specimens
collected consecutively should be abnormal.

A 24 hour
urinary collection is gold standard for detection of microalbuminuria.

                         Screening for microalbuminuria

ABNORMALITIES IN
ALBUMIN EXCRETION

Screening should
not be performed in the presence of conditions that increase UAE, such as
urinary tract infection, hematuria, acute febrile illness, vigorous exercise, short-term
pronounced hyperglycemia, uncontrolled hypertension,

and heart
failure.

Serum creatinine
should be measured at baseline and annually in all diabetics,regardless of UAE
rate.

Estimated
GFR(eGFR ) is usually calculated by the “modification of diet in renal
disease(MDRD) study” equation.

MDRD
study equation:

GFR(mL/min/1.73
m2 )=175×(Scr)-1.154 × (Age) -0.203 × (0.742
if female)×(1.212 if African –american)

Based on eGFR
,chronic kidney disease (CKD) is graded into five stages(G1 to G5).In
combination with degree of albuminuria (A1,A2,A3),CKD stages are classified
into various risk categories for progression of CKD.

TREATMENT
OF END STAGE RENAL DISEASE:

The renal replacement
modalities available for patients with ESRD from diabetes include peritoneal dialysis,
hemodialysis, and renal transplantation.

Diabetic
patients with autonomic dysfunction or diastolic dysfunction are more often likely
to develop hypotension during hemodialysis due to poor toleration
of volume shifts. Due to gradual fluid removal in continuous ambulatory
peritoneal dialysis, the procedure is not usually associated with hypotension
unless the patient is volume-depleted,and it is thus better suited for patients
with diabetes.

Peripheral
vascular disease is common in older patients with type-2 diabetes and this
limits the ability to create and sustain adequate vascular access for HD.

Mortality and
morbidity are substantially higher in patients with diabetes maintained on
dialysis than in their nondiabetic counterparts with cardiovascular disease and
infections being the leading causes of death.

Renal transplantation
is associated with better survival, improved quality of life, and a higher degree
of rehabilitation compared to dialysis.

Recurrence of DN
can occur in the allografts. This occurs as a result of poor glycemic control
and/or insulin deficiency. Offering the patient with type-I diabetes combined
pancreas-kidney transplantation can prevent

recurrence of DN.

PREVENTION
OF DN:

Primary
prevention:

The goal of
primary prevention is to keep people from developing diabetes.

Weight control
and regular exercise are two lifestyle changes that have been demonstrated to
either prevent or postpone the onset of diabetes.

Additionally,
exercise improves insulin sensitivity and blood cholesterol levels, lowers
blood pressure, increases endothelial health, and decreases the proportion of
total and belly fat.

The left
ventricle's diastolic and vasodilator functions.

It has also been
shown that pharmacologic therapies involving glucose-lowering medications in
high-risk individuals significantly reduce the incidence of diabetes.

However,
medication therapy was less effective and linked to serious negative side
effects when compared to lifestyle approaches.

Secondary
prevention:

Strict
management of blood pressure, cholesterol, and blood sugar levels is part of
secondary prevention. Proteinuria screening and the implementation of suitable
treatment constitute tertiary prevention.

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