Diabetic nephopathy

Tbilisi referral hospital

Nino Maglakelidze
 Diabetic nephropathy

Epidemiology:

Diabetes - leading cause of

chronic kidney disease (CKD)
end-stage kidney disease (ESKD).

The prevalence of diabetes in the United States - increased

over the last 20 years from 6 to 10 percent,

The proportion of people with diabetes who also have

CKD - remained relatively stable - 25 to 30 percent
Epidemiology

•The prevalence of persistent moderately to severely increased

albuminuria (ie, a urine albumin-to-creatinine ratio ≥30 mg/g) in
diabetic patients decreased from approximately 21 percent during
the period from 1988 to 1994 to 16 percent during the period from
2009 to 2014.

•The prevalence of decreased estimated glomerular filtration rate

(eGFR), defined as an eGFR <60 mL/min/1.73 m2, increased
from 9 to 14 percent.

United States, more than 58,000 people have ESKD attributed to

diabetes, accounting for nearly 50 percent of all patients with
ESKD.
Epidemiology

Annual incidence rates of ESKD due to diabetic kidney disease

are rising and vary from

•10 per 1 million in Romania

•67 per 1 million in Malaysia;
•the United States ranks from 10 up to 47 cases per 1 million.

The true incidence and prevalence of ESKD from diabetes is

impossible to know because kidney biopsies (the gold standard
for diagnosis of diabetic kidney disease) are infrequently
performed in diabetic patients with diabetic kidney disease.
It is unclear whether the natural history and rate of progression
of diabetic kidney disease differs according to diabetes type.

The vast majority of people with type 2 diabetes, disease onset

is after the age of 40 years, and other factors such as

age-related senescence of the kidney

hypertension
Obesity , high BMI

can participate in kidney function decline to varying degrees.

Risk factors

In addition, type 2 diabetes can be asymptomatic for years,

resulting in a delay in diagnosis;

Therefore, the true time of onset of the hyperglycemic exposure

is usually unknown.

Risk factors for diabetic kidney

Risk factors for diabetic kidney disease — Diabetic kidney

disease is a complex disease with multiple phenotypes:
Risk factors:

Age
Race /ethnicity
Sex/gender
Low socio economic status
Obesity
Smoking
Hypertension
Hyperglycemia
Genetic factors
Acute kidney injury
 Risk factors

Age — Increasing age is directly related to the prevalence of

diabetic kidney disease with decreased eGFR.

Rising from:
8 percent in the 5th decade
19 percent in the 6th decade
35 percent in the 7th decade of life

Race/ethnicity — Compared with their white counterparts,

African American, Latino, and American Indian populations
have higher rates of albuminuria, decreased eGFR, and ESKD.
 Risk factors

Sex/gender — Both CKD in general and diabetic kidney disease

in particular are more common in women.

Men have a significantly higher risk of progression from late-stage

CKD to ESKD (hazard ratio [HR] 1.37;

The reasons for greater CKD prevalence in women, but higher

risk of progression in men, are uncertain, but differences in
genetic architecture, sex hormone exposure, body composition
(eg, muscle mass), and lifestyle factors (eg, smoking, obesity,
physical activity, and diet) have been proposed as possible
mediators.
 Risk factors

Low socioeconomic status - Albuminuria and decreased

eGFR (<60mL/min/1.72 m2) is more common among individuals
with lower education level, even after controlling for
sociodemographic and clinical factors.

After controlling for race, the incidence rate of ESKD in one

study was 4.5-fold higher among populations in which more than
25 percent lived below the poverty level as compared with
populations in which fewer than 5 percent lived below the poverty
level.

Socioeconomic status in people with type 1 diabetes is also

associated with pathogenic factors involved in diabetic kidney
disease, including glomerular hyperfiltration and levels of
certain cytokines.
 Risk factors

Mediators of the association between low socioeconomic

status and diabetic kidney disease are numerous.

Obesity — Even in the absence of diabetes, obesity leads to

a form of secondary focal segmental glomerulosclerosis.

40 percent of these patients have features of diabetic kidney

disease (mesangial expansion, glomerular basement membrane
thickening, and nodular glomerulosclerosis), even in the absence
of diabetes.

Obesity is a significant risk factor for type 2 diabetes.

 Risk factors

Smoking — in the absence of diabetes, smoking can

result in nodular sclerosis of the kidney that is indistinguishable
from diabetic glomerulosclerosis.

Smoking triggers many of the same pathogenic pathways that

are active in diabetic kidney disease:

endothelial dysfunction,
oxidative stress,
inflammation.
 Risk factors

Hyperglycemia — restoration of normal glycemic

control with pancreatic transplantation in patients with type 1
diabetes can improve kidney disease in the long term.

In both type 1 and type 2 diabetes lower HbA1c levels are

associated with reversal of hyperfiltration, increased albuminuria
regression, reductions in worsening albuminuria, rapid eGFR
decline, and the development of stage 3 CKD.

Hypertension — A systolic blood pressure greater than 140

mmHg has consistently been found to increase the risk for the
development of severely increased albuminuria and stage 3
CKD.
 Risk factors

Genetic factors - APOL1 variants are associated with an

increased risk for progression of diabetic kidney disease in
African Americans.

Acute kidney injury - diabetic kidney disease, AKI-induced

injuries involve the podocyte and endothelium of the glomerulus
and induce myofibroblast transformation of tubular cells.

As a result, both the glomerulopathy and tubulointerstitial fibrosis

associated with diabetic kidney disease may be accelerated
by AKI.
 Pathogenesis

Glomerular hemodynamics - Hyperglycemia in diabetic

patients results in production of advanced glycation end-products
(AGE) and reactive oxygen species. These aberrant metabolic
products activate intercellular signaling for proinflammatory and
profibrotic gene expression with production of a host of mediators
for cellular injury.

While hyperglycemia undoubtedly plays a central role,

hyperinsulinemia and insulin resistance also may incite
pathogenic mechanisms, possibly accounting for variation in
histopathology between type 1 and type 2 diabetes.
 Pathogenesis

The diabetic mellitus activates the renin-angiotensin-aldosterone

system (RAAS) and numerous other downstream mediators,
triggering kidney hypertrophy, increased renal plasma flow (RPF),
and increased filtration fraction (FF), which together result in
an abnormally elevated glomerular filtration rate (GFR)
Increased circulating vasodilators, such as atrial natriuretic
peptide, nitric oxide, and prostanoids, and a relative deficiency
or resistance to insulin have a preferential impact on reducing
afferent arteriole resistance. The imbalance in tone between
afferent and efferent arterioles increases intraglomerular pressure
that, over time, triggers a sclerotic response in diabetic kidney
disease.
 Pathogenesis

Glomerular hyperfiltration — Hyperfiltration can be defined at

the level of the single nephron, wherein the ratio between GFR
and effective RPF (ie, FF) is elevated due to either altered
glomerular hemodynamics or glomerular damage with hypertrophy
of remnant nephrons.

Oxidative stress and inflammation — Hyperglycemia, insulin

resistance and dyslipidemia cause increased formation of
NF-kappaB, Protein kinase C, endothelial nitric oxide (eNOS) and
endothelin 1 and vascular endothelial growth factor (VEGF),
which promotes endothelial instability and NF-kappaB stimulated
cytokine production.
Mesangial cell hypertrophy and matrix accumulation, hallmarks
of diabetic glomerulosclerosis, are mediated by the transforming
growth factor-beta (TGF-beta) system ; Vascular proliferation and
endothelial permeability are increased in diabetic kidney disease
and are thought to be mediated by VEGF;
 Pathogenesis

Interstitial fibrosis and tubular atrophy (IFTA) — As diabetic

kidney disease progresses, there is a clear relationship between
the degree of interstitial fibrosis/tubular atrophy (IFTA) and decline
in eGFR ;
 Diagnosis

The term "diabetic nephropathy" was historically defined by the

presence of albuminuria accompanied by retinopathy in patients
with type 1 diabetes.

Kidney biopsy revealed in the diabetic glomerulopathy:

thickening glomerular basement membrane,

endothelial damage,
mesangial expansion and nodules,
and podocytes loss.
Kidney biopsy

(A)Normal glomerulus.
(B) Diffuse mesangial
expansion with mesangial
cell proliferation.
(C) Prominent mesangial
expansion with early
nodularity and
mesangiolysis.
(D) Accumulation of
mesangial matrix forming
Kimmelstiel–Wilson nodules.
(E) Dilation of capillaries
forming microaneurysms,
with subintimal hyaline
(plasmatic insudation).
(F) Obsolescent glomerulus.
 Kidney biopsy

) Structural changes in diabetic glomerulopathy found with electron microscopy. C indicates

arked expansion of the mesangium. D indicates marked diffuse thickening of capillary basement
embranes (to 3 times the normal thickness in this case). E indicates segmental effacement of the
sceral epithelial foot processes. Original magnification, ×3500.

) Normal glomerulus.
Renal Pathology Society classification:

•Class I – Isolated glomerular basement membrane thickening.

Basement membranes are greater than 430 nm in males and
395 nm in females over the age of nine years. There is no
evidence of mesangial expansion, increased mesangial matrix,
or global glomerulosclerosis involving >50 percent of glomeruli.

•Class II – Mild (Class IIa) or severe (Class IIb) mesangial

expansion. A lesion is considered severe if areas of expansion
larger than the mean area of a capillary lumen are present in >25
percent of the total mesangium.

•Class III – At least one Kimmelstiel-Wilson lesion (nodular

intercapillary glomerulosclerosis) is observed on biopsy, and
there is <50 percent global glomerulosclerosis.
 Renal pathology Sociaty classification:

Class IV – Advanced diabetic glomerulosclerosis. There is

>50 percent global glomerulosclerosis that is attributable to
diabetic nephropathy
 Clinical features:

The most common clinical abnormalities of diabetic kidney

disease are:

•persistently elevated urine albumin excretion

•and/or persistently decreased estimated glomerular filtration rate
(eGFR).

In severe cases, albuminuria levels can be above the nephrotic

threshold of 3.5 g per 24 hours, often resulting in the nephrotic
syndrome .
 Clinical features:

These manifestations are typically asymptomatic and are therefore

usually detected through routine, periodic testing.

Urine albumin excretion can be estimated using a spot urine

sample and the albumin-to-creatinine ratio, or measured using the
more traditional approach of a timed (24 hours or other) urine
collection.

Testing is recommended to commence in patients with type 1

diabetes five years after diagnosis. In patients with type 2 diabetes,
testing for kidney disease is recommended to be undertaken at
the time of diagnosis.
 Clinical features:

Albumin excretion in urine in diabetic kidney paitents can be:

Moderately increased albuminuria (30 to 300 mg/g or mg/day) —

Previously termed "microalbuminuria," moderately increased
albuminuria is defined as either an estimated or a measured urine
albumin excretion between 30 and 300 mg/g creatinine or mg/day ;

Severely increased albuminuria (>300 mg/g or mg/day) —

Previously termed "macroalbuminuria," severely increased
albuminuria is defined as either an estimated or a measured urine
albumin excretion >300 mg/g or mg/day
 Clinical features:

GFR can be estimated using several different creatinine-based

equations; however, the Chronic Kidney Disease Epidemiology
(CKD-EPI) and Modification of Diet in Renal Disease (MDRD)
equations are most commonly used.

The urine sediment in diabetic kidney disease may reveal the

following:

microscopic hematuria,
In patients with nephrotic-range proteinuria - oval fat bodies or
lipid droplets.
Dysmorphic red blood cells and red blood cell casts.
 Treatment

Main goals of treatment in diabetic kidney disease:

Blood pressure control

Glycemic control
Lifestyle modification
Lipid lowering
Blood pressure control — It is recommended intensive blood
pressure lowering in patients with DKD. In general, more intensive
versus less intensive blood pressure lowering in patients with
chronic kidney disease (CKD) reduces mortality and prevents
cardiovascular morbidity; in addition, more intensive blood
pressure lowering may prevent end-stage kidney disease (ESKD)
in patients with severely increased albuminuria.

Initial antihypertensive therapy in patients with DKD typically

consists of either an angiotensin-converting enzyme (ACE)
inhibitor or angiotensin receptor blocker (ARB) but not both
simultaneously.

Combination antihypertensive therapy will be required for most

individuals with DKD. In such cases, the combination of an ACE
inhibitor or ARB plus a dihydropyridine calcium channel blocker
is often preferred or diuretic may be preferred.
Glycemic control — In patients with type 1 diabetes, intensive
blood glucose control may prevent the development of DKD.

The glycemic control target in patients with type 1 diabetes and

DKD is ideally a glycated hemoglobin (A1C) of 7 percent or less.

The approach (to target an A1C of 7 percent or less, if tolerated)

is similar in patients with type 2 diabetes.

A separate issue is that certain glucose-lowering medications

should be avoided or used at a reduced dose in patients with DKD,
depending upon the degree of reduced kidney function.
 Treatment

Glycemic control – The short-acting sulfonylureas, glipizide

(initial dose 2.5 mg/day) or glimepiride (initial dose 1 mg/day), are
the preferred agents among nondialysis CKD patients who have an
estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2.
Glyburide and other long-acting sulfonylureas are generally not
recommended in any CKD patient with type 2 diabetes, because of
the risk of hypoglycemia.
 Treatment

Glycemic control :

Metformin, which is a preferred agent in patients without kidney

disease, should not be used among CKD patients with an eGFR
of <30 mL/min/1.73 m2 because of an increased risk of lactic
acidosis.

Other agents including thiazolidinediones, alpha-glucosidase

inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors are
generally not considered first-line agents among CKD patients,
because of limited data regarding long-term safety and efficacy.
 Treatment:

Glycemic control :
Patients who fail therapy with oral agents are treated with insulin.
The indications for initiating insulin therapy and the principles
underlying insulin therapy are the same for nondialysis CKD
patients as for the general diabetic population.

No dose adjustment is required if the GFR is >50 mL/min.

The insulin dose should be reduced to approximately 75 percent
of baseline when the GFR is between 10 and 50 mL/min.
The dose should be reduced by as much as 50 percent when
the GFR is <10 mL/min.
 Treatament

Lifestyle modification – Diabetic patients, regardless of the

presence of kidney disease, should be counseled on healthy
eating, regular exercise, and if needed, weight loss and smoking
cessation.

Lipid lowering – Most patients with DKD are at high

cardiovascular risk and should therefore be treated with a
statin, atorvastatin or fluvastatin are often preferred because
they do not require dose adjustment based upon the GFR.
 Treatment

Type 2 diabetes: SGLT2 inhibitors - Patients with type 2

diabetes and DKD with a sodium-glucose co-transporter 2
(SGLT2) inhibitor. Initiating SGLT2 inhibitors should generally be
avoided among patients with an eGFR <30 mL/min/1.73 m2 and
among those with a prior lower extremity amputation or current
threat of amputation;

SGLT2 inhibitors can be continued among patients whose eGFR

falls below 30 mL/min/1.73 m2. If canagliflozin is used, the target
dose is 100 mg once daily. Starting doses of other SGLT2
inhibitors (eg, 10 mg once daily of empagliflozin or 5 mg once
daily of dapagliflozin) are reasonable as treatment of DKD in
patients with type 2 diabetes.