Diabetic Nephropathy

(ÖnTanı)

Dr. Rümeyza Kazancıoğlu

 The goals

• Be able to define DNP

• Know the epidemiology of DNP
• List the stages of DNP
• Know the pathogenesis of DNP
• Describe the treatment options
• Define the KRT options for DNP
The references
 Normal Kidney

Diabetic Kidney
Diabetic Nephropathy

• Definiton:
Type 1 Diabetes
• 2 out of 3 urine tests + for microalbuminuria (start screening 5 years after the
initial diagnosis)
• presence of proliferative diabetic retinopathy
Diabetic Nephropathy

• Definiton:
Type 2 Diabetes
• 2 out of 3 urine tests + for microalbuminuria (start
screening at the time of diagnosis of diabetes)
• presence of diabetic retinopathy
Diabetic Nephropathy

• DN occurs in 35-40% of patients with type I

diabetes (IDDM) whereas it occurs only in 15-20%
of patients with type II diabetes (NIDDM).

• More frequent in Native Americans, Hispanics and

possibly Asian Indians.
Epidemiology

Type 1 Diabetic
• 25 - 45% will develop diabetic nephropathy
• 80 - 90% with microalbuminuria will progress to
overt diabetic nephropathy in 5 - 10 years
• nearly 100% with gross proteinuria will progress to
ESKD in 7 - 10 yrs
Epidemiology

Type 2 Diabetic
• 50% will have microalbuminuria at the
time of presentation probably secondary
to HTN
• 10-20% with microalbuminuria will
progress to overt nephropathy
• minority populations have a 2 to 20-fold
higher incidence of diabetic nephropathy
Diabetic Nephropathy
• Diabetic nephropathy is the leading cause of chronic kidney
failure in the industrialised world.

• It is also one of the most significant long-term complications

in terms of morbidity and mortality for individual patients
with diabetes.

• Diabetes is responsible for 30-40% of all end-stage kidney

disease (ESKD) cases in the United States.

• Although both type 1 diabetes mellitus and type 2 diabetes

mellitus lead to ESKD, the great majority of patients are those
with NIDDM.
ESKD Patients with DNP Singapur/Singapore
Malezya/Malaysia
Katar/Qatar
66.4
66.2
63.9
Hong Kong/Hong Kong 52
Kore Cum./Rep. of Korea 48.8
Kuveyt/Kuwait 47.1
Jalisco (Meksika/Mexico) 47
ABD/USA 46.9
İsrail/Israel 46.8
Tayvan/Taiwan 46.2
Kolombiya/Colombia 45
Japonya/Japan 42.5
Uruguay/Uruguay 38.8
Kanada/Canada 37.7
Türkiye/Turkey 36.8
Brezilya/Brazil 36.3
Arjantin/Argentina 36
Aguascalientes (Meksika/Mexico) 35.9
Finlandiya/Finland 31.6
Portekiz/Portugal 30.8
Bosna Hersek/Bosnia&Herzegovina 28.9
Birleşik Krallık/United Kingdom 26.5
Endonezya/Indonesia 26.1
İsveç/Sweden 25.6
Yunanistan/Greece 24.1
Ukrayna/Ukraine 23
Fransa/France 22.2
Tayland/Thailand 21.3
Arnavutluk/Albania 20.5
Macaristan/Hungary 19.4
İzlanda/Iceland 17.9
Güney Afrika/South Africa 17.5
Norveç/Norway 16.8
İtalya/Italy 16.7
Litvanya/Lithuania 14.6
Çin/China 13.3

0 10 20 30 40 50 60 70

Yüzde / Percent
USRDS 2018 and 2020
ESKD Patients with DNP

USRDS 2021
 Yüzde / Percent

0
10
20
30
40
50
1991 4.5

1997 10

1998 11.6

1999 12

2000 12

2001 14.6

2002 17.4

2003 19.2

2004 23.1

2005 24.3

2006 23.7

2007 26.1
ESKD Patients with DNP

2008 27.9
Prevalent HD patients

2009 30.6

2010 30.5

2011 32.4
Registry of The Nephrology, Dialysis and Transplantation in Turkey, Registry 2021

2012 34.9

2013 33.8

2014 33.6

2015 34.6

2016 35.4

2017 35.9

2018 35.8

2019 39

2020 36.5

2021 35.7
Risk factors for diabetic nephropathy
Stages of Diabetic Nephropathy

• Stage I – Hyperfiltration - increased blood flow

through the kidney, early renal hypertrophy
• Stage II - Glomerular lesions without clinically
evident disease
• Stage III - Incipient nephropathy with
microalbuminuria - alb/cr ratio .03 - .3 or albumin
20-200 mcg/min on timed specimen
Stages of Diabetic Nephropathy

• Stage IV - Overt diabetic nephropathy with

proteinuria >500 mg/24 hr
- creatinine clearance <70 ml/min
• Stage V – End stage kidney disease (ESKD)
- creatinine clearance <15 ml/min
- creatinine = 6mg/dl
Natural History of Diabetic Nephropathy
 Stage 1 (very early diabetes)
• Increased demand upon the kidneys is indicated
by an above-normal glomerular filtration rate
(GFR)

• Hyperglycemia leads to increased kidney filtration

• This is due to osmotic load and to toxic effects of

high sugar levels on kidney cells

• Increased Glomerular Filtration Rate with enlarged

kidneys

18
Stage 2 (developing diabetes)
• Clinically silent phase with continued hyper
filtration and hypertrophy

• The GFR remains elevated or has returned to

normal, but glomerular damage has progressed to
significant microalbuminuria (small but above-
normal level of the protein albumin in the urine).

• Significant microalbuminuria will progress to end-

stage kidney disease (ESKD).

• Therefore, all diabetes patients should be

screened for microalbuminuria on a routine basis.
Stage 3 (dipstick-positive diabetes)

• Glomerular damage has progressed to clinical

albuminuria.

• Basement membrane thickening due to AGEP

• The urine is "dipstick positive," containing more

than 300 mg of albumin in a 24-hour period.

• Hypertension (high blood pressure) typically

develops during stage 3.
Stage 4 (late-stage diabetes)

• Glomerular damage continues, with increasing

amounts of protein albumin in the urine.

• The kidneys’ filtering ability has begun to decline

steadily, and blood urea nitrogen and creatinine has
begun to increase.

• The glomerular filtration rate decreases about 10%

annually. Almost all patients have hypertension at
stage 4.
Stage 5 (ESKD)

• GFR has fallen to <10 ml/min and kidney

replacement therapy (i.e., hemodialysis,
peritoneal dialysis, kidney transplantation) is
needed.
Pathogenesis
• Glomerular Hyperfiltration
• Glomerular Hypertension
• Glomerular Hypertrophy
• GBM thickening
• Mesangial Expansion
Pathogenesis

• Kidney lesions mainly related to extracellular matrix accumulation

- Occurs in glomerular & tubular basement
membrane
- Principal cause of mesangial expansion
- Contributes to interstitium expansion
Pathogenesis

• Extracellular matrix accumulation

- Imbalance between synthesis & degradation of
ECM components
- Linkage between glucose concentration & ECM
accumulation
- Transforming growth factor-Beta associated with
increased production of ECM molecules
Pathogenesis

• Extracellular matrix accumulation

- TGF-B can down regulate synthesis of ECM
degrading enzymes & upregulate inhibitors of
these enzymes
- Angiotensin II can stimulate ECM synthesis
through TGF-B activity
- Hyperglycemia activates protein kinase C,
stimulating ECM production through cyclic AMP
Pathway
Diffuse and Nodular Glomerulosclerosis in Diabetic
Nephropathy

From UpToDate
v 6.2
Courtesy
H. Rennke, M.D.
Diffuse and Nodular Glomerulosclerosis in Diabetic
Nephropathy

Accumulation of mesangial matrix forming Kimmelstiel–Wilson nodules

Diabetic Nephropathy
Diabetic Nephropathy
Advanced Diabetic Glomerulosclerosis

From: UpToDate
v 6.2
Courtesy
H. Rennke, M.D.
Glomerular Basement Membrane Thickening

From: UpToDate
v 6.2
Courtesy
H. Rennke, M.D.
Glomerular Basement Membrane Thickening
 Diabetic Nephropathy

Normal glomerulus Diffuse glomerular lesion

Nodular lesion (Kimmelstiel-Wlson nodule)

& mesangial expansion Nodular expansion of the matrix
Natural History of IDDM

Clinical type 1 diabetes

Functional changes*

Structural changes†

Microalbuminuri
a
Proteinuria

Rising blood pressure

Proteinuria

Rising serum
creatinine levels
End-stage
kidney disease

CV events

2 5 10 20 30
Onset of
diabetes
Years
* Kidney size ­, GFR ­.
†
GBM thickening ­, mesangial expansion ­
 Natural History of Nephropathy
in Type 1 Diabetes

Normo Stage of Micro Macro Azotemia End stage

albumi- hyper- albumi- albumi- (Kidney kidney
nuria filtration nuria nuria failure) disease

15 - 20 yrs 4 - 5 yrs 1 yrs

Natural History of NIDDM

Clinical type 2 diabetes

Functional changes*

Structural changes†

Rising blood pressure

Microalbuminuria

Proteinuria
Rising serum
creatinine levels
End-stage
kidney disease
Cardiovascular death

Onset of 2 5 10 20 3
diabetes 0
Years
* Kidney size ­, GFR ­.
†
GBM thickening ­, mesangial expansion ­
 Albuminuria
Albuminuria Albuminuria Albumin / Creatinine
(mg/24 hours) (mg/min) Ratio (mg/g)

Normo- < 30 < 20 M: < 25

albuminuria F: < 35

Micro- 30-299 20-199 M: 25-299

albuminuria F: 35-299

Macro- > 300 > 200 > 300

albuminuria
Potential Mechanisms Leading to Hypertension
in Type 2 Diabetics
Clinical Evaluation of DNP
Indications for Kidney Biopsy

• If retinopathy is not present in type 1 diabetes with proteinuria or

moderately impaired kidney function (absence of retinopathy

does not exclude diabetic nephropathy in type 2 diabetes).

Indications for Kidney Biopsy

• If the onset of proteinuria has been sudden and rapid, particularly

in type 1 diabetes, and if the duration of type 1 diabetes has been

less than 5 years or if the evolution has been atypical, e.g.,

without transition through the usual stages, particularly

development of nephrotic syndrome without previous

microalbuminuria.
Indications for Kidney Biopsy

• If macroscopic hematuria is present or an active nephritic urinary

sediment is found that is suggestive of glomerulonephritis.

• If the decline of kidney function is exceptionally rapid or if kidney

dysfunction is found without significant proteinuria (first,

renovascular disease must be excluded).

 Nephron Changes in Diabetes and After
Administration of an ACE inhibitor or ARB
Management
Management
Management

• ACEI or AII RB- in both expt & human

• Reduce glomerular hypertension
• Reduce proteinuria independent of hemodynamic
effects
• Reduce glomerular hypertrophy
• well tolerated apart from hyperkalemia &
worsening of anemia in severe CRF
• Cautious use in presence of severe renovascular
disease
Management
Management
Management

SGTL 2 inhibitors
• The beneficial effects on the conventional risk factors for kidney disease
(such as blood pressure, hyperglycaemia, body weight and serum uric acid
levels)

• Reduction in the intraglomerular pressure, the changes in the local and

systemic degree of activation of the renin-aldosterone-angiotensin system
and a shift in renal fuel consumption towards more efficient energy substrates
such as ketone bodies
ADA Position Statement
Screening:

Perform an annual test for the presence of

microalbuminuria in
1) type 1 diabetic patients who have had diabetes
> 5 years and
2) all type 2 diabetics patients starting at
diagnosis.

American Diabetes Association: Position Statement Diabetes Care 25:S85-S89, 2002

ADA Position Statement

Treatment:
• In the treatment of albuminuria/nephropathy
both ACE inhibitors and ARBs can be used:
• In hypertensive and nonhypertensive type 1
diabetic patients with microalbuminuria or clinical
albuminuria, ACE inhibitors are the initial agents
of choice

TUS SORU
ADA Position Statement

Treatment:
• In hypertensive type 2 diabetic patients with
microalbuminuria or clinical albuminuria, ARBs
are the initial agents of choice.
• If one class is not tolerated, the other should be
substituted

TUS SORU
 Additional Problems in Patients with
Diabetic Nephropathy
Microvascular Complications
 Retinopathy
 Polyneuropathy, autonomic neuropathy (gastroparesis,
neurogenic bladder, erectile dysfunction, ortostatic hypotension)
Macrovascular Complications
 Coronary heart disease
 Cerebrovascular complications (stroke)
 Peripheric arterial disease
Mixed Complications
 Diabetic foot (neuropathic, vascular)
 Kidney Replacement Therapies

 Since vascular problems are common in these patients,

vascular access should be performed earlier than other

patients, when GFR is 20 – 25 ml/min

 Dialysis therapy should be started earlier, when GFR <

15 ml/min
Kidney Replacement Therapies

 Hemodialysis
 Peritoneal Dialysis
 Transplantation
 Kidney
 Kidney + Pancreas
 Transplantation in
Diabetic Nephropathy
 Posttransplant cardiovascular complications are
common.
 A detailed pretransplant cardiovascular evaluation
should be performed.