Diabetic nephropathy

SPEAKER
DR. ANKUR NANDAN VARSHNEY

Definition
Diabetic nephropathy, is a chronic condition
developing over many years, characterized by:
 gradually increasing urinary albumin excretion (UAE)
 High blood pressure (BP)
 Declining glomerular filtration rate
 Absence of other renal/renal tract disease
 Presence of diabetic retinopathy.

( Brenner 9th edition )

Incidence
According to US RENAL DISEASE REGISTRY:
 In 2006, the proportion of individuals with diabetes
beginning renal replacement therapy (RRT) was 20 – 44%
 The number of people with diabetes requiring RRT
increased by 50% between 1996 and 2006.
 A European report covering 1998 – 2002 demonstrated a
9.9% per year increase.
According to ICMR study,
 India has largest number of diabetics in the world with
prevalence of 3.8% in rural and 11.8% in urban adults
 25-40% of these develop End Stage Renal Disease .
(Anjana RM et al J Diabetes Sci Technol 2011 Jul 1;5(4):906-14)

Pathophysiology
 Usually Multifactorial
1. Metabolic pathway
2. Hemodynamic pathway
3. Genetic

Hyperglycemia
 Duration and magnitude of hyperglycemia strongly
correlated with the extent and progression of
microvascular complications as DN
 Hyperglycemic damage occur to those cell types that
develop intracellular hyperglycemia such as
endothelial cells and vascular smooth muscle cells

(Lachin JM, Genuth S, Nathan DM, et al, DCCT/EDIC Research Group. Effect of
glycemic exposure on the risk of microvascular complications in the Diabetes
Control and Complications Trial–revisted. Diabetes. 2008;57:995-1001.)

Mechanism of hyperglycemia
induced damage
 Four major hypothesis have been generated
1. Increased polyol pathway flux
2. Increased hexosamine pathway flux
3. Increased intracellular formation of advanced
glycation end products
4. Activation of protein kinase C

 Earlier thought
1. Sorbitol induced osmotic distress

 Recent thought
 decreased GSH
 increase in ratio of NADPH/NAD+, that inhibits the
activity of glyceraldehyde-3-phosphate dehydrogenase.

(Vikramadithyan RK, Hu Y, Noh HL, et al. Human aldose reductase expression
in transgenic mice. J Clin Invest. 2005 Sep;115:2434-2443.)

 O-linked N-acetylglucosamine , reducing expression
of insulin responsive genes, leading to selective insulin
resistance in vascular endothelial cells.
(Yang X, Ongusaha PP, Miles PD, et al. Phosphoinositide signalling links
O-GlcNAc transferase to insulin resistance. Nature. 2008;451:964-969. )

Activation of Protein Kinase C

 In experimental studies , PKC activation had been
shown to produce following effects:-
1. Renal blood flow abnormalities
2. Glomerular mesangial proliferation
3. Increased endothelial cell permeability

(Geraldes P, Hiraoka-Yamamoto J, Matsumoto M, et al. Activation of PKC-
delta and SHP-1 by hyperglycemia. Nat Med. 2009;15:1298-1306.)

Advanced Glycation End products
 Earlier, it was thought that they arise from nonenzymatic
reaction between extracellular proteins and glucose.
 Now, it is thought they arises by
1. Intracellular autooxidation of glucose to glyoxal
2. Decomposition of the amadori product to 3-
deoxyglucosone
3. Fragmentation of glyceraldehyde phosphate to
methylglyoxal (most common)

(Monnier VM et al. The role of the amadori product in the
complications of diabetes Ann N Y Acad Sci. 2008 Apr;1126:81-8.)

 Methylglyoxal enhances antiapoptotic by direct
modification of heat shock protein repressing
cytochrome C mediated caspase activation
( Sakamoto H, Mashima T, Yamamoto K, et al. Modulation of heat-shock protein
27 (Hsp27) anti-apoptotic activity by methylglyoxal modification. J Biol Chem.
2002;277:45770-45775 )

 AGE inhibit lateral association of molecules of
basement membrane ,increasing it’s premeability to
albumin.
(Dobler D, Ahmed N, Song L, et al. Increased dicarbonyl metabolism in
endothelial cells in hyperglycemia . Diabetes. 2006;55:1961-1969. )

Hemodynamic pathway
 Earlier it was thought that systemic hypertension
causes adverse effect on renal function through
vasoconstriction and arteriolar nephrosclerosis.
 Now, studies revealed that systemic hypertension leads
to increase in glomerular hydrostatic pressure in such
a way that lead to hyperperfusion , increased capillary
pressure , hyperfilteration and proteinuria
 The direct pressure effect causes stretch of mesangium
causing protien kinase C activation– activates- TGF-
B1, fibrinonectine
(Rossing K, Christensen PK, Hovind P, et al. Progression of nephropathy in
type 2 diabetic patients. Kidney Int. 2004;66(4):1596-1605.)

 Impaired or abolished renal autoregulation of GFR
and renal plasma flow increases vulnerability to
hypertension or ischemic injury to glomerular
capillaries
.(Reich HN, Oudit GY, Penninger JM, et al. Decreased glomerular and tubular
physiology in patients with type 2 diabetes and kidney disease. Kidney Int.
2008;74(12):1610-1616.)

 Succinate, formed by the tricaboxylic acid cycle,
provides a direct link between high glucose and renin
release in the kidney through G protein coupled
receptor for succinate.
(Toma I, Kang JJ, Sipos A, et al. Succinate receptor GPR91 provides a
direct link between high glucose levels and renin release in murine and
rabbit kidney. J Clin Invest. 2008;118(7):2526-2534.)

Role of aldosterone
 Had widespread genomic and non genomic effects
 Besides electrolyte and fluid homeostasis, it’s role
include
1. Upregulation of prosclerotic growth factors as
plasminogen activator inhibitor-1 and transforming
growth factor beta
2. Promotion of macrophage infiltration
 Ultimately leads to renal fibrosis
(Ritz E, Tomaschitz A. Aldosterone, a vasculotoxic agent—novel functions for an
old hormone. Nephrol Dial Transplant. 2009;24(8):2302-2305.)

Genetics
 Different patients with similar duration and degree of
hyperglycemia differ markedly in their susceptibility to
micro vascular complications.
 Only 25-40% of patients with hyperglycemia and other risk
factors develop diabetic nephropathy suggesting a genetic
role
 Family studies reveal that first degree relatives of patients
with DN has higher incidence of DN (83%) than diabetic
without these complications.(17%)
 Chromosome 3, 7 and 20 have shown susceptibility loci for
diabetic nephropathy

(Pezzolesi MG, Poznik GD, Mychaleckyj JC, et al. Genome-wide
association scan for diabetic nephropathy susceptibility genes in type
1diabetes. Diabetes. 2009;58(6):1403-1410)

ACE(I/D) polymorphism
 282 nucleotide repetitive sequence
 3 phenotypes DD, ID, II
 Strongly associated with level of circulating ACE level
 D allele has been found to have deleterious effect on kidney
functions with 95% of DD developing ESRD within 10 yrs
 Act as progression promoter, independently influenced
sustained rate of decline in GFR
 Increased risk of coronary heart disease
(Parving H-H, de Zeeuw D, Cooper ME, et al. ACE gene polymorphism and
losartan treatment in type 2 diabetic patients with nephropathy. J Am Soc
Nephrol. 2008;19(4):771-779.)

 Multiple variations in superoxide dismutase 1 were
significantly associated with persistent
macroalbuminuria and severe nephropathy.
(Al-Kateb H, et al. Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are
associated with the development and progression of diabetic nephropathy: the Diabetes Control and
Complications Trial/Epidemiology of Diabetes Interventions and Complications Genetics study.
Diabetes. 2008;57:218-228.)

 Three EPO promoter genes were found to be
associated with increased chances of PDR and ESRD
(Tong Zet al, Genetics of Diabetes and Diabetic Complication Study Group. Promoter polymorphism of
the erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci U S A.
2008;105:6998-7003. )

 Osteoprotegerin , a secretory glycoprotein of tumor
necrosis factor receptor superfamily, involved in
vascular calcification, has been found elevated in
diabetic with microvascular complications.
(Rasmussen LMet al. Plasma osteoprotegerin levels are associated with glycaemic
status, systolic blood pressure, kidney function and cardiovascular morbidity in type 1
diabetic patients. Eur J Endocrinol.2006;154(1):75-81.)

 Adiponectin , shown to possess antiinflammatory
and antiatherogenic properties , affects podocyte and
levels are increased in patients with diabetic
nephropathy.
(Sharma K, et al. Adiponectin regulates albuminuria and podocyte function in
mice. J Clin Invest.2008;118(5):1645-1656.)

Risk factors associated with
progression

Proteinuria induced renal
damage

Anemia and DN
 In patients with DN, anemia is an independent risk
factor associated with decline in GFR.
 Renal hypoxia resulting from anemia aggravates
interstitial fibrosis by the stimulation of factors like
TGF-β and VEGF.
 Hypoxia-inducing factor-1 (HIF-1), and ANG-II also
plays a major role in this.
(Thomas MC, Cooper ME, Rossing K, et al. Anaemia in diabetes: is
there a rationale to TREAT? Diabetologia. 2006;49(6):1151-1157.)

 Obesity, BMI> 40 kg/m2, considered as an
independent risk factor for progression of
nephropathy.

( Krikken JA, Bakker SJ, Navis GJ. Role of renal haemodynamics in the
renal risks of overweight. Nephrol Dial Transplant. 2009;24(6):1708-1711)

 Smoking, may act as progression promoter in patients
with diabetes and proteinuria.
(Hovind P, Rossing P, Tarnow L, et al. Smoking and progression of
diabetic nephropathy in type 1 diabetes. Diabetologia.
2002;45:A361:abstract.)

Mogenson’s classification
 Stage 1: Hyperfiltration

• Increased Glomerular Filtration Rate (GFR >90ml/min)

• Result of concomitant renal hypertrophy (glomerular and
tubular)

• Various factors contributing:
1. Intra renal hemodynamic abnormalities
2. TGF-beta
3. Increased salt absorption

 Stage 2 : The Silent Stage

• The GFR has returned to normal (GFR 60-89ml/min)
with no evidence of albuminuria

 Glomerular damage occur in the form of basement
membrane thickening and mesangial expansion.

 Ambulatory BP monitoring studies have shown
modest rise in BP and absence of nocturnal dip

 Stage 3: Incipient nephropathy /Microalbuminuria

• Urine AER has increased upto 30 to 300 mg/24 hrs
• Renal functions could be normal or reduced.
• 30-50% of patients may show reversal of
microalbuminuria.
• Persistent microalbuminuria , if untreated, will progress to
end-stage renal disease (ESRD).
• Therefore, all diabetes patients should be screened for
microalbuminuria on a routine basis.
(Perkins BAet al. Regression of microalbuminuria in type 1 diabetes. N Engl J Med.
2003;348:2285-2293. )

 Stage 4 : Macroalbuminuria/Overt Nephropathy

• The urine AER more than 300 mg of albumin in a 24-
hour period.

• Two peaks of incidences defined as SLOW and FAST
TRACKERS

• Over two thirds of patient in this stage have
Hypertension .

 If untreated a vicious cycle of progressive renal
impairment develops leading to ESRD.

 Stage 5: Uremia

 GFR has fallen to <15 ml/min and renal replacement therapy
(i.e., haemodialysis, peritoneal dialysis, kidney transplantation)
is needed.

 Screening should be done when the person is free from
acute illness and in stable glucose control
 Early morning urine sample must be preferred
 Serum creatinine level should also be measured
annually
 Recently serum cystatin C , a naturally circulating
protein , freely filtered by glomerulus ,has been
suggested as an alternative to creatinine measurement.
(MacIsaac RJ , Tsalamandris C , Thomas MC , Premaratne E ,Panagiotopoulos S ,
Smith TJ , et al. Estimating glomerular fi ltration rate in diabetes: a comparison
of cystatin C and creatinine – based methods . Diabetologia 2006 ; 49 : 1686 –
1689 .)

Treatment

 Major therapeutic interventions include-
1. Control of blood glucose to near normal level
2. Antihypertensive treatment
3. Lipid lowering therapy
4. Restriction of dietary proteins
5. Cessation of smoking

Glycemic control
 Primary prevention:-
 Diabetic Control and Complications Trial showed that
intensive glycemic control reduces the occurrence of
microalbuminuria

 ADVANCE study and VETERAN trial recently confirmed
similar findings. (ADVANCE Collaborative Group, Patel A, MacMahon S, et al.
Intensive blood glucose control and vascular outcomes in patients with type 2diabetes. N
Engl J Med. 2008;358(24):2560-2572)
(Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular
complications in veterans with type 2 diabetes. N Engl J Med.2009;360(2):129-
139)

 The HbA1c level to be kept
1. < 7.5 % in patients receiving insulin
2. <6.5 % in patients not on insulin

 Secondary prevention :-
 UKPDS proves that tight glycemic control reduces
progression from microalbuminuria to overt
nephropathy

A recent trial also confirms that ESRD development was
retarded by multifactorial interventions
(Gaede P, Lund-Andersen H, Parving H-H, et al. Effect of a multifactorial
intervention on mortality in type 2 diabetes. N Engl J Med.2008;358(6):580-
591.)

 Nephropathy:-
 once overt nephropathy develops , results are
disappointing regarding metabolic control preventing
furthur progression of disease.
(Breyer JA, Bain P, Evans JK, et al. Predictors of the progression of renal
insufficiency in patients with insulin-dependent diabetes and overt
diabetic nephropathy. Kidney Int. 1996;50:1651-1658.)

Blood pressure control
 Primary prevention:-
 Initial trials showed that normotensive diabetics treated with ACE
inhibitors had a beneficial effect on microalbuminuria.(The EUCLID. Study
Group. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-
dependent diabetes and normoalbuminuria or microalbuminuria. Lancet. 1997;349:1787-1792.)

 but recent trials showed that RAS blockade has been effective in
reducing development of microalbuminuria in hypertensive
normoalbuminuric patients, not in normotensive patients (Patel
A, ADVANCE Collaborative Group, MacMahon S, et al. Effects of a fixed combination of
perindopril and indapamide on macrovascular and microvascular outcomes in patients
with type 2 diabetes mellitus(the ADVANCE trial): a randomised controlled trial. Lancet.
2007;370(9590):829-840)

 ADA does not recommend antihypertensive agents for primary
prevention of nephropathy in normotensive normoalbuminuric
patients.(American Diabetes Association. Standards of medical care in diabetes—2009. Diabetes
Care. 2009;32(suppl 1):S13-S61)

 BP to be reduced to
1. <125/75 mm of Hg if proteinuric or GFR < 60
2. < 130/80 mm of Hg

 Secondary prevention:-
 IRMA trial showed that irbesartan is renoprotective
independent of it’s blood pressure lowering effect in
patients with type 2 diabetes and microalbuminuria (Parving
H-H, Lehnert H, Bröchner-Mortensen J, et al. The effect of irbesartan on the
development of diabetic nephropathy in patients with type2 diabetes. N Engl J Med.
2001;345:870-878)
 STENO2 study also gives similar results with risk
reduction made upto 50%(Gaede P, Tarnow L, Vedel P, et al. Remission to
normoalbuminuria during multifactorial treatment preserves kidney function in
patients with type 2diabetes and microalbuminuria. Nephrol Dial Transplant.
2004;19(11):2784-2788)

 ADA states that in patients with diabetes, hypertension
and microalbuminuria, both ACE inhibitors and ARB has
shown to delay progression to macroalbuminuria (American
Diabetes Association. Standards of medical care indiabetes—2009. Diabetes Care.
2009;32(suppl 1):S13-S61.)

 Nephropathy:-
 RENAAL study and IDNT trial showed that losartan
and irbesartan conferred significant renal benefits
independent of it’s blood pressure lowering effect.
(Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and
cardiovascular outcomes in patients with type 2 diabetes andnephropathy. N
Engl J Med. 2001;345:861-869.)
(Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the
angiotensin-receptor antagonist irbesartan in patients with nephropathy due to
type 2 diabetes. N Engl J Med. 2001;345(12):851-860)
 ADA states “ in patients with type 2 diabetes,
hypertension, macroalbuminuria and renal
insufficiency ARBs have been shown to delay
progression”

Lipid lowering agents
 Increased risk of cardiovascular diseases
 FIELD STUDY showed improved regression
microalbuminaria to normoalbuminuria in pts with
type 2 diabetes
(Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate
therapy on cardiovascular events in 9795 people with type 2 diabetes
mellitus (the FIELD study): randomised controlled trial. Lancet.
2005;366(9500):1849-1861.)
 A meta analysis shows a small positive effect on
urinary albumin excretion and renal function
(Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects of statins in patients
with chronic kidney disease: meta-analysis and meta-regression of randomised
controlled trials. BMJ. 2008;336(7645):645-651.)

Dietary Protein Restriction
 A low protein diet reduces urinary albumin
excretion and hyperfiltration independently of
changes I glucose control and blood pressure
changes.
(Hansen HP, Tauber-Lassen E, Jensen BR, et al. Effect of dietary protein
restriction on prognosis in patients with diabetic nephropathy. Kidney
Int.2002;62(1):220-228.)
(Pedrini MT, Levey AS, Lau J, et al. The effect of dietary protein restriction
on the progression of diabetic and nondiabetic renal diseases: meta-
analysis.Ann Intern Med. 1996;124:627-632)
 Kidney Disease Outcomes Quality Initiative
Guidelines currently recommends dietary protein
intake of 0.8 g/kg bodyweight per day
(KDOQI Clinical Practice Guidelines and Clinical Practice
Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney
Dis. 2007;49(2 suppl 2):S12-S154.)

ALISKERIN
 Mechanism of action: a direct renin inhibitor, binds to
S3 binding pocket of renin, blocks conversion of angiotensinogen
to angiotensin 1
 Was FDA approved in 2007 for hypertension

 In 2008, AVOID (n= 599) trial shows that treatment with 300 mg
of aliskiren daily reduces albuminuria in patients with
hypertension, type 2 diabetes, and proteinuria who are receiving
the recommended maximal renoprotective treatment with
losartan and optimal antihypertensive therapy
( Parving et al.N Engl J Med 2008; 358:2433-2446)

 But in December 2011, ALTITUDE 8606 study a phase 3 trial was
withdrawn prematurely due to side effects of the drug.

Ruboxistaurin
 an inhibitor of protein kinase C –beta
 Was FDA approved in 2006 for diabetic
retinopathy
 A pilot study (n=123) over 1 year showed that In
persons with type 2 diabetes and nephropathy,
treatment with ruboxistaurin reduced albuminuria
and maintained eGFR
(Tuttle KR et al.Diabetes Care. 2005 Nov;28(11):2686-90.)
 Phase 3 studies are going on, results awaited

Pentoxifyllin
 competitive nonselective phosphodiesterase inhibitor and
inhibits synthesis TNF-ALFA, IL 1, IL-6
 Role of inflammatory markers in pathogenesis of DN
(Navarro JF et al. Am J Nephrol 2006;26:562–570)

 Studies showed that administration of PTX 800 mg per day is
safe and effective for reducing proteinuria in patients with
proteinuric primary glomerular diseases. This beneficial effect
occurs in close association with a reduction of urinary MCP-1
excretion.
(Lin SL et al. Kidney Int. 2006 Apr;69(8):1410-5.)

 Pentoxifylline for Renoprotection in Diabetic Nephropathy
(PREDIAN) study , clinical trial is going on, results awaited
(Navarro-González JF et al. J Diabetes Complications. 2011 Sep-Oct;25(5):314-9.
Epub 2010 Dec 8)

Advanced glycation end-products
inhibitor
 Benfotiamine leads to increased intracellular thiamine
diphosphate levels a cofactor of transketolase. This enzyme
directs advanced glycation and lipoxidation end products
(AGE's, ALE's) substrates to the pentose phosphate pathway.
benfotiamine lowered AGE by 40%
(Sourris KC, Forbes JM, Cooper ME. Therapeutic interruption of advanced
glycation in diabetic nephropathy: do all roads lead to Rome? Ann N Y Acad
Sci.2008;1126:101-106

 Alagebrium break some important AGE crosslinks ,does not
disrupt the natural carbohydrate modification to proteins, intra-
molecular crosslinking or peptide bonds that are responsible for
maintaining the normal integrity of the collagen
(Park J et al.Nephrol Dial Transplant.2011 Nov;26(11):3474-84)
(Watson AM et al.Diabetes. 2012 Aug;61(8):2105-13. Epub 2012 Jun 14)

Advanced glycation end-products
inhibitor
 Pyridoxamine (a vitamin B6 derivative) an effective
scavenger of reactive oxygen species and a potent
inhibitor of advanced glycation end products by
scavenging reactive carbonyl molecules halting disease
process
(Chen JL et al.J Am Soc Nephrol. 2012 Jan;23(1):6-8. Epub 2011 Dec
8.)

Kremezin
 Kremezin(AST-120) is an oral adsorbent charcoal
that absorbs uremic toxins through GI tract and excrte
them in faeces, slows down the progression of chronic
renal failure (CRF) by removing uremic toxins.
(Oral administration of AST-120Kremezin) is a promising
therapeutic strategy for advanced glycation end product (AGE)-
related disorders. In: Med Hypotheses. 2007;69(3):666-8. Epub
2007 Feb 28.)
 A clinical trial (NCT00860431) is going on , results to
be declared in september 2013.

Paricalcitol
 Vitamin D receptor activation is associated with improved
survival in patients with chronic kidney disease, but the
mechanism is unclear.
 A phase 2 trial (n=24) showed paricalcitol-induced
reduction in albuminuria in patients with diabetic
nephropathy
(Alborzi P et al. Hypertension. 2008; 52: 249-255 )
 Selective Vitamin D Receptor Activator for Albuminuria
Lowering (VITAL) Study is undergoing and results are
awaited.
(Lambers Heerspink HJ, Agarwal R, Coyne DW, et al. The Selective Vitamin D
Receptor Activator for Albuminuria Lowering (VITAL)Study: study design
and baseline characteristics. Am J Nephrol.2009;30(3):280-286.)

 Soludexide, glycosaminoglycan ,mixture of heparin sulfate
and dermatan sulfate, is also found to reduce albuminuria
in a pilot study
(Heerspink HL, Greene T, Lewis JB, et al. Effects of sulodexide in patients
with type 2 diabetes and persistent albuminuria. Nephrol Dial
Transplant.2008;23(6):1946-1954)
However in a RCT ,the drug fail to achieve it’s primary goal.
(Lewis EJ et al. Am J Kidney Dis. 2011 Nov;58(5):729-36. Epub 2011 Aug 26.)
 Tranilast , an antifibrotic agent that reduces collagen
synthesis in fibroblasts and inhibit production of IL-6 in
endothelial cells, has also been found to reduce
albuminuria
(Soma J, Sato K, Saito H, et al. Effect of tranilast in early-stage diabetic
nephropathy. Nephrol Dial Transplant. 2006;21(10):2795-2799.)

Take Home Message
 Diabetic nephropathy is a disease that develops over a long
duration .

 If early intervention done, progression can be delayed.

 There are no signs and symptoms of early disease so
screening of all patients is important.

 Aggressive treatment of Blood glucose, BP, Lipids helps in
prevention of renal function and can improve the outcome

Diabetic nephropathy

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