Diabetic nephropathy

1
Diabetic nephropathy

• 12/21 ???????? Nephro Fellow 1 ???

2
Introduction
3
Introduction

• Diabetic nephropathy occurs in type 1, type 2
  diabetes mellitus and other secondary forms of
  diabetes mellitus
• A glomerulopathy defined by characteristic
  structural and functional changesmesangial
  expansion, glomerular basement membrane
  thickening, and glomerular sclerosis
• Major clinical manifestation are albuminuria,
  progressive chronic kidney disease, and less
  often hematuria.

American Journal of Kidney disease vol 44, No
1, July 2004
4
Pathogenesis

• Glomerulosclerosis result form
• a. Intraglomerular hypertension due to
  renal
• vasodilatation
• b. Ischemic injury induced by hyaline
  narrowing of
• the vessels supplying the glomeruli
• ? and why renal vasodilatation and
  glomeruli
• vessels hyaline narrowing ????

5
Pathogenesis

• There appear to be some different pathogenetic
  processes
• 1. Glomerular hyperfiltration
• 2. Hyperglycemia and AGEs
• 3. Prorenin
• 4. Cytokines
• 5. Nephrin expression
• 6. Impaired podocyte-specific insulin
  signaling

6
Glomerular hyperfiltration

• In an animal model of diabetic nephropathy
• a. BP, intra-renal Ang II level, and
  type IV collagen
• expression are higher in
  prediabetic rats
• b. Renin-angiotensin system blockade
  reduced
• intrarenal Ang II, type IV collagen
  expression,
• risk of proteinuria and improved
  glomerular
• structure.

Temporary angiotensin II blockade at the
prediabetic stage attenuates the development of
renal injury in type 2 diabetic rats. J Am Soc
Nephrol. 200516(3)703.
7
Glomerular hyperfiltration

• gt glomerular hypertension and hyperfiltration
  have
• roles in diabetic nephropathy
• gt Antagonizing the profibrotic effects of
  angiotensin
• II has benefit for diabetic nephropathy

Temporary angiotensin II blockade at the
prediabetic stage attenuates the development of
renal injury in type 2 diabetic rats. J Am Soc
Nephrol. 200516(3)703.
8
Hyperglycemia and AGEs (advanced
glycation end products)

• Hyperglycemia stimulates mesangial expansion and
  mesangial cell apoptosis via increased matrix
  production or glycation of matrix protein
• Excess glucose combines with free amino acids on
  circulating or tissue protein ? circulating and
  tissue AGE accumulation ? crosslinking with
  collagen ? renal and microvascular complication
• Hyperglycemia activates protein kinase C ?
  upregulation of heparanase expression as a
  decrease in cell surface heparan sulfate ?
  glomerular basement membrane permeability to
  albumin

Increased expression of heparanase in overt
diabetic nephropathy. Kidney Int.
200670(12)2100.
9
Cytokines

• Activation of cytokines, profibrotic elements,
  inflammation, and VEGF maybe involved in the
  matrix accumulation in diabetic nephropathy.
• 1. Hyperglycemia stimulates VEGF expression
• VEGF blockde improves albuminuria in diabetic
• nephropathy
• 2. Hyperglycemia induced decrease in activated
  protein
• C --gt structural lesion of diabetic
  nephropathy
• and worsens proteinuria in mice

Blockade of vascular endothelial growth factor
ameliorates diabetic albuminuria in mice. J Am
Soc Nephrol. 200617(11)3093.
Activated protein C protects against diabetic
nephropathy by inhibiting endothelial and
podocyte apoptosis. Nat Med. 200713(11)1349.
10
Cytokines

• 3. TGF-ß contributes to cellular hypertrophy and
• enhances collagen synthesis
• ? hyperglycemia increases expression of
  TGF-ß in
• the glomeruli and matrix protein
• 4. Renal bone morphogenic protein-7 (BMP-7)
  counter
• the profibrogenic actions of TGF-ß
• ? diabetes is associated with decreased
  expression
• of BMP-7

Molecular mechanisms of diabetic renal
hypertrophy. Kidney Int. 199956(2)393.
Renal bone morphogenetic protein-7 protects
against diabetic nephropathy. J Am Soc Nephrol.
200617(9)2504.
11
Prorenin

• Prorenin binds to a specific tissue receptor that
  promotes activation of the mitogen-activated
  protein kinases(MAPK)p44/p42A
• ? Prolonged prorenin receptor blockade
  abolished
• MAPK activation prevent diabetic
  nephropathy
• despite an unaltered increase in
  angiotension II
• activity

Prorenin receptor blockade inhibits development
of glomerulosclerosis in diabetic angiotensin II
type 1a receptor-deficient mice. J Am Soc
Nephrol. 200617(7)1950.
12
_at_
13
Nephrin expression

• Impaired in diabetic nephropathy and congenital
  mutations ? result in severe nephrotic syndrome
• Diabetic nephropathy has markedly lower renal
  nephrin expression and fewer electron dense slit
  diaphram than minimal change and controls ?
  podocin and CD2AP expression are similar amont
  the three groups.

Selective impairment of gene expression and
assembly of nephrin in human diabetic
nephropathy. Kidney Int. 200465(6)2193.
14
Schematic of the slit diaphragm and other
important proteins involved in maintaining foot
process assembly.
Quaggin S E , Kreidberg J A Development
2008135609-620
15
Impaired podocyte-specific insulin signaling

• Mouse models (podocyte-specific insulin receptor
  deficiency)
• In the absence of hyperglycemia, affected
  mice
• developed albuminuria, effacement of foot
• processes, apoptosis, glomerular basement
  
• membrane thickening, accumulation of
  mesengial
• matrix and glomerulosclerosis
• ? activation of the insulin receptor
  remodeling
• MAPK 42/44 and Phosphatidylinositol 3
  (PI3)
• kinase signaling pathways ? proteinuria
  decrease

16
clinical implications of basic research Proteinuri
a, the Podocyte, and Insulin Resistance N Engl J
Med 2010 3632068-2069 November 18, 2010
17
Risk factors

• Family history of diabetes
• Black race, Mexican-American or Pima Indian
  ancestry
• Higher systemic blood pressures
• Poor glycemic control
• Smoking
• Oral contraceptives
• Obesity
• Old age

18
Treatment

• Glycemic control
• Blood pressure control
• Lipid control
• Salt and protein restriction
• Weight reduction
• Angiotensin inhibition
• Calcium channel blocker
• PPAR-gamma agonists
• Other agents

19
Glycemic control

• Delay the development of elevated albumin
  excretion, slow the rate of progressive renal
  injury
• Reverse the glomerular hypertrophy and
  hyperfiltration, improves glomerular structure
• a. mesengial and mesengial matrix volume
  decrease
• b. glomerular and tubular basement
  membranes
• return to normal,
• nodular glomerular
• lesions disappear
• c. tubular atrophy
• improves

N Engl J Med 1993329977
20
Diabetic nephropathy reverses after pancreas
transplantation N Engl J Med 1998 33969
21
Blood pressure control

• United Kingdom Prospective Diabetes Study (UKPDS)
  
• a. SBP decrease 10 mmHg ? 12 risk reduction
  in
• diabetic complication (Plt0.001)
• b. the lowest risk occurred at SBP below
  120mmHg

22
Blood pressure control

• Irbesartan Diabetic Nephropathy Trial (IDNT)
• a. progressively lower SBP to 120mmHg was
  associated
• with decreased cardiovascular death,
  heart failure,
• serum creatinine doubling and ESRD risk
• b. BP lt 120/85 mmHg increased the risk of
  all-cause
• mortality, cardiovascular death and
  heart failure

Strict BP control is important for preventing
progression of diabetic nephropathy in type 2 DM,
but the optimal lower limit for BP is unclear.
23
Lipid control

• Elevation in lipid levels lead to promote
  systemic atherosclerosis and glomerulosclerosis
  in CKD patient.
• In type 1 diabetes mellitus patient, plasma
  cholesterol gt 220mg/dL was an important risk
  factor for progressive renal disease,
  particularly if the diastolic pressure gt 85 mmHg.

Hypercholesterolemia--a determinant of renal
function loss and deaths in IDDM patients with
nephropathy. Kidney Int Suppl. 199445S125.
24
Lipid control

• The rate of progression from normal albumin
  excretion to microalbuminuria decreases with
  fenofibrate (a peroxisome proliferator activated
  receptor (PPAR)-alpha specific ligand)
• Possible mechanisms of fenofibrate
  benefit
• PPAR-a activity --gt inflammation
  and
• production of type 1 collagen in
  mesangial cells

PPARalpha agonist fenofibrate improves diabetic
nephropathy in db/db mice. Kidney Int.
200669(9)1511.
25
Salt restriction

• High salt intake blunt the antiproteinuric
  effects of angiotensin inhibitors
• Salt restriction and/or diuretics enhance the
  effect of renin-angiotensin blockade on
  proteinuria.
• Salt restriction to lt 70 meq /day enhance the
  antiproteinuric effects of ARB in T2DM patient
• gt If it is difficult to achieve
• a. restrict sodium intake to 100 lt
  100meq/d
• b. give diuretic partially corrects
  the loss of
• antiproteinuric effect due to high
  sodium intake

26
Protein restriction

• Protein reduction reduce the rate of progression
  in DM patient with overt nerphropathy.
• gt Suggest avoid a high protein diet
  (1g/kg/d)

Effect of dietary protein restriction on
prognosis in patients with diabetic
nephropathy. Kidney Int. 200262(1)220.
27
Weight reduction

• Marked decreases in proteinuria may be observed
  in obese diabetics who lose weight
• Proteinuria significantly decreased at five
  months among dieters versus the non-dieters
  control group ( mean weight loss of 4 in the
  diet group)
• No significant differences in renal function were
  reported in either group.

Beneficial effects of weight loss in overweight
patients with chronic proteinuric nephropathies.
Am J Kidney Dis.
200341(2)319.
the length of follow-up was probably too short to
have observed renoprotection effect.
28
Angiotensin inhibition

• Primary prevention for diabetic nephropathy
• Preservation of renal function

29
Angiotensin inhibition

• Primary prevention for diabetic nephropathy
• Diabetes induces renal vasodilation,
• intraglomerular hypertension and
  glomerular
• hypertrophy
• ACEI and ARB reduce intrarenal vascular
  resistance
• and inhibit TGF-ß
• ? reduce intraglomerular pressure,
  minimize
• glomerular injury, inhibit
  cellular hypertrophy
• and collagen synthesis

Chronic angiotensin II receptor blockade reduces
(intra)renal vascular resistance in patients with
type 2 diabetes. J Am Soc Nephrol.
200516(4)1135.
30
Captopril reduces (intra)renal vascular
resistance in patients with type 2
diabetes Kidney Int 198936526.
31
Angiotensin inhibition

• Preservation of renal function
• T1DM
• a. ACEI decreases albumin excretion, CKD
  
• progression rate, risk of overt
  nephropathy,
• ESRD or death.

NEJM 19933291456.
32
Angiotensin inhibition

• b. ACEI ARB produces a greater reduction in
• protein excretion (in 2 short-term
  studies, 8 wks)
• --- due to better BP control ???

Dual blockade of the renin-angiotensin system
versus maximal recommended dose of ACE inhibition
in diabetic nephropathy. Kidney Int.
200363(5)1874.
33

• T2DM renal protection with ARBs
• a. Irbesartan Diabetic Nephropathy Trial
  (IDNT)
• _at_Irbesartan has lower risk (23) in doubling
  of Scr,
• proteinuria, ESRD or death than
  amlodipine (and placebo)
• _at_Renal failure risk doubles with each
  doubling of
• baseline protein excretion
• _at_The renal outcomes are best at SBP lt134mmHg

34

• b. RENAAL study
• _at_Losartan reduced the albuminuia, incidence
  of
• creatinine doubling and ESRD by 25 and
  28
• _at_ SBP every 10mmHg gt ESRD or death risk
  6.7
• _at_ Albuminuria every 50 gt CV risk 18,
  ESRD risk
• _at_ Baseline retinopathy has poor renal outcome
• Both of studies show ARB has clear benefits in
  T2DM patients with overt nephropathy
• ARB had significant reductions in the development
  of heart faliure. However, CV mortality has no
  obvious reduction.

? too short duration of the studies??
35

• T2DM renal protection with ACEIs
• a. ADVANCE trial
• perindopril-indapamide combination vs
  placebo
• _at_ significant reduction of new onset
  microalbuminuria
• or worsening of protienuria (19.6 vs
  23.6 )
• _at_ significant decrease in mean BP (5.6/2.2
  mmHg)
• _at_ no significant defference in CKD
  progression
• gt the renal benefits are due to the ACEI or BP
  control ??

36

• b. DETAIL trial
• enalapril vs. telmisartan vs. placebo
• _at_ at 5 yrs, enalapril has smaller GFR
  decline (NS)
• _at_ similar findings of BP, Scr, albuminuria,
  ESRD, CV
• events and mortality.
• ACEIs are at least as effective as ARBs in
  diabetic patient with microalbuminuria
• ACEIs or ARBs has renoprotection in patient with
  diabetic nephropathy (progress slowly)
• 1/3 of renoprotective effect with ACEI or ARB is
  due to proteinuria reduction in first 12 months
  of therapy

37

• ACEI ARB ???
• small studies
• decrease proteinuria in T1DM T2DM
• ONTARGET study
• proteinuria and GFR gt
• ESRD and mortality rate gt
• CKD progression gt NS

38

• ARB aliskiren
• _at_ AVOID trial aliskiren losartan vs.
  losartan
• aliskiren losartan has 20 greater
  reduction
• in proteinuria (no significant on
  BP)
• role of aliskiren in preventing CKD
  progression ??

39
Aldosterone antagonism

• small study 81 patient, f/u 48weeks
• lisinopril sprionolactone or losartan
  or placebo
• spironolactone lisinopril urine ACR decre
  34 (S)
• losartan lisinopril urine ACR 17
  (NS)
• no long term data about CKD progression with
  
• ACEI/ARB aldosterone blockade
• Serum pottasium is significant high in both
  group

Antagonists of aldosterone and proteinuria in
patients with CKD an uncontrolled pilot
study. Am J Kidney Dis. 200546(1)45.
40

• Another small studies 268 patient, f/u 40wks
• ACEI eplerenone or placebo
• ? eplerenone has additive antiproteinuria
  effect,
• similar hyperkalemia rate
• Aldosterone antagonists appear to reduce
  proteinuria when used alone or combination with
  ACEI/ARB in type 1 and type 2 diabetes.
• gt suggestion avoid NSAID, combine
  kaliuretic
• diuretic therapy

Beneficial impact of spironolactone in diabetic
nephropathy. Kidney Int. 200568(6)2829.
41
Calcium channel blocker

• Non-dihydropyridine calcium channel blockers slow
  the rate of progression of diabetic nephropathy
• diltiazem and verapamil is as effective
  as
• ACEI/ARB in lowering protein excretion
  in diabetic
• patients
• the antiproteinuric effects of verapamil
  and ACEI
• may be addictive
• However, diltiazem increases
  tubulointerstitial
• fibrosis andglobal glomerulosclerosis.
  The effect
• was prevented by combined an ACE
  inhibitor.

Effects of different antihypertensive treatments
on morphologic progression of diabetic
nephropathy in uninephrectomized dogs. Kidney
Int. 199446(1)161.
42
Antihypertensives and urinary protein
excretion in diabetic nephropathy Kidney Int.
199246(1)161.
Superior antiproteinuric effect with combination
of antihypertensive therapy Kidney Int.
199857(1)193.
43
Superior antiproteinuric effect with combination
of antihypertensive therapy Kidney Int.
199351(5)129.
44

• The antiproteinuric mechanism of
  nondihydropyridine calcium channel blockers
• 1. possible reduction in intraglomerular
  pressure
• 2. reduce the associated glomerular
  hypertrophy
• 3. diltiazem may improve glomerular size
• permselectivity.

Differential effects of calcium channel blockers
on size selectivity of proteinuria in diabetic
glomerulopathy. Kidney Int. 199854(3)889.
Uncertain clinical relevance. The
efficacy in the preservation of renal fucntion in
relation to ACEI has not yet been
evaluated in humans
45

• Dihydropyridine calcium channel blockers ( such
  as amlodipine, nifedipine, nitrendipine) have a
  variable effect ranging from increased protein
  excretion to no effect to a fall in protein
  excretion in different studies.
• Beta-blockers have shown a variable response of
  protein excretion decrease

46
PPAR-? agonists

• Peroxisome proliferator-activated receptors
  (PPAR) which are ligand-activated transcritption
  factors, have a role in regulating adipogenesis,
  lipid metabolism, insulin sensitivity,
  inflammation, blood pressure, and development of
  T2DM nephropathy.
• PPAR-? agonists, such as the thiazolidinediones
  (eg, pioglitazone and rosiglitazone), induce
  reductions in fibrosis, mesangial cell
  proliferation, and inflammation in animal models
  of diabetic nephropathy .

Effect of pioglitazone on cardiovascular outcome
in diabetes and chronic kidney disease. J Am Soc
Nephrol. 200819(1)182.
47
PPAR-? agonists

• In small studies, PPAR-gamma agonists reduce
  urinary albumin excretion at various stages of
  nephropathy and to reduce blood pressure.
• ? Larger studies are required to detect a
  renoprotective effect
• A post hoc analysis of the PROACTIVE trial failed
  to show a definitive benefit on cardiovascular
  risk reduction with pioglitazone in people with
  stage 3 or higher nephropathy

Effect of pioglitazone on cardiovascular outcome
in diabetes and chronic kidney disease. J Am Soc
Nephrol. 200819(1)182.
48
Other agents
49
Bardoxolone methyl

• An antioxidant inflammatory modulator that may
  also have prostaglandin-like effects. It has been
  beneficial in animal models of drug-induced or
  ischemic acute kidney injury.
• In the Bardoxolone Methyl Treatment Renal
  Function in CKD/Type 2 Diabetes (BEAM) trial,
  Bardoxolone methyl therapy at all three doses
  significantly increased eGFR at 52 weeks of
  follow-up by 6 to 10 mL/min per 1.73 m2, while
  placebo therapy had no effect.

50
Bardoxolone methyl

• The disadvantages of Bardoxolone methyl therapy
• a. significantly increased albuminuria
• ? The change in albuminuria was
  significantly
• correlated with the change in eGFR.
• ? Increase in eGFR may be mediated by
• increase in intraglomerular
  hydrostatic pressure
• b. significantly increased adverse events --
  
• muscle spasms, nausea, and SBP 24
  mmHg.

Bardoxolone methyl and kidney function in CKD
with type 2 diabetes. N Engl J Med.
2011365(4)327.
51
Other agents

• limited data, including a meta-analysis, suggest
  that pentoxifylline lowers proteinuria and may
  have similar antiproteinuric effects as ACE
  inhibitors.
• Endothelin receptor antagonists, protein kinase C
  inhibitors,), sulodexide, and fish oil.
• There are insufficient data on any of these
  agents to advocate their use for the treatment or
  prevention of diabetic nephropathy.

The effect of pentoxifylline on proteinuria in
diabetic kidney disease a meta-analysis. Am J
Kidney Dis. 200852(3)454.
Fenofibrate reduces progression to
microalbuminuria over 3 years in a
placebo-controlled study in type 2 diabetes
results from the Diabetes Am J Kidney Dis.
200545(3)485.
52
Summary of treatment

• Primary prevention for diabetic nephropathy
• Angiotensin inhibition
• Strict glycemic control
• PPAR gamma agonist ?
• Preservation of renal function
• Antihypertensive therapy (particularly
  with an ACEI)
• ARB/ACEI (T2DM with overt nephropathy)
• Protein restriction (T1DM with overt
  nephropathy) ?

53
Combined therapy

• Steno type 2 diabetes study
• mean follow-up 7.8 yrs, intensive therapy reduced
  albumin excretion, microvascular and
  macrovascular disease
• GFR fall to the same degree in both groups.

54
120/75 mmHg vs
130/80mmHg Aggressive blood pressure control has
benefits in chronic kidney disease patient NEJM.
199468(6)2829.
55
Recommendations

• Type 1 DM
• a. check urine ACR yearly after the first
  5 yrs.
• If positive ? follow up 3-6 m x 2
  (at least)
• ? confirm the diagnosis by at least 2
  of 3
• positive samples
• b. strict glycemic and lipid control
• c. give ACEI if BP gt 130/80 mmHg or
• persistent microalbuminuria
• d. give loop diuretics to attain dry
  weight

56
Recommendations

• e. If BP gt 130/80 mmHg or proteinuria
  gt500
• 1000mg/d under ACEI treatment
• ? give nondihydropyridine calcium
  channel
• blocker (diltiazem/verapamil)
  or long-acting
• dihydropyridine calcium channel
  blocker if
• the patient already being
  treated with a beta-
• blocker
• f. If overt nephropathy ? take sodium lt
  90meq/d
• to achieve maximal antiproteinuric
  effects with
• ACEI
• g. Avoid high protein diet ( 1g/kg/d)

57
Recommendations

• Type 2 DM
• a. give a ARB or ACEI ( not combine them
  !!)
• b. if BP gt 130/80mmHg or proteinuria gt
  500
• 1000mg/d ? give diltiazem or
  verapamil
• c. if edema or renal insufficiency ? give
  loop
• diuretic to attain dry weight
• d. if overt nephropathy ? take sodium lt
  90meq/d
• to achieve maximal antiproteinuric
  effects with
• ACEI
• e. Avoid high protein diet ( 1g/kg/d)

58
Thanks for your attention !!