Diabetic Kidney Disease, is it preventable?

1. Diabetic Kidney Disease
Is it preventable?
DR.SANJAY MAITRA
MD,DM(PGI,CHD),CLIN.FELLOWSHIP TORONTO UNIV.
SR.CONSULTANT NEPHROLOGIST,APOLLO HEALTH CITY, HYDERABAD

2. What is Diabetic Nephropathy?

3. What is Diabetic Nephropathy?
 It is one of the long term microvascular complications of Diabetes
 It is a clinical syndrome characterized :
 Persistent albuminuria (>300 mg/d or >200 μg/min) that is confirmed on at least 2
occasions 3-6 months apart
 Progressive decline in the glomerular filtration rate (GFR)
 Elevated arterial blood pressure
 Present in patients with
 Worse glycaemic control
 Hypertension
 Glomerular Hyperfiltration
 Genetic Predisposition

4. Typical progression of diabetic kidney disease
Exposure to diabetes is required for diabetic
nephropathy to develop in susceptible patients.
The time at which the complication becomes
clinically apparent and the rate at which it
progresses is variable and can be modified by
careful management of glycemia, hypertension,
and glomerular hypertension.
ESRD, End-stage kidney disease.
Risk of developing Diabetic Nephropathy equal in
Type 1 & Type 2 Diabetes

6. Why is it important to know about
Diabetic Nephropathy?

7. Diabetes: A global emergency
35-40% of Diabetics end up having CKD

8. What is CKD- Current understanding
Heterogeneous group of disorders characterized by alterations in kidney structure
and function, which manifest in various ways depending upon the underlying
cause or causes and the severity of disease
Structural or functional abnormalities of the kidneys for ≥3 months as
manifested by
Kidney damage with or without decreased GFR ,as defined by
1.)Pathologic abnormalities
Markers of Kidney damage like
Urinary abnormalities(proteinuria)
Blood abnormalities (renal tubular syndromes)
Imaging abnormalities
Kidney transplantation
2.)GFR < 60ml/min/1.73m2 ,with or without kidney damage
CKD – Chronic Kidney Disease, GFR- Glomerular Filtration Rate

9. STAGES OF CHRONIC KIDNEY DISEASE

15. Incidence of CKD in India – 800 per million population
Incidence of ESRD in India- 150-200 per million population

16. Cross sectional study involving 52,273 patients
Mean age 50.1±14.6 yrs
M:F ratio 70:30
Diabetic nephropathy –commonest cause of CKD (31%)
CKD of unknown aetiology (16%)
CGN (14%)
Hypertensive nephrosclerosis (13%)

17. Monthly Cost Of haemodialysis at 3 HD/wk Rs 12,000- Rs 30,000
Monthly cost Of Erythropoeitin per month Rs 7,000-Rs 10,000
Monthly cost of CAPD 3 exchanges per day Rs. 20,000-Rs 25,000
Cost of transplant procedure Rs 3,00,000- Rs, 7,00,000
Cost of immunosuppressive medicines
(Using Tacrolimus,MMF and steroids)
Rs 10,000-Rs 15,000 per
month
Approx.cost of Renal replacement therapy in India

18. Diabetic nephropathy increases CVS
disease Risk

22. How do you diagnose diabetic kidney
disease?

26. How do you distinguish diabetic from other
glomerular diseases?
 Short history of Diabetes Mellitus, typically less than 5 years
 Absence of Diabetic Retinopathy
 Active Urinary Sediment
 Unusual rate of decline of renal function , sudden AKI
 Prior history of other diseases like Collagen Vascular disease or
others

27. Aetiopathogenesis of Diabetic Nephropathy

28. Aetio-pathogenesis of Diabetic Nephropathy

29. Treatment strategies at present

30. Current treatment regimens for treating
Diabetic kidney disease
 Strict Glycaemic Control
 ACE Inhibitors/ARB for
 BP control
 Primary prevention
 Proteinuria reduction
 Preservation of renal functions
 Mineralocorticoid Receptor antagonists
 Endothelin antagonists
 Role of Diltiazem and verapamil
 Cholesterol control
 Lifestyle modification-Weight reduction/Smoking
 Diet –Sodium and protein restriction

33. Rationale for tight glycaemic control in
diabetic patients

43. Currently Available Classes of Anti-hypoglycaemic agents
Mech. Of action Classes of drugs
Insulin sensitizers Biguanides
Thiazolidinediones
Stimulators of Insulin secretion Sulphonylureas
Meglitinides
Decrease GI carbohydrate abs Acarbose
Stmulates Insulin secretion,decreases
glucagon production, increases
satiety
GLP-1 agonists
Decreases inactivation of
incretins(GLP-1)
DPP-4 inhibitors
SGLT-2 Inhibitors Prevent glucose re-absorption
in kidneys
Increases glucose utilisation Insulins

44. Which of the anti-diabetic agents are
promising as per current data?

45. SGLT -2
Inhibitors

46. Patients with established Cardiovascular disease and e-GFR of at least 30ml/min
Assigned to Empagliflozin 10mg, 25mg or placebo once daily + Standard therapy
Assessed for incident or worsening nephropathy
Progression to mac roalbuminuria ,doubling of S. Creatinine, RRT initiation or death from renal disease

47. EMPA-REG OUTCOME Trial
Parameters Empagliflozin Group
Incident or worsening nephropathy 39% Risk reduction
Doubling of Serum creatinine 44% Risk reduction
Initiation of Renal Replacement Therapy 55% Risk Reduction

48. Evaluation of the Effects of Canagliflozin on Renal and
Cardiovascular Outcomes in Participants With Diabetic
Nephropathy (CREDENCE)
Presently ongoing trial with the goal
 To assess whether canagliflozin has a renal and vascular protective
effect
 In reducing the progression of renal impairment relative to placebo
 In patients with type 2 diabetes mellitus (T2DM), Stage 2 or 3
chronic kidney disease (CKD) and macroalbuminuria,
 Who are receiving standard of care including a maximum tolerated
daily dose of an ACE or ARB

49. Week -4 0 24 27
Randomized Treatment
Follow-up
Background diabetes treatment and optimal ACEi/ARB treatment
Randomized
1:1:1
Dapagliflozin 10 mg N=150
Placebo N=150
Double-blind
treatment period
Lead-in
period
S
c
r
e
e
n
i
n
g
Single-blinded
placebo
Saxa+Dapa arm:
Co-Primary objective : Change in HbA1c and % UACR vs Pbo
Secondary objectives: Change in weight, FPG, SBP, HbA1c <7%, 30% UACR reduction
Saxa 2.5 mg and Dapa 10 mg N=150
Dapa arm:
Primary objective: Change in % UACR vs Pbo
Secondary objectives: Change in weight, FPG, A1c, SBP, HbA1c <7%, 30% UACR reduction
Estimated completion 2017
DELIGHT Study Design: Effect of Dapagliflozin +/- Saxagliptin on Albuminuria in Patients
With Type 2 Diabetes and CKD3
-6
Available at:https://www.clinicaltrials.gov/ct2/show/NCT02547935?term=dapagliflozin+and+renal&rank=15. Last accessed 6 Nov 2015.

50. Reduction in albuminuria with Dapagliflozin in Patients With Type 2
Diabetes and Moderate Renal Impairment
CI=confidence interval; DAPA=dapagliflozin; PBO=placebo. Sjöström CD et al.
World Congress of Nephrology. March 13-17, 2015; Cape Town, South Africa. Poster SAT-461. T2D=type 2 diabetes; CKD=chronic kidney disease;
SGLT=sodium-glucose cotransporter; eGFR=estimated glomerular filtration rate; GFR=glomerular filtration rate; UACR=urine albumin:creatinine ratio.
Kohan DE et al. Kidney Int. 2014;85:962-971. Yale JF et al. Diabetes Obes Metab. 2013;15:463-473. Barnett AH et al. Lancet Diabetes Endocrinol.
2014;doi:10.1016/S22138587(13)70208-0. Gilbert RE. Kidney Int. 2013; doi:10.1038/ki.2013.451
The reduction in interglomerular
pressure induced by SGLT2 inhibitors
may provide benefits to patients with
CKD
Dapagliflozin demonstrates potential
nephroprotective effects in combination
with renin-angiotensin system blockade,
as significant reductions in UACR over 50
weeks in patients with T2D and
moderate renal function were observed
UACR: Urine Albumin Creatinine Ratio

51. LEADER TRIAL
9000 patients treated with 1.8 mg SC of GLP-1 agonist Liraglutide or placebo
In addition to standard of care therapy
Follow up of 42-60 months
Rate of death from any cause was lower with Liraglutide, while MI, Stroke and CHF not different

52. Possible microvascular benefits of Liraglutide

53. One-year treatment with Liraglutide improved renal function in
patients with type 2 diabetes: A pilot prospective study
 This study analyzed the effects of liraglutide on renal function in patients with type 2
diabetes.
 A twelve-month longitudinal prospective post-marketing study was performed.
 According to eGFR (estimated glomerular filtration rate) calculated with CKD-EPI equation,
84 consecutive patients were divided in Group A (eGFR > 90 ml/min) and Group B
(eGFR < 90 ml/min). BMI, glucose, HbA1c, serum creatinine, microalbuminuria, and eGFR
were evaluated at baseline and after 12 months of treatment.
 A reduction in fasting plasma glucose (p < 0.01), HbA1c (p < 0.003), BMI (p < 0.01), and
systolic (p < 0.01) and diastolic blood pressure (p < 0.006) was recorded irrespective of eGFR
category.
Endocrine, 2015, Page 1
Marco Zavattaro, Marina Caputo, Maria Teresa Samà,

54. Role of DPP-4 Inhibitors
DPP4 inhibitors
 Help control blood sugars with minimal side effects
 Linagliptin ,Alogliptin and Sitaglyptin have shown to reduce proteinuria
independent of HbA1c
 These findings need to be confirmed by RCT

55. Diabetes Care 36:3460–3468, 2013

56. Role of Intensive Blood pressure control

57. Blood Pressure Control reduces Progression of Renal Function deterioration

58. American Journal of Kidney Diseases 2014 63, S3-S21DOI: (10.1053/j.ajkd.2013.10.050)
Copyright © 2014 National Kidney Foundation, Inc. Terms and Conditions
Systolic Blood pressure levels < 115mm of Hg increase all cause mortality

59. Intensive BP control-SPRINT TRIAL
THE SPRINT TRIAL

60. Role of ACE Inhibitors/ARB’s in
Diabetic Nephropathy

61. Figure 1 The renin–angiotensin system and potential therapeutic strategies to
inhibit the progression of diabetic nephropathy
Declèves, A.-E. & Sharma, K. (2010) New pharmacological treatments for improving renal
outcomes in diabetes
Nat. Rev. Nephrol. doi:10.1038/nrneph.2010.57

63. Role of ACE inhibitors/ARB’s
Target BP<130/80mm0Hg
Effective in all situations except primary prevention of
normotensive normo-albuminuric pts.
 Reduce intra-glomerular hypertension
 Anti-pleotropic effects
 Proteinuria reduction, control hypertension
 Prevent progression of diabetic nephropathy
ACE/ARB’s
Work here

64. Role of ACE inhibitors/ARB’s
 ACE or ARB’s –not much data
 ADVANCE & DETAIL-Looks like both are effective if started early
 ACE +ARB’s
 Decreases proteinuria ,but not renal failure or death, increases
complications
 Evidenced by ONTARGET, ALTITUDE & VA NEPHRON-D trials
 Aliskerin +ACE/ARB
 Does not prevent progression, increases complications
 Altitude Trial prematurely stopped
 Renal & overall safety of RAS blockade in elderly CKD patients has
been questioned
 ROADMAP trial –Olmesartan delayed the onset of albuminuria, had lower
BP, but CVS deaths were higher

65. Aldosterone Inhibitors
Spironolactone,Epleronone & Finerenone
 Aldosterone has direct pro-inflammatory and pro-fibrotic
actions
 Aldosterone inhibitors have anti-proteinuric properties in
humans
 Have shown some benefit in ↓ renal progression
 Weigh Risk of hyperkalemia in mod.renal failure patients
 PRIORITY TRIAL & few other trials are on

67. Role of Endothelin antagonists
 Endothelin a potent vasoconstrictor acts through ETA and ETB receptors
 Promotes renal vasoconstriction and increases BP
 Promotes inflammation, fibrosis and podocyte injury
 Initial studies with Avosentan were terminated because of fluid retention
 Later studies with Atrasentan (RADAR trials) showed significant reduction of
proteinuria without increase in adverse events
 Based on these results SONAR study was planned
 Will look into cardiovascular morbidity and mortality , albuminuria and GFR change

69. Effect of reducing bodyweight and
controlling lipids, decrease salt intake
 In obese patients with Type2 Diabetes
 Weight reduction is the first step to reduce proteinuria
 Works well for early and late stages
 Works for non-diabetics also
 Lipid abnormalities cause CVS problems in diabetics
 KDIGO recommends to treat all DM +CKD with statins & Ezetmibe
,avoid fenofibrate
 Small trials suggest that statins might also delay the progression of
Diabetic kidney disease
 Sharp trial failed to show a decrease of ESRD but reduced
atherosclerotic events
 Excess salt intake blunts the +ve effect of RAS blockade on reducing
proteinuria-Target <100meq/day

70. Effect of protein restriction in diabetic nephropathy
These results were not
replicated in a later
trial.
May cause malnutrition

71. Role of Xanthine oxidase inhibitors
 High uric acid is a risk factor for CKD Progression
 Initial study with Allopurinol showed a possibility to prevent
progression
 PERL study with allopurinol & FEATHER study with febuxostat are
assessing whether they can prevent progression in patients with
CKD

72. Phophodiesterase inhibitors
 Pentoxifylline is an anti-inflammatory and immuno-
regulatory agent for PVD
 Pentoxifylline +Dual RAS blockage showed significantly
reduced protein
 PREDIAN study –Assesing effect of Pentoxifylline + RAS
blockade in Diab.CKD 3-4 stages
 CTP-499,an active metabolite of pentoxifylline and PF-
00489791 ,a phosphodiesterase type 5 inhibitor is being
evaluated in trials

73. The Failed Trials
Drug Reason for failure
Bardoloxone Methyl Beacon Phase 3 –Terminated for
CCF
Vit D (paracaltitol) Not found to be useful
AGE Inhibitors(Pimagedine &
Pyridoxamine)
Not helpful, Pimagedine trial
stopped
Sulodoxide Not helpful
Anti-oxidants: Vit C, Vit E,ß-carotene, N-
Acetyl Cysteine
Not helpful
Protein Kinase C inhibitors and
agents
Withdrawn
Endothelin Receptor antibody-Avosentan Withdrawn because of CCF

74. Summary
 Diabetic Kidney Disease is a common problem in long standing
Diabetics
 The effort should be to identify the problem early and try to control
its progression
 If not managed properly patients end up in ESRD and/or severe CAD
 Multifactorial approach to treatment shows benefits but is not fool-
proof
 Newer modalities are being constantly tried to deal with this menace,
certain groups of anti-diabetic medicines have shown promise

75. Thank You