Diabetic Nephropathy

Growing Problem of T2DM and CKD

Deaths due to
~422
adults are
living with T2DM and CKD
diabetes
MILLION 94%

Number of Deaths
30 to 40%
of these patients will develop CKD 1990 2012

1. World Health Organization. Global Report on Diabetes. 2016.

2. Yee J. Diabetes Spectr. 2008;21(1):8-10.
3. Alicic RZ, et al. Clin J Am Soc Nephrol. 2017;12(12):2032-2045.
 Diabetic nephropathy (DKD) among native Asian-Indians

• DKD is a contemporary challenge in Kidney disease (KDIGO)

• Diabetic nephropathy is one of the leading causes of chronic

renal failure in India. It has been reported that among 4837
patients with chronic renal failure seen over a period of 10
years, the prevalence of diabetic nephropathy was 30.3%.

• These have contributed to increase in no of Dialysis & Renal

Replacement Therapy.

Vijay Viswanathan, Type 2 diabetes and diabetic nephropathy in India—magnitude of the problem, Nephrology Dialysis Transplantation, Volume 14, Issue 12, December 1999,
Pages 2805–2807, https://doi.org/10.1093/ndt/14.12.2805
 DKD Shortens Life Span by 16 Years

.
Wen CP, et al. Kidney Int. 2017;92(2):388-396
 People with diabetes 6-12X more likely to be
hospitalized for CKD or End-stage renal disease

Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).
Diabetes is #1 Cause of New Cases of ESRD

Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).
Heart failure in diabetes…on fertile soil of DKD
Mortality due to DM
Overview of major established and proposed mechanisms of CVD in
patients with DM and CKD

DM
CKD

Hypertension Calcium & Phosphate Metabolism

Atherogenic dyslipidemia derangements
Endothelial dysfunction Volume overload
Hypercoagulability Anaemia
Chronic inflammation Hormone imbalances
Oxidative stress Uremic toxins
RAAS & Sympathetic nervous system
overactivity

Adv Chronic Kidney Dis. 2014 May; 21(3): 273–280.

Adv Chronic Kidney Dis. 2014 May; 21(3): 273–280.

Risk of Mortality, Cardiovascular, and Renal Outcomes in Relation
to Kidney Disease
UACR <30 mg/g UACR 30–299 mg/g UACR ≥300 mg/g

Levey AS, et al. Kidney Int. 2011;80(1):17-28.

Cardio-kidney risk factor management
 Cream of Kidney Protection

• Optimal glycemic control

• Optimal BP control

• ACE-inhibitor or ARB

• SGLT2 inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin)

• Optimal protein intake

ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure
 EDIC: Early Glycemic Control Reduces
Long-term Risk of Impaired GFR
Risk reduction with intensive therapy
50%
(95% CI 18-69; p=0.006)

DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-76.

 ACE-inhibitor in Type 1 diabetes with
MAU Reduces Progression to Clinical
Proteinuria

Proportion with Event

Months of Therapy
Laffel LM et al. Am J Med 1995;99(5):497-504.
MAU, microalbuminuria
 ACE-inhibitor in Type 1 diabetes with
Macroalbuminuria Reduces Renal
Outcomes

Lewis EJ et al. N Engl J Med 1993;329:1456-62.

ARB in Type 2 diabetes with MAU reduces progression

Primary endpoint: Time to onset of diabetic nephropathy* (n=590)

Placebo

Irbesartan
150mg

Irbesartan
300mg

*defined by persistent albuminuria in overnight specimens,

with urinary albumin excretion rate <200 μg/min and ≥30% higher than baseline level

Parving et al. N Engl J Med 2001;345:870-8

MAU, microalbuminuria
 ARB in Type 2 diabetes with
Macroalbuminuria Reduces Renal
Outcomes
Primary endpoint: Time to doubling of serum creatinine,
ESRD, or death (n=1513)

50 Placebo
patients with event

Risk reduction = 16%

Cumulative % of

40
p=0.02
30

20 Losartan

10

0
0 12 24 36 48
Months

Brenner et al. N Engl J Med 2001;345:861-9

ESRD, end stage renal disease
 ARB in T2DM with Macroalbuminuria
Reduces Renal Outcomes
Primary endpoint: Time to doubling of serum creatinine,
70 ESRD, or death (n=1,715)
Irbesartan
60 RRR 23%
Amlodipine p=0.006
RRR 20%
p=NS p=0.02
50
Placebo
Patients (%)

40

30

20

10

0 6 12 18 24 30 36 42 48 54 60
Lewis et al. N Engl J Med 2001;345:851-60 Follow-up (mo)
ESRD, end stage renal disease
Renoprotection in T2DM with risk factors
 Reduction in progression and induced
regression of albuminuria with Canagliflozin

27% reduction in Progression of 1.7 times Regression of

albuminuria albuminuria
(Normo >> Micro >> Macro) (Normo << Micro << Macro)

Neal B, et al. N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925.

 P a r t ic ip a n t s w it h a n e v e n t ( % )
Primary Outcome:
ESKD, Doubling of Serum Creatinine, or Renal or CV Death

Participants with an event (%)

Hazard ratio, 0.70 (95% CI, 0.59–0.82) 340 participants
P = 0.00001

245 participants

25

20

15
Placebo
10 Canagliflozin
5 30%
reduction
6 12 18 24with Cana
30 36 42
0
0 26 52 78 104 130 156 182

Months since randomization

No. at risk
Placebo 2199 2178 2132 2047 1725 1129 621 170
Canagliflozin 2202 2181 2145 2081 1786 1211 646 196
Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.
 m in / 1 . 7 3 m 2 )
Acute and Long-term Effects on eGFR
LS M e a n C h a n g e (± S E)
Canagliflozin Placebo
Baseline 56.4 56.0
eGFR (mL/min/1.73 m2)
( m L /in

60% reduction in the rate of eGFR

i n e G F R(SE)

decline with canagliflozin

–1.85/year
LS mean change

0
-2
-4
-6
–4.59/year
-8 Chronic eGFR slope
-10
-12
Difference: 2.74/year (95% CI, 2.37–3.11)
-14
-16
-18
6 12 18 24 30 36 42
0 26 52 78 104 130 156 182

Months since randomization

No. of Participants
Placebo 2178 2084 1985 1882 1720 1536 1006 583 210
Canagliflozin 2179 2074 2005 1919 1782 1648 1116 652 241
Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306. On treatment
Major Cardiovascular Events: CV Death, MI, or Stroke

Participants with an event (%) 25

Hazard ratio, 0.80 (95% CI, 0.67–0.95) Placebo
P = 0.01 Canagliflozin
20

269 participants
15
217 participants
10

20% Reduction
5 with Cana

0
0 26
6 52
12 78
18 104
24 130
30 156
36 182
42
Months since randomization
No. at risk
Placebo 2199 2152 2100 2022 1717 1143 635 168
Canagliflozin 2202 2163 2106 2047 1756 1196 642 198
 Summary of Key Renal and CV Outcomes
Hazard ratio
(95% CI) P value
Primary composite outcome 0.70 (0.59–0.82) 0.00001
Doubling of serum creatinine 0.60 (0.48–0.76) <0.001
ESKD 0.68 (0.54–0.86) 0.002
eGFR <15 mL/min/1.73 m2 0.60 (0.45–0.80) –
Dialysis initiated or kidney transplantation 0.74 (0.55–1.00) –
Renal death 0.39 (0.08–2.03) –
CV death 0.78 (0.61–1.00) 0.0502
CV death or hospitalization for heart failure 0.69 (0.57–0.83) <0.001
CV death, MI, or stroke 0.80 (0.67–0.95) 0.01
Hospitalization for heart failure 0.61 (0.47–0.80) <0.001
ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) <0.001
0.25 0.5 1.0 2.0 4.0
Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.
Favors Canagliflozin Favors Placebo
 Canagliflozin: Reduction of eGFR decline & need of Dialysis

60 Average CREDENCE
50
patient
–1.8 Age = 63 years
40 –4 5/y eGFR = 56
.5 ear
eGFR

30 9 /y
20 ea
Average
r 15.1 years
patient would 10
delay develop eGFR < 10 mL/min/1.73 m2
0
eGFR 10 by 0 5 10 15 20 25 30
over 15 years Years
Placebo/SOC Canagliflozin
by taking Age = 73 years Age = 88 years
Canagliflozin eGFR = 10 eGFR = 10

Perkovic V. NEJM. 2019 10.1056/NEJMoa1811744.

Effect on albuminuria: CREDENCE TRIAL

Decline in albuminuria with Canagliflozin almost constant upto 42 months of follow-up

DAPA - CKD

N Engl J Med 2020; 383:1436-1446

 Trial Design

(Stage 2-4)

International,
multicenter ( 386
centers in 21
countries),
randomized, double
blind, placebo-
controlled study
(N= 4304)
Results
 Conclusion

In patients with CKD, with and without type 2 diabetes, Dapagliflozin

compared to placebo significantly

• Reduced the risk of kidney failure

• Reduced the risk of CV death or heart failure hospitalization

• Prolonged survival
Protein guideline for adults with diabetes and non-dialysis CKD

Patients treated with hemodialysis, and particularly peritoneal dialysis, should

consume between 1.0 and 1.2 g protein/kg (weight)/day.

KDIGO CLINICAL PRACTICE GUIDELINE 2019

Thank You!