3. Approx. 6% of the world's population—more than 420
million people—live with either type 1 or type 2 diabetes 1
Of whom ~ 40% will develop CKD 2
1.The Lancet Diabetes & Endocrinology. 2021 Jun 1;9(6):325-7
2. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2032-45
4. Diabetic kidney disease (DKD) greatly amplifies risks of CV
complications and death
Even with treatment of the major risk factors (hyperglycaemia
and hypertension), DKD risk remains high
Clin J Am Soc Nephrol 2017;12: 2032–45
5. No current test can predict diabetic kidney disease
Enormous human suffering and societal costs
Unmet need for therapy to delay disease progression
Until recently, ACEi/ARBs- the mainstay of treatment
6. Past few years - A robust armamentarium for DKD
Despite the new treatments, very few patients received reno-
protective therapies in the real world
Screening of disease, awareness and dissemination of the new
therapies is ‘The Need Of The Hour’
7. 5yrs after Dx in T1D and at time of Dx in T2D
Using -
i. Albuminuria- estimated (spot urine ACR), or measured (24-hour
urine collection)
ii. eGFR - creatinine based equations (CKD-EPI, MDRD)
eGFR equations are not sufficiently accurate except when eGFR is <60
eGFR 60 to 90 mL/min/1.73 m2 - clinical implication unclassified
8. American Diabetes Association (ADA 2022)
Annual testing for eGFR and urine albumin excretion (e.g., spot uACR)
Twice annually – if uACR ≥300 mg/g and/ or eGFR 30–60 mL/min/1.73 m2
High biological variability of >20% between measurements in albumin excretion
Abnormal results - confirm by repeat testing over a period of 3 to 6-months
2 of 3 specimens of uACR collected within a 3 to 6-month period should be
abnormal before considering a patient to have high or very high albuminuria
Diabetes Care 2022;45(Suppl. 1):S175–85
9.
10. DKD is typically a clinical (or presumptive) diagnosis
Kidney biopsy is rarely performed to confirm the diagnosis
Kidney biopsy when an alternative diagnosis+
11. A presumptive diagnosis of DKD should be avoided in:
Severely elevated albuminuria (ie, ≥300 mg/day or mg/g) in <5 years of onset of
T1D, or severely elevated albuminuria prior to the onset of T2D
RBC casts, dysmorphic red blood cells, or WBC casts in the urine sediment
Presence of another systemic disease (eg, systemic lupus erythematosus)
A sudden ↑ albuminuria or a rapid decline in eGFR (albuminuria >5- to 10-fold
over a period of < 1-2 years and eGFR decline >5 mL/min/1.73 m2 per year)
13. 2022
*ACEi or ARB should be first-line therapy for HTN when albuminuria is present, otherwise
dihydropyridine CCB or diuretic can also be considered; all three classes often needed to attain BP targets.
25. Reduce/discontinue....
Symptomatic hypotension
Uncontrolled hyperkalemia despite the medical treatment
To reduce uremic symptoms while treating kidney failure (eGFR <15
ml/min per 1.73 m2)
Avoid in women who consider pregnancy or who become
pregnant
29. CJASN April 2017, 12 (4) 700-710
Diabetes Care 2021 Jan; 44(Suppl 1): S151-67
RAAS
Oxidative stresses
30.
31. N Engl J Med 2019;
Lower relative risk of primary outcome by 30%, ESRD by 32%
Lower renal specific outcome (ESKD, 2x creat, death from renal causes) by 34%
32. N Engl J Med 2020;
383:1436-6
HR 0.56
Composite kidney outcome: 44% relative risk reduction
33. N Engl J Med 2015; 373:2117-2128
Kidney outcome (2x creat, RRT initiation, death from kidney cause): 46% relative risk reduction
34.
35. A systematic review and meta-analysis of 4 major trials
SGLT2i substantially reduced….
Risk of dialysis, transplantation, or renal death by 33%
End-stage kidney disease by 35%
Acute kidney injury by 25%
Lancet Diabetes Endocrinol. 2019 Nov;7(11):845-54
36. CVD-REAL 3: a multinational observational cohort study
Dapagliflozin, Empagliflozin, Canagliflozin, Ipragliflozin,
Tofogliflozin, and Luseogliflozin accounted for 57·9%, 34·1%, 5·7%,
1·4%, 0·5%, and 0·4% of SGLT2i initiation episodes, respectively
Initiation of SGLT2i was associated with a 51% reduced risk of
composite kidney outcome ( >50% eGFR decline or kidney failure)
Lancet Diabetes Endocrinol. 2020 Jan;8(1):27-35
37. The largest and most inclusive SGLT2i trial in CKD to date
CKD-EPI eGFR ≥20 to <45 mL/min/1.73m² or
CKD-EPI eGFR ≥45 to <90 mL/min/1.73m² with urine ACR ≥200 mg/g (or PCR
≥300 mg/g)
Expected results in end of 2022
Evidence strong ---Terminated early (5 July 2022)
38. KDIGO 2022
T2D, CKD with
eGFR ≥20 ml/min per 1.73 m2 (1A)1
High priority- uACR ≥200 mg/g creatinine, heart failure
ADA 2022
T2D and DKD patients with..
eGFR ≥20 mL/min/1.73 m2 and urinary albumin ≥200 mg/g creatinine (A)2
eGFR ≥20 mL/min/1.73 m2 and urinary albumin normal to 200 mg/g (B)2
1. KDIGO 2022 (Upcoming/under public review)
2. Diabetes Care 2022;45(Suppl. 1):S175–S185
39. Once initiated, it is reasonable to continue an SGLT2i even if
the eGFR falls below 20 ml/min per 1.73 m2
Unless not tolerated or renal replacement therapy is initiated
40.
41. AKI safety and GFR ‘dip’
Reversible and not a sign of injury
Up to 30% rise in creatinine is acceptable
Risk factors for AKI (eg, hypovolemia, chronic renal insufficiency, heart
failure, nephrotoxic drugs etc.)
AKI risk is also reduced in Real-World Evidence
42. For illness, excessive exercise or alcohol intake…
Temporarily withhold SGLT2i
Keep drinking and eating (if possible)
Check blood glucose and blood ketone levels more often
43. Inform risk of eDKA
Blood glucose and blood ketone levels on admission
Withhold SGLT2i
On the day of day-care procedures and limit fasting to minimum
At least 2 days in advance and the day of surgery requiring one or more days in
hospital and/or bowel preparation
Restart only when eating and drinking normally
53. 1.N Engl J Med 2020;383:2219-29
2.N Engl J Med. 2021 Aug 28.
Two recent trials: FIDELIO-DKD and FIGARO-DKD
54. Finerenone phase III trial included
patients across the spectrum of
DKD severity
55. 1st non-steroidal MRA to be approved for adults with T2D-
associated CKD/DKD
Fills a significant treatment void for millions of patients
July 2021
57. Dose:
eGFR ≥60 : 20 mg once daily
≥25 to <60: 10 mg once daily
<25 : Use not recommended
Maintenance: dose determined by serum potassium
Monitoring: Serum potassium (at baseline, 4 weeks of therapy or dosage
adjustments, and periodically during therapy with increased frequency in patients at risk
for hyperkalemia); eGFR (at baseline and periodically during therapy)
58. 2nd Non-steroidal MRA
Reduces albuminuria in patients with DKD1
Higher rates of ↑K+ compared to finerenone1,2
Effects on mortality and ESKD are unknown
1.Clin J Am Soc Nephrol. 2020;15(12):1715
2.Clin J Am Soc Nephrol. 2019;14(8):1161
59. Correlation is Confusion not Causation: The Case of Uric Acid in CKD/DKD
Is Uric acid lowering beneficial ?
60. N Engl J Med. 2020 Jun 25;382(26):2504-13
Conclusion: Uric acid lowering by Allopurinol has no effect on CKD progression
61. N Engl J Med. 2020 Jun 25;382(26):2493-2503
Conclusion: Uric acid lowering by Allopurinol has no clinically meaningful effect in
T1DM with mild-moderate DKD
64. Role of dietary protein restriction is unclear in DKD
Often being treated with fat and carbohydrate restriction
Slow progression of kidney disease? Conflicting data
65. Cochrane systematic review:
Compared VLPD (0.3–0.4 g/kg/d), LPD (0.5–0.6 g/kg/d) or normal-protein
diet (0.8 g/kg/d) for 12 months
Little or no effect on death and/or ESKD (moderate quality evidence). The
quality of the evidence was downgraded because of imprecision and
inconsistency
The question of the use of a VLPD combined with keto acids in diabetes was
not included
Cochrane Database Syst Rev. 2020 Oct 29;10:CD001892
66. CKD 3-5ND and who has diabetes:
Protein 0.6-0.8 g/kg/day to maintain a stable nutritional status and
optimize glycemic control (OPINION)
Am J Kidney Dis. 2020 Sep;76(3 Suppl 1):S1-107
76. RAS inhibitors (standard-of-care for treatment) remains under
utilized in clinical practice
As in the clinical trials- Critical to deliver the standard-of-care
i.e. RASi , as background therapy
77. ‘Time to Spread the Word that New therapies for
diabetic kidney disease have arrived’
Thanks