Recent advances in DKD management presented by Dr C.Malsawmkima, Nephrologist , Civil Hospital Aizawl during IMA Mega CME

1. Recent Advances in Treatment
Of
Diabetic Kidney Disease
Dr.C.Malsawmkima
MD (Med), DM(Nephrology)
Civil Hospital Aizawl
Date: 23-09-2022
IMA Mega CME@ZMC, Falkawn

2.  Introduction
 Screening and diagnosis
 Management and recent advances
 Take home message

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

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)

12. Management of Diabetic Kidney Disease

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.

14. Diabetes Care 2022;45(Suppl. 1):S144–S175

15.  Individualized target and monitoring frequency

16. 2022

18. RASi
SGLT2i
GLP1-RAs
Non-steroidal MRAs
Uricosuric drugs?
Protein restriction?
Acidosis
Slowing Drivers of Disease Progression

21. Am J Kidney Dis. 2021 Aug;78(2):309-11

22. Am J Kidney Dis. 2021 Aug;78(2):309-11

23.  KDIGO 2022
 Diabetes + hypertension + albuminuria: Recommended
 Diabetes + albuminuria + normal BP : May consider
 Titrated to the highest approved dose that is tolerated
 ADA 2022
 uACR ≥ 300mg/g and/or eGFR<60 : Strong recommendation (A)
 Diabetes + hypertension + uACR 30-299mg/g: Recommended (B)
1. KDIGO 2022 (Upcoming/under public review)
2. Diabetes Care 2022;45(Suppl. 1):S175–S185

24. 2022

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

26. Am J Kidney Dis. 2021 Aug;78(2):309-11

27.  SGLT2i and kidneys
 Important clinical trials
 Threshold to initiate?
 When to stop?
 General precautions

28. Nat Rev Nephrol. 2017 Jan;13(1):11-26

29. CJASN April 2017, 12 (4) 700-710
Diabetes Care 2021 Jan; 44(Suppl 1): S151-67
RAAS
Oxidative stresses

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

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

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

44. Glucagon like peptide-1 receptor agonist
(GLP-1RAs)
The preferred add on therapy

45. Am J Kidney Dis. 2021 Aug;78(2):309-11

46. Not clearly understood

49. Non-steroidal MRAs and DKD

50.  MR overactivity is largely under addressed
 Inflammation and fibrosis in the kidneys
 Compromised filtration, albuminuria, and a GFR decline

51. Kidney Int. 2019 Aug;96(2):302-19

52. Am J Kidney Dis. 2021 Aug;78(2):309-11

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

56.  Manageable hyperkalemia with not much clinical impact
 Simple strategy to minimise impact

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

62. Am J Kidney Dis. 2018 Dec;72(6):798-10

63. The role of Protein Restriction

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

68. CJASN 2019;14:
1011–20

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