CKD: The Story ofmy Seventy-Eight Year Old Patient

Ajay K. Singh, MB, FRCP

Renal Division

Brigham and Women’s Hospital

Senior Associate Dean, Postgraduate Medical Education

Harvard Medical School

Ajay K. Singh Bio

▪Attending Nephrologist, Brigham and Women’s Hospital

▪Senior Associate Dean for Postgraduate Medical Education, Harvard Medical School

▪Research interests: Anemia of CKD and CKDu

▪Clinical interests: managing patients with CKD

Disclosures

▪Gilead – stock ownership

▪GSK – Research Support

Case History

• 78 year old man

• T2DM, HTN

• Scr of 1.32 mg/dL. eGFR >60 ml/min/1.73m2.

• Otherwise healthy.

• PMH- hypertension ≈15 years duration, type 2 diabetes mellitus for 8 year; Hypercholesterolemia treated with atorvastatin.

• BP-- in the 150-160 mmHg range.

• Medications: lisinopril, ASA, hydrochlorthiazide, atorvastatin, metformin, glipizide.

Case History

• PE: BP 152/68 mmHg, HR 72 bpm. Weight 120 kg, Rest of the examination negative.

• Lab values

• Dipstick urinalysis shows SG 1015, pH 6.0, trace to 1+ alb, rest is negative

• BUN 28, Serum creatinine 1.32 mg/dL, HbA1C 7.8

• Does he have kidney disease?

We don’t want to call something a disease when it isn’t

Lindeman, R. D., J. D. Tobin, and N. W. Shock. Longitudinal

studies on the rate of decline in renal function with age. J.

Am. Geriatr. Soc. 33: 278–285, 1985.

xx

7

1. Does he have risk factors for CKD?

• Susceptibility Risk Factors

• Diabetes

• Hypertension

• Older age

• Family history of CKD

• Racial or ethnic minority

• Other: low income, minimal education, kidney-mass

reduction, known kidney disease

Levey et al. Ann Intern Med. 2003;139:137-147..

The Risk of Kidney Failure Is Not Uniform

Relative risks compared to Whites:

African Americans 4.45 X

Native Americans 3.57 X

Asians 1.59 X

Xue, et al., 2000

2. Obtain laboratory Data

b.) Renal USa.) UA dipstick /Sediment

Assess albuminuria – ACR

Risk for progression

or CVD

3. Evaluate Risk of Kidney FailureKidney Failure Risk Equation (KFRE)

▪Tangri’s laboratory based equation to predict CKD progression

▪Accurately predicts CKD stage 3-5 progression over 5 years (C statistic 0.84-0.91)

▪ 3 variable KFRE – Age, Sex, eGFR

▪ 4 variable KFRE – Age, Sex, eGFR, ACR

▪ 8 variable KFRE + Ca, Phos, Bicarb, alb

Tangri et al JAMA 2011, 2016

Rate of GFR Decline in Normals and CKD Patients

25 35 45 55 65 75

Age, years

GF

R m

l/m

in

0

10

20

30

40

50

60

70

80 9

0 1

00

ESRD

1ml/min/year starting at age 45yrs

(normal ageing)

Collister D,et al, Seminars in Nephrol 36, 273-282 2016

http://www.sciencedirect.com/science/article/pii/S027092951630033X

≈ 2-3 ml/min/year

Manage Progression factors for CKD?

• Susceptibility Risk Factors

• Progression Factors

• Diabetes

• Hypertension

• Older age

• Family history of CKD

• Racial or ethnic

minority

• Other: low income,

minimal education,

kidney-mass

reduction, known

kidney disease

• Higher level of

albuminuria

• Higher BP

• Poor glycemic

control

• Smoking

• Hyperlipidemia

• Drug use

Levey et al. Ann Intern Med. 2003;139:137-147.

Algorithm for this 78 year old man

eGFR ml/min/1.73m2

Does he have risk factors?

HTN, DM

High risk group

ACRRenal US

UA and sediment?

Does he have CKD? = YES

NEXT STEPS>>>>

Keys to managing patients with CKD

• Treat BP – goal BP <130/80, multiple agents will be needed

• SPRINT Trial <120/80 goal did not include T2D pts

• Manage diabetes, GLP1RA

• ACEI/ARB

• SGLT2 inhibitor (T2D and non-diabetic patients)

• MRA - Finerenone

• Consider other interventions: low protein diet, statin

ACEi and ARBs; CCBs

• ACEi and ARB have similar antiproteinuric effects

• Combination of ACEi and ARB: 20% reduction in albuminuria – over and above either agent alone

• Dual blockade not recommended

• CCBs - Strong antihypertensive agents

• Dihydropyridine CaCBs (e.g., amlodipine): No effect on CKD progression

• Non-dihydropyridine CaCBs (e.g., diltiazem): Reduces albuminuria, but not very effective for BP reduction

Newer therapy for renal progression in T2 Diabetics: YES… SGLT2 inhibitors

• Reduction in

HbA1c ≈0.5-1.5%

without inducing

hypoglycaemia

•Weight loss of ≈

2-3kg, (calorie loss

via renal glucose

excretion (loss of

80-85g glucose per

day) at around 6

months

•Decrease SBP ≈2-

5 mmHg

• Double blind RCT, N=4401

• T2D with CKD, eGFR 30-90, UACR 0.3 to 5 g alb/g cr

• Canagliflozin, (SGLT2 inhibitor), at a dose of 100 mg daily vs. placebo

• Median F/U 2.62 years

• Primary Outcome: Reduction ≈ 30% in RR of composite of ESRD

(dialysis, transplantation, or a sustained estimated GFR of <15 ml per

minute per 1.73 m2), a doubling Scr, or death from renal or CVD causes

• Components of Primary endpoint reduction ≈ 30%

• CVD and HF benefits

June 13, 2019

CREDENCE: SGLT2 and T2DM

Percovic V et al N Engl J Med 2019; 380:2295-2306

Both diabetics and non-diabetics benefit from SGLT2 inhibition

Oct 8, 2020

• RCT, N= 4304

• eGFR of 25 to 75 ml/min/1.73 m2, UACR 200 to 5000 mg/d, T2DM and

nonT2DM

• Dapagliflozin (10 mg once daily) vs. placebo.

• Primary outcome: composite of a sustained decline eGFR >50%, ESRD, or

death from renal or cardiovascular causes

• Median FU 2.4 years,

• Fewer primary outcomes in dapa (197 of 2152 participants (9.2%)) vs.

placebo (312 of 2152 participants (14.5%)) (hazard ratio, 0.61; 95% CI 0.51

to 0.72; P <0.001

• Number needed to treat to prevent primary=19

SGLT2 and CKD

Heerspink HJL et al N Engl J Med 2020;383:1436-46. DOI: 10.1056/NEJMoa2024816

Effect of non-steroidal mineralocorticoid receptor antagonist in CKD and T2DM

• Double blind RCT, N= 5734

• CKD and type 2 diabetes in a 1:1 ratio to receive finerenone or placebo.

• UACR 30 to <300 mg/g cre, eGFR 25 <60 ml /min/1.73 m2 and diabetic retinopathy,

or UACR 300 to 5000 and eGFR of 25 <75 ml /min/1.73 m2 . All treated with RAAS

inhibitor blockade

• Primary composite outcome: kidney failure, sustained decrease of >40% in the

eGFR from baseline, or death from renal causes.

• median follow-up of 2.6 years

• Fewer primary outcome event in finerenone (504 of 2833 (17.8%)) vs. Placebo (600

of 2841 patients (21.1%)) HR 0.82; 95% CI0.73 to 0.93; P=0.001

• Hyperkalemia-related discontinuation of the trial regimen was higher with finerenone

than with placebo (2.3% and 0.9%, respectively)

Dec 3, 2020

MRA for CKD and T2DM

Bakris GL, Agarwal R, Anker SD, et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl

J Med. 2020;383(23):2219-2229.\

GLP1-RAs and T2DM▪ Glucagon-like peptide-1 (GLP-1) regulates appetite and BS

• GLP-1 RAs mimic the actions GLP-1

– Slow stomach emptying

– Increase insulin production

– Reduce sugar released from the liver

▪ Short-acting (QD or BID)

– exenatide (Byetta)

– lixisenatide (Adlyxin)

– oral semaglutide (Rybelsus)

▪ Long-acting (QD-QW)

– dulaglutide (Trulicity) QW

– exenatide extended-release (Bydureon) QW

– liraglutide (Victoza) QD

– semaglutide (Ozempic) QW

▪ All GLP-1 RAs SC, except oral semaglutide

Slowing kidney progression in patients w/ CKD and T2DM

SOURCE: Sridhar VS et al, AJKD March 2021. https://doi.org/10.1053/j.ajkd.2021.02.324

SGLT2, sodium/glucose cotransporter 2; GLP-1RA, glucagon-like peptide 1 receptor agonist; MRA, mineralocorticoid

receptor antagonist; ERA, endothelin-1 receptor antagonist; ACE, angiotensin-converting enzyme; ARB, angiotensin

receptor blocker; RAAS, renin-angiotensin-aldosterone system.

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Summary

- Use GFR equations and albuminuria to make diagnosis of CKD

- Use a kidney failure risk equation

- Use multiple agents for BP control

- Use ACEi/ARB, but not in combination

- Add SGLT2 inhibitor and/or MRA for CKD+T2DN, but with modest-to-well preserved GFR

- Consider GLP1RA

References

▪ Lindeman, R. D., J. D. Tobin, and N. W. Shock. Longitudinal studies on the rate of decline in renal function with age. J. Am. Geriatr. Soc. 33: 278–285, 1985.

▪ Tangri N, Grams ME, Levey AS, et al. Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis [published correction appears in JAMA. 2016 Feb 23;315(8):822]. JAMA. 2016;315(2):164-174. doi:10.1001/jama.2015.1820

▪ Collister D, http://www.sciencedirect.com/science/article/pii/S027092951630033X

▪ Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi:10.1056/NEJMoa1811744

▪ Bakris GL, Agarwal R, Anker SD, et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219-2229.\

▪ Heerspink H.J.L.Stefansson B.V.Correa-Rotter R.et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446