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1. CHRISTIAN W. MENDE, MD
FACP, FACN, FASN, FASH, FAHA
Clinical Professor of Medicine
University of California, San Diego
La Jolla, Calif.
Chronic Kidney Disease

2. Outline
1) Discuss CKD
a) definition , incidence , causes , risk factors
b) CKD is risk factor for CV Events and Heart Failure
c) Cardiorenal axis
2) Albuminuria
a) risk factor for CKD progression and CV events
3) Diabetic Kidney Disease ( DKD )
a) definition , incidence, causes, complications and therapy
b) DAPA CKD
4) SGLT2 inhibitors
a) postulated mechanism of action
b) renal indications ( KDIGO 2020 )

3. Definition of CKD
Chronic Kidney Disease , present ≥ 3 months :
a) eGFR < 60 ml/min / 1.73 m² or
b) Albuminuria ≥ 30 mg
c) Abnormal Histology ( Biopsy ) or Transplantation
d) Imaging abnormalities ( PCK )
Albuminuria
UACR > 30mg/g Creatinine
Incidence :
> Age 30 ~ 10%
( eGFR < 60 ml/min +/-Albuminuria )

5. Age and Renal Function ( eGFR)
Normal Loss of eGFR ( starting Age 40 )
~ 0.7 ml /Year ( 0.63* – 0.80^ )
Age >70 = 50% of all People = eGFR < 60ml/ min
Type II Diabetes ( well controlled )
A1C < 7%, BP < 130/80 mmHg , LDL < 100 mg%
> 2.0 ml /Year
* Denic, A et.al. 2016 Adv Chronic Kidney Dis 23 (1) : 19
^ Weinstein J. et.al. 2010 Adv Chronic Kidney Dis 17 (4) : 302

6. Causes of CKD
1) Diabetes type 1 and 2
2) Glomerulonephritis
3) Interstitial Nephritis ( allergic reaction to drugs , toxins )
4) Systemic infections
post streptococcal , HIV, hepatitis B and C , endocarditis
5) Genetic
Polycystic Kidney disease ( PCK )
Alport’s syndrome
Fabry’s disease
6) Hypertension ( uncontrolled )
7) Acute kidney Injury ( AKI ) leading to chronic CKD
8) Nephrotoxic drugs ( Amphotericin , Aminoglycoside, NSAID , Chemotherapy

7. 7
Structural Changes to the Kidney
• Thickening of glomerular
basement membrane
• Capillary and tubular
basement membrane
thickening
• Loss of endothelial
fenestrations
• Mesangial matrix
expansion
• Loss of podocytes
with effacement of
foot processes
Reference: Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032–2045. doi:10.2215/CJN.11491116

8. Glomerulonephritis ( GN )
Immunological mechanism trigger inflammation and proliferation in the glomerulus , leading to damage to the
endothelium
basement membrane
podocytes
mesangium .
Classification :
acute : sudden onset with red cell cast, hypertension edema and rapidly rising creatinine
chronic : silent onset with albuminuria and gradually declining eGFR
Many different types (depending on the immnune complex and mechanism ) :
IgA nephropathy,
Lupus nephritis
Membranous GN
FSGS ( focal segmental glomerulpsclerosis )
Post Streptococcal GN

9. IgA Nephropathy
Incidence
Most common GN : up to 10% of all GN in USA
40% in Asia
Clinical Features
acute : 50% gross hematuria +/- albuminuria
chronic : hematuria +/ - albuminuria , edema
hypertension
Therapy :
ACE inhibitors or AEB’s for albuminuria or hypertension
Omega 3 Fatty acids
Steroids , Immunosuppression ( Cyclosporin )
( ? DAPA pending FDA )

10. Albuminuria and eGFR independently predict
Renal and CV Outcomes ( ADVANCE)
10,640 T2D Patients , followed for 4.3 Years
Albuminuria (median UACR 15 mg/g) = 10 fold Rise to > 150 mg/ g
Event Risk Cardiovascular 2.5 x
Renal 10.5 x
Renal Function (median eGFR 76 ml /min ) = 50% Loss of eGFR
Event Risk Cardiovascular 2.2 x
Renal 22 x
Both eGFR < 60 ml /min and UACR > 300 mg/g
Event Risk Cardiovascular 3.2 x
Renal 22.5 x
CV Event = 3-MACE, Renal Event = doubling Creatinine to > 2.26 mg , ESRD , renal Death
Ninomiya,T. et.al. 2009 J Am Soc Nephrol 20 :1813

11. Albuminuria
When to test for UACR (Urine/Albumin/Creatinine Ratio)
Present in many Conditions :
Metabolic Syndrome
Pre-diabetes
Diabetes
Obesity
Renal Diseases ( Glomerulonephritis, Lupus, etc. )
Heart Failure
Hypertension ( usually Stage II , uncontrolled SBP)
Significance
1) Sign of endothelial Dysfunction ( “ renal hCRP ” )
2) Risk of Progression to higher albuminuria levels
3) Risk for CKD progression
4) Criterium for CKD , even with normal eGFR
5) Sustained > 30% Albuminuria Reduction = 24 % reduced ESKD Risk *

12. Drug-induced Reduction of Albuminuria and subsequent Renoprotection
(Meta-analysis)
21 Trials with 78,342 Patients with Albuminuria, Age 12- 68, eGFR 19 - 92 ml/ min,
followed for 11- 56 months .
Results (average for all trials )
Albuminuria Reduction = 19 %
ESRD Risk Reduction = 17 %
Conclusion :
> 30% Reduction of Albuminuria = 24% ESRD Risk Reduction
( Findings are consistent regardless of Drug Class )
REASSURE Consorium , Heerspink, H. etal. 2015 JASN ;26 (8) : 2055

13. 13
Data Source: Special analyses, Medicare 5% sample. Abbreviations: AF, atrial fibrillation; AMI, acute myocardial infarction; CAD,
coronary artery disease; CKD, chronic kidney disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; CVD,
cardiovascular disease; HF, heart failure; PAD, peripheral arterial disease; SCA/VA, sudden cardiac arrest and ventricular
arrhythmias; VHD, valvular heart disease; VTE/PE, venous thromboembolism and pulmonary embolism
Prevalence of cardiovascular Diseases with or without CKD,
2016
2018 Annual Data Report
Volume 1 CKD, Chapter 4

14. CKD and Cardiovascular Risk
1) AGE > 60 = Linear Relationship between CKD (eGRF < 60 ml ) and
Risk of Heart Failure
CVA
CAD
MI
PAD
2) UACR > 300 Major Risk for CVD
= IRRESPECTIVE of eGFR ( including Dementia ! )
Conclusion:
CKD and / or Albuminuria are CVD Risk Factors
independent of
Hypertension
Diabetes
Comorbidities ( smoking , Obesity )
van der Velde M et al Clin J Am Soc Nephrol 2010; 5 :2053

15. 15
Data Source: Special analyses, Medicare 5% sample. Patients aged 66 and older, alive, without end-stage renal disease, and
residing in the United States on 12/31/2016 with fee-for-service coverage for the entire calendar year. Abbreviation: CKD, chronic
kidney disease.
Heart Failure in Patients with or without CKD,
MEDICARE 2016
2018 Annual Data Report
Volume 1 CKD, Chapter 4

17. Cardio – Renal Syndrome ( Type 2 )
Chronic HF causing progressive CKD
CKD Incidence :
1/3 of all CVD patients (1)
1/2 of chronic HF patients (2)
60% of patients with HF and T2D
Risk Factors for CVD and CKD development are the same :
diabetes, hypertension, hyperlipidemia, obesity , smoking
CKD per se is major CVD Risk Factor and Predictor of Prognosis
Prevention
Renal : RAAS blockade ( 20% lower eGFR progression )
SGLT2 inhibitors
( MRA antagonist , pending FDA approval of Fineronone )
CVD : RAAS blockade
SGLT2 inhibitors
MRA ( Mineralocorticoid antagonists : Spironolactone , Eplenrenon)
Beta Blockers
Statins
Antiplatelet therapy
(1) Kundhal ,K et.al. Nephron Clin Practice ,2005; 101(2) : c 52
(2) Ahmed,A. et.al . Am J Cardiology 2007 ; 99 (3) : 393

18. Stage CKD 3 a ( eGFR 45 – 59 ml /min )
> Age 21 = 22 %
> Age 65 = 43 %
Stage CKD 3 b ( eGFR 30 – 44 ml / min )
> Age 21 = 9 %
> Age 65 = 18 %
Overall CKD incidence in Diabetes = 40%
Bailey RA et.al BMC Research Note , 2014 ;7:421
DKD Incidence in T 2 Diabetes (USA)

20. What causes DKD ?
Factors in Diabetes contributing to the risk of DKD :
Hyperglycemia ( prolonged and uncontrolled )
a) associated hyperinsulinemia / Insulin resistance
Hypertension BP > 140/ 90 mmHg)
Obesity ( ~ 3 x higher CKD risk for BMI > 30 )
Dyslipidemia
Heart Failure ( see chronic cardio- renal syndrome )
Smoking
Age
Family history of CKD
Race Afro- American , Hispanic , Pacific Islanders American Indian
High protein diet ( above 1.2 gm of protein / kg weight per day )

21. How does Hyperglycemia affect the kidney ?
Hyperglycemia
causes decreased pre- glomerular vasodilation ( TGF )
increased post glomerular vasoconstriction ( RAAS )
both causing a) hyperfiltration
b) glomerular hypertension
Consequences : damage to the filter ( loss of podocytes , mesangial proliferation ) with
a) loss of kidney function
b) albuminuria ( subsequent interstitial fibrosis )
Indirect effects include renal injury secondary to :
Advanced glycation products ( AGE’s)
Renal insulin resistance
RAAS activation
Oxydative stress
Inflammation and Fibrosis
Mitochondrial dysfunction

22. DKD Progression and Cardiovascular Risk
30,222 type 2 diabetes , with newly diagnosed DKD in UK
~ Age 64 , eGFR 52 / ml/min, without HF, MI or CVA followed for 2 years :
DKD compared to T2D without CKD .
eGFR loss of 3.0 ml /min in 2 years ( 1.5 ml /year ) increased cardiovascular risks by :
HF 50%
MI 39%
MACE 45%
Conclusion :
CKD strong independent risk factor for CVD
Cabrera, CS (AstraZenica + University Gothenburg) KI Reports 2020; 5 : 1651

23. Cardiovascular Risks in DKD
1) Cardiovascular Risk in Diabetes ( MI, CVA ,CHF ) greater than
CKD Progression:
70 % CVD Mortality
4 % only reach ESRD ( Dialysis , Transplantation )
2) eGFR < 45 ml /min = MAJOR Risk Factor for CVD ( +/- Diabetes )
3) Obesity independent Risk Factor for = CVD , CKD , Diabetes
Hypertension
4) Sleep Apnoe = Risk Factor for Diabetes, Hypertension , CKD
Combination of Diabetes + CKD = 4- fold Risk of CVD and Mortality

24. Complications of CKD
1) Hypertension causing a) worsening CKD
b) CVD
2) CVD Heart Failure ( LVH, Arrhythmias, sudden Death )
Myocardial infarction, CVA , PAD
3) Anemia low Fe and EPO
4) Mineral Bone Disorders low Vit.D, high P04 and PTH
5) S alt and Water Retention Edema and Hypertension
6) Metabolic Acidosis ( HCO3 < 23 )
7) Hyperkalemia ( K > 5.5 meq/L )

25. DAPA CKD

32. Unique Renal Aspects of DAPA CKD
1) 90 % had an eGFR < 60 and ~ eGFR 43 ml / min
a) compared with 60 % and ~ eGFR 57 ml/min in Credence
b) included IgA nephropathy
2) 14% had an eGFR < 30 ml/ min = CKD 4 with an eGFR as low as 25 ml/ min
a) > 100 CKD patients continued DAPA until dialysis ( NO safety issues / side effects )
3) Diabetes or No Diabetes = same Benefit
a) No difference in any subgroup ( CKD stages , Diuretics, MRA, Albuminuria, etc )
b) 44% reduction of RENAL endpoint
4) eGFR Slope = 0.93 ml / Year reduced Loss ( vs Placebo )
( 2.86 ml vs. 3.79 ml / Year )
5) Heart Failure admissions were impressively reduced by 29 %
( CKD is present in 40 - 50% of Heart Failure )

35. DKD Management (KDIGO 2020)
All Patients
1) Glycemic control ( A1C < 6.5 - < 8.0 % )
2) BP control ( ideally < 130 /80 mmHg , if tolerated )
3) Lipid management
4) Exercise , Nutrition and Smoking cessation
Most Patients
1) Metformin and SGLT2 inhibitors ( for eGFR > 30)
2) RAAS blockade
Some Patients
1) Antiplatelet therapy

36. DKD Management
Hypertension
BP Goal = < 140 / 90 mmHg ( for all diabetes )
( ADA 2020 ) < 130 /80 in DKD and > 300 mg albuminuria
ACEI or ARB “ drug of choice “ for albuminuria with or without hypertension
( Not indicated for Diabetes per se !)
Glycemia Therapy
A1C GOAL < 6.5% - < 8.0%
Metformin and SGLT2 inhibitor for eGFR > 30 ml/ min ( KDIGO 2020 )
Sodium Intake < 5 gm Salt ( 2,500 mg Na )
Protein Intake < 0.8 g / kg / Day
Healthy Lifestyle 150 min / week of Physical Activity
BMI 20 - 25 ( most desirable )
NO Smoking

37. What Drugs are available for the treatment of DKD ?
1) Ace inhibitors or Angiotensin receptor blockers ( ARB’s ) reduce
a) albuminuria by 40-50 %
b) progression of DKD by about 20 % .
2) Sodium glucose cotransport inhibitors ( SGLT2 inhibitors) reduce
a) Albuminuria by 35- 45 % *
b) DKD progression by 35 – 45 %
3) GLP 1 agonists
a) reduce albuminuria 25 - 30%
b) early data = slowing of DKD ( renal trial ongoing)
4) Non steroidal Mineralocorticoid antagonist ( pending FDA approval )
FIDELIO –DKD ( Finerenone ) reduced
a) primary renal endpoint ( kidney failure , 40% sustained eGFR loss or renal death ) by 18%
b) secondary endpoint ( 3- MACE and HHF ) by 14 % ( Bakris, G et.al. NEJM ; online Oct. 23 , 2020 )
*( additional in use with ACE inhibitors or ARB’s )

39. Renal Effects of SGLT2 inhibition (1)
1) Natriureses : ~ 40 meq/ day for ~ 3 days then level off
a) additional effect of collateralization of NHE -3
b) reduced Na content of skin (DAPA)
2) Diuresis : ~ extra 450 ml /day x 3-4 days then 150 ml daily
a) resulting in 7% lower plasma volume = 250 ml lower ECV
( interstitial > intravascular compartments )
3) Acute eGFR Decline : 3- 5 ml/ min , return to baseline 8-12 weeks
3) SBP lower by ~ 5 mmHg ( natriuresis and vasodilation , mechanism ? , improved non-dipping BP )
4) Improved renal cortical Hypoxia Hypoxia of cortex in T2D caused by higher ATP need with increased glucose + NaCl
reabsorption and mitochondrial dysfunction
5) Increased Hematocrit ~ 3% secondary to higher Erythropoetin , lower Hepcidin , reduced plasma volume
6) Albuminuria Reduction = 30 – 50 % ( in addition to ~ 40 % with RAAS blockade)
secondary to lower intra –glomerular P by 5 - 7 mmHg ( via pre-glomerular vasoconstriction)

40. Renal Effects of SGLT2 inhibition (2)
7) Uric acid lowered by 10- 15 % ( uricosuric , w/o stone formation , reduce gout attacks )
8) Increased Mg by ~ 10 % ( no hypermagnesemia reported )
9) In DKD slowed CKD/ onset of ESRD by ~ 30%
a) reduce eGFR loss with albuminuria > 300 mg/g by 2.75 ml/min /year = 60% ( CREDENCE )
b) reduce eGFR loss regardless of albuminuria in CKD (+/- T2D ) by 0.93 ml/min ( DAPA CKD )
10) Lowered hCRP ( 26%) , IL 6 ,
KIM -1 , Leptin ,
renal Angiotensinogen production ,
NLRP-3 inflammasome
11) Adiponectin increased , Leptin reduced
13) Ketone production increased ( beta oxidation of Fatty Acids) “ Thrifty Fuel Hypothesis”
14) Improved mitochondrial function (Autophagy restored )

41. AKI Acute Kidney Injury
( loss of > 50% eGFR over 2 days )
Albuminuria > 1000 mg / g
CKD Progression a) > 5 ml Loss / year or change in Stage
b) eGFR < 45 ml/min
Active sediment : Red cell cast , WBC infection
Resistant Hypertension : Not at Goal on 3 Drugs ( CCB, RAAS ,Diuretic)
Recurrent Nephrolithiasis ( 2 or more Episodes )
Hyperkalemia ( persistent K > 5.6 meq /L )
Hereditary Kidney Disease ( i.e. PCK )
Nephrology Referral

42. What Test should be done before Referral ?
Lab :
CA , PO4
PTH
Serum iron studies
Vitamin D3
If UACR > 500 mg/g
a) 24 hour urine albumin
b) serum and urine electrophoresis
Renal Ultrasound

43. Key Aspects of DAPA CKD for HCP ( and Nephrologists )
1) First SGLT 2 inhibitors to show Benefits in slowing GFR Loss by 0.93 ml / Year for BOTH
a) Diabetic Kidney Disease ( DKD)
b) Non- diabetic Chronic Kidney Disease ( CKD)
Reduction of Renal endpoint by 39 % ( 50% sustained eGFR Loss , ESKD , Renal or CV death )
c) Benefits seen in all eGFR categories and albuminuria levels
2) Hypoglycemia in Type 2 Diabetes = low incidence ( unless co –use of Sulfonylurea or Insulin )
No hypoglycemia or DKA risk without Diabetes
3) Initial eGFR reduction
a) about 3-5 ml after first dose secondary to afferent vasoconstriction ( hemodynamic effect)
b) reduced hyperfiltration and intraglomerular pressure ( see albuminuria reduction )
c) No increase in Acute Kidney Injury ( AKI actually about 25 % lower incidence )
4) No Electrolyte Disorder No Hyperkalemia or Hyponatremia
5) Reduced HF admissions and CV Death by 29%
6) SGLT2 inhibitor Features not FDA approved
a) reduce Uric Acid 10-15 % ( No nephrolithiasis)
b) reduce Albuminuria by ~ 30 to 50 % ( in addition to reduction from ACE Inhibitors or ARB’s)
c) increase Mg by 8-10 % ( no hypermagnesemia seen)
d) lower SBP by ~ 5 mmHg
e) Weight by ~ 5 lbs

44. What concerns Nephrologists about SGLT2 inhibitors ?
1) Initial ~ 5 ml/min decline in eGFR
a) occurs after single dose irrespective of baseline eGFR (only ~ 2 ml / min in CKD 4)
2) Acute Kidney Injury ( AKI )
a) data actually show an about 20- 25 % lower incidence
b) avoid volume depletion and excessive BP reduction in first week
3) Hypoglycemia
a) risk only on SU or Insulin therapy ( reduce SU by 50% and Insulin by 10 -20 %)
b) No hypoglycemia in non- diabetic CKD
4) DKA
a) risk is double but small
b) “ sick day rule “ : no food no drink = No drug
5) Genital mycotic infections
a) relatively easy to treat
6) When to avoid SGLT 2 inhibitors
History of DKA
recurrent severe GMI , catherized patients ( UTI risk high)
PCK
immunosuppressed CKD patients

45. Summary : Risk Modification in CKD ( KDIGO 2020)
1) Stop Smoking
2) A1C < 6.5 % - < 8.0 % ( diabetes )
3) Keep BMI as close as possible to ~25
4) Exercise 150 min / week ( at least )
5) Statin Therapy ( LDL > 100 )
6) BP Control to < 130 / 80 mmHg (AHA / ACC 2017)
a) use ACEI or ARB’s first line unless Creatinine rise > 30%
7) Correct Anemia = Hgb in 11- 12 gm Range
8) Treat Albuminuria with ACEI or ARB ( NOT both ! )
9) Keep HCO3 > 22 meq /L , PO4 < 4.5 mg /dl
10) Diet protein restriction to 0.8 g/kg/ day ( less animal more plant type)
reduce salt intake to < 5 gm NaCl ( or 2000 mg Na )
11) Avoid Nephrotoxic Drugs ( NSAID’s )
12) DKD = use Metformin + SGLT2 inhibitor for eGFR > 30 ml/min