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Fundamentals of Chronic Kidney Disease (CKD) for Basic and Clinical Neuroscientists
Kam Kalantar-Zadeh, MD, MPH, PhDTwitter/Facebook/LinkedIn: @KamKalantar
Professor of Medicine, Pediatrics, Public Health, and Nursing Sciences Chief, Division of Nephrology and Hypertension and Kidney Transplantation
University of California Irvine (UCI) School of MedicineHarold Simmons Center for Kidney Disease Research & Epidemiology, Orange, CA Tibor Rubin Veteran
Administrations’ Long Beach Healthcare System, Long Beach, CAProfessor of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA
World Kidney Day (WKD) Steering Committeewww.WorldKidneyDay.org
Past PresidentThe International Society of Renal Nutrition & Metabolism (ISRNM)
www.RenalNutrition.com
ISN Council member (2016-2019)International Society of Nephrology (ISN) Council
www.RenalNutrition.com
Editor-in-ChiefJournal of Renal Nutrition (JREN)
www.JRNjournal.org
University of California Irvine Medical Center, Orange, CA
University of California Irvine Medical Center, Orange, CA
University of California Irvine Medical CenterIn the heart of Disneyland
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Dr. K. Kalantar‐Zadeh has received honoraria and/or support in different forms from Abbott, Abbvie, Alexion, Amgen, ASN
(American Society of Nephrology), Astra‐Zeneca, Aveo, Chugai, DaVita, Dr. Schaer, Fresenius, Genentech, Haymarket Media, Hofstra Medical School, IFKF (International Federation of
Kidney Foundations), ISH (International Society of Hemodialysis), International Society of Renal Nutrition & Metabolism (ISRNM), JSDT (Japanese Society of Dialysis Therapy), Hospira, Kabi, Keryx, Novartis, NIH (National
Institutes of Health), NKF (National Kidney Foundations), Pfizer, Relypsa, Reata, Resverlogix, Sandoz, Sanofi, Shire, US Renal
Care, Vifor, UpToDate, ZS‐Pharma.
Kamyar Kalantar-Zadeh, MD, MPH, PhD
Objectives:1. Review the symptoms, screening and diagnosis
of CKD
2. Evaluate the major risk factors and causes of CKD: Diabetes and HTN
3. Examine Poor Outcomes in CKD
4. Assess the major complications associated with CKD
5. Review management of CVD in CKD patient including evaluation and treatment options
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Section 1
CKD Diagnosis and Classification
Glomerular Filtration & Creatinine Clearance
Glomerular Damage CKD
CKD Epidemiology
Diabetic Nephropathy
Proteinuria CKD progression
CKD Cardiovascular Risk
Beyond serum creatinine
Management of CKD
Nephrology Referral
CKD Comorbid DisordersDO NOT
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Glomerular Filtration & Creatinine Clearance
Glomerular Damage CKD
CKD Epidemiology
Diabetic Nephropathy
Proteinuria CKD progression
CKD Cardiovascular Risk
Beyond serum creatinine
Management of CKD
Nephrology Referral
CKD Comorbid Disorders
Glomerulus
Mesangial Matrix
Efferent Renal Arteriole
Mesangial Cells
Renal Sympathetic
Nerves
Bowman’s Capsule
DistalConvoluted Tubule
Proximal Convoluted Tubule
Adventitial Mast Cell/Macrophage
Components of the Normal Nephron
Vascular Smooth Muscle Cells
Afferent Renal Arteriole
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Glomerular Filtration
Glomerular Filtration Rate (GFR): 90-130 ml/min
Creatinine Clearance
Equation to estimate Creatinine Clearance (CrCl) eGFR
• If 24 hr urine can be collected:
CrCl = (Vu x Ucr ) / Pcr
• If no urinary data available (only serum creatinine is available):Cockroft-Gault (0.85 for women)
eGFR = 0.85 * ( Wt x [140-age] ) / Pcr x 72
• Other equations: MDRD
eGFR = 170 * Pcr-0.999 * age-0.176 * sex * race * BUN-0.170 *albumin0.318
(Female: 0.762, AA:1.18)
• Other equations: CKD-EPI
100 eGFR ~ ------
Pcr
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MDRD Equation
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Diabetes50%
Hypertension27%
Glomerulonephritis13%
Other10%
Primary Diagnoses for Patients Who Start Dialysis
United States Renal Data System (USRDS) 2016-2019 Annual Data Report • WWW.USRDS.ORGDO N
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Diabetes Complications
• A. Macro-angiopathies – CAD (Coronary artery dis.)– PVD (Peripheral vascular dis.)– CVD (Cerebro-vascular dis.)
• B. Microangiopathies– Retinopathy– Neuropathy– Nephropathy
– Diabetic Foot ulcer
CKD ESRD
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Natural History of Diabetic Nephropathy
0
20
40
60
80
100
120
140
0 5 10 15 20 25 30
Duration of Diabetes (y)
0
100
200
300
400
500
600
Uri
nar
y A
lbu
min
(m
g/2
4 h
)
Microalbuminuria
Albuminuria
eGFRAlbumin
Courtesy of Mark E. Molitch, MD.
eGF
R (
mL
/min
/1.7
3 m
2)
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Glomerular Filtration & Creatinine Clearance
Glomerular Damage CKD
CKD Epidemiology
Diabetic Nephropathy
Proteinuria CKD progression
CKD Cardiovascular Risk
Beyond serum creatinine
Management of CKD
Nephrology Referral
CKD Comorbid Disorders
•Glomerular HTN
•Hyperfiltration
•Glomerular barrier dysfunction
•Proteinuria
•Mesangial cell hyperplasia
•Intrarenal inflammatory processes
•Endothelial dysfunction
Normal Kidney
Mechanisms of Kidney Damage in CKD ( GFR)
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Mechanism of Kidney Damage in CKD:Glomerular Hypertension
Increased intra-glomerular pressure
Loss of nephrons or irreversible damage
Compensatory hyperfiltrationDamage to
glomerulus structure
CKD is a progressive disorder ESRD
vicious cycle
Hostetter T H, Olson J L, Rennke H G, Venkatachalam M A & Brenner B M. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Amer. J. Physioi. 241:F85-93, 1981
Natural Progression of CKD(Chronic Kidney Disease)
The rate of progression of GFR is usually predictable.
GFR
Time
01/18 3/19 5/20 7/21 1/22
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Natural Progression of CKD(Chronic Kidney Disease)
Previous record of S-creatinine:1/18: 1.8 9/19: 2.1 4/20: 2.0 8/20: 2.2 11/20: 2.9 9/21: 3.4 1/22: 3.3
eGFR [1/crea]
Time01/18 3/19 5/20 7/21 1/22
1/crea curve can help identify Acute-Kidney Injury: 1/22: S-creat 5.2 mg/dL
Target for Feb 2022: S-creat ~ 3.5 mg/dL
100 CrCl ~ ------
Pcr
Definition of Acute Kidney Injury (AKI) based on “Acute Kidney Injury Network” (AKIN Criteria)
Stage Increase in Serum Creatinine
Urine Output
1 1.5-2 times baseline OR0.3 mg/dl increase from baseline
<0.5 ml/kg/h for >6 h
2 2-3 times baseline <0.5 ml/kg/h for >12 h
3 3 times baseline OR0.5 mg/dl increase if baseline>4mg/dlORAny RRT given
<0.3 ml/kg/h for >24 hORAnuria for >12 h
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Glomerular Filtration & Creatinine Clearance
Glomerular Damage CKD
CKD Definition & Epidemiology
Diabetic Nephropathy
Proteinuria CKD progression
CKD Cardiovascular Risk
Beyond serum creatinine
Management of CKD
Nephrology Referral
CKD Comorbid Disorders
Definition of CKD(Chronic Kidney Disease)
The presence of kidney damage, or level of kidney function
for 3 months or more, irrespective of diagnosis
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Definition of Chronic Kidney Disease (CKD)
• Criterion 1. Kidney damage for 3 months, as defined by structural of functional abnormalities of the kidney, with or without decreased GFR, manifest by either:
– Pathological abnormalities; or
– Markers of kidney damage, includingabnormalities in the composition of the blood or urine, or abnormalities in imaging tests
• Criterion 2. GFR (or Creatinine Clearance) <60mL/min/1.73m2 for 3 months, with or without kidney damage
National Kidney Foundation K/DOQI Guidelines 2001
Staging of CKDStage Description GFR
(mL/min/1.73m2)Action*
At increased risk >90(with CKD risk factors)
>Screening>CKD risk reduction
1 Kidney Damage withNormal or ↑GFR >90
>Diagnosis and treatment.>Treatment of comorbid conditions,>Slowing progression,>CVD risk reduction
2 Kidney Damage withMild ↓GFR 60-89 >Estimating progression
3 Moderate ↓ GFR 30-59 >Evaluating and treating complications
4 Severe ↓ GFR 15-29 >Preparation for Kidney Replacement Rx
5 Kidney Failure <15(pre-ESRD or dialysis)
>Renal Replacement Rx (dialysis/Trsp)[if uremia present]
CKD = Chronic Kidney Disease National Kidney Foundation K/DOQIDO NOT
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Staging of CKDStage Description GFR
(mL/min/1.73m2)Action*
At increased risk >90(with CKD risk factors)
>Screening>CKD risk reduction
1 Kidney Damage withNormal or ↑GFR >90
>Diagnosis and treatment.>Treatment of comorbid conditions,>Slowing progression,>CVD risk reduction
2 Kidney Damage withMild ↓GFR 60-89 >Estimating progression
3 Moderate ↓ GFR 30-59 >Evaluating and treating complications
4 Severe ↓ GFR 15-29 >Preparation for Kidney Replacement Rx
5 Kidney Failure <15(pre-ESRD or dialysis)
>Renal Replacement Rx (dialysis/Trsp)[if uremia present]
CKD = Chronic Kidney Disease National Kidney Foundation K/DOQI
2012 refinement/revision by KDIGO
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The Chronic Kidney Disease Epidemic
Coresh J et al. JAMA. 2007;298:2038-2047; United States Renal Data System (USRDS) 2005 Annual Data Report.
3.6
6.5
15.5
0.7 0.450
2
4
6
8
10
12
14
16
1 2 3 4 5
Mil
lio
ns
of P
eo
ple
≥90 60-89 30-59 15-29 <15
CKD StageeGFR(mL/min/1.73 m2)
CKD Affects ~16% of the US Population
USA: Dialysis Dependent Patients540,000 US Americans and growing680,000 ESRD = dialysis + Transplants
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Kovesdy & Kalantar-Zadeh. Enter the dragon: a Chinese epidemic of CKD?
Lancet 2012 Mar 3;379(9818):783-5
USA: 26 millions China: 119 millions
CKD-EPI EquationMatsushita … Levey, JAMA. 2012 May 9; 9;307(18):1941-51
EDITORIAL: Kalantar-Zadeh & Amin. JAMA. 2012 May 9;307(18):1976-7
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CKD-EPI EquationMatsushita … Levey, JAMA. 2012 May 9; 9;307(18):1941-51
EDITORIAL: Kalantar-Zadeh & Amin. JAMA. 2012 May 9;307(18):1976-7
• Estimating GFR based on filtration markers such as serum• creatinine or cystatin C concentration should serve as a screening tool
and should be interpreted conservatively to avoid labeling healthy individuals with the diagnosis of CKD stage 3 before timed-urine collection or other tests are assessed carefully.
• Although use of the CKD-EPI equation may mitigate this problem, and this equation should now replace the MDRD equation, the search for better filtration markers and estimated GFR equations continues. In the interim, a wiser cutoff level at which patients should be warned about possible kidney disease, such as an estimated GFR lower than 45 mL/min/1.73m2 by the CKD-EPI equation, would be prudent.
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Glomerular Filtration & Creatinine Clearance
Glomerular Damage CKD
CKD Definition & Epidemiology
Diabetic Nephropathy
Proteinuria CKD progression
CKD Cardio/cerebro-vascular Risk
Beyond serum creatinine
Management of CKD
Nephrology Referral
CKD Comorbid Disorders
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No EventsESRDDeath
Increased Mortality in Patients With Diabetes, CKD, or Both: 2-Y Clinical Outcomes
DM = diabetes mellitus; ICD-9-CM = International Statistical Classification of Diseases, 9th Revision, Clinical Modification.CKD identified as ICD-9-CM diagnosis code, includes CKD from diabetes, hypertension, obstructive uropathy, and other diagnosis codes reported to USRDS.Collins et al. Kidney Int. 2003;64(suppl 87):S24-S31.
Medicare Cohort
84.0
15.729.5 32.3
67.6 61.6
0
20
40
60
80
100
+ DM,- CKD
- DM,+ CKD
+ DM,+ CKD
Pat
ien
ts (
%)
0.3
2.96.1
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Patient population: health plan patients with estimated GFR <90 followed up until RRT, death, or disenrollment from health plan. N=27,998.
Keith et al. Arch Intern Med. 2004;164:659
0
20
40
60
80
100
Died RRT Event-free Disenrolled
5-Year Follow-UpP
erce
nt
of
Pat
ien
ts (
%)
10%
75%
15%
20% 24%
46%
63%
16% 10%
64%
7%
1.3%
28%
19%
1.1%
GFR 60-89No Proteinuria
GFR 60-89+ Proteinuria
GFR 30-59 GFR 15-29
†
DEATH IS MORE COMMON THAN DIALYSIS IN CKD
.1%
CKD 2 CKD 2 CKD 3 CKD 4
CKD and Age-Standardized Rates of Hospitalization, CV Events and Death in 1.1 Million Outpatients over 3 yrs
0
5
10
15
20
>60 45-59 30-44 15-29 < 15Age-
Sta
ndar
diz
ed R
ates
HOSPITALIZATIONS/10 person-yrs
CV EVENTS/50 person-yrs
ALL CAUSE DEATH/100 person-yrs
Go et al, New Engl J Med 351:1296, 2004
CKD-5D
Dialysis Pts
~18% /yrCKD-1 & 2 CKD-3a CKD3b CKD-4 CKD-5
b6
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b6 X and Y axis lines are blank. Y is labelled "age-standardized rates". X is not labelled.bnewsome, 10/8/2004
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Sarnak. Am J Kidney Dis. 2000;35(suppl 1):S117.
Cardiac and Cardiovascular Mortality
GP Male
GP Female
GP Black
GP White
DP Male
DP Female
DP Black
DP White
100
10
1
0.1
0
25–34 35–44 45–54 55–64 65–74 75–84 >85
Age (years)
An
nu
al M
ort
alit
y (%
)
General Population (GP)
Dialysis Population (DP)
What do people with CKD die from?Cardiovascular disease is a major cause
USRDS, 2010‐2019 ADRNational Vital Statistics Report, CDC 2010‐2018
Cardiovasculardisease42.0%
Infection3.6%
Withdrawal9%
All other33.0%
Malignancy4%
Cardiovasculardisease31.0%
All other33.1%
Malignancy23.2%
Lung disease5.3%
Self‐harm1.4%Alzheimers
3.1%
Infection12%
ESRD, USA General population, USA
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Glomerular Filtration & Creatinine Clearance
Glomerular Damage CKD
CKD Definition & Epidemiology
Diabetic Nephropathy
Proteinuria CKD progression
CKD Cardiovascular Risk
Beyond serum creatinine
Management of CKD
Nephrology Referral
CKD Comorbid Disorders
Creatinine Levels
Problems with Serum Creatinine?
• Insensitive for detecting kidney dysfunction• Product of muscle breakdown – so reflects nutritional status• This may be a problem particularly in the elderly
NutritionalStatus
KidneyFunction
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Cystatin C(0.53-0.95 mg/dL)
• Nonglycosylated, low molecular mass (13 kDa) protein produced by all nucleated cells.
• Its low molecular mass & its high isoeletric point (pI) allow it to be freely filtered by the glomeruli.
• Serum concentration of cystatin C correlates with GFR.
• Serum levels of cystatin C are independent of weight and height, muscle mass, age (>1 yr.) or sex, making GFR estimates much less variable than those with creatinine.
• Measurements can be made and interpreted from a single random sample.
• Jung et al, Nephron 1995
Mortality from all causes according to quintile of kidney function
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COST! (but much less expensive in recent years)More data is still needed re inflammation, thyroid
disease, HIV, etc)? Few reports suggested that cystatin C is affected
by: changes in thyroid function Inflammation (CRP) corticosteroids active HIV infection Certain malignancies?
Inker … Levey, NEJM 2012
BETTER than either of them? Combine both!
The combined creatinine–cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for CKD.
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Glomerular Filtration & Creatinine Clearance
Glomerular Damage CKD
CKD Definition & Epidemiology
Diabetic Nephropathy
Proteinuria CKD progression
CKD Cardiovascular Risk
Beyond serum creatinine
Management of CKD
Nephrology Referral
CKD Comorbid Disorders
Management of CKD (Chronic Kidney Disease)
• Can CKD be cured or reversed? • No!
• Can the progression of CKD be stopped?• No!
• Can the rate of progression of CKD be slowed down?• Yes!
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Can the rate of CKD progression be modified?
The rate of progression of CKD is usually predictable.
eGFR(1/Cr)
Time
01/13 3/14 5/15 7/16 10/17 12/18
with ACEI
without ACEI
Started on ACEI
Pathologic Processes Leading to Glomerular Injury and Proteinuria
afferent
Increasedglomerularpressure
efferent
Urinary protein
Efferent arteriolar
constriction
=angiotensin AT1receptor
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Many nephrologists are trained to learn that “MDRD Study” was a failure!
“Low Protein Diet has no effect” ???
Low Protein Low SaltDiet Therapy for the Management of CKD
Pathologic Processes Leading to Glomerular Injury and Proteinuria
afferent
Increasedglomerularpressure
efferent
Urinary protein
Efferent arteriolar
constriction
=angiotensin AT1receptor
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Amino acids (dietary protein intake) deliveryincreases intracapillary glomerular pressure and GFR
Aminoacids• Glom. flow • Cap. glom. pressure• GFR
Glomerular aff. arteriole
Glomerular eff. arteriole
Tubule
Glomerule
Studies in rats and healthy manhave shown vasodilation of the glomerular afferent arteriole
GFR
Kalantar-Zadeh & Foque, Nutritional Management of CKD. NEJM Nov 2, 2017
Amino acid (dietary protein intake) restrictiondecreases intracapillary glomerular pressure and GFR
Aminoacids • Glom. flow • Cap. glom. Pressure • GFR
Glomerular aff. arteriole Glomerular eff. arteriole
Tubule
Glomerule
GFR
vasoconstriction of the glomerular afferent arteriole
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2016/10/5 57
Observational studies about the effect of high protein (HP) diet on renal function
Ko, Obi, Tortorici and Kalantar-Zadeh, Curr Opin Clin Nutr Metab Care 2016
LPD to sVLPD: effect on CKD progression? MDRD study (CKD stage 3) NEJM 1994
MDRD: Modification of Diet in Renal Disease
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MDRD study 1: secondary analysis
Levey AS et al, J Am Soc Nephrol 1999; 10: 2426-2439
MDRD: Modification of Diet in Renal Disease
MDRD: Modification of Diet in Renal Disease
MDRD study 1: secondary analysis
Levey AS et al, J Am Soc Nephrol 1999; 10: 2426-2439
effect?
Kalantar-Zadeh & Fouque, NEJM, Nov 2017
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Low Protein Diet for 5 Categories of CKD Severity
Kalantar-Zadeh & Foque, Nutritional Management of CKD. NEJM Nov 2, 2017
Glomerular Filtration & Creatinine Clearance
Glomerular Damage CKD
CKD Definition & Epidemiology
Diabetic Nephropathy
Proteinuria CKD progression
CKD Cardiovascular Risk
Beyond serum creatinine
Management of CKD
Nephrology Referral
CKD Comorbid DisordersDO NOT
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Management of CKD Comorbidities
• 1. Anemia• 2. Bone Disease• 3. Acidosis and electrolyte disarrays• 4. Hypertension• 5. Nutrition• 6. Medication Dose adjustment• 7. Preparation for Renal Replacement Therapy
Anemia of Renal Failure: Progression
• Hakim RM, Lazarus JM Biochemical parameters in chronic renal failure. Am J Kidney Dis 1988 Mar;11(3):238-47
Hematocrit vs. creatinine
0
10
20
30
40
50
1 2 3 4 5 6 7 8 9
serum creatinine
hem
ato
crit
ESRDCKD 1 → 2 →3→4→5normal
CKD
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• 3 N-linked (CHO) chains
• Maximum 14 sialic acids
• MW ~ 30,400 daltons
• 40% carbohydrate
• 5 N-linked (CHO) chains
• Maximum 22 sialic acids
• MW ~ 37,100 daltons
• 51% carbohydrate
Additional carbohydrate
side chains
Receptor 1
AranespTM
Receptor 2 Receptor 1
rHuEPO
Receptor 2
carbohydrate side chains
Molecular Comparison of EPO (erythropoietin alpha) and Aranesp (darbepoetin alfa)
Resistance to EPO Therapy
• 1. Iron deficiency• 2. Insufficient dialysis• 3. Aluminum intoxication • 4. Hyperparathyroidism • 5. Deficiency of folate or vitamin B12
• 6. Blood loss • 7. Inhibitory cytokines • Infections• Inflammation / Malnutrition• Neoplasms• 8. ACE inhibitors • 9. Hemoglobinopathies• 10. Antibodies against EPO• 11. Unknown factorsDO N
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Management of CKD Comorbidities
• 1. Anemia• 2. Bone Disease• 3. Acidosis and electrolyte disarrays• 4. Hypertension• 5. Malnutrition• 6. Medication Dose adjustment• 7. Preparation for Renal Replacement Therapy
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Secondary Hyperparathyoridism
Ca = calcium; CVD = cardiovascular disease; P = phosphorus.
PTH
Bone DiseaseFracturesBone pain
Marrow fibrosisErythropoietin resistance
Serum P1,25D
Calcitriol
Renal Failure
PTH
Systemic ToxicityCVD
HypertensionInflammationCalcification
Immunological
25D
Ca++
Decreased Vitamin D Receptors and Ca-Sensing Receptors
FGF-23
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0
50
100
150
200
250
300
>80 79-70 69-60 59-50 49-40 39-30 29-20 <20
eGFR Interval (mL/min/1.73 m2)
iPT
H L
evel
(p
g/m
L)
05101520253035404550
iPTH 1,25 Vitamin D 25(OH) Vitamin D
1,25
Vit
amin
D (
pg
/mL
)25
(OH
) V
itam
in D
(n
g/m
L)
Mean Values of iPTH, 1,25(OH)2D3, and 25(OH)D3 by eGFR
N = 1814
*P<0.001.Bakris et al. Poster presented at: American Society of Nephrology Renal Week 2005; November 8-13, 2005; Philadelphia, PA. Abstract F-PO732.
(n = 61) (n = 117) (n = 230) (n = 396) (n = 355) (n = 358) (n = 204) (n = 93)
*
*
Stage 2 Stage 4Stage 3
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Vitamin D3 25-Hydroxyvitamin D25(OH)D
1,25-Dihydroxyvitamin D3
1,25 (OH)2D3, Calcitriol
(Active Vitamin D)
Brown et al. Am J Physiol. 1999;277:F157-F175.
Liver and Kidney Function Are Essential for Vitamin D Precursor Activation to Calcitriol
HO
OH
OHHO
OH
HO
liver kidney
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Management of CKD Comorbidities
• 1. Anemia• 2. Bone Disease• 3. Acidosis and electrolyte disarrays• 4. Hypertension• 5. Nutrition• 6. Medication Dose adjustment• 7. Preparation for Renal Replacement Therapy
Metabolic Acidosis
• Metabolic acidosis with moderate anion gap (AG: ~15 meq/L)
• Due to retention of sulfuric and phosphoric acids
• Treatment: NaBicarbonate 650-1300 mg po bid– Na Bicarbonate:
• better than citrate (aluminum absorption)– Newer agents: proton binders: veverimer
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Hyperkalemia
• K>5.3 meq/dL especially with ACEI/ARB• Etiology: distal nephron sodium delivery low, RTA 4
• Rx: 1. low K diet (avoid banana, avocado, etc): Not healthy diet2. furosemide 40-120 mg qd to tid3. Na-bicarb 650-1300 mg bid4. Florinef 0.1-0.5 mg qd (in HTN contraindicated!5. Lower ACEI/ARB dose 6. Older K binder: Kayexalate 15 gm qd or qod7. Newer K-binders:
1. Patiromer (Valtassa): 8.4 g qd2. Zerconium (Lokelma): 5 g qd
Management of CKD Comorbidities
• 1. Anemia• 2. Bone Dz• 3. Acidosis and electrolyte disarrays• 4. Hypertension• 5. Malnutrition• 6. Medication Dose adjustment• 7. Preparation for Renal Replacement Therapy
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Recommendations for BP and RAS Management in CKD
BP = blood pressure; RAS = renin angiotensin system; CCB = calcium channel blocker; BB = -blocker; JNC 7 = The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.ADA. Diabetes Care. 2005;28(suppl 1); Chobanian et al. JAMA. 2003;289:2560-2572; Kidney Disease Outcomes Quality Initiatives (K/DOQI). Am J Kidney Dis. 2004;43(5 suppl 1):S1-S290.
PatientGroup
Goal BP(mm Hg) First Line Adjunctive
+ Diabetes <130/80 ACE-I or ARB Diuretics then CCB or BB
Diabetes + Proteinuria <130/80 ACE-I or ARB Diuretics then CCB or BB
Diabetes Proteinuria <130/80
No specific preference:
Diuretics then ACE-I, ARB, CCB, or BB
EXPECT TO NEED TO USE 3+ AGENTS TO ACHIEVE GOALSRecommendations largely consistent across JNC 7, ADA, and K/DOQI
Q13
JNC8 JAMA 2014
There is strong evidence to support treating HTN in persons >60 years to a BP
goal <150/90 mmHg and persons 30-59 years to a diastolic goal <90 mmHg
There is insufficient evidence in <60 years for a systolic goal, or in <30 years for a diastolic goal, so the panel recommends BP <140/90 based on expert opinion.
What is the best BP target in NDD-CKD pts?
Should sBP <120 mmHg be targeted in CKD?
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Observational modeling of strict vs. usual BP control‐association with all‐
cause mortalityCsaba P. Kovesdy, Jun L. Lu, Miklos Z. Molnar, Jennie Z. Ma, Robert B. Canada, Elani Streja, Kamyar Kalantar‐Zadeh, and Anthony J. Bleyer
JAMA Intern Med 2014
The Systolic Blood Pressure Interventional Trial (SPRINT) trial17 is the first major clinical trial of blood pressure lowering with a primary aim to prevent cardiovascular events and mortality that specifically enrolled patients with CKD, but its results will not be available for several years, and its strict inclusion/exclusion criteria may limit the generalizability of its findings to a narrow spectrum of the CKD population
Higher Death Hazardfor sBP<120:
1.70 (1.63‐1.78)
N=77,765 CKD veterans: N=5,760 sBP <120 mm HgN=72,005 sBP 120-139 mm Hg
Median follow-up: 6.0 years
Death: 19,517 patients: Death rates:
in sBP <120 mm Hg: 81/1000 patient-yrs
in sBP 120-139 mm Hg” 42/1000 patient-yrs)
(P < .001).
The mortality hazard ratio of sBP <120 vs. 120 to 139 mm Hg:
1.70 (95%CI: 1.63-1.78) after adjustment for propensity scores.DO N
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2013
N= 651,749 patients over 7 years
Kovesdy … Kalantar‐Zadeh,
Annals Int Med 2013
Management of CKD Comorbidities
• 1. Anemia• 2. Bone Disease• 3. Acidosis and electrolyte disarrays• 4. Hypertension• 5. Nutrition: Plant Dominant Low Protein Diet• 6. Medication Dose adjustment• 7. Preparation for Renal Replacement Therapy
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Protein Intake Restriction• Mixed data (MDRD Study)
• Recommended: 0.6-0.8 g/kg/day
• Measure 24-hr urine urea nitrogen:
Estimated protein intake == 6.25 * UUN
Kopple et al. Kidney Int. 2000 Maroni et al. Kidney Int. 1985
Management of CKD Comorbidities
• 1. Anemia• 2. Bone Disease• 3. Acidosis and electrolyte disarrays• 4. Hypertension• 5. Nutrition• 6. Medication Dose adjustment• 7. Preparation for Renal Replacement Therapy
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Management of CKD Comorbidities
• 1. Anemia• 2. Bone Disease• 3. Acidosis and electrolyte disarrays• 4. Hypertension• 5. Nutrition• 6. Medication Dose adjustment• 7. Preparation for Renal Replacement Therapy
Who has higher mortality: Cancer or Dialysis?
High Risk for Death in ESRD Patients
Go et al. NEJM
• AIDS + HAART >95% five year survival
• Testicular cancer 95%
• Breast cancer 85%
• Bladder cancer 75%
• Kidney transplant 75%
• Rectal cancer 62%
• Cervix cancer 60%
• Colonic cancer 54%
• Dialysis 46% (10 yr survival <15%)
• Ovarian cancer 44%
• Stomach cancer 20%
• Lung cancer 10%
Sources;Cancer Research UK 2005UK Renal Registry 2006USRDS 2006
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Transition to ESRDprelude vintage
-5 -4 -3 -2 -1 +1 +2 +3 +4 +5 years
Annualized Mortality
40%
30%
20%
10%
Costs of Patient Care ($)
eGFR(ml/min)
25
20
15
10
5
↑UremiaCKD5 eGFR <15 eGFR <10 eGFR <5
• Watch for uremia Sx & Sx:
• Loss of appetite, nausea, vomiting• MS, ↓ concentration, seizure, coma• Camps, pruritus• Uremic pericarditis (rub)• Uremic bleeding tendency (Rx: dDAVP, estrogen)• Volume overload, CHF Sx & Sx without CHF• Electrolyte disarray (K, Ca) and acidosis
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Historical Background:In 1972 the US Congress extended Medicarecoverage to all persons under age 65 suffering from ESRD (End-Stage Renal Disease), i.e. individuals who cannot survive without kidney dialysis treatment, to cover all costs related to their dialysis Rx.
The intent of this law (PL 92-603, the Social Security Amendments of 1972) was to allow allAmericans access to an emerging and very expensive technology, regardless of their ability to pay.
The effectiveness of the ESRD program:
No Kidney Function = No Life Dialysis = Life (?)
550,000 Dialysis Patients in the USA
Fast growing population: ESRDAnd 120,000 new dialysis patients are added each year
Conclusions• Low GFR and proteinuria are independent risk factors for
development of CVD. Patients with CKD are likely to die from CVD
• Low protien-, low salt diet may help slow progression of CKD and improve proeinuria.
• BP control is important but too low BP values (sBP<100) in patients with established CKD should be avoided as hypotension may be assocaitated with worse CKD outcomes.
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Acknowledgement
Investigators and Staff• Elani Streja, MPH, PhD• Connie M. Rhee, MD, MSc• Hamid Moradi, MD• Wei Ling Lau, MD• Joline Chen, MD, MPH• Vanessa Ravel, MPH• Foad Ahamdi, MD• Paungpaga Lertdumrongluk, MD• Megha Doshi, MD• Sepideh Rezakhani, MD• Melissa Soohoo, MPH• Bryan Shapiro, MPH• Rochelle Roger, MPH• Amanda Brown, RD• Tracy Nakata • Nany Lopez• Catherine Guillen• Jennie Jing, MS• Kamyar Kalantar-Zadeh, MD, MPH,
PhD
Collaborators:• Csaba P. Kovesdy, MD• Rajnish Mehrotra, MD• Joel D Kopple, MD• Matthew Budoff, MD• Steven S. Jacobsen, MD,
PhD• Rajiv Saran, MD, MSc.• Miklos Z. Molnar, MD, PhD• Jongha Park, MD• Daniel Gillen, PhD• Danh Nguyen, PhD• Allen Nissenson, MD, • Steven Brunelli, MD, MS
The Harold Simmons Center for Kidney Disease Research & Epidemiology
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