1. Chronic Kidney Disease: Progression Modifying Therapies Chapter 46
Pharmacotherapy: A Pathophysiologic Approach
The McGraw-Hill Companies

2. Abbreviations ACEI: angiotensin-converting enzyme inhibitor
ARB: angiotensin receptor blocker
CCB: calcium channel blocker
CKD: chronic kidney disease
DCCT: Diabetes Control and Complications Trial
ESRD: end-stage renal disease
GFR: glomerular filtration rate
HMG-CoA:β-hydroxy-β-methylglutaryl coenzyme A (reductase)
IIT: intensive insulin therapy
K/DOQI: Kidney Dialysis Outcomes and Quality Initiative
MAP: mean arterial blood pressure
MDRD: Modification of Diet in Renal Disease
NHANES III: Third National Health And Nutritional Examination Survey
USRDS: United States Renal Data System

3. Key Concepts Chronic Kidney Disease (CKD) US Prevalence
~19 million
The Kidney Disease Outcomes Quality Initiative (K/DOQI)
CKD risk factor categories
susceptibility factors
initiation factors
progression factors

4. Key Concepts Mechanisms of CKD progression 5 CKD stages based on
reduction in kidney mass
glomerular hypertension
intratubular proteinuria
5 CKD stages based on
structural damage
renal function

5. Key Concepts Serum creatinine (SCr):
unreliable marker of kidney function in select patients
elderly
malnourished
children
estimate GFR
used to evaluate rate of disease progression

6. Key Concepts Stage 5 CKD symptoms:
asterixis
pruritus
dysgeusia
nausea, vomiting
anorexia, weight loss
susceptibility to bleeding
Signs/symptoms of uremia foundational to decision to implement kidney replacement therapy

7. Key Concepts
Titrate ACEI/ARB to maximal suppression of urinary albumin excretion for DM patients with persistent microalbuminuria despite intensive insulin therapy
even without HTN
ACEIs/ARBs: key pharmacologic treatments
hemodynamic & BP reduction effects limit kidney
disease progression

8. Key Concepts Supportive therapies may slow CKD progression
dietary protein restriction
lipid-lowering medications
smoking cessation
anemia management
Limit progression with hyperglycemia & HTN treatment

9. Epidemiology Worldwide public health problem: “silent epidemic “
CKD affects ~5% of adult US population
CKD defined as SCr > 1.2 to 1.5 mg/dL
The Third National Health And Nutritional Examination Survey (NHANES III)
nationally representative sample of US adult population
> 10.9 million people have SCr > 1.5 mg/dL
CKD prevalence ~10.9% of US population age > 20 yrs (19 million) if microalbuminuria & proteinuria included
Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: Evaluation,
classification, and stratification. Ann Intern Med 2003;139:137–147.
Jones CA, McQuillan GM, Kusek JW, et al. Serum creatinine levels in the U.S. population: Third National Health and Nutrition
Examination Survey. Am J Kidney Dis 1998;32:992–999. 

10. Etiology Susceptibility factors:
advanced age
low income or education
racial/ethnic minority status
reduced kidney mass
low birth weight
family history
Useful for identifying populations at high risk for CKD

11. Etiology Initiation factors: Most common causes of CKD in the US:
result in direct kidney damage
modifiable by pharmacologic therapy
DM, HTN, autoimmune diseases, polycystic kidney disease, systemic infections, urinary tract infections, urinary stones, lower urinary tract obstructions, drug toxicity
Most common causes of CKD in the US:
diabetes mellitus
HTN
glomerular diseases

12. Etiology Progression factors: Predictors of progressive CKD:
associated with further kidney damage
evident as increased decline in kidney function in patients who already have kidney damage
proteinuria, elevated BP, smoking
Predictors of progressive CKD:
persistence of underlying initiation factors DM
HTN
glomerulonephritis
polycystic kidney disease

13. The Kidney 2 million nephrons Primary regulator
filter
reabsorb
excrete solutes
excrete water
Primary regulator
Na+ & H2O balance
acid–base homeostasis
Hormone production necessary for RBC synthesis & Ca2+ homeostasis

14. Pathophysiology Heterogeneous causes
diabetic nephropathy: glomerular mesangial expansion
hypertensive nephrosclerosis: kidney's arterioles have arteriolar hyalinosis; renal cysts present in polycystic kidney disease
initial structural damage may depend on the 1˚ disease
Progressive nephropathies result in irreversible renal parenchymal damage & ESRD
Key pathway elements
loss of nephron mass
glomerular capillary hypertension
proteinuria

16. Pathophysiology Initiation factor exposure
remaining nephrons hypertrophy to compensate for loss of nephron mass and renal function
compensatory hypertrophy may be adaptive
hypertrophy may lead to intraglomerular hypertension
possibly mediated by angiotensin II

17. Kidney Disease/Injury
acute renal failure:
rapid loss of kidney function
hours to weeks
50% increase in SCr (> 0.5 g/dL)
chronic kidney disease:
also called chronic renal insufficiency, progressive kidney disease
progressive loss of function
months to years
gradual replacement of normal kidney architecture with interstitial fibrosis

18. Kidney Disease Classification
National Kidney Foundation's (NKF) Kidney Dialysis Outcomes & Quality Initiative (K/DOQI) CKD classification system (stages 1 to 5)
Categories based on structural kidney damage &/or functional changes in GFR for > 3 months
stage 1: mild structural changes evidenced by microalbuminuria with "normal" kidney function
stage 5: analogous to end stage renal disease: dialysis or kidney transplantation may be necessary
increasing number: more advanced stage of disease
SCr: inaccurate index of GFR

19. Kidney Disease Normal adult kidney function
GFR ~120 mL/min/1.73 m2
Can diagnose CKD when GFR > 90 mL/min/1.73 m2 based on:
proteinuria
hematuria
evidence of structural damage from kidney biopsy

20. CKD Stages Stage GFRa Prevalencec 1 > 90b 10,500,000 2 60–89
7,100,000 3
30–59
7,600,000 4
15–29
400,000 5
< 15d
300,000
a Glomerular filtration rate (mL/min/1.73 m2) b CKD can be present with normal/near normal GFR if other markers of kidney disease are present
c Based on elevated albumin to creatinine ratio dincludes patients on dialysis
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:

21. Presentation/Diagnosis
Development & progression may be insidious
CKD diagnosis
measure SCr, estimate GFR
assess urine for protein &/or albumin
CKD stages 3, 4, 5 require additional workup
anemia
CV disease
metabolic bone disease
malnutrition
fluid & electrolyte disorders

22. CKD Risk Factors Susceptibility Advanced age
Reduced kidney mass and low birth weight
Racial/ethnic minority
Family history
Low income or education
Systemic inflammation
Dyslipidemia
Initiation  
Diabetes mellitus
Hypertension
Glomerulonephritis
Progression  
Glycemia (among diabetic patients)
Proteinuria
Smoking
Obesity
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:

23. Diabetes
Not all individuals with diabetic nephropathy progress to stage 5 CKD; however, high lifetime risk
Multiple Risk Factor Intervention Trial (MRFIT)
prospective study
> 300,000 individuals screened
~3% of DM patients develop stage 5 CKD
DM subjects: 12-fold greater RR of stage 5 CKD
increased risk of nondiabetic CKD causes
suggests underlying genetic susceptibility
Brancati FL, Whelton PK, Randall BL, Neaton JD, Stamler J, Klag MJ. Risk of end-stage renal disease in diabetes mellitus:
A prospective cohort study of men screened for MRFIT. Multiple Risk Factor Intervention Trial. JAMA 1997;278:2069–2074. 

24. Diabetes & CKD Type 1 DM patients: 40% lifetime risk of developing CKD
Greater prevalence of type 2 DM compared to type 1
10:1 ratio in most countries
majority of CKD due to DM among type 2 DM patients
Hasslacher C, Ritz E, Wahl P, Michael C. Similar risks of nephropathy in patients with type I or type II diabetes mellitus.
Nephrol Dial Transplant 1989;4:859–863. 

25. Hypertension Increases CKD risk
Exact role as cause/consequence debated
Kidney has a role in HTN development/modulation
Generally develops concomitantly with progressive kidney disease
Early HTN treatment to aggressive goals slows CKD progression

26. Hypertension Multiple Risk Factor Intervention Trial 1˚ prevention
evaluated effect of an intervention on CHD mortality
16 year follow-up
lifetime risk of stage 5 CKD for patients with HTN: 5.6%
risk varied dramatically by BP
0.33% SBP 140 to 150 mm Hg &/or DBP 90 to 100 mm Hg
4.5% for SBP > 180 mm Hg or DBP > 110 mm Hg
Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996;334:13–18. 

27. Hypertension Elevated BP increases risk for developing CKD
Prospective study (n=316,675) managed care patients
increased stage 5 CKD risk in patients with elevated baseline BP
odds ratio for CKD development:
2.0 (95% confidence interval [CI] 1.6 to 2.5) for SBP 120 to 129 mm Hg & DBP 80 to 84 mm Hg diastolic
4.3 (95% CI 2.6 to 6.9) for SBP > 210 mm Hg or DBP >120 mm Hg compared to BP SBP < 120 and DBP < 80 mm Hg
Perneger TV, Nieto FJ, Whelton PK, Klag MJ, Comstock GW, Szklo M. A prospective study of blood pressure and serum creatinine. Results from the "Clue" Study and the ARIC Study. JAMA 1993;269:488–493.
Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pressure and risk of end-stage renal disease in subjects
without baseline kidney disease. Arch Intern Med 2005;165:923–928.

28. Glomerulonephritis
Glomerular diseases: initiation factors with variable epidemiology, pathophysiology
Goodpasture's disease or Wegener's granulomatosus may progress rapidly to stage 5; cause ARF
Immunoglobulin (Ig) A nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, lupus nephritis, & others more indolent cause of CKD
chronic glomerular diseases progress at variable rates
loss of GFR 1.4 to 9.5 mL/min/year

29. Interesting, right?
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