kidney disease

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-CoAß-hydroxy-ß-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
• 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 gt 1.2 to 1.5 mg/dL
• The Third National Health And Nutritional
  Examination Survey (NHANES III)
• nationally representative sample of US adult
  population
• gt 10.9 million people have SCr gt 1.5 mg/dL
• CKD prevalence 10.9 of US population age gt 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 2003139137147.
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 199832992999. 
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
• 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
• 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
• filter
• reabsorb
• excrete solutes
• excrete water
• Primary regulator
• Na H2O balance
• acidbase 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

15
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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 (gt 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 gt 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 gt 90 mL/min/1.73 m2
  based on
• proteinuria
• hematuria
• evidence of structural damage from kidney biopsy

20
CKD Stages
Stage GFRa Prevalencec
1 gt 90b 10,500,000
2 6089 7,100,000
3 3059 7,600,000
4 1529 400,000
5 lt 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 http//www.accesspharmacy.c
om
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) Hypertension Proteinuria Smoking Obesity
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
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
• gt 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
199727820692074. 
24
Diabetes CKD

• Type 1 DM patients 40 lifetime risk of
  developing CKD
• Type 2 DM patients 50 lifetime risk of
  developing CKD
• Greater prevalence of type 2 DM compared to type
  1
• 101 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 19894859863. 
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 gt 180 mm Hg or DBP gt 110 mm Hg

Klag MJ, Whelton PK, Randall BL, et al. Blood
pressure and end-stage renal disease in men. N
Engl J Med 19963341318. 
27
Hypertension

• Elevated BP increases risk for developing CKD
• Prospective study (n316,675) 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 gt 210 mm Hg or
  DBP gt120 mm Hg compared to BP SBP lt 120 and DBP lt
  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
1993269488493.
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
2005165923928.
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
Progression Factors

• Associated with further kidney damage
• Increased rate of kidney function decline in
  patients with existing renal dysfunction
• Predictors of progressive CKD

• DM
• HTN
• glomerulonephritis

• polycystic kidney disease
• proteinuria
• smoking

30
Proteinuria

• Promotes progressive nephron loss through direct
  cellular damage
• Filtered proteins toxic to kidney tubule cells
• albumin
• transferrin
• complement factors
• immunoglobulins
• cytokines
• angiotensin II

31
Proteinuria

• Studies demonstrate presence of proteins in renal
  tubules activates tubular cells
• upregulated inflammatory/vasoactive cytokines
• Associated with complement component activation
  on proximal tubule apical membranes
• Intratubular complement activation may be key
  mechanism of progessive damage
• interstitial scarring
• progressive loss of nephrons
• reduction in GFR

32
Smoking

• May promote initiation progression of CKD in DM
  patients
• Increased rate of CKD progression
• cigarette pack years independent predictive
  factor for CKD progression among DM patients
• associated with CKD in HTN
• especially among hypertensive black subjects
• studies demonstrate association between smoking,
  microalbuminuria stage 5 CKD

Regalado M, Yang S, Wesson DE. Cigarette smoking
is associated with augmented progression of renal
insufficiency in severe essential hypertension.
Am J Kidney Dis 200035687694. 
33
Dyslipidemia

• Prevalence increases as kidney function declines
• Characteristic of nephrotic syndrome
• 85 to 90 of patients with decreased kidney
  function, proteinuria gt 3 g/day
• elevated plasma total low-density lipoprotein
• 50 of patients have low levels (lt 35 mg/dL) of
  high-density lipoprotein cholesterol
• 60 have triglyceride concentrations gt 200 mg/dL
• Lipid abnormality treatment may slow CKD
  progression

Kasiske BL. Hyperlipidemia in patients with
chronic renal disease. Am J Kidney Dis
199832S142S156.
34
Obesity

• Association of obesity with stage 5 CKD
• 47,504 men, 53,249 women 1983 community-based
  screening in Japan
• BMI associated with increased ESRD men (not
  women)
• Population-based study
• BMI gt 25 kg/m2 at age 20 years associated with
  threefold increase in CKD risk compared to BMI lt
  25 kg/m2
• obesity (BMI 30) among men morbid obesity (BMI
  35) among women three- to fourfold increased CKD
  risk

Iseki K, Ikemiya Y, Kinjo K, Inoue T, Iseki C,
Takishita S. Body mass index and the risk of
development of end-stage renal disease in a
screened cohort. Kidney Int 20046518701876.
Ejerblad E, Fored CM, Lindblad P, Fryzek J,
McLaughlin JK, Nyren O. Obesity and risk for
chronic renal failure. J Am Soc Nephrol
20061716951702
35
Angiotensin II

• May mediate renal disease progression through
  nonhemodynamic effects
• potent afferent efferent arteriole
  vasoconstrictor
• preferentially affects efferent arterioles
• increased glomerular capillary pressure,
  filtration fraction
• intraglomerular hypertension correlates with
  systemic arterial hypertension
• animal studies demonstrate high intraglomerular
  capillary pressure impairs size-selective
  function of the glomerular permeability barrier
• increased urinary albumin excretion, frank
  proteinuria

36
CKD Symptoms

• Generally absent in stages 1 2
• May be minimal in stages 3 4
• General symptoms
• cold intolerance
• shortness of breath
• palpitations
• cramping, muscle pain
• depression, anxiety
• fatigue
• sexual dysfunction

37
Signs of CKD Stages 1 to 4
System Signs of CKD
Cardiovascularpulmonary edema, worsening hypertension, electrocardiographic evidence of left ventricular hypertrophy, arrhythmias, hyperhomocysteinemia, dyslipidemia
Gastrointestinal GERD, weight loss
Endocrine 2 hyperparathyroidism, decreased vitamin D activation, ß2-microglobulin deposition, gout
Hematologic anemia of CKD, iron deficiency, bleeding
Fluid/electrolytes hyper- or hyponatremia, hyperkalemia, metabolic acidosis
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
38
Anemia

• Kidneys secrete 90 of erythropoietin endogenous
  hormone necessary for erythropoiesis
• Declining kidney function leads to erythropoietin
  deficiency anemia
• Prevalence of Hgb lt 12 g/dL in patients with GFR
  gt 80 mL/min per 1.73 m2 1 to 30

Hsu CY, McCulloch CE, Curhan GC. Epidemiology of
anemia associated with chronic renal
insufficiency among adults in the United States
Results from the Third National Health and
Nutrition Examination Survey. J Am Soc Nephrol
200213504510.
39
Anemia

• Other factors ethnicity, age, gender, blood loss
  (particularly in stage 5 CKD)
• NKF K/DOQI guidelines recommend evaluating Hgb
  levels in all patients with CKD
• Prevalence of Hgb lt 12 g/dL increases in stages 3
  to 5 CKD

KDOQI Clinical Practice Guidelines and Clinical
Practice Recommendations for Anemia in Chronic
Kidney Disease. Am J Kidney Dis
200647S11S145.
40
Anemia

• Mild anemia can be asymptomatic
• Patients with more severe anemia may experience
  fatigue, weakness, shortness of breath
• Anemia treatment may improve/resolve symptoms
• may stabilize kidney function
• Early correction of anemia does not reduce CV
  risk
• Erythropoietin stimulating agents used to correct
  anemia

Drueke TB, Locattelli F, Clyne N, et al.
Normalization of hemoglobin level in patients
with chronic kidney disease and anemia. N Engl
J Med 20063552071-84.
KDOQI Clinical Practice Guidelines and Clinical
Practice Recommendations for Anemia in Chronic
Kidney Disease. Am J Kidney Dis
200647S11S145.
41
Cardiovascular Disease

• CKD high rate of CV morbidity mortality
• CKD patients 16 to 37 the life expectancy of
  matched population without kidney disease
• Epidemiologic study gt 300,000 patients
  demonstrated strong relationship between GFR and
  CV disease
• lower GFR higher incidence of CV disease
• stage 2-4 CKD patients more likely to die from
  CV complications than require renal-replacement
  therapy

Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY.
Chronic kidney disease and the risks of death,
cardiovascular events, and hospitalization. N
Engl J Med 200435112961305.
K/DOQI clinical practice guidelines for
cardiovascular disease in dialysis patients. Am J
Kidney Dis 200545S1S153.
Keith DS, Nichols GA, Gullion CM, Brown JB, Smith
DH. Longitudinal follow-up and outcomes among a
population with chronic kidney disease in a
large managed care organization. Arch Intern Med
2004164659663. 
42

Correlation between decline in kidney function
(estimated by GFR) and increasing incidence of CV
complications death from CV disease
GFR (mL/min/1.73 m2)Blue gt 75.0 Yellow
60.074.9 Green 45.059.9 Purple lt 45
43
Ca2 Phosphorus Homeostasis

• Abnormalities in Ca2 phosphorus metabolism
  typically occur in CKD stages 3, 4, 5
• 2 hyperparathyroidism can develop at GFR lt 80
  mL/min/1.73 m2 despite normal Ca2 phosphorus
  levels
• Monitor parathyroid hormone concentration (PTH),
  vitamin D, Ca2, phosphorus starting in stage 3
  CKD
• Ca2, phosphorus, PTH correction may reduce CV
  risk
• Phosphate binders AlOH, calcium carbonate,
  calcium acetate, lanthanum carbonate, sevelamer

Martinez I, Saracho R, Montenegro J, Llach F. The
importance of dietary calcium and phosphorous in
the secondary hyperparathyroidism of patients
with early renal failure. Am J Kidney Dis
199729496502.
National Kidney Foundation. K/DOQI clinical
practice guidelines for managing dyslipidemias in
chronic kidney disease. Am J Kidney Dis
200341S1S92.
44
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45
Anorexia Malnutrition

• Limited data defining CKD stage where
  malnutrition develops
• NKF K/DOQI guidelines evaluate for signs of
  malnutrition when GFR lt 60 mL/min/1.73 m2
• stages 3, 4, 5

Kopple JD. National kidney foundation K/DOQI
clinical practice guidelines for nutrition in
chronic renal failure. Am J Kidney Dis
200137S66S70.
46
Anorexia Malnutrition

• Nutrition assessment
• dietary protein
• calorie intake
• serum albumin
• urine protein

Kopple JD. National kidney foundation K/DOQI
clinical practice guidelines for nutrition in
chronic renal failure. Am J Kidney Dis
200137S66S70.
47
Treatment Goals

• Delay progression
• Minimize complications
• modest dietary protein restriction may be
  beneficial
• pharmacologic therapy control underlying
  conditions
• (e.g. DM, HTN) prevent functional decline
• Generally requires multimodality treatment
• ACEIs /or ARBs key therapeutic component for
  most patients

48
Nonpharmacologic Therapy

• Dietary Protein Restriction
• experimental animal studies suggest dietary
  protein restriction delays rate of decline in
  kidney function
• Modification of Diet in Renal Disease (MDRD)
• randomized controlled trial randomized by
  dietary protein intake BP
• evaluated benefit of dietary protein restriction
  BP reduction on CKD progression
• subjects with moderate CKD (GFR 25 to 55
  mL/min/1.73 m2)

Brenner BM. Hemodynamically mediated glomerular
injury and the progressive nature of kidney
disease. Kidney Int 198323647655.
Levey AS, Adler S, Caggiula AW, et al. Effects of
dietary protein restriction on the progression of
advanced renal disease in the Modification of
Diet in Renal Disease Study. Am J Kidney Dis
199627652663.
49
MDRD

• Mean follow-up 2.2 years protein restriction
  did not show benefit in slowing CKD progression
  in 1 analysis
• 2 analysis (patients compliant with dietary Rx)
  
• GFR lt 25 mL/min/1.73 m2
• protein intake of 0.6 g/kg/day associated with
  decreased rate of progressive renal disease
• different statistical method from primary
  analysis
• progression to ESRD reduced by 41 for each 0.2
  g/kg/day reduction in dietary protein intake

Levey AS, Adler S, Caggiula AW, et al. Effects of
dietary protein restriction on the progression of
advanced renal disease in the Modification of
Diet in Renal Disease Study. Am J Kidney Dis
199627652663
50
Nonpharmacologic Therapy

• Data suggest small benefit from dietary protein
  restriction
• Low protein diets may lead to malnutrition with
  advanced CKD nephrotic-range proteinuria
• NKF K/DOQI advocates dietary protein 0.6
  g/kg/day for patients with GFR lt 25 mL/min/1.73
  m2
• Titrate protein intake to 0.75 g/kg/day when
  patients cannot achieve or maintain adequate
  nutritional status with lower-protein diet (0.6
  g/kg/day)

Kopple JD. National kidney foundation K/DOQI
clinical practice guidelines for nutrition in
chronic renal failure. Am J Kidney Dis
200137S66S70.
51
Treatment Diabetic CKD

• CKD treatment guidelines recognize differences in
  pathogenesis course of diabetic/nondiabetic CKD
• BP reduction in type 1 type 2 DM patients
  reduces rate of CKD progression
• Benefit of BP control confirmed in studies of
  type 2 DM patients with microalbuminuria
• using an ACEI or ARB
• likely beneficial nonhemodynamic effects on CKD
  progression
• BP lowering effects as well

52
Effects of Antihypertensives on Renal Blood Flow
(RBF) Glomerular Filtration Rate (GFR)
Antihypertensive Agent Mechanism of Action Effects on Renal Hemodynamics
ACE inhibitors/ARBs Reduce intraglomerular pressure Decrease sodium and volume retention Preserve GFR Decrease GFR, RBF
Diuretics Sodium and volume depletion Increase vasodilatory prostaglandin levels (IV loop diuretics) Renal vasoconstriction (IV thiazide diuretics) Decrease GFR, RBF Increase RBF  Decrease GFR, RBF
ß-Adrenergic blockers Decrease Cardiac output  Increase renal vascular resistance (nonselective agents) Increase renal vascular resistance (ß1-selective agents) Decrease GFR, RBF Decrease GFR, RBF No change in GFR, RBF
Centrally acting antiadrenergic drugs Decrease renal vascular resistance (methyldopa) Decrease renal perfusion pressure (clonidine, a2-adrenergic agonist) No change in GFR, RBF Decrease GFR, RBF
Peripherally acting antiadrenergic drugs Direct vasodilation (postsynaptic a1-adrenoreceptor blocking agents) No change in GFR, RBF
Direct vasodilator agents Decrease renal vascular resistance (hydralazine, minoxidil) Arterial vasodilation plus dilatation of venous capacitance vessels (nitroprusside) Increase RBF, no effect on GFR Decrease GFR RBF (acute effect)
Calcium channel blockers Decrease renal vascular resistance by vasodilation of afferent arterioles (hypertensive patients)  Increase RBF, no change in GFR
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
53
HTN Control in DM CKD

• JNC 7 goal BP lt 130/80 mm Hg for CKD patients
• gt 3 antihypertensives generally required BP
  often difficult to control
• HTN DM 6 fold higher ESRD risk than patients
  with DM alone
• BP control reduces GFR decline albuminuria in
  hypertensive DM patients
• ACEIs reduce glomerular capillary pressure
  volume preserve renal function

Chobanian AV, Bakris GL, Black HR, et al. Seventh
report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure. Hypertension
20034212061252.
Bakris GL, Williams M, Dworkin L, et al.
Preserving renal function in adults with
hypertension and diabetes A consensus approach.
National Kidney Foundation Hypertension and
Diabetes Executive Committees Working Group. Am J
Kidney Dis 200036646661.
54
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56
Antihypertensives - ACEIs

• Beneficial effects on renal function (patients
  DM)
• both type 1 2 DM
• different degrees of kidney damage
• ACEI therapy
• begin at a low dose increase dose at 4-week
  intervals to reduce microalbuminuria (even
  normotensive patients)
• antiproteinuric effects not necessarily attained
  at antihypertensive doses
• increase dose until proteinuria reduced by 30 to
  50
• titration limited by adverse effects elevated
  SCr K

57
ELITE Trial

• The Evaluation of Losartan In The Elderly (ELITE)
• Losartan vs captopril in diabetics nondiabetics
• Comparable renal benefits of both ARBs ACEIs in
  HF patients
• Shows efficacy of both ACEIs ARBs in type 2 DM
• Only ACEIs adequately evaluated in type 1 DM
  patients

Pitt B, Segal R, Martinez FA, et al. Randomised
trial of losartan versus captopril in patients
over 65 with heart failure (Evaluation of
Losartan in the Elderly Study, ELITE). Lancet
1997349747752.
Hostetter TH. Prevention of end-stage renal
disease due to type 2 diabetes. N Engl J Med
2001345910912.
58
CALM Study

• Candesartan And Lisinopril Microalbuminuria
  (CALM)
• Evaluated ACEI/ARB monotherapy combination
  therapy in type 2 DM patients
• 12 to 24 week study
• 3 groups
• lisinopril 20 mg/day
• candesartan 16 mg/day
• combination of both

Mogensen CE, Neldam S, Tikkanen I, et al.
Randomised controlled trial of dual blockade of
renin-angiotensin system in patients with
hypertension, microalbuminuria, and non-insulin
dependent diabetes The Candesartan and
Lisinopril Microalbuminuria (CALM) study. BMJ
200032114401444.
59
CALM Study

• Greater reduction in urinary albumin-to-creatinine
  ratio with combination therapy (50)
• lisinopril alone (39)
• candesartan alone (24)
• Significantly greater BP reduction with
  combination
• Unclear if combination enhances antiproteinuric
  effect or if albumin-to-creatinine ratio
  reduction attributable to greater BP reduction

Mogensen CE, Neldam S, Tikkanen I, et al.
Randomised controlled trial of dual blockade of
renin-angiotensin system in patients with
hypertension, microalbuminuria, and non-insulin
dependent diabetes The Candesartan and
Lisinopril Microalbuminuria (CALM) study. BMJ
200032114401444.
60
CKD Patients With HTN

• No ACEI shown to be superior to any other ACEI
• 1 goal treat BP to target
• 2 goal control proteinuria
• Antihypertensive ceiling effect for ACEI dose
  titration not confirmed for lowering urinary
  protein excretion
• ACEIs generally more cost-effective than ARBs
• Adverse effects with an ACEI switch to an ARB
  may be appropriate

Kshirsagar AV, Joy MS, Hogan SL, Falk RJ,
Colindres RE. Effect of ACE inhibitors in
diabetic and nondiabetic chronic renal disease
A systematic overview of randomized
placebo-controlled trials. Am J Kidney Dis
200035695707.
61
Nondihydropyridine CCBs

• Diltiazem/verapamil decrease glomerular injury
  without negatively changing renal hemodynamics
• May have beneficial effects on proteinuria
  similar to ACEIs
• Studies suggest efficacy of combination therapy
  with ACEIs nondihydropyridine CCBs may be
  superior in proteinuria reduction than either
  agent alone
• Generally 2nd line when ACEIs or ARBs not
  tolerated

Dworkin LD, Benstein JA, Parker M, Tolbert E,
Feiner HD. Calcium antagonists and converting
enzyme inhibitors reduce renal injury by
different mechanisms. Kidney Int 199343808814. 
Epstein M. Effects of ACE inhibitors and calcium
antagonists on progression of chronic renal
disease. Blood Press Suppl 19952108112. 
62
Clinical Controversy

• ONgoing Telmisartan Alone and in combination with
  Ramipril Global Endpoint Trial (ONTARGET)
• 1 endpoint composite of death, dialysis, SCr
  doubling
• Prospective, randomized, multicenter,
  double-blind trial
• randomized patients to ramipril, telmisartan, or
  combination of both
• 25,620 patients age gt 55 yr with diabetes
  end-organ damage or established atherosclerotic
  vascular disease
• Combination therapy reduces proteinuria more than
  monotherapy but worsens major renal outcomes

Mann JF, Schmieder RE, McQueen M, et al. Renal
outcomes with telmisartan, ramipril, or both, in
people at high vascular risk (the ONTARGET
study) a multicentre, randomised, double-blind,
controlled trial. Lancet 2008372547-543.
63
Non-diabetic Patients

• BP reduction key to decreasing CV renal
  complications
• Antihypertensive agents not equal in kidney
  function preservation despite similar BP
  reduction
• ACEIs ARBs 1st line in CKD patients because
  they reduce intraglomerular pressure

64
Antihypertensives ACEIs

• BP reductions done over weeks to allow the kidney
  to adapt to reduced perfusion pressures
• Typically acute but sustained 25 to 30 GFR
  reduction
• 3 to 7 days after ACEI initiation
• reduced intraglomerular pressure
• If sustained SCr increase gt 30, consider
  discontinuation
• Monitor for hyperkalemia, acute GFR reduction

Chobanian AV, Bakris GL, Black HR, et al. Seventh
report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure. Hypertension
20034212061252.
Apperloo AJ, de Zeeuw D, de Jong PE. A short-term
antihypertensive treatment-induced fall in
glomerular filtration rate predicts long-term
stability of renal function. Kidney Int
199751793797.
65
Antihypertensives ARBs

• ARBs have similar efficacy to ACEIs for kidney
  protection in patients with several forms of
  glomerulonephritis  
• Proteinuria reduction 25 to 47
• Most clinicians use ACEI/ARB therapy in patients
  with nondiabetic CKD proteinuria

66
Antihypertensives ARBs

• Selection of ACEIs vs ARBs
• cost of therapy
• patient tolerance
• clinician preference

67
Antihypertensives CCBs

• Effective for HTN in patients with nondiabetic
  CKD
• Only nondihydropyridine CCBs shown to reduce rate
  of renal function decline
• No data to suggest higher doses needed to reduce
  proteinuria compared to antihypertensive doses

68
Antihypertensives Others

• Diuretics commonly used to treat fluid overload
  HTN no compelling data to suggest renal
  protection
• Can use central peripherally acting
  antihypertensive agents in CKD patients
• Consider dose reductions for renal impairment
  /or supplemental doses due to dialysis removal
  of hydrophilic ß-blockers
• nadolol
• acebutolol
• atenolol

69
Smoking Cessation

• Adverse effects of smoking
• acute GFR reduction
• nicotine
• ? urinary albumin excretion
• ? BP
• ? HR
• Educate patients regarding risks
• Institute appropriate therapeutic options

70
Anemia Management

• Anemia may increase rate of CKD progression
• Cardiorenal anemia syndrome" describes
  interrelationship between anemia, HF, CKD
• Erythropoietin stimulating agents
• higher target Hgb (13.o to 15.0 mg/dL) increases
  CV risk without improving quality of life
• target Hgb 10.5 to 11.5 mg/dL associated with
  fewer CV events than target Hgb level in the
  normal range

Drueke TB, Locattelli F, Clyne N, et al.
Normalization of hemoglobin level in patients
with chronic kidney disease and anemia. N Engl
J Med 20063552071-84.
Siiningh AAK, Szczech L, Tang KT, et al.
Correction of anemia with epoetin alpha in
chronic kidney disease and anemia. N Engl J Med
20063552085-98.
71
Costs of CKD Treatment

• High financial societal costs
• 0.5 of total Medicare population accounts for 5
  of Medicare expenditures
• Annualized expenditures per beneficiary
• 36,000 for patients lt 24 years of age
• 51,000 for patients gt 75 years of age
• Costs for care of advanced CKD estimated to
  increase dramatically over the next decade
• 28 billion dollars by 2010 for Medicare alone

USRDS. USRDS 2001 Annual Data Report. Bethesda,
MD National Institutes of Health, National
Institute of Diabetes and Digestive and Kidney
Disease, 2001.
72
Conclusions DM Patients

• Pharmacologic interventions limit CKD progression
• Screening for microalbuminuria
• type 1 DM patients 5 years after diagnosis
• type 2 DM patients annually
• urinary albumin excretion or urinary
  albumin-to-creatinine ratio
• Maintain blood glucose close to the normal range
  

Standards of medical care in diabetes2007.
Diabetes Care 2007200130(Suppl 1)S4S41.
73
Conclusions DM Patients

• 1st Line ACEI therapy
• persistent microalbuminuria 30 to 300 mg/day
• overt albuminuria gt 300 mg/day
• even if not hypertensive
• titrate to maximal reduction in urinary albumin
  excretion
• evaluate SCr K within 1 wk of initiation/dose
  change

74
Conclusions DM Patients

• ARBs
• another 1st line therapy in type 2 DM patients to
  reduce persistent proteinuria, albuminuria
• Nondihydropyridine CCBs
• may be effective 2 agent in patients unable to
  tolerate ACEI or ARB

75
Conclusions DM Patients

• Combination ACEI/ARB may result in greater
  proteinuria or albuminuria reduction than either
  agent alone
• may be alternative for patients that are not
  maximally responding to single-agent therapy
• Aldosterone receptor blocker consider for
  subjects with documented aldosterone escape

76
Diabetic Patients
DM Patients
77
Diabetic Patients
DM Patients
78
Conclusions Non-DM Patients

• Monitor nutrition frequently
• MDRD study
• moderate renal dysfunction GFR 25 to 55
  mL/min/1.73 m2
• low-protein diet of variable benefit
• standard-protein diet reasonable unless rapid
  disease progression
• severe renal dysfunction GFR 13 to 24
  mL/min/1.73 m2
• low-protein diet (0.6 g/kg/day) may reduce rate
  of renal function decline, time to reach
  end-stage kidney disease, onset of uremic
  symptoms

Jacobson HR, Striker GE. Report on a workshop to
develop management recommendations for the
prevention of progression in chronic renal
disease. Am J Kidney Dis 199525103106. 
Levey AS, Adler S, Caggiula AW, et al. Effects of
dietary protein restriction on the progression of
advanced renal disease in the Modification of
Diet in Renal Disease Study. Am J Kidney Dis
199627652663.
79
Non-diabetic Patients
80
Non-diabetic Patients
81
Conclusions Non-DM Patients

• BP goal lt 130/80 mm Hg
• CKD proteinuria gt 3 g/day
• 1st line ACEI or ARB
• treat hyperlipidemia to reduce CV risk

82
Conclusions Non-DM Patients

• CKD stage 4 prepare patients for
  renal-replacement therapy
• discuss hemodialysis, peritoneal dialysis, renal
  transplant
• early referral to clinician specializing in care
  of CKD patients (e.g. nephrologist)
• dialysis vascular access placement
• evaluate for uremia symptoms
• Identify/treat metabolic abnormalities

Eknoyan G, Levin N. NKF-K/DOQI Clinical Practice
Guidelines Update 2000. Foreword. Am J Kidney
Dis 200137S5S6.
83
Acknowledgements

• Prepared By/Series Editor April Casselman,
  Pharm.D.
• Editor-in-Chief Robert L. Talbert, Pharm.D.,
  FCCP, BCPS, FAHA
• Chapter Authors Melanie S. Joy, Pharm.D., FCCP
• Abhijit Kshirsagar, MD, MPH
• Nora Franceschini , MD, MPH
• Section Editor Gary R. Matzke, Pharm.D.