Chronic Kidney Disease

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Chronic Kidney Disease

• Mark Unruh MD MSc
• Assistant Professor
• Renal-Electrolyte Division
• University of Pittsburgh School of Medicine

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Goals and Learning Objectives

• The student will
• Learn that chronic kidney disease is widely
  prevalent and a public health problem
• Understand pathophysiology underlying progression
  of nephron loss
• Learn of strategies to slow progression of kidney
  disease

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Definitions

• Chronic Kidney Disease
• Kidney damage for gt3 months, as defined by
  structure of functional abnormalities of the
  kidney, with or without decreased GFR, manifest
  by either
• Pathological abnormalities
• Markers of kidney damage, including abnormalities
  in the composition of the blood or urine, or
  abnormalities in imaging tests.
• GFR lt60 mL/min/1.73 m2 for gt 3 months with or
  without kidney damage

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Etiology of kidney failure and natural history of
the disease
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When identifying kidney disease, recall the
relationship between S Cr and GFR
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Kidney Failure Rapidly Increasing
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Risk factors for CKD
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Target diagnosis and treatment to delay
progression of kidney disease
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Goals and Learning Objectives

• The student will
• Learn that chronic kidney disease is widely
  prevalent and a public health problem
• Understand underlying progression of nephron loss

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Mechanisms of Kidney Disease Progression

• Adaptive changes lead to maladaptive consequences
• Hypertension
• Hyperfiltration
• Elevated glomerular pressure
• Glomerular growth
• Increased wall stress
• Increased ammoniagenesis
• Complement activation and tubulo-interstitial
  disease

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Remnant kidney model
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Pathogenesis of renal injury in renal mass
reduction model
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Angiotensin II has diverse effects to increase
ECV and CO
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Mal-adaptation to nephron loss
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Angiotensin II also plays a key role in kidney
injury
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Goals and Learning Objectives

• The student will
• Learn that chronic kidney disease is widely
  prevalent and a public health problem
• Understand pathophysiology underlying progression
  of nephron loss
• Learn of strategies to slow progression of kidney
  disease

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Target diagnosis and treatment to delay
progression of kidney disease
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Preventing Progressive renal disease

• Treat underlying disorder
• Control hypertension
• Prevent hyperfiltration ( Ace-inhibitor, AII
  Blocker, low protein diet)
• Tobacco cessation
• Metabolic control (Acidemia, PO4, lipids)

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Identification of Reversible Decreases in Renal
Function

• Decreased renal perfusion
• Hypotension (myocardial dysfunction,
  pericarditis, CHF)
• Volume depletion (vomiting, diarrhea, diuretic
  use)
• Infection (sepsis)
• Use of drugs that lower GFR (NSAIDs and ACEIs)
• Administration of nephrotoxic drugs
• Aminoglycoside antibiotics
• Radiographic contrast material
• Urinary tract obstruction

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Role of Hypertension in Progression to Renal
Failure
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Risk for progression increases with proteinuria
greater than 1g/d
Jafar Ann Int Med Aug 19 2003
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ACE-I and AII Blockers are good kidney medications
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Low protein diet slows progression
Kasiske AJKD 1998
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Smoking is bad for the kidney

• Nicotine infused into renal artery increases GFR,
  urine flow and Na excretion
• Increased catecholamine release cortisol and
  aldosterone levels also increase
• Tubulotoxic effect--increased excretion of NAG
  and impaired cation transport
• Vascular effects increased platelet aggregation
  and vasoconstrictor prostaglandins decrease
  vasodilatory prostaglandins endothelial cell
  injury and impaired endothelial cell-dependent
  vasodilatation

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Lipids are bad for the kidney
Increased LDL
Cytokines Growth factors Chemoattractants
Altered vasoactive substances
Mesangial Cell Dysfunction Endothelial Cell
Dysfunction
Oxidized LDL
Mesangial cell inury and proliferation Increased
mesangial matrix
GLOMERULOSCLEROSIS
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Nephrotoxins
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Treatment plan of early identification
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Goals and Learning Objectives

• The student will
• The student will
• Understand the clinical manifestations of uremia
• Review renal adaptation
• Learn the common complication of chronic kidney
  disease
• Anemia
• Bone and Ca/Phosphate Metabolism
• Cardiovascular

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Uremia as a Clinical Syndrome

• Renal excretory failure
• Retained products of metabolism
• Related to protein intake
• Partially dialyzable
• Exact nature is unknown
• E.g. Small molecules (Urea etc.), lipid soluble
  molecules, middle molecules
• urea, hormones, polyamines, middle molecules,
  serum proteases, trace elements, pyridine
  derivatives, b2-microglobulin
• Loss of metabolic and endocrine functions
  normally performed by the intact kidney

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Uremia Common Symptoms

• GI Nausea, vomiting, diarrhea
• CVS Dyspnea, edema, chest pain
• Neuro Restless legs, twitching, confusion
• Skin Pruritus, bruising, uremic frost
• MSK Bone pain, arthritis

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Dermatologic Manifestations in CRI
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Uremia The Common Signs

• Sallow pallor, bruising
• Uremic fetor
• Hypertension
• Pericardial rub
• Alteration of consciousness
• Neuropathy

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The patient with CKD may be completely
asymptomatic until GFR decreases to 15-20 ml/min.
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Goals and Learning Objectives

• The student will
• The student will
• Understand the clinical manifestations of uremia
• Review renal adaptation

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Adaptation to nephron loss to maintain homeostasis

• Chronic renal failure limits the ability of the
  kidney to regulate fluid and electrolyte
  homeostasis
• Adaptations in tubular function and extrarenal
  systems maintain fluid and electrolyte
  homeostasis as the GFR declines
• These adaptations have both immediate benefits
  and adverse consequences

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Regulation of solutes with progressive nephron
loss Plasma concentration and urine
concentrating ability by GFR
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Limited Flexibility in Sodium and Water Balance
with advanced kidney disease
GFR 100 ml/min
GFR 10 ml/min
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Physiologic Basis of Adaptation

• Increased solute excretion per remaining
  functional nephron

Fractional excretion increases as GFR decreases
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Sodium Balance
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Sodium Balance in CRFThe Problem

• Large variations in Na intake
• 10 - 500 mEq/day
• Fractional excretion
• lt 1
• Fractional reabsorption
• gt 99

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Sodium balance maintained by increased fractional
excretion
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Pathophysiologic Basis of Sodium Retention in CKD
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Sodium Retention in CKD

• The Input Solution
• Dietary Na Restriction in proportion to the
  decrement in GFR
• The output solution

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Mechanisms of Adaptive Natriuresis in CKD

• Signal ECF volume expansion
• Potential effectors
• Atrial natriuretic peptide (ANP)
• Other circulating natriuretic factors
• Local renal vasoactive factors

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Clinical Manifestation of Sodium Balance in CKD

• Common
• Weight gain
• Peripheral edema
• Pulmonary edema
• Uncommon
• Renal Na wasting (ECF volume depletion)
• Weight loss
• Systemic hypotension

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Water Balance
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Determinants of Urine Volume
UV Filtered Load Tubular Reabsorption

• Filtered Load GFR
• Tubular Reabsorption
• Water Balance (ADH levels)
• Solute Balance (Umax)

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Determinants of Urine Volume
ADH
UV
Cosm
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Adaptation of Renal Water Handling in CKD
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Physiology Review of Urinary Concentration

• Gradient Generation
• Sodium reabsorption (ALOH)
• (countercurrent multiplication)
• Urea reabsorption (MCD)
• Gradient Maintenance
• Countercurrent exchange (vasa recta)
• Gradient Utilization
• ADH-dependent water reabsorption (CD)

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Pathophysiologic Basis of Impaired Urinary
Concentration in CKD

• Structural damage
• Medullary hypoxia and sensitivity to ischemic
  injury (esp. ALOH, MCD, VR)
• Tubulointerstitial inflammation and fibrosis
• Functional defects (ADH resistance)
• Down regulation of the V2 vasopressin receptor
• Downregulation of the apical membrane water
  channel (aquaporin-2)
• ANP and PGE2 excess

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Physiology Review of Urinary Dilution

• Separation of salt and water
• Medullary diluting site (ALOH)
• Cortical diluting site (DCT)
• Maintenance of CD water impermeability
• Suppression of ADH release
• Pathophysiology of Impaired Urinary Dilution in
  CKD
• Structural damage (esp. tubulointerstitial)
  impairs separation
• Hypothalamic-posterior pituitary axis functions
  normally in CKD In the absence of countermanding
  hemodynamic stimuli, ADH release is appropriately
  suppressed by hypotonicity

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Clinical Manifestations of Water Balance in CKD

• Decreased concentrating ability
• Nocturia, polyuria
• Hypernatremia (if water intake is compromised)
• Decreased diluting ability
• Hyponatremia (if water intake is excessive)
• Kidney Failure Isosthenuria the restriction of
  operating urine osmolality to prevailing plasma
  osmolality

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Potassium Balance
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Physiology Review of Potassium Balance

• Renal K Handling
• Near complete reabsorption of filtered K in PT
  and ALOH
• Variable secretion in DCT and C D
• Aldosterone
• Tubular flow
• Cellular K Uptake
• Insulin

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Renal K Handling in CKD

• K balance is very well maintained with
  progressive nephron loss
• Filtered load of K decreases as GFR falls
• K reabsorption is similar in normal and diseased
  kidneys
• Adaptation Distal K secretion is increased in
  proportion to the decrement in GFR

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Mechanisms of Adaptive K Secretion in CKD

• Enhanced Na,K-ATPase activity
• Extracellular K concentration
• Aldosterone
• Increased distal tubular flow
• Adaptive natriuresis
• Osmotic diuresis per nephron
• Chronic metabolic acidosis

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Hyperkalemia in CKD

• Aldosterone-related
• Hypoaldosteronism
• Idiopathic (Diabetes Mellitus)
• ACE inhibitors
• Pseudohypoaldosteronism
• K-sparing diuretics
• Distal flow-related
• ECF volume depletion
• Congestive heart failure (without diuretics)
• Insulin-related
• Diabetes mellitus
• Fasting
• Malnutrition
• Miscellaneous
• B-adrenergic agonists (esp. in diabetics)
• Dietary indiscretion

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Acid-Base Balance
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Physiology Review of Acid-Base Balance

• Filtered HCO3 is reclaimed in the PT
• Electrically neutral Na-H exchange
• HCO3 utilized by the buffering reaction is
  regenerated in the DT
• Electrogenic H secretion
• NH4 is the most important urinary buffer
  Urinary net acid excretion is critically
  dependent on NH4 generation and excretion

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Pathophysiology of Renal Proton Retention in CRF

• Protons are retained as GFR declines
• Hyperchloremic metabolic acidosis (GFR gt 25
  ml/min)
• Anion gap metabolic acidosis (GFR lt 25 ml/min)
• Mechanisms
• Reduced ammoniagenesis
• Proximal tubular HCO3 wasting
• Reduced titratable acid excretion (phosphate
  binders)
• Adaptation
• Renal Increased fractional ammonium excretion
• Extrarenal adaptation

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Impaired Ammoniagenesis in CRF

• Reduced renal mass (nephron drop out)
• Metabolic inhibitors
• Hyperkalemia (Type IV RTA)

Welbourne J Clin Invest 51 1852
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Impaired Proximal Tubular HCO3 Reabsorption in CKD

• PTH
• Chronic hypocarbia
• Adaptive natriuresis
• Osmotic diuresis
• Fanconis syndrome

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Maintenance of Acid-Base Balance in CKD

• Tissue buffering
• Bone matrix (Ca phosphate and carbonate)
• Consequence Osteoporosis
• Cellular buffering (more important in buffering
  acute rather than chronic acid loads)
• Consequence K redistribution
• Chronic hyperventilation
• Consequence Decreased proximal tubular HCO3
  reabsorption

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Goals and Learning Objectives

• The student will
• Learn that chronic kidney disease is widely
  prevalent and a public health problem
• Understand renal adaptation and progression of
  nephron loss
• Learn strategies to slow progression

68
Goals and Learning Objectives

• The student will
• Understand the clinical manifestations of uremia
• Review adaptation
• Learn the common complication of chronic kidney
  disease
• Anemia
• Bone and Ca/Phosphate Metabolism
• Cardiovascular

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Anemia and Kidney Failure

• Primary factors
• Relative erythropoietin deficiency
• Shortened rbc lifespan
• uremic toxins
• EPO may be a red blood cell survival factor
• Inhibitors of erythropoiesis--uremic toxins

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Relationship between renal function and
hematocrit
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Features of the anemia of CRF Normocytic and
normochromic Low reticulocyte count Normal bone
marrow--and usually not needed to diagnose Serum
erythropoieitin level low-normal--not needed to
diagnose
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Erythropoietin physiology

• Red blood cell growth factor
• Stimulates erythropoiesis via a specific receptor
  on bone marrow erythroid precursor cells (BFU-E,
  CFU-E)
• gt90of EPO is produced by the kidneys
• lt 10 is of hepatic origin
• Renal interstitial fibroblasts are the primary
  source of EPO
• Renal interstitial fibroblasts have a
  heme-protein based oxygen sensor in the cell
  membrane

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Biochemical Structure and Pharmacokinetics of
rHuEPO

• Produced using recombinant DNA technology in a
  mammalian cell expression system in order to have
  3 N-linked carbohydrate chains which are needed
  for biological activity
• Same amino acid structure and biological activity
  as native EPO
• NESP (novel erythropoiesis stimulating protein)
• 5 amino acid changes in EPO creating 2
  additional N-linked carbohydrate moieties
• terminal half-life 3 times greater than rHuEPO

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Adverse effects of rHuEPO therapy

• Iron deficiency
• Hypertension
• about 25 of dialysis patients treated with
  rHuEPO develop hypertension or an increase in
  blood pressure
• very rarely this may be severe with hypertensive
  encephalopathy and seizures
• mechanism
• increased peripheral resistance as anemia
  improves while cardiac output remains above
  normal
• increased red blood cell and plasma volume
• direct vascular effects of rHuEPO are postulated
• Hemodialysis access thrombosis
• primarily a concern with synthetic arteriovenous
  synthetic grafts

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Manifestation of Hyperphosphatemia
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Coronary Calcification in Young Adults with ESRD
Goodman, et al NEJM 2000
Elevated Ca x P product and cumulative use of
calcium-containing P-binders are correlated with
coronary calcification
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Renal Tubular Handling of Calcium
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Vitamin D Metabolism
Skin
Liver
Kidney
Kidney
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Calcium and Phosphate Metabolism in Renal Failure
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Bone/Ca/Phos/PTH Management

• Low Phosphate diet
• Maintain Ca X Phos product less than 55mg2/dl2
• Phosphate binders with meals
• Use of Calcitriol or D3 analogues
• Monitor Ca, Phos, PTH
• Avoid the use of aluminum

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Kidney failure patient has a 10-100x risk of
heart disease
Foley et al AJKD 1998
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Risk Factors for Cardiac Disease in Chronic Renal
Failure

• Age
• Diabetes mellitus
• Smoking
• Hypertension
• Dyslipidemia
• Physical inactivity
• Menopause
• Obesity
• Hemodialysis fistula

• Anemia
• Hyperparathyroidism
• Hyperphosphatemia
• Hypocalcemia
• Effects of dialysis
• Hypoalbuminemia
• Dietary factors
• Hyperhomocysteinemia

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Anemia Hypertension Hypervolemia AV fistula
Anemia Hypertension Hypervolemia AV fistula
Hyperlipidemia Diabetes mellitus Hyperhomocysteine
mia
Hyperlipidemia Diabetes mellitus Hyperhomocysteine
mia
Hyperparathyroidism Ca and P abnormalities Uremia
Malnutrition
Hyperparathyroidism Ca and P abnormalities Uremia
Malnutrition
Concentric LVH LV Dilatation Systolic
dysfunction Diastolic dysfunction
Concentric LVH LV Dilatation Systolic
dysfunction Diastolic dysfunction
CAD Vascular calcification
CAD Vascular calcification
Cardiomyopathy
Ischemic heart disease
Cardiomyopathy
Ischemic heart disease
Cardiac Failure
Cardiac Failure
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Goals and Learning Objectives

• The student will
• Learn that chronic kidney disease is widely
  prevalent and a public health problem
• Understand renal adaptation and pathophysiology
  underlying progression of nephron loss
• Learn strategies to slow progression
• Understand the clinical manifestations of uremia
• Learn the common complication of chronic kidney
  disease
• Anemia
• Bone and Ca/Phosphate Metabolism
• Cardiovascular