18 Chronic Kidney Disease Flashcards Preview

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Flashcards in 18 Chronic Kidney Disease Deck (34)
1

Definitions

  • Kidney damage
  • Chronic kidney disease (CKD)
  • End stage renal disease (ESRD) or kidney failure
  • Uremia

  • Kidney damage
    • Structural or functional abnormalities of the kidney > 3 months
      • Initially: w/o decreaed GFR
      • Over time: decreased GFR
    • Markers of kidney damage
      • Ex. proteinuria, polycystic kidneys, hx of kidney transplant, etc.
      • Abnormalities in the composition of the blood or urine
      • Abnormalities in imaging tests of the kidney
  • Chronic kidney disease (CKD)
    • Decreased GFR or kidney damage
  • End stage renal disease (ESRD) or kidney failure
    • Severely decreased renal function (GFR < 15 ml/min/1.73m2)
    • Requires renal replacement therapy (i.e. hemodialysis / peritoneal dialysis or transplant)
  • Uremia
    • Signs & symptoms attributable to advanced reanl failure or ESRD

2

Stages of CKD

  • Stage 1
  • Stage 2
  • Stage 3
  • Stage 4
  • Stage 5
  • CKD
  • Very significant independent risk factor for mortality & morbidity
  • How we define/stage CKD

  • Stage 1
    • Kidney damage (structural or functional) with normal or ↑ GFR
    • GFR > 90
  • Stage 2
    • Kidney damage (structural or functional) with mild ↓ GFR
    • GFR = 60-89
  • Stage 3
    • Moderate ↓ GFR
    • GFR = 30-59
  • Stage 4
    • Severe ↓ GFR
    • GFR = 15-29
  • Stage 5
    • Kidney failure
    • GFR < 15 or dialysis
  • CKD
    • Stages 3-5
  • Very significant independent risk factor for mortality & morbidity
    • Proteinuria
  • How we define/stage CKD
    • Albuminuria
    • Reduced eGFR (< 60 ml/min/1.73m2)

3

Measurement & assessment of GFR

  • Commonly used indicators of GFR in clinical practice
  • Plasma creatinine vs. GFR
  • Creatinine production varies with...& is influenced by...
  • Take home

  • Commonly used indicators of GFR in clinical practice
    • Serum creatinine and blood urea nitrogen (BUN) concs
    • Lab measurement of creatinine and urea is accurate and reliable, but normal values may vary from lab to lab
  • Plasma creatinine vs. GFR
    • Semi-logarithmic relationship
    • Small values (steep part of the curve): a relatively small change in creatinine indicates a large change in GFR
    • Large values: a large change in creatinine reflects only a small change in GFR
  • Creatinine production varies with...& is influenced by...
    • Muscle mass
      • Changes in lean body weight over time influence the serum creatinine level
    • Age, sex, race influence muscle mass
  • Take home
    • All of these are reasons why an eGFR is preferred in estimating renal function

4

Etiology & natural history of CKD

  • Most chronic nephropathies
  • Rate of decline
  • Electrolyte homeostasis, causes of progressive decline in function, and manifestations of kidney failure

  • Most chronic nephropathies demonstrate inexorable progression to kidney failure
  • The rate of decline ≈ 7-12 ml/min/year in those with untreated chronic nephropathies such as diabetic nephropathy
  • Electrolyte homeostasis, causes of progressive decline in function, and manifestations of kidney failure
    • Similar enough across the dif pathologies
    • --> common underlying routes to progression, symptoms, and (hopefully) amelioration of CKD

5

Prevalence of CKD, risk factors for development, & progression

  • Prevalence of CKD
  • Risk factors
    • CKD is largely a disease of...
    • Comorbidities
  • Majority of pts with CKD
  • Prevalence of ESRD

  • Prevalence of CKD
    • ~14.7% of the US adult population has some form of CKD
    • 30x as many pts have CKD than ESRD
    • >75 million have an increased risk of developing CKD
  • Risk factors
    • CKD is largely a disease of older adults
      • Higher rates of comorbidities + age related decline in GFR
      • GFR decline of ~8ml/min for each decade after 40
    • Comorbidities
      • DM
      • HTN
      • Dyslipidemia
      • Obesity
  • Majority of pts with CKD
    • Not aware, even those with an eGFR of 15-30 ml/min/1.73m2
    • No clear, early, identifiable signs
    • Increae in creatinine is often subtle
  • Prevalence of ESRD
    • Increasing rapidly
    • Will continue for the next few decades
  • Mortality
    • After ESRD is reached (dialysis), mortality rate is very high
  • Cost
    • > $20 billion
  • Qualtiy of life
    • Burden on pt & families comparable to other devastating illnesses

6

Risk factors for CKD

  • Non-modifiable
  • Modifiable

  • Non-modifiable
    • Older age
    • Black race
      • Black > native americans > hispanics > asians / pacific islanders
    • Genetic predisposition
    • Prematurity
    • Important for screening purposes & for studying CKD progression
  • Modifiable
    • HTN
    • Diabetes
    • Obesity
    • Dyslipidemia
    • Hyperuricemia
    • Smoking
    • Heavy consumption of analgesics
    • Improtant for understanding the pathophysiology of CKD & possible options for intervention & therapy

7

Pathophysiology of progression of renal disease

  • CKD is characterized by...
  • Renal adaptation --> maladaptive processes
    • 2 major consequences
    • Short term --> 
    • Long term -->
  • Remnant kidney animal model
  • Glomerular capillary HTN is mediated by...
  • RAAS primary mediators

  • CKD is characterized by...
    • Loss of functioning nephrons (not decreased output/function of the same number of nephrons)
  • Renal adaptation --> maladaptive processes
    • 2 major consequences
      • Elevated glomerular pressure --> hyperfiltration by remaining nephrons
      • Glomerular / tubular growth --> increased wall stress/inflammation --> hypertrophy
    • Short term --> increased single nephron GFR --> hyperfiltration
    • Long term --> increased glomerulosclerosis & tubular atrophy
  • Remnant kidney animal model
    • Remove one kidney & large fraction of other kidney --> decreased nephron mass
    • --> increased RPF & GFR in remaining nephrons
    • --> glomeruli: increased blood flow, filtration rate, & size
  • Glomerular capillary HTN is mediated by AII
    • ACE-Is or ARBs --> AII blockade --> prevents glomerular HTN
    • Increase renin mRNA synt --> increase DNA synth --> mesangial cells multiply, epithelial cells hypertrophy, epithelial foot processes increase in #, & glomerular capillary length increases
  • RAAS primary mediators
    • AII, IGF-1, PDGF, prostaglandins, RANTES, endothelin, & AVP
    • Modulate renal cell growht in culture &/or circulating blood levels after nephrectomy

8

Glomerulosclerosis

  • Most pts have progressiv ekidney disease due to...
  • First stage
  • Second stage
  • Third stage

  • Most pts have progressiv ekidney disease due to...
    • HTN
    • Diabetes
    • Other chronic glomerulonephropathy
  • First stage: endothelial injury & inflammation
    • Damaged endothelium loses its anticoagulation, anti-inflammatoyr property
    • Endothelium becomes primed for the proliferative stage
  • Second stage: proliferation
    • Kidney damage is characterized by stretched epithelial cells & proliferated/dedifferentiated mesangial cells
  • Third stage: fibrosis
    • Hyaline material accumulates int he mesangium & subendothelial regions of the glomerulus
    • Hyaline material eventually --> collapse of capillaries (glomerulosclerosis)

9

CKD pathophysiology take home points

  • 2 major processes important for CKD progression
  • These events eventually lead to...
  • RAAS inhibition

  • 2 major processes important for CKD progression
    • GLomerular hyperfiltratoin
    • Glomerulra hypertrophy
  • These events eventually lead to...
    • Fiborsis & sclerosis of glomeruli
  • RAAS inhibition
    • Prevent development of glomerular HTN & subsequent CKD progression

10

Strategies to slow CKD progression

  • Early diagnosis & treatment
  • (1) Treat underlying causes
  • (2) Control BP
    • BP goals
      • Urine albumin < 30 mg/ 24 hrs
      • Urine albumin > 30 mg / 24 hr
    • Risk of progression of CKD is modified by...
    • Antihypertensives
  • (3) Protein intake
  • (4) Smoking cessation
    • Nicotine
    • Tubuloxic effect
    • Vascular effects
    • Bottom line
  • (5) Nephrotoxins
    • Most concerning
    • Others
    • AKI vs. CKD

  • Early diagnosis & treatment
    • Interventions slow progression of, but don't reverse, kidney disease
      • May help pt avoid dialysis, transplant & kidney failure complications
    • Optimal treatment can slow rate of progression from 10 to 2-4 ml/min/year
  • (1) Treat underlying causes
    • Identify reversible factors
    • Ex. volume depletion, uncontrolled HTN, obstructive uropahty, nephrotoxins
  • (2) Control BP
    • BP goals
      • Urine albumin < 30 mg/ 24 hrs: < 140/80
      • Urine albumin > 30 mg / 24 hrs: < 130/80
    • Risk of progression of CKD is modified by proteinuria
    • Antihypertensives: ACE-Is & ARBs
      • Block AII --> decrease glomerular capillary HTN --> decrease proteinuria --> decrease AII fibrosing effects
      • Delay progression + cardiovascular benefits
      • Don't ever discontinue
      • Side effects: increased creatinine, increased K, angioedema, & cough (ACE-I only)
  • (3) Dietary protein restriction
    • Decreased protein intake --> decreased hyperfiltration --> slowed progression
  • (4) Smoking cessation
    • Nicotine
      • Increases GFR, urine flow, & Na excretion
      • Increases catecholamines, cortisol, & aldo
    • Tubuloxic effect
      • Increased excretion of NAG & impaired cation transport
    • Vascular effects
      • Increased platelet aggregation & vasoconstrictor prostaglandins
      • Decreased vasodilatory prostaglandins
      • Endothelial cel linjury & impaired endothelial cell-dependent vasodilation
    • Bottom line
      • Tobacco potentiates GFR loss & can cause/worsen proteinuria
  • (5) Avoid nephrotoxins
    • Most concerning: NSAIDs & herbal meds
    • Others: tacrolimus/prograf/cyclosporine, aminoglycosides, amphotericin, colistin, & IV contrast
    • AKI --> CKD & CKD --> AKI

11

Cardiovascular disease (CVD)

  • Cause of disparity b/n # of pts receiving renal replacement & # w/ CKD
  • CKD vs. CVD
  • Traditional risk factors
  • Non-traditional risk factors
  • Both traditional & non-traditional factors
  • Treatment

  • Cause of disparity b/n # of pts receiving renal replacement & # w/ CKD
    • Most pts w/ CKD die from CVD prior to requiring dialysis or transplantation
    • Even on dialysis, risk of death from CVD is higher than in general population
  • CKD vs. CVD
    • Pts w/ CKD are high-risk pts for CVD
    • CKD = coronary equivalent
    • Pts w/ lower GFRs & microalbuminuria/proteinuria carry a high risk of CVD (equivalent to a prior hx of coronray disease
  • Traditional risk factors
    • Ex. age, diabetes, lipids, HTN, smoking, etc.
    • Account for only a portion of the CVD risk associated w/ CKD
  • Non-traditional risk factors
    • Ex. anemia, volume overload, hyperparathyroidism, Ca/phosphate disturbances, uremia, & malnutrition/inflammation
    • Play a role in increasing CVD risk in CKD
  • Both traditional & non-traditional factors
    • --> cardiomyopathy & ischemic heart disease
  • Treatment
    • Optimize management of known CVD risk factors
    • Focus on BP, exercise, aspirin, & statins
    • High suspicion b/c CKD pts often presnet w/ atypical CVD symptoms

12

Early identification treatment plan / model of care for pts w/ CKD

  • Screen
  • Diagnose
  • Treat
  • Prepare

  • Screen for CKD
    • Older pts
    • Hx of kidney problems
    • Family hx
    • African-american
    • HTN
    • Diabetics
  • Diagnose CKD
    • Serum creatinine --> eGFR, urine ablumin, or protein
  • Treat kidney disease & CVD
    • Manage BP
    • Reno-protective meds (ACE-Is, ARBs)
    • Smoking cessation
    • Treat complications
  • Prepare for renal replacement therapy
    • Dialysis
    • Transplant

13

Uremia

  • General
  • Basic abnormality
  • Symptoms vs. GFR
  • Uremic symptoms result from...
  • Uremia is related to...
  • Variability in measuring kidney function
  • Usual physical signs can be rapidly assessed by...
  • Indication for initiation of dialysis
  • Presence of uremic symptoms in a chronic dialysis pt often reflects...

  • General
    • Pathologic manifestation of kidney disease in its most severe untreated form
    • Clinical expression of symptoms/signs of decreased GFR (renal failure)
  • Basic abnormality
    • Presence of waste products that the kidney is no longer removing form the body
    • Retained products of metabolism
  • Symptoms vs. GFR
    • CKD pts may be asymptomatic until GFR < 15-20 ml/min --> uremia
  • Uremic symptoms result from...
    • Renal excretory failure
      • Retention of urea, hormones, polyamines, trace elements, serum proteases ("middle molecules"), pyridine derivatives, beta2-microglobulin, etc.
    • Loss of normal metabolic & endocrine functions
  • Uremia is related to protein intake
    • Low protein diet --> decreased symptoms
  • Multisystem disorder: manifestations include...
    • GI: nausea, vomiting, diarrhea, dysguesia, changes in appetitie
    • CVS: dyspnea, edema, chest pain
    • Neuro: restless legs, twitching, confusion, sleep & memory problems
    • Skin: pruritus, bruising, uremic frost
    • MSK: bone pain (endocrine), arthritis
    • Hematologic
  • Variability in measuring kidney function
    • CKD pts develop complications s& symptoms at dif thresholds
    • Makes it difficult t ouse GFR as the only factor in decision making
  • Usual physical signs can be rapidly assessed by...
    • BP, pericardial rub, rales, etc.
  • Indication for initiation of dialysis
    • Development of & failure to alleviate uremic manifestations w/ conservative/pharmacologic therapy
  • Presence of uremic symptoms in a chronic dialysis pt often reflects...
    • Inadequate treatment
    • Need to increase dialysis dose

14

Uremia

  • Common signs
  • Multisystem disorder: manifestations include...
    • Cardiovascular
    • Endocrine disorders
    • Hematologic
    • GI
    • Neuropsychiatric
    • Immunologic
    • Musculoskeletal
    • Dermatologic

  • Common signs
    • Sallow pallor, bruising
    • Uremic fetor
    • Hypertension
    • Pericardial rub
    • Alteration of consciousness
    • Neuropathy
    • Malnourished state
  • Manifestations
    • Cardiovascular
      • HTN
      • Ischemic cardiac disease
      • Pericardial disease (pericarditis)
      • CHF
      • Dyspnea
      • Edema
      • Chest pain
    • Endocrine disorders
      • Secondary hyperparathyroidism
      • Glucose intolerance (uremic diabetes)
      • Hyperlipidemia
      • Sexual dysfunction / infertility
    • Hematologic
      • Anemia
      • Bleeding diathesis
    • GI
      • Anorexia
      • Nausea
      • Vomiting
      • Gastritis
      • Duodenitis
      • Dysgeusia
      • Changes in appetite
    • Neuropsychiatric
      • Peripheral neuropathy
      • CNS disturbances
      • Seizures
      • Sleep disorders
      • Restless leg
      • Twitching
      • Confusion
      • Memory problems
    • Immunologic
      • Leukopenia, lymphocytopenia
      • Decreased antibody responses
      • Decreased cell-mediated immune respones
      • Increased susceptibility to infection
    • Musculoskeletal
      • Mineral & bone disease
      • Myopathies
      • Carpal tunnel syndrome
      • Bone pain
      • Arthritis
    • Dermatologic
      • Pruritus
      • Uremic pigmentation
      • Uremic frost
      • Calciphylaxis
      • Nail changes
      • Bruising

15

Renal adaptation

  • Pt awareness of their kidney disease
  • Asymptomatic CKD
  • Basis of adaption

  • Pt awareness of their kidney disease
    • >10-12 million adults in the US have CKD w/ GFR < 60 ml/min
    • Majority aren't aware
  • Asymptomatic CKD
    • CKD is often asymptomatic until late in the disease course
    • Renal reserve allows remaining nephrons to hyperfilter/increase their level of function
    • Additional compensatory processes maintain adequate homeostasis
  • Basis of adaption
    • Adaptations in glomerular & tubular function & extra-renal systems maintain electrolyte balance but may contribute to adverse consequences
    • Adaptation --> increased solute excretion per remaining functional nephron
    • Fractional excretion increases as GFR decreases

16

Mechanisms that help explain the diseased kidney's ability to function

  • Intact nephron hypothesis
  • Functional reserve
  • Hyperfiltration
  • Osmotic diuresis

  • Intact nephron hypothesis
    • Diseased kidney continues to regulate appropriately by responding to varying intake of solutes & water in an organized fashion
    • Diseased kidney behaves as a reduced # of nephrons that are each functioning normally or above normally
    • Abnormalities that occur are generally explained by the overall reduction in renal mass rather than by the general loss of glomerular or tubular functions
  • Functional reserve
    • Ability of kidneys to increase their function/work
    • Severely diseased kidney is functioning at or near its max capacity to maintain homeostasis
      • Extreme variations in itake are poorly tolerated
      • Upper & lower limits for solute & water excretion converge in advanced CKD
        • Dietary indiscretions or inappropriate meds may not be well tolerated
  • Hyperfiltration
    • Abnormal increase in filtration rate of functioning glomeruli
    • Decrease renal mass --> hyperfiltraiton in remaining nephrons --> glomerular sclerosis & proteinuria
    • Seconary change in remaining nephrons + increased filtered load --> CKD progression
  • Osmotic diuresis
    • Decrease renal mass --> each remaining nephron handles increased solute
    • Increased solute excretion per nephron --> osmotic diuresis (associated increased water loss)
    • Reduced ability to produce max concentrated urine
    • --> nocturia & polyuria in moderate to advanced CKD

17

Impact of declining kidney function on fluid/electrolyte balance

  • Nephron loss vs. solute regulation
    • Creatinine, urea nitrogen, & additional nitrogenous waste products
    • Bicarb, Ca, & organic phosphate
    • Water, Na, & K
  • Plasma concs of creatinine & BUN
  • Plasma concs of phosphorus & bicarb
  • Plasma concs of Na & K
  • Plasma H conc
  • Additional physiologic stressors in advanced CKD

  • Continued solute regulation despite progressive nephron loss
    • Little regulation of creatinine, urea nitrogen, & addiitonal nitrogenous waste products (+ other uremic toxins)
    • Partial regulation of bicarb, Ca, & organic phosphate is maintained until there's significant nephron loss (GFR < 30-45 ml/min)
    • Near complete regultaion of water, Na, & K are maintained until ~9/10 nephrons are lost (GFR < 10-15 ml/min)
  • Plasma concs of creatinine & BUN
    • Readily increase as GFR deteriorates
  • Plasma concs of phosphorus & bicarb
    • Change to a lesser degree as GFR deteriorates
  • Plasma concs of Na & K
    • Relatively stable until there's severe decrement in GFR
  • Plasma H conc
    • Tightly regulated
  • Additional physiologic stressors in advanced CKD
    • Although most homeostatic mechs are robust, in advanced CKD the kidney has a very limited ability to cope w/ additional physiologic stressors
    • Adaptation is limited due to decreased GFR

18

Renal handling of specific fluid/electrolytes:
Creatinine & nitrogenous compounds

  • Cr & urea when GFR decreases
  • Cr vs. GFR
  • Urea vs. GFR

  • Cr & urea when GFR decreases
    • Excretion of Cr & urea is maintained by increasing serum levels
    • At a higher serum Cr level, the diseased kidney is able to filter and excrete the usual daily production of Cr (i.e., re-establish steady state)
    • There are minimal adaptive mechs to maitnain "normal" serum levels of Cr/urea
  • Cr vs. GFR
    • Increased serum Cr is directly proportional to decreased GFR
    • Good measure of GFR
  • Urea vs. GFR
    • Increased serum urea is directly proportional to decreased GFR
    • Urea is also affected by other factors like urine flow, dietary protein, catabolic state, & drugs (ex. steroids & tetracycline)

19

Renal handling of specific fluid/electrolytes:
Na excretion

  • Challenge for the kidney in Na homeostasis
  • FENa in healthy patients
  • Most CKD patients are able to excrete the daily Na load in the setting of a reasonable dietary Na+ intake
    • Due to...
    • Mechs
  • FENa in CKD pts
  • Excretory range in CKD
  • Na homeostasis in CKD pts is maintained by...
    • Input sol'n
    • Output sol'n
  • Marked Na retention occurs if...
  • Clinical manifestations of Na imbalance in CKD
    • Common
    • Less common

  • Challenge for the kidney in Na homeostasis
    • Large variations in daily dietary Na intake from 10 - 500 mEq/day (0.2-11g/day)
  • FENa in healthy patients
    • Varies depending on intake
    • <1% w/ intake b/n 2-5g
  • Most CKD patients are able to excrete the daily Na load in the setting of a reasonable dietary Na+ intake
    • Due to increased fractional excretion by tubules
      • Tubules are filtering less Na due to decreased GFR
      • --> higher fractional excretion is adaptive
    • Mechs
      • Decrease Na/K/2Cl (loop) & Na/Cl (thiazide) transporters
      • Increase natriuretic factors (ex. atrial natriuretic peptide)
      • Adaptive natriuresis
        • Modest hypervolemic status --> pressure natriuresis
        • --> further Na excretion --> establish a new steady tate
  • FENa in CKD pts
    • Increased FENa --> decreased fractoinal reabsorption via...
      • Decreased N/K/2Cl & Na/Cl transporters
      • Increased ANP
      • Increased adaptive natriuresis
        • Initial + Na balance --> increased EC volume --> increased BP --> pressure natriuresis --> re-establishes steady state
  • Excretory range in CKD: narrowed
    • Dietary Na intake increases (decreases) --> volume overload (depletion)
  • Na homeostasis in CKD pts is maintained by...
    • Input sol'n: dietary Na restriction in proportion to decreased GFR
    • Output sol'n: increased Na excretion
  • Marked Na retention occurs if...
    • Intake >>> max ecretion level or GFR is very low (<10%)
    • To prevent this: dietary Na restriction of 2g/day
  • Clinical manifestations of Na imbalance in CKD
    • Common: weight gain, peripheral edema, pulm edema
    • Less common (GI illness, etc.): weight loss, tachycardia, systemic HoTN

20

Renal handling of specific fluid/electrolytes:
Water excretion

  • Water balance is maintained in advanced CKD via...
  • Changes are due to...
  • What limits kidney's concentrating ability
  • Fractional reabsorption of water per nephron
  • Urine osmolality
  • Inability to concentrate urine -->
  • Inability to dilute urine -->

  • Water balance is maintained in advanced CKD via...
    • Normal thirst mech
    • Free access to water
  • Changes are due to...
    • Decreased GFR --> limited ability to clear water (limited diluting capacity)
  • What limits kidney's concentrating ability
    • Structural damage in the medulla & tubulointerstitium
    • FUnctional defects affecting ADH receptors & AQP channels
    • Osmotic diuresis
  • Fractional reabsorption of water per nephron: decreased
    • Adaptive to maintain adequate water excretion in the setting of reduced filtration
    • Limtis kidney's concentrating ability
    • Limits kidney's ability to tolerate water deprivation
  • Urine osmolality: isosthenuria (~300 mOsm/L)
    • Sudden water load or deprivatoin is poorly tolerated
    • Kidney can't dilute or concentrate urine
  • Inability to concentrate urine -->
    • Nocturia
    • Modest polyuria
    • Hypernatremia (if water intake is limited)
  • Inability to dilute urine -->
    • Hyponatremia (if water intake is excessive)

21

Renal handling of specific fluid/electrolytes:
K excretion

  • Filtered load of K vs. distal K secretion
  • K excretion is increased by...
  • Distal K secretion vs. GFR
  • Hyperkalemia (in most pts w/ CKD)
  • Hyperkalemia (in some pts w/ CKD)

  • Filtered load of K vs. distal K secretion
    • Decreased filtered load of K --> increased distal K secretion --> increased FEK
  • K excretion is increased by...
    • Increased aldo
    • Increased EC K
    • Increased distal tubular flow due to...
      • Adaptive natiuresis (Decreased fractional reabsorption of Na)
      • Osmotic diuresis per nephron
      • Pressure natriuresis
  • Distal K secretion vs. GFR
    • Increase distal K secretion --> decrease GFR (proportionally)
  • Hyperkalemia is uncommon in most pts w/ CKD on a normal diet until GFR < 15 ml/min or oliguria develops due to...
    • Increased GI losses
    • Increased secretion by distal nephrons
  • Some pts w/ moderate CKD will develop hyperkalemia
    • Inadequate aldo
      • Idiopathic (diabetes w/ type IV renal tubular acidosis, RTA)
      • ACE-Is, ARBs, K sparing drugs
    • Distal flow-related
      • Volum edepletion
      • CHF w/o diuretics (decreased ECV)
    • Lack of insulin
      • DM
      • Fasting
    • Dietary indiscretion/meds
      • ACE-Is
      • K sparing drugs

22

Renal handling of specific fluid/electrolytes:
Acid-base balance

  • NH4
  • Metabolic acidosis in CKD
  • Mechs
    • Major
    • Minor
    • Very late CKD
    • Net result
  • Adaptation of proton retention in CKD
  • 2 patterns of acidosis
    • Early
    • Late

  • NH4
    • Most important urinary buffer
    • Urinary excretion is dependent on NH4 generation/excretion
  • Metabolic acidosis in CKD
    • Serum HCO3 decreases to 15-20 mEq/L
    • GFR < 25-30 ml/min
  • Mechs
    • Major: decreased # of functioning nephrons --> decreased NH4 excretion
    • Minor: increased K or ECFV --> proximal bicarb wasting
    • Very late CKD: decreased sulfate/phosphate excretion
    • Net result: positive H balance
      • Despite an adaptive increase in fractional NH4 excretion
      • Retained acid is buffered in bone
  • Adaptation of proton retention in CKD
    • Increased fractional excretion of NH4
    • Increased fractional excretion of phosphate
    • Bone buffering --> osteoporosis
  • 2 patterns of acidosis
    • Early hyperchloremic non-AG acidosis
      • Mild to moderate CKD (GFR < 30 ml/min)
      • Primarily due to decreased NH4+ excretion
    • Late hyperchloremic AG acidosis
      • Due to retained sulfates, phosphates, etc.
      • Seen w/ severely reduced GFR (< 10 ml/min) (ex. uremia / ESRD)

23

Example: ability to cope w/ stressors

  • A healthy medical student on a surgical rotation spends all day/night in the OR.  Ignoring insensible losses and assuming he needs to excrete 600mosms of waste/day, how much fluid would she need to drink today to excrete her daily waste?
    • What is the ~ maximum concentrating ability?
    • Assuming he maximally concentrates, how much water will it take to excrete 600mosm (i.e., 1 d of waste)?
  • A medical student was mysteriously kidnapped and drugged one night.  He awakes in a bathtub full of ice with bilateral flank pain.  A note on the floor says: We just removed 1 and 9/10 of your kidneys, find a good nephrologist.  Ignoring insensible losses and assuming he needs to excrete 600mosms of waste/day, how much fluid should he drink each day?
    • What is the ~ maximum concentrating ability?
    • Assuming he maximally concentrates, how much water will it take to excrete 600mosm (i.e., 1 d of waste)?

  • A healthy medical student on a surgical rotation spends all day/night in the OR.  Ignoring insensible losses and assuming he needs to excrete 600mosms of waste/day, how much fluid would she need to drink today to excrete her daily waste?
    • What is the ~ maximum concentrating ability?
      • 1200 mOsm/L
    • Assuming he maximally concentrates, how much water will it take to excrete 600mosm (i.e., 1 d of waste)?
      • 0.5 L
  • A medical student was mysteriously kidnapped and drugged one night.  He awakes in a bathtub full of ice with bilateral flank pain.  A note on the floor says: We just removed 1 and 9/10 of your kidneys, find a good nephrologist.  Ignoring insensible losses and assuming he needs to excrete 600mosms of waste/day, how much fluid should he drink each day?
    • What is the ~ maximum concentrating ability?
      • 300 mOsm/L
    • Assuming he maximally concentrates, how much water will it take to excrete 600mosm (i.e., 1 d of waste)?
      • 2 L

24

Common complications of CKD:
Hematological Disorders

  • Anema
    • General
    • Characteristics
    • Primary cause of anemia in CKD
    • Secondary causes of anemia in CKD
    • Management
    • Adverse effects w/ meds
  • Platelet dysfunctio

  • Anemia
    • General
      • Decrease in hematorcit correlates w/ severity of disease
      • Prevalence of anemia increases as GFR decreases < 45 ml/min
      • Most pts w/ GFR < 30 ml/min --> at least mildly anemic
    • Characteristics
      • Hypoproliferative (normal) bone marrow + normal red cell indices --> normochromic, normocytic anemia
      • Low reticulocyte count
      • Serum erythropoieitin level low to normal (not usually checked)
      • Normal bone marrow (not usually needed to diagnose)
      • Lack of an alternative diagnosis (e.g., vitamin deficiency, iron deficiency, etc)
    • Primary cause of anemia in CKD: decreased erythropoietin production
      • Erythropoietin is produced in the kidney
      • CKD --> decreased erythropoietin --> deprives bone marrow of stimulus to produce RBC
    • Secondary causes of anemia in CKD
      • Uremic inhibitors of erythropoietin (limiting its efficacy)
      • Decreased RBC half-life
      • Functional or absolute iron deficiency due to occult/overt GI bleeding from gastritis, duodenitis, or angiodysplasia
    • Management
      • Synthetic erythropoietin treats anemia in CKD
      • Erythropoiesis-stimulating agents (ESAs): additioanl recombinant forms
        • Treat anemia, improve quality of life, & decrease need for transfusions & hospitalizations
    • Adverse effects w/ ESAs in CKD
      • Iron deficiency
        • RBC production outstrips iron stores
        • Address w/ supplement iron
      • HTN
        • Rarely --> severe hypertensive encephalopathy & seizures
      • Increased risk of CV events
        • Using ESAs to achieve near normal HgB in pts w/ anemia & CKD carries greater risks than benefits
  • Platelet dysfunction
    • CKD pts have a bleeding diathesis due to an acquired defect of platelet function
    • Cause: retention of a uremic toxin
    • Responsible for prolonged bleeding & easy bruising

25

Common complications of CKD:
Mineral & bone disease

  • CKD is associated w/...
  • Management

  • CKD is associated w/...
    • Abnormalities of divalent ions (Ca, Phos) and of the hormones that regulate the conc of these minerals in body fluids
    • Dysregulation of these divalent ions is a possible source of CV disease
      • CKD --> increased vascular Ca depositoin & calcificaiton of heart valves
  • Management
    • Low phosphorus diet
    • Phosphate binders w/ meals
      • Prevents hyperphosphatemia by blocking GI absorption
    • Calcitriol (1,25 Vit D) or analogues
      • If/when PTH is elevated
      • Directly suppresses PTH
    • Maintain Ca * Phos product < 55mg2/dl2
      • Decreases extra-skeletal calcifications
    • Careful monitoring of Ca, phosphate, PTH
    • Avoid aluminum

26

Common complications of CKD:
Mineral & bone disease:
Phosphorus

  • Phosphorus levels as GFR decreases
  • Phosphorus levels w/ further decreases in GFR
  • As GFR declines further...

  • Phosphorus levels are initially unchanged as GFR falls, due to decreased reabsorption
    • Fibroblast growth factor 23 (FGF-23) increases as GFR decreases
      • FGF-23 increases phosphaturia
    • Elevations in PTH also enhance phosphaturia
  • With further decreases in GFR (<30ml/min), phosphate levels increase
    • Hyperphosphatemia stimulates the secretion of parathyroid hormone (PTH) and FGF-23
  • As GFR declines further, these progressive elevations increase renal phosphate excretion (but not back to normal)

27

Common complications of CKD:
Mineral & bone disease:
Vitamin D metabolism

  • 1-alpha-hydroxylase enzyme
  • Calcitriol
  • When GFR < ~30 ml/min...

  • 1-alpha-hydroxylase enzyme
    • Catalyzes the conversion of 25-hydroxyvitamin D into its active form, 1,25 dihydroxyvitamin D (i.e., calcitriol)
  • Calcitriol
    • Enhances GI absorption of calcium and phosphorus
  • When GFR < ~30 ml/min, low circulatory levels of calcitriol are found
    • Low calcitriol levels contribute to the hypocalcemia seen in advanced CKD
    • Worsened renal function (less 1-alpha-hydroxylase enzyme), 25-hydroxyvitamin D deficiency, and increased FGF-23/phosphorus levels all play a role in decreasing calcitriol levels

28

Common complications of CKD:
Mineral & bone disease:
Calcium

  • Elevated serum phosphorus
  • Intestinal absorption of Ca...
  • When GFR < 30%...

  • Elevated serum phosphorus
    • Causes Ca-Phos deposits
    • Decreases serum Ca
  • Intestinal absorption of Ca progressively decreases with advancing renal disease, in part due to a lack of 1,25 (OH)2D3
    • Relatively low Ca state stimulates PTH release
    • Elevated PTH helps maintain normocalcemia
  • When GFR < 30%, serum Ca may fall
    • Frank hypocalcemia is relatively uncommon until advanced CKD (GFR < 10-15 ml/min)
    • This homeostasis comes at the cost of elevated PTH levels

29

Common complications of CKD:
Mineral & bone disease:
Parathyroid hormone (PTH)

  • Among the earliest detectable abnormalities in CKD
  • 2 main inhibitors of PTH
  • Reactive elevation in PTH
  • PTH normally stimulates...
  • CKD skeletal resistance
  • CKD also...
  • Secondary hyperparathyroidism

  • Among the earliest detectable abnormalities in CKD
    • Increased PTH
    • Can occur at a GFR = ~45-60 ml/min or earlier
  • 2 main inhibitors of PTH
    • (1) Ionized Ca
    • (2) 1,25 (OH)2D3 (calcitriol)
    • Both are reduced in CKD
  • Reactive elevation in PTH
    • Due to elevated phosphorus, decreased calcium, and low 1, 25 (OH)2D3 levels
    • Partially adaptive in the setting of CKD
  • PTH normally stimulates...
    • Renal phosphorus excretion
      • Brings phosphorus levels down towards normal
    • Renal tubular Ca reabsorption
      • Increases serum Ca
    • Bone resorption
      • Increases serum Ca
    • Increased synthesis of 1 alpha hydroxylase in the kidney
      • Enhances renal conversion of 25OH-VitD to calcitriol
      • Augments GI Ca absorption
  • CKD pts demonstrate skeletal resistance to PTH action
    • Higher levels are required to induce a given amount of Ca resorption from bone
    • Due to reduction in the number of PTH receptors on bone
  • CKD also...
    • Decreases efficient production of calcitriol
      • Limits possible GI augmentation of Ca absorption
    • Llimits Vit D negative feedback on PTH
  • Secondary hyperparathyroidism
    • Skeletal resistance to PTH + decreased production of calcitriol + progressive phosphate retention (as GFR worsens) + the decreased Ca levels --> further elevations in PTH
    • Maintains normocalcemia despite reduced calcitriol levels
    • Increases phosphorus excretion by the kidney by reducing reabsorption
    • Does this at the cost of increased PTH & bone resporption

30

Mineral & bone disease summary

  • Hyperphosphatemia
  • 1,25 (OH)2 D deficiency (calcitriol)
  • Hypoclacemia
  • Secondary hyperpraathyroidism
  • Results of these disturbacnes
    • Renal osteodystrophy (includes osteitis fibrosa)
    • Rickets / osteomalacia
    • Adynamic bone disease

31

Common complications of CKD:
Osteodystrophy:
Osteitis fibrosa

  • Occurs in...
  • Driven by...
  • Bone turnover
  • Clinical manifestations

  • Occurs in ~40% of ESRD pts
  • Driven by secondary hyperparathyroidism
  • Bone turnover is increased with increased osteoblast and osteoclast activity
    • --> weakened bones
      • --> increased osteoid (unmineralized bone)
      • --> increased peritrabecular fibrosis
  • Clinical manifestations
    • Joint aches, bony pain, pruritus, increased risk of fractures
    • Extraskeletal calcifications (e.g., vascular)
    • Infrequent but dreaded, calciphylaxis (medial calcification of the arterioles leading to ischemia and subcutaneous necrosis)

32

Common complications of CKD:
Osteodystrophy:
Adynamic bone disease

  • Occurs
  • General
  • Due to...
  • Risk factors
  • Over suppression of PTH -->
  • Decreased bone activity -->

  • Occurs in ~40% of ESRD pts
  • Bone turnover is decreased and fracture risk is elevated
  • Due to...
    • Calcitriol deficiency
    • PTH resistance
    • Excessive suppression of parathyroid glands while trying to prevent/treat osteitis fibrosa
  • Risk factors
    • DM
    • Advanced age
    • Peritoneal dialysis
  • Over suppression of PTH --> reduced osteoblastic and osteoclastic activity
    • Decreased bone formation & bone mass
  • Decreased bone activity -->
    • Increased extraskeletal calcifications (bone not available to take up Ca, Phos)
    • Fracture risk (higher than osteitis fibrosa)

33

Common complications of CKD:
Osteodystrophy:
Rickets & osteomalacia

  • Children
  • Adults
  • Occurs in...
  • General
  • Due to...

  • Children: rickets
  • Adults: osteomalacia
  • Occurs in <5% of ESRD (uncommon)
  • General
    • Defective mineralization of osteoid
    • Bone turnover is decreased
  • Due to Vitamin D deficiency or aluminum deposition
    • When aluminum based phosphate binders were used in the past, they are now avoided

34

Common complications of CKD:
Osteodystrophy:
Mixed renal osteodystrophy

  • Mix of...
  • Pts can also develop...

  • Mix of...
    • Osteitis fibrosa
    • Adynamic bone disease
    • Rickets / osteomalacia
  • Pts can also develop soft tissue calcifications from deposition of calcium phosphorus in the skin
    • Calcification in the small blood vessels in skin --> necrosis of skin and fatty tissue --> rare, but excruciatingly painful and life-threatening calciphylaxis
    • Pprimary cause of death in calciphylaxis: secondary infection of the ulcers, and sepsis