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

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)

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

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

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

Strategies to slow CKD progression Early diagnosis & treatment (1) Treat underlying causes (2) Control BP BP goals 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: \ 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

18 Chronic Kidney Disease Flashcards by Heather Acuff

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

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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)

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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

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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

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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

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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

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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

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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: e__ndothelial 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)

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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

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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

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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

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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

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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

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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

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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

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

Intact nephron hypothesis
Functional reserve
Hyperfiltration
Osmotic diuresis

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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

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

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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

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

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

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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)

Renal handling of specific fluid/electrolytes:
Na excretion

Challenge for the kidney in Na homeostasis
FE_Na 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
FE_Na 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

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Challenge for the kidney in Na homeostasis
- Large variations in daily dietary Na intake from 10 - 500 mEq/day (0.2-11g/day)
FE_Na 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
FE_Na in CKD pts
- Increased FE_Na –> 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

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 –>

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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)

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)

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Filtered load of K vs. distal K secretion
- Decreased filtered load of K –> increased distal K secretion –> increased FE_K
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

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

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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)

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)?

Study These Flashcards

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

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

Study These Flashcards

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

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

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)

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

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**

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

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

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)

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)**

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

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

18 Chronic Kidney Disease Flashcards

(34 cards)