Med3C

Mora Chronic Kidney Disease

Course: Nephrology
Lect urer: Dr. Mora
Source: L ecture, Handout

Nephro

Week: 5-6
Topic: Chronic Kidney
Disease
Mgmt of Hpn in CKD ............................................................................................... 5

Table of Contents

Hematologic Abnormalities in CKD ............................................................... 5

Chronic Kidney Disease .......................................................... 1

Anemia ......................................................................................................................... 5
Consequences ........................................................................................................... 5
Causes ...................................................................................................................... 5
Management ............................................................................................................. 5
Abnormal hemostasis .................................................................................................... 5
Clinical Manifestations .............................................................................................. 5
Treatment ................................................................................................................. 5

Epidemiology..................................................................................1
Definition ......................................................................................1
NKF K/DOQI US Definition ..................................................................... 1
NKF K/DOQI US Classification ................................................................................ 1

KDIGO 2012 - New ...................................................................................... 2

Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012 .......................... 2

Neuromuscular Abnormalities in CKD ........................................................... 5

Pathophysiology ..............................................................................2
Risk Factors for CKD .................................................................................... 3
Staging CKD ..................................................................................3
Estimate GFR ............................................................................................... 3
Measure Albuminuria .................................................................................... 3

Clinical Manifestations .................................................................................................. 5

Early Stage................................................................................................................ 5
Late Stage ................................................................................................................. 5
Advanced Untreated Cases ........................................................................................ 5
Peripheral neuropathy ............................................................................................... 5

Gastrointestinal & Nutritional Abnormalities in CKD ..................................... 5

Endocrine/Metabolic Disturbances in CKD ................................................... 5

Uremic Toxins? ............................................................................................................. 3

Biochemistry of Uremia ................................................................................. 3

Impaired glucose metabolism ......................................................................................... 5

Elevated plasma insulin level ......................................................................................... 5
Women with CKD ........................................................................................................ 5
Men with CKD ............................................................................................................. 5

Urea and Creatinine ...................................................................................................... 3

Uremia: Spheres of Dysfunction..................................................................................... 3

Manifestations of CKD .....................................................................3

Na+ and water homeostasis ........................................................................... 3
Potassium Homeostasis ................................................................................. 3

Clinical Renoprotection .................................................................... 6

T280-6 Clinical Action Plan ........................................................................................... 6

Defense against hyperkalemia ........................................................................................ 3

Precipitants of hyperK+(~see at >5 GFR) ...................................................................... 3
Hypokalemia in CKD .................................................................................................... 3

Slowing Progression of CKD .......................................................................... 6

Reducing Intraglomerular Hypertension and Proteinuria ................................................ 6
Antihypertensives as renoprotective agents................................................................. 6
ACEis and ARBs ...................................................................................................... 6
2 Possible Responses ................................................................................................. 6

Metabolic Acidosis ........................................................................................ 3

Divalent Cation Dsos of CKD (Calcium and Phosphate) ................................ 3
Bone manifestations of CKD ......................................................................................... 3
High bone turnover ................................................................................................... 3
Low bone turnover .................................................................................................... 3
Treatment: Phosphate binders ........................................................................................ 4

Slowing Progression of Diabetic Renal Dse ..................................................... 6

Control of Blood Glucose .............................................................................................. 6
Control of BP and Proteinuria ........................................................................................ 6
Protein Restriction ......................................................................................................... 6

Cardiovascular Abnormalities of CKD ........................................................... 4

Managing Other Complications ...................................................................... 6

Ischemic Vascular Dse and CKD ................................................................................... 4

Risk Factors .............................................................................................................. 4
Heart Failure and CKD ................................................................................................. 4
Low Pressure Pulmonary Edema ................................................................................... 4
Hypertension and LVH and CKD .................................................................................. 4
Causes of absence of Hpn in CKD ............................................................................. 4

Medication Dose Adjustment......................................................................................... 6

Preparation for Renal Replacement Therapy (RRT) ........................................................ 6
Clear Indications for Initiation ................................................................................... 6
Patient Education .......................................................................................................... 6

Chronic Ki dney Disease

Imgs: Fistulas; Bipedal and pulmonary; Calciphylaxis manifestation of abn bone metabolism; Uremia vomiting; Economic burden >2B reimbursed by PhilHealth for 2012

EPIDEMIOLOGY

Prevalence: 120/1M
2013 opp est 97M
814200
Incidence 12,122 2012
Prev 18868
50% will die this year
1 death per hour
th
7 leading cause of death
14% newly diagnosed ESRD die w/o tx (vs 25% in 2011)
Renal failure pts go through a continuum of progressive
attrition of nephron number
o
If recognized earlier you have time intervene and
delay progression
Img: Kidney Int 2007 international society of nephrology

NKF K/DOQI US Classification

NKF K/DOQI US Definition

3
4
5

Spectrum (mild to very severe) of different pathophysiologic

processes (HPN, DM, GN, TIN as initial insult_ associated with
abnormal kidney function and progressive decline in GFR (all
ending at a common pathway of ESRD).
o
So much so you cannot determine what may have
been the start. Ex. DM will invariably lead to HPN but
by the time you get to ESRD it would be difficult to
determine what was the initial and most important
insult

Lecture

Kidney damage for >3 mos as defined by structural or

functional abnormality of kidney wowo decreased GFR,
manifest as either
o
Patho abn
o
Markers of kidney damage (proteinuria, abn urine
sediment, abn renal imaging
GFR <60 ml/min/1.73m2 for >3 months, w/o kidney damage

Stage
1

DEFINITION

Chronic Renal Failure: Continuing significant irreversible

reduction in nephron number
End Stage Renal Disease:Stage of CKD where the
accumulation of toxins, fluids and electrolytes normally
excreted by the kidneys results in the Uremic Syndrome

Description
Kidney damage w/normal or high
GFR
Kidney damage and mild decrease in
GFR
Moderate decreased in GFR
Severe decrease in GFR
Kidney failure

GFR
90
60-89
30-59
15-29
15 (or
dialysis)

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Mora Chronic Kidney Disease

Nephro

KDIGO 2012 - New

Abnormalities of kidney structure of nc, present for >3 months, with implications for health
Classified based on cause, GFR, category and albuminuria category (CauseGFRAlbuminria classification)
o
Ex Diabetic nephropathy, G3b, A3
o
Get randomalbumin

Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012

PATHOPHYSIOLOGY

Long-term reduction of
renal mass

Compensatory hypertrophy (vasoactive

molecules, cytokines, growth factors) no
new growth but has a lot of mediators

Short term (initial

response)
adaptive
hyperfiltration" (glom
erullary capillary
pressure & flow)
endothelial damage

Long term
maladapative
response (sclerosis)
the healing/scarring
process

Initial renal insult, kidney can recover but if not able goes to insuffience;
essential mxn of functional adaptation is RAAS and the ANG II, a very powerful
vasoconstrictor, causing peripheral capillary vasoconstriction, hypertension
and eventually glomerular hypertension, which once present it creates a
vicious circle and why BP control is so important and the use of ACEI comes
into play, the other thing is that Ang II is important in aldosterone release
which is produced in the zona glomerulosa and once released acts in the
mineralocorticoid receptor at the basolatoreral membrane at the _____ cell at
the cortical collecting ______. Once elaborated and epithelial Na channel in
apical membrane causing absorption of sodium Increased plasma volume
(expanded) BP and most common complication of CKD is Hpn and most
common cause of hpn in CKD is volume overload state .Culminates in
glomerlosclerosis and interstitial fibrosis two most important pathologic
hallmarks in irreversible renal injury.

The same mxn that heals and adapts is the same one that
becomes detrimental in long-term renal outcome

Lecture

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Mora Chronic Kidney Disease

Risk Factors for CKD

MANIFESTATIONS OF CKD

Not everyone develops, but some are prone to develop

Hypertension
Diabetes
Autoimmune dse
Old age (after 30yo GFR falls 1 per year)
African ancestry cause unknown
Family hx of renal dse
Previous episode of ARF
o
AKI formerly thought of as reversible, but now we
know that a lot of follow up is actually required
(+) Proteinuria, abn urinary sediment or structural abn of the
urinary tract

Nephro

Na+ and water homeostasis

Total body Na+ and H2O increased

D/t disruption of glomerulotubular balance
ECFV expansion Htn accelerated nephron injury
o
Management

Salt/water restriction

Loop diuretic metolazone diuretics are

really anatriuretics

Dialysis if fluid overload state is

unresponsive to diuretics
Impaired renal conservation of Na+ and H20
o
Filtered Na+ inadequately reclaimed ECFV
depletion Acute-on-Chronic renal Failure
o
Management: cautious fluid repletion

Potassium Homeostasis
Common to see hyperK in ESRD but GFR has to be <5 already b/c
the homeostatic mxn in place will work up until that point

Defense against hyperkalemia

STAGING CKD

Urinary K+ secretion- aldosterone dependent

Augmented K+ secretion in GI tract

Intake, protein catab, hemolysis, hemorrhage

Metabolic acidosis, blood transfusion of stored RBC (K+
moves from RBCs into plasma, packed RBCs can make pt
hypokalemic, and whole blood can make pt hyperkalemic)
Drugs (ACEI, ARB, spironolactone)

Precipitants of hyperK+(~see at >5 GFR)

Estimate GFR
MDRD equation
Cockcroft-Gault equation

Normal GFR ~120/mL/min/1.73m2

Loss of 1 pt (1 mL/min/1.732m ) every year after 30

Hypokalemia in CKD

Measure Albuminuria

Monitoring nephron injury

Response to therapy

Uremic Toxins?
A Conundrum no common toxin found

Products of bacterial
metabolism as
aromatic amines,
and skatoles

Urea and breakdown

product

Products of
nitrogenous
metabolism,
Guanidino
compounds

Uremic
toxins?

Metabolic Acidosis

Compounds
retained in
circulation, or
underproduced

Biochemistry of Uremia
Urea and Creatinine

Most commonly used marker of renal excretory function

Incomplete surrogate markers
o
Toxins cannot yet be assayed so this is as close as
we can get, since their levels should parallel these 2
Do not account for the many s/sx of uremia

Uremia: Spheres of Dysfunction

i.
ii.

iii.

Lecture

Very low K+ intake

Diuretic therapy
GI losses
Renal K+ wasting
o
Fanconis syndrome abn of reabsorbing all types
of solutes in PCT
o
RTA proximal or distal
o
Tubulointerstitial dse e.g. chronic pyelonephritis

Consequent to accumulation of toxins

a.
Kidneys are the garbage collector of the body
Consequent to loss of other renal fncs
a.
Fluid and electrolytes
b.
Hormones EPO for RBC maturation
Progressive systemic inflammation and its vascular and
nutritional consequences
a.
Malnutrition Inflammation Atherosclerosis
(MIA)/calcification syndrome
b. CKD is a proinflammatory state and have
high levels of CRP

At GFR <15
Less ammonia production (initially) less proton
excretion non-anion gap acidosis
o
Initially
o
Ammonia comes from glutamine combines with
H+ which is eliminated form body thru urine == acid
elimination by the body dysfnc means more
retention of H+/protons
Worsening renal fnc urinary net daily acid excretion
to 30-40mmol Anion gap acidosis
o
Over time
Net effect: net protein catabolism malnutrition
Management: start alkali supplementation when HCO3 falls
below 20-23 mmol/L (n AKI wait until 15 but here we have to
prevent bone problem d/t malnutrition)
o
Consider need for diuretic avoid volume overload

Divalent Cation Dsos of CKD (Ca & Ph)

Bone manifestations of CKD
High bone turnover

Low bone turnover

PTH
Classic ex: Osteitis fibrosa
cystica

Low or normal PTH

Adynamic bone dse
(problem with bone
mineralization)
Most common ex (esp
adults): Osteomalacia
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High bone turnover CM

Bone pain and fragility

Brown tumors

Compression syndromes

Erythropoietin resistance
blood cell forming elements
are destroyed

Muscle weakness

Fibrosis of cardiac muscles

Constitutional sx

Mora Chronic Kidney Disease

Ischemic Vascular Dse and CKD

Adynamic bone dse

Reduced bone volume and

mineralization

Excessive suppression of
PTH production (VitD,
excess calcium exposure)

Fractures

Vascular & cardiac

calcification
Osteomalacia

Accumulation of
unmineralized bone matrix

Vit D def, aluminum

toxicity, met acidosis

Traditional classic

Hypertension
Hypervolemia
Dyslipidemia
Sympathetic overactivity
Hyperhomocysteinemia

Nontraditional CKD
related

Calcium carbonate, calcium acetate

o
Most commonly used, least expensive
o
Problem: Total body calcium
Sevelamer very good, w/o deleterious effects of high
calcium
Lanthanum carbonate Phosphrenol? Very expensive
Calcitriol and Vit D analogues for pt w/low Ca2+ and high
level Ph+
Calcimimetics for pt that are already hypercalcemic, acts
directly
Target iPTH (for CKD stage 3-5): 150-300 pg/mL

Anemia
Hyperphosphatemia
Hyperparathyroidism
Sleep apnea
(sympathetic activity
BP)
Generalized inflammation
(chronic inflamm state)

Reduced renal function

High CRP, High

cytokine, Low
albumin, Low fetuin

Inflammatory state

Accelerated vascular
occlusive dse & Rapid
vascular calcification(w/low
fetuin level)

Low NO, ROS,

Dialysis
hypotension &
hypovolemia

Attenuated coronary
reserve

Heart Failure and CKD

Causes
o
MI vascular calcification
o
LVH chronic hpn
o
Cardiomyopathy anemia and high output failure
o
Salt and water retention
Can be systolic or diastolic

Low Pressure Pulmonary Edema

Cardiovascular Abnormalities of CKD

Coronary, cerebrovascular, and peripheral vascular

Risk Factors

Treatment: Phosphate binders

Nephro

Leading cause of mortality and morbidity - 40%

Risk of CVD in CKD is 10-200 fold
30-50% of CKD Stage 5 has advanced CV complications at
time of dx

See on X ray but pt looks dehydrated causes common

misperception in residents
SOB
CXR: Bat wing distribution
Absence of ECFV overload
Normal PCWP may see rapid decompensation, severe
imitation in gas exchange pt req intubation
Permeability of alveolar capillary membranes d/t uremia

Hypertension and LVH and CKD

Most common complication of CKD

Develops early, adverse outcomes
More rapid loss of renal fnc

Salt-wasting nephropathy ex: uric acid nephropathy, chronic

pyelonephritis
Effect of anti-hypertensives
Volume depletion
Poor LV fnc
Reverse causation low BP worse prognosis than
high BP
o
Implies, decreased perfusion to the rest of the
body

Causes of absence of Hpn in CKD

Estimated event rate; each color for different stages of CKD

Lecture

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Mora Chronic Kidney Disease

Neuromuscular Abnormalities in CKD

Mgmt of Hpn in CKD

Overall goals

Slow progression of renal dse

Prevent extra-renal complications of Htn

Targets

130/80 mmHg

(+) DM or proteinuria >1gm/d 125/75 mmHg

Agents

Early Stage

Hematologic Abnormalities in CKD

Anemia
Normocytic, normochromic at Stage 3
Universal at Stage 4

O2 delivery & utilization

CO
Ventricular dilatation & hypertrophy
Angina, HF, cognition & mental acuity, impaired defense vs
infection

Causes
Relative deficiency of erythropoietin
Diminished RBC survival
Bleeding diathesis
Iron deficiency
Hyperparathyroidism/BM fibrosis
Chronic inflammation
Folate or vitamin B12 deficiency
Hemoglobinopathy

Target: Hgb 100-115g/L

Recombinant EPO
Darbepoeitn
Blood transfusion
o
Easiest way to correct in sx pt req surgery
o
Limitations: (Pre-) Sensitization, Infection, Iron
overload

Iron supplements

Studies show req to keep Hgb at pace w/EPO syn in the body

Folate and Vit B12

o

Lowered to avoid thrombotic states

Prolonged bleeding time

Decreased platelet factor II activity
Abnormal platelet aggregation and adhesiveness
Impaired Prothrombin consumption

Bleeding & bruising

Prolonged surgical bleeding
Menorrhagia
Spontaneous GI bleeding esp w/uremic gastropathy
Greater tendency to thromboembolism (esp if Hgb >130)

Desmopressin (DDAVP)
Cryoprecipitate
IV conjugated estrogen works well but takes time
Blood transfusion always improves
EPO therapy
Optimal dialysis pre-surgery avoid intraop coagulopathy

Neuromuscular
irritability (hiccups,
cramps, fasciculations,
muscle twitching)

Adv Untx

Asterixis
Seizures
Coma

Stage 4 CKD
Sensory nerves > motor nerves
Lower extremities > upper extremities
Distal > proximal
Restless leg syndrome
o
Ill-defined sensation
o
Debilitating
o
Relieved by frequent leg movement
Onset of sensory abn indication to start dialysis
Dialysis & KT may reverse neurologic dysfunction

Uremic fetor
o
Breakdown of urea to ammonia in saliva
o
Dysgeusia
Gastritis, peptic ulcer dse, mucosal ulceration
Constipation
o
Worsened by calcium & iron supplements
Anorexia, nausea, vomiting
o
Protein restriction
Protein-energy malnutrition
o
Protein restricted diet
o
Resistance to anabolic action of insulin & other
growth factors
o
Indication for RRT

Slow rate of blood glucose decline after a glucose load

FBS usually normal
Mild glucose intolerance does not require treatment

Elevated plasma insulin level

Clinical Manifestations

Diminished renal degradation of insulin

Reduction in insulin dose with worsening renal function
Hypoglycemia

Women with CKD

Treatment
Reversal of abn bleeding and coagulopathy

Low estrogen level

Menstrual abnormalities
Inability to carry pregnancy to term
GFR 40mL/min spontaneous abortion; 20% live births
Pregnancy may hasten progression of CKD

Men with CKD

Anticoagulation prevention of thromboembolism

Warfarin (?) atrial fibrillation is the only indication!
LMWH avoided or dose adjusted; monitor Factor Xa
Better to use fractionated heparin
Not proven to help, unless co-existing IHD
o
Aspirin + Dypriidamole
o
Clopidogrel
Lecture

Endocrine/Metabolic Disturbances in CKD

Impaired glucose metabolism

Abnormal hemostasis

Late Stage

Gastrointestinal & Nutritional Abnormalities in

CKD

Management

Memory
Concentration
Sleep
disturbances

Peripheral neuropathy

Consequences

CNS, PNS, autonomic neuropathy, abnormal muscle structure

and function
Retained nitrogenous metabolites and middle molecules
Parathyroid hormone
Stage 3 CKD

Clinical Manifestations

Salt restriction and diuretics first choice

ACEi, ARB - slow rate of decline, if any proteinuric dse
Kaliuretic agents to prevent hyper K+ , loop diuretics

Nephro

Low testosterone
Sexual dysfunction
Oligospermia
Delayed sexual maturation
Metformin

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Mora Chronic Kidney Disease

Nephro

CLINICAL RENOPROTECTION
Reading assignment; note below taken from Harrisons

Helpful to sequentially measure and plot rate of GFR decline

o
Initiate therapy before significant GFR drop
o
Any acceleration search for superimposed controllable process, e.g., ECFV depletion, uncontrolled hpn, UTI, new obstructive
uropathy, nephrotoxic agents, NSAIDs, radio dye, reactivation or flare of original dse (e.g., lupus)

T280-6 Clinical Action Plan

Stage
1

Description
Kidney damage w/ N or Inc GFR

GFR
>90

Kidney damage w/ mild dec in

GFR
Moderate dec in GFR
Severe dec in GFR
Kidney failure

60-89

3
4
5

30-59
15-29
<15 (or
dialysis)

Action
Diagnosis & treatment, tx of comorbids, slowing progression, CVD risk
reduction
Estimating progression
Evaluating & treating complications
Preparation for RRT
Renal replacement (if uremia present)

Slowing Progression of CKD

Reducing Intraglomerular Hypertension and Proteinuria

Antihypertensives as renoprotective agents

Elevated BP proteinuria
If agent reduces BP it proteinuria and slows GFR decline;
their effectiveness is measured in proteinuria reduction
Basis for guideline of maximum 125/75 mmHg as target BP in
proteinuric CKD pts

Managing Other Complications

Medication Dose Adjustment

ACEis and ARBs

Inhibit angiotensin-induced vasoconstriction of efferent

arterioles of glomerular microcirculation
Intraglomerular filtration pressure and proteinuria
Good for diabetic and nondiabetic CKD
Combo tx
o
If one is not effective usu greater reduction
o
H/e possible risk of ARF and adverse cardiac
events
ACEi SE: cough, angioedema
ACEi, ARB SE: naphylaxis, hyperkalemia

Progression assoc w/ syteic and intraglomerular hpn and

proteinuria diabetic nephron, glomerular dse ACEi &
ARBs successful
Progression w/mild or absent proteinuria APKD,
tubulointerstitial dses consider other agents for hpn e.g.
CCBs

Diabetic nephropathy now a leading cause of CKD requiring

RRT
o
Poor prognosis, comparable to some cancers

Recommended pre-prandial glucose be kept in 5.0-7.2

mmol?L (90-130 mg/dL) range and HA1C <7%
As GFR declines must consider changing diabetic med
dosages in face of renal dysfnc (e.g. chlorpropamide ,
metformin lactic acidosis, thiaxolidinediones volume
overload, cardiac events)
Insulin degradation will also decline, less is needed

Control of BP and Proteinuria

Hpn in majority of Type 2 + correlating microalbuminuria

use ACEi or ARB

Protein Restriction

Uremic pericarditis
Encephalopathy
Intractable muscle cramping
Anorexia
Nausia not attributable to reversible causes
Evidence of malnutrition
Fluid and electroly abn (*hyperK or ECF volume overload)

Patient Education

Control of Blood Glucose

Pt may have grown accustomed to uremic sx but will feel

much improved after dialysis
Benefit of early-start (before onset of sx) is still in
question
Will depend on the pt but preparation is always better than
temporary/emergency dialysis procedures

Clear Indications for Initiation

Slowing Progression of Diabetic Renal Dse

Loading dose is not affected

Maintenance doses will need to be adjusted
o
Unless >70% of excretion is nonrenal (e.g. liver)
Avoid metformin, meperidine, oral hypoglycemic elim by
kidney, NSAIDs, nephrotoxic radiocontrast agents, gadolinium
Reduce many antibiotics, antihypertensives, antiarrhythmics

Preparation for Renal Replacement Therapy (RRT)

2 Possible Responses

Evidence that protein-mediated hyperfiltration

contributes to decline
KDOQUI clinical practice guidelines daily protein intake of
btwn 0.60 and 0.75 g/kg/day
o
Depending on pt adherence, comorbidities,
proteinuria level, nutritional status
o

Effort to stabilize or slow decline in renal fnc

Social, psychological and physical preparation for RRT

transition
Gradual approach
Multidisciplinary team
Educational program no later than Stage 4
o
More educated pts easier, better are the
decisions
o
Likely to pick home-based w/c is easier for everyone
Explore social services
Educate family
Kidney transplantion offers best potential for complete
rehab, to be discussed later

Reduces sx assoc w/uremia

Also may slow rate of renal decline in earlier stages

Lecture

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