CHRONIC KIDNEY DISEASE

(Harrisons. 18th ed. 2010, KDOQI Guidelines, NEJM. 2010;362:56)

Introduction

Chronic kidney disease (CKD): continuing, irreversible reduction in

nephron number leading to reduced GFR occurring over a period >
3mo
o eGFR < 60cc/min/1.73cm2 or presence of renal damage
Kidney failure: eGFR < 15
Complications of CKD doesnt usually manifest until eGFR < 30
(stage 4)
Uremia: literally urine in the blood. The accumulation of toxins that
lead to a disturbance in homeostatic mechanisms regulated by the
kidney
o Occurs in CKD stage 5
o Urea is not the toxin is a surrogate for the toxins
Symptoms arent usually present until stage 3 or greater
disease
Population prevalence = 14%
o 6% have CKD Stage 1-2
o 8% have CKD Stage 3-4
MDRD is the best way to estimate GFR (better than CockcroftGault)
o All the calculations of GFR dont work at extremes of failure
Diabetic nephropathy is the MCC of CKD followed by HTN
The leading cause of death in CKD is coronary artery disease
people do not die from renal failure w/ renal replacement
therapy

Classification

Etiology of CKD

Hypertension is MCC in age > 65

Hypertensive nephropathy
o Primary: subtle changes in the glomerulus that look like FSGS
w/o nephrotic or nephritic features
o Secondary: due to ischemia from atherosclerosis and systemic
vascular disease

Pathophysiology of CKD

Incipient event
o Something smokes the nephrons and gets the processes started
o Most commonly, diabetes or immune complexes
Propagating events
o Glomerular hypertrophy/hyperfiltration:
After a bunch of nephrons die, the remaining beef up their
function. No one really knows how
If you remove one kidney, the overall function by this
mechanism will get you back to 80% of normal GFR
o Renal progression:
If the overall nephron number is reduced to < 20% we
progress to ESRD
The tubules start to die and become fibrotic

Many mechanisms postulated. Likely related to cascade of

events cumulating in severe, irreversible inflammation
(lymphocytic infiltration)
o The response to inflammation is to ultimately lay down collagen
matrices fibrosis
Sequelae of glomerular disruption
o Glomerulosclerosis
Loss of autoregulation: as the initial nephrons stop
working, they no longer regulate the glomerular pressure
Paradoxically, the response to this is increasing
angiotensin II and aldosterone systemic
hypertension and glomerular damage
Both these hormones further destroy the glomerulus
The overall result is that all the nephrons in the kidney
start seeing systemic pressures hit the glomerulus they
scar
o Interstitial fibrosis/tubular atrophy
As the glomerulus becomes more destroyed leaked
protein sets off a downstream cascade of inflammation
Ultimately leads to fibrosis and disruption of normal
tubular cell function
Complications of CKD these start to occur @ eGFR < 30
o

Volume overload (due to

high Na)

Hyperkalemia

Low Calcium

High Phosphate
Low Vit D

High PTH (secondary

hyperPTH)

Metabolic acidosis

Bone disease

ATII and aldosterone are ramped up increases tubular Na+

absorption
Dietary Na+ >> renal Na+ excretion
Increased Na+ increased osmolality increased ADH
release increased isotonic ECV hypervolemia + HTN
HypoNa only occurs if H2O intake > renal H2O excretion
In stage 5 due to GFR
< stage 5 due to a combination of underlying disease (DM)
and medications (ACE/ARB/Aldactone) that impair renal
excretion from principal cell
Precipitated by RBC infusion, hemorrhage, hemolysis, acidosis
Decreased NH4 decreased urinary buffer and H+ excretion
Retained organic anions anion-gap MA
Due to combination of increased PO4 and decreased calcitriol
production
Due to decreased renal excretion
Renal failure decreased expression of 25-OH 1-a-hydroxylase
decreased conversion of calcidiol to calcitriol
Due to combination of:
o Hyperphosphatemia
o Decreased 1,25-OH Vit D (calcitriol)
o Hypocalcemia
Parathyroid tissue becomes hyperplastic can be diffuse or
localized
Osteitis fibrosa cystica due to high PTH and high bone
turnover
Osteomalacia unmineralized bone matrix accumulates due
to decreased Vit D, Aluminum accumulation and metabolic


Low FGF-23

acidosis
Adynamic bone disease reduced bone volume and density
due to excessive suppression of PTH and vitamin D
supplementation
A hormone that interacts with Vit D and PO4
Tries to decrease PO4 by directly increasing renal excretion,
increasing PTH and decreasing calcitriol (gut absorption)
Turning out to be an independent risk factor for cardiac dz and
indicator for PO4 Rx

Pathophysiology of Uremia

Uremia is the point where the kidney fails to do its job such that
maintaining life is impossible without renal replacement therapy
(transplant or dialysis) stage 5 CKD
Creatinine and urea are used as surrogates of toxic build up from
impaired renal excretion
o Themselves are not toxic
Uremia is the product of failure of 3 major renal functions +
chronic systemic inflammatory damage in response:
o Toxic metabolite excretion
o Electrolyte, acid-base and water regulation
o Hormonal regulation

Caveats in CKD

Hypovolemia
o CKD = loss of ECV control. Sodium exchange is broken
o Volume loss improper renal response + acute on chronic injury
o You need to give this person back isotonic saline carefully to
avoid dialysis

Calculating GFR (eGFR)

Just remember that creatinine is a good surrogate (see AKI), but

doesnt start to rise until > 50% decline in GFR
Modification of Diet in Renal Disease (MDRD) is the best
o Takes into account gender and race
Cockcroft-Gault was historically used, but is now outdated

APPROACH TO CKD
(Harrisons. 18th Ed. 2010, KDOQI Guidelines)

Suspect CKD:
o Presence of risk factors for CKD and conditions that cause CKD

Age > 65
African, SE Asian, Hispanic ancestry
FHx of CKD
Prior AKI
Nephrolithiasis
Proteinuria
Structural abn of urinary tract (VER,
recurrent pyelo)

Think of the differential diagnosis

o Break this into diabetes or not
o NOT diabetes list is very similar to the AKI list, but with a couple
variations
o Any AKI cause can potentially progress to CKD if the initial insult
leaves an injury lasting > 3mo

Risk Factors for CKD

Major Causes of CKD

Diabetes
HTN
Autoimmune disease: SLE, vasculitis
Infections: IE, HIV, hepatitis, schisto,
malaria
Drugs or toxins: NSAIDs, dye,
antibiotics, etc.

DIABETES

Type 1 or Type 2 DM
PRE-RENAL
Decreased EABV
o Hypovolemia, 3rd spacing
o Cardiac impairment
o Systemic vasodilation

HRS

Anaphylaxis
o Sepsis (has independent toxicity)
Renal vasoconstriction
o NSAIDS
o ACE-I
o Contrast
o Hypercalcemia
Large/medium vessel disease
o HTN
o Bilat stenosis + ACE-I
o Atheroemboli
o Thombosis (APLA, AFib, IE)
o Vasculitis
o Compression (abdominal HTN)
RENAL
Glomerular
o Glomerulonephritis

IgA nephropathy

Anti-GBM, immune complex, pauci-immune

o Nephrotic syndrome lesions (non-inflammatory)
o Alports syndrome
Tubular
o ATN: ischemia, toxins, contrast
o Obstructive nephropathy:

Cancer

Myeloma

Nephrolithiasis

o Fabrys disease
Interstitial (can start as AIN)
o Allergic: beta-lactams, sulfa drugs, NSAIDs, PPIs
o Infection: pyelo (xanthogranulomatous infection), legionella, TB
o Infiltrative: sarcoid, lymphoma/leukemia
o Autoimmune: Sjogrens, TINU, IgG4, SLE
Small-vessel disease
o Cholesterol emboli
o Thrombic microangiopathy

TTP/DIC

Pre-eclampsia

APLA

Scleroderma

HTN
Cystic diseases
o Polycystic kidney disease
o Tuberous sclerosis
o Von Hippel Lindau
Transplant kidneys
o Rejection
o Drug toxicity
o Recurrence of disease

Do a good history based on your DDx. Always think about the

MCC:
o DM
o HTN
o Glomerular disease
o Interstitial (allergies, drugs)
o Cystic kidney disease

Do a good physical exam. Dont forget to look for comorbidities:

o Diabetes
o CHF
o COPD
o HTN changes

Dont forget to look for indications for dialysis

Order the basics for ALL patients with new CKD:

CBC, electrolytes
Serum creatinine, BUN & measure GFR w/ MDRD

Urine dip

HbA1C, fasting BGL, lipid profile

Urine microscopy looking for RBC/WBC/crystals

Urine protein or albumin (if DM)/Urine Creatinine ratio
o Multiply x 8.8 to get 24hr estimation
SPEP/UPEP
HIV/HBsAg/anti-HCV
Renal U/S

If eGFR < 30 think about CKD sequeale:

PTH, Ca/PO4/Mg, Vitamin D

Practically, you will have most of this when you 1st see the
patient
o Using the above DDx, start narrowing down the list based on if
the urine has isolated protein, blood or both
Based on H + P and initial work-up, do more if needed

MANAGEMENT
(NEJM. 2010;362:56)
Therapy

GFR < 30
Rapidly declining
kidney function
GN
Remove
exacerbators
Diet
Weight
Exercise

Evidence
BASICS
Referral to Nephrologist Arch Int
Med 2002;162:20026

Comments

Drugs (NSAIDs)
Low Na+, PO4, K+ (if
oliguric), protein
BMI < 25
Abdo circ < 102 (men);
< 88 (women)
> 30min/d modintensity > 4x/wk

Treat underlying
disease
Hypertension

SLOW DISEASE PROGRESSION

Target: BP < 130/80
General:

Na+ < 2g/d

1st line:

ACE/ARB
2nd:

Beta-blockers

CCB (only if on
ACE/ARB)
Additional:

Lasix

Metalazone

Check Cr, lytes in 1

week
Be careful when K
> 5.4 prior to
initiation
Stop if Cr 30%
Initial in GFR
expected
Consider co-

morbidities in
selection (DM, CAD)

Proteinuria

Glycemic control
PTH

Cardiovascular

Anemia

Metabolic Acidosis

Etacrynic acid in
pts with sulfa allergy
Independent RF for
disease progression

Target: < 500mg/d

General:

< 1g/kg/d
protein diet
1st line:

ACE/ARB
Target: HbA1C 7.0

Also reduces CV
risk/death

No evidence

CKD SEQUELAE
Target:

Stage 3: < 70

Stage 4: < 110

Stage 5: < 300

General: low PO4 diet
1st line: PO4 binders

PO4, Ca:
CaCO4

PO4 + Ca:
Sevelamer

PO4: AlOH
(short)
2nd line:

Calcitriol
3rd line:

Cinacalcet
Target:

LDL < 2.6

General: low fat diet,
exercise, wt loss
1st line:

Just LDL: Lipitor

HDL and LDL:

Crestor
Target:

HgB 100-120
g/L

TSat > 20%

General:

Iron
supplementatio
n
1st line:

EPO
(darbapoeitin,
erythropoietin)
Target:

HCO3 > 22
1st line:

Start NaHCO3 if
HCO3 < 22

ACE + ARB
controversial
See Diabetic
Nephropathy
High PTH
independently
increases CV
mortality

Only need dose

adjust for fibrates
Consider co-morbid
for targets

Increased mortality,
CV events w/ Hgb >
120

Watch Na+ load in

patients with CHF