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

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

Occurs in CKD stage 5

Urea is not the toxin ( is a surrogate for the toxins

Symptoms arent usually present until stage 3 or greater disease

Population prevalence = 14%

6% have CKD Stage 1-2

8% have CKD Stage 3-4

MDRD is the best way to estimate GFR (better than Cockcroft-Gault)

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

Primary: subtle changes in the glomerulus that look like FSGS w/o nephrotic or nephritic features

Secondary: due to ischemia from atherosclerosis and systemic vascular disease

Pathophysiology of CKD

Incipient event

Something smokes the nephrons and gets the processes started

Most commonly, diabetes or immune complexes

Propagating events

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

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)

The response to inflammation is to ultimately lay down collagen matrices ( fibrosis

Sequelae of glomerular disruption

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

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

Volume overload (due to high Na)

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

Hyperkalemia

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

Metabolic acidosis

Decreased NH4 ( decreased urinary buffer and H+ excretion

Retained organic anions ( anion-gap MA

Low Calcium

Due to combination of increased PO4 and decreased calcitriol production

High Phosphate

Due to decreased renal excretion

Low Vit D

Renal failure ( decreased expression of 25-OH 1-a-hydroxylase ( decreased conversion of calcidiol to calcitriol

High PTH (secondary hyperPTH)

Due to combination of:

Hyperphosphatemia

Decreased 1,25-OH Vit D (calcitriol)

Hypocalcemia

Parathyroid tissue becomes hyperplastic ( can be diffuse or localized

Bone disease

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 acidosis

Adynamic bone disease ( reduced bone volume and density due to excessive suppression of PTH and vitamin D supplementation

Low FGF-23

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

Themselves are not toxic

Uremia is the product of failure of 3 major renal functions + chronic systemic inflammatory damage in response:

Toxic metabolite excretion

Electrolyte, acid-base and water regulation

Hormonal regulation

Caveats in CKD

Hypovolemia

CKD = loss of ECV control. Sodium exchange is broken

Volume loss ( improper renal response + acute on chronic injury

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

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:

Presence of risk factors for CKD and conditions that cause CKD

Risk Factors for CKD

Major Causes of CKD

Age > 65

African, SE Asian, Hispanic ancestry

FHx of CKD

Prior AKI

Nephrolithiasis

Proteinuria

Structural abn of urinary tract (VER, recurrent pyelo)

Diabetes

HTN

Autoimmune disease: SLE, vasculitis

Infections: IE, HIV, hepatitis, schisto, malaria

Drugs or toxins: NSAIDs, dye, antibiotics, etc.

Think of the differential diagnosis

Break this into diabetes or not

NOT diabetes list is very similar to the AKI list, but with a couple variations

Any AKI cause can potentially progress to CKD if the initial insult leaves an injury lasting > 3mo

DIABETES

Type 1 or Type 2 DM

PRE-RENAL

Decreased EABV

Hypovolemia, 3rd spacing

Cardiac impairment

Systemic vasodilation

HRS

Anaphylaxis

Sepsis (has independent toxicity)

Renal vasoconstriction

NSAIDS

ACE-I

Contrast

Hypercalcemia

Large/medium vessel disease

HTN

Bilat stenosis + ACE-I

Atheroemboli

Thombosis (APLA, AFib, IE)

Vasculitis

Compression (abdominal HTN)

RENAL

Glomerular

Glomerulonephritis

IgA nephropathy

Anti-GBM, immune complex, pauci-immune

Nephrotic syndrome lesions (non-inflammatory)

Alports syndrome

Tubular

ATN: ischemia, toxins, contrast

Obstructive nephropathy:

Cancer

Myeloma

Nephrolithiasis

Fabrys disease

Interstitial (can start as AIN)

Allergic: beta-lactams, sulfa drugs, NSAIDs, PPIs

Infection: pyelo (xanthogranulomatous infection), legionella, TB

Infiltrative: sarcoid, lymphoma/leukemia

Autoimmune: Sjogrens, TINU, IgG4, SLE

Small-vessel disease

Cholesterol emboli

Thrombic microangiopathy

TTP/DIC

Pre-eclampsia

APLA

Scleroderma

HTN

Cystic diseases

Polycystic kidney disease

Tuberous sclerosis

Von Hippel Lindau

Transplant kidneys

Rejection

Drug toxicity

Recurrence of disease

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

DM

HTN

Glomerular disease

Interstitial (allergies, drugs)

Cystic kidney disease

Do a good physical exam. Dont forget to look for co-morbidities:

Diabetes

CHF

COPD

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

Urine microscopy looking for RBC/WBC/crystals

Urine protein or albumin (if DM)/Urine Creatinine ratio

Multiply x 8.8 to get 24hr estimation

HbA1C, fasting BGL, lipid profile

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

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

Evidence

Comments

BASICS

GFR < 30

Rapidly declining kidney function

GN

Referral to Nephrologist

Arch Int

Med 2002;162:2002-6

Remove exacerbators

Drugs (NSAIDs)

Diet

Low Na+, PO4, K+ (if oliguric), protein

Weight

BMI < 25

Abdo circ < 102 (men); < 88 (women)

Exercise

> 30min/d mod-intensity > 4x/wk

Treat underlying disease

SLOW DISEASE PROGRESSION

Hypertension

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)

Etacrynic acid in pts with sulfa allergy

Proteinuria

Target: < 500mg/d

General:

< 1g/kg/d protein diet

1st line:

ACE/ARB

Independent RF for disease progression

Also reduces CV risk/death

ACE + ARB controversial

Glycemic control

Target: HbA1C 7.0

No evidence

See Diabetic Nephropathy

CKD SEQUELAE

PTH

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

High PTH independently increases CV mortality

Cardiovascular

Target:

LDL < 2.6

General: low fat diet, exercise, wt loss

1st line:

Just LDL: Lipitor

HDL and LDL: Crestor

Only need dose adjust for fibrates

Consider co-morbid for targets

Anemia

Target:

HgB 100-120 g/L

TSat > 20%

General:

Iron supplementation

1st line:

EPO (darbapoeitin, erythropoietin)

Increased mortality, CV events w/ Hgb > 120

Metabolic Acidosis

Target:

HCO3 > 22

1st line:

Start NaHCO3 if HCO3 < 22

Watch Na+ load in patients with CHF