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Chronic Kidney Disease

Rachel Brock, DO

Nephrology Associates of MI

Objectives

• Define CKD

• Identify the stages of CKD

• Know who to screen

• Understand the consequences of CKD

• Learn how to treat the sequelae of CKD

• Apply above knowledge to daily practice

Our Guidelines

• Kidney Disease Outcome Quality Initiative 1997, mgd by the NKF (www.kidney.org)

• www.kdoqi.com

• Kidney Disease Improving Global Outcomes, 2004

• www.kdigo.com

Introduction to CKD

• Disproportionate financial resources consumed by ESRD patients

• NIH and Surgeon General’s Office are attempting to educate the public

• Nephrology work force shrinking

• Burden of work up and management falls on PCP’s

KDOQI

Definition of CKD

• Decreased function is usually noted by the eGFR

• Doesn’t identify a cause

• Doesn’t imply symptoms

Stages of Chronic Kidney Disease National Kidney Foundation–Kidney Disease Outcome Quality Initiative

Stage Description GFR

(ml/min)

1 Kidney damage w/ normal GFR >90

2 Mild decrease in GFR 60-89

3a “early” moderate kidney dysfunction 45-59

3b “late” moderate kidney dysfunction 30-44

4 Severe kidney dysfunction 15-29

5 Kidney failure < 15

Stages of CKD

• Cut-offs are arbitrary, based upon informed opinion

• Progression of kidney disease varies depending upon disease entity and patient

Figure 5. Based on 2008 US Renal Data System data. Notably, diabetes and hypertension account for almost two thirds of all cases of end-stage renal disease in the United States.

Causes of CKD

Vol 1, CKD, Ch i 10

Data Source: National Health and Nutrition Examination Survey (NHANES), 1988–1994, 1999-2004 & 2007–2012 participants age 20 & older; single-sample estimates of eGFR & ACR. Adj: age, sex, & race; eGFR calculated using the CKD-EPI equation. Whisker lines indicate 95% confidence intervals. Abbreviations: BMI, body mass index; CKD, chronic kidney disease; CVD, cardiovascular dise ase;

DM, diabetes mellitus; HTN, hypertension; SR, self-report. This graphic also appears as Figure 1.9.

Figure i.2 Adjusted odds ratios of eGFR <60 ml/min/1.73m2 in NHANES participants by age & other risk factors, 1998-2012

(A) Age category (B) CKD risk factor

Proteinuria matters

• Worsening proteinuria is the most significant risk factor for progressive kidney disease/worsening of eGFR

– Compared with normoalbuminuria, pts with

proteinuria have a 3-4x increased risk of progression to ESRD

– Risk for renal failure doubles with doubling of baseline

level of proteinuria

• The worse the proteinuria, the worse the renal prognosis

• Lowering proteinuria lowers risk of progression to ESRD

Misnomers

• “Microalbuminuria” is NOT small albumin

• “Macroalbuminuria” is NOT big albumin

• Normal urine albumin level = A1

• Microalbuminuria is being replaced by A2 proteinuria or “moderate proteinuria”

• Macroalbuminuria is being replaced by A3 proteinuria or “overt proteinuria”

Vol 1, CKD, Ch i 14

Data Source: Medicare patients from the 5 percent sample, age 65 or older with Part A & B coverage in the prior year. Tests tracked during each year. Abbreviations: CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension. This graphic is adapted from Figure 2.3A.

Figure i.5 Unadjusted cumulative probability for urine albumin testing, among Medicare patients age 65+ without a diagnosis of CKD, 2000-2012

Vol 1, CKD, Ch i 15

Data Source: Medicare patients from the 5 percent sample, age 65 or older with Part A & B coverage in the prior year. Tests tracked during each year. Abbreviations: CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension. This graphic is adapted from Figure 2.4A.

Figure i.6 Unadjusted cumulative probability of urine albumin testing, among Medicare patients age 65+ with a diagnosis of CKD, 2000-2012

Vol 1, CKD, Ch i 16

Data Source: Medicare 5 percent sample. This graphic also appears as Figure 2.1 .

Figure i.4 Temporal trends in CKD prevalence, overall and by CKD stage, among Medicare patients age 65+, 2000-2012

Vol 2, ESRD, Ch 1 17

vol 2 Figure 1.7 Trends in (a) ESRD incident cases, in thousands, and (b) adjusted* ESRD incidence rate, per

million/year, by primary cause of ESRD, in the U.S. population, 1980-2012

(a) Incident Cases (b) Incidence Rates

Data Source: Reference tables A.1, A.2(2). *Adjusted for age, sex, and race. The standard population was the U.S. population in 2011. Abbreviation: ESRD, end-stage renal disease.

Vol 2, ESRD, Ch 1 18

vol 2 Figure 1.4 Trends in (a) ESRD incident cases, in thousands, and (b) adjusted* ESRD incidence rate, per million/year, by age

group, in the U.S. population, 1980-2012

Data Source: Reference tables A.1, A.2(2). *Adjusted for sex and race. The standard population is the U.S. population in 2011. Abbreviation: ESRD, end-stage renal disease.

(a) Incident Cases (b) Incidence Rates

Vol 1, CKD, Ch i 19

Data source: Medicare 5 percent sample. January 1 point prevalent Medicare patients age 66 and older. Adj: age/sex/race/prior year hospitalization/comorbidities. Ref: 2012 patients. Abbreviations: CKD, chronic kidney disease. This graphic also appears as Figure 3.1.

Figure i.7 Unadjusted and adjusted all-cause mortality rates (per 1,000 patient years at risk) for Medicare patients aged 66 and older, by CKD status and year, 1995-2012

(A) Unadjusted (B) Adjusted

Vol 1, CKD, Ch i 20

Data Source: Medicare 5 percent sample. Medicare patients aged 66 and older who had both Medicare Parts A & B, no Medicare Advantage plan (Part C/HMO), no ESRD by first service date from Medical Evidence form on 1/1/2011, and were discharged alive from a first AKI hospitalization in 2011. For each time point, the denominator is all patients alive, without ESRD, not in a Medicare Advantage plan and with Medicare Parts A & B. Physician visits are from physician/supplier claims with provider specialty codes for primary care (01, 08-family practice, 11-internal medicine), cardiology (06), and nephrology (39) and claim source indicating an outpatient setting. Abbreviations: AKI, acute kidney injury. This graphic also appears as Figure 5.9.

Figure i.13 Outpatient physician visits within one year of live discharge from first AKI hospitalization in 2011 for Medicare patients aged 66+ by physician specialty and time

Consider screening in patients potentially at risk for CKD

• Advanced age

• DM

• HTN

• + family hx

• Hx of ARF

• Obesity/metabolic syn

• Smokers

• Herbals

• Chemo/Lithium/CNIs

• Most minorities

• NSAID users

• Low income/education

• Reduced kidney size, structural disease

• Hepatitis C, HIV

• CT/autoimmune diseases

• Stone patients/recurrent UTI

• Obstruction

How to Screen for CKD

• In high-risk patients, obtain:

– BUN and Serum creatinine

– BP reading using standardized BP measurement

techniques

– Urine for protein level

• Use standard or albumin-specific dipsticks for

screening

• Quantify protein excretion by the protein-to-

creatinine or albumin-to-creatinine ratio

– Urinalysis to look for white cells or red cells

– Imaging

Vol 1, CKD, Ch i 23

Data Source: National Health and Nutrition Examination Survey (NHANES), 1988–1994, 1999-2004 & 2007–2012 participants age 20 & older. Abbreviations: CKD, chronic kidney disease. This graphic also appears as Figure 1.11.

Figure i.3 NHANES participants with CKD aware of their kidney disease, 1999-2010

Tell your patients!

Recognizing CKD

A 64yo white female with a SCr of 1.0, has a GFR of 59ml/min (CKD 3)

SCr 1.2, 60yo pt

What’s the eGFR ?

AAM = 70ml/min

WM = 66

AAF = 59

WF = 49

Serum Creatinine

• Wide range of normal

– interpret in the clinical context

• 10% lab error in serum creatinine depending upon calibration of serum creatinine assays

• Used to calculate the GFR

• High variation with volume status

GFR

• Glomerular filtration rate = GFR

• GFR doesn’t equal creatinine clearance

• Multiple formulae

– MDRD

– CKD-EPI

• Formulae have limitations

MDRD

• 1999, new version 2007

• Requires steady state

• Falsely elevated in states of malnutrition (nephrosis, liver disease, vegetarian diet), high meat diet

• Less accurate in extremes of disease (high GFR and low GFR), extremes of body size and age

CKD-EPI

• 2009, CKD Epidemiology Collaboration Eq

• Slightly more precise & accurate, esp GFR > 60

• Should reduce over reporting of CKD

– reduces prevalence of CKD 45 y/o

– increases prevalence of CKD > 65 y/o

• No African Americans included in studies (done in Europe)

SCr and GFR

• Remember SCr and GFR correlate only in steady state

• In late CKD, SCr no longer estimates GFR as well

• In late CKD a 24hr CrCl is more useful

– Adequacy: 20-25mg/kg Cr for men, 15-20mg/kg Cr for women

When SCr OVERestimates GFR

• Nephrotic syndrome

• AKI

• Intestinal bacterial overgrowth

• Low muscle mass states

– Liver disease

– Elderly, Debility

– Malnutrition

– Obesity

– Systemic illness, catabolic states

When SCr UNDERestimates GFR

• Recovery phase of AKI

• Reduced tubular secretion

– Trimethoprim, Cimetidine, Dronaderone

• Alterations in Cr assay

– Acetoacetate, Cefoxitine, Flurocytosine

• After a massive protein load

Hyperfiltration

• Common in diabetic nephropathy

• GFR appears good, but this is compensatory, and can be an early indicator of damage

• afferent arteriolar vasodilation as seen in patients with

diabetes

• efferent arteriolar vasoconstriction owing to activation of the RAAS

• leads to glomerular hypertension and ultimately renal

injury (drop in eGFR)

Creatinine Clearance

• Inulin is the gold standard

– Impractical

• Radionuclide and radiocontrast markers

– 123I-orthoiodohippuran

– radioiodinated hippuran

– Iohexol

– 99mTc-DPTA or 99mTc-MAG3

Urine Studies

• Urinalysis

– Assume: quality sample, no infection

– Evaluate: sp gr, pH, blood, protein

• Urine sediment: WBC, RBC, crystals, casts

• Urine immunofixation if > 50 years

Proteinuria

• Urine dipstick

– Albumin based

– Misses light chains

– Concentration dependent

Proteinuria

• A1 “Normo”albuminuria: < 30µg/mg (or mg/g)

• Diagnose with a random albumin to creatinine

ratio (ACR)

• Technically, ACR and not a spot albumin alone

correlates with 24hr urine studies.

• 2/3 tests over 6 months needed for “positivity”

• Spot albumins fluctuate and AM checks are most

accurate.

Example:

U prot 60mg/L

U Cr 125mg/dL

Referred for proteinuria 0.5g/d

But 60mg/L = 6mg/dL

UPC is 0.05g/d

24 Hour Urine Collections

• Cumbersome, fraught with patient error, noncompliance

• Utility in select patients (where formulae are inaccurate): – Extremes of age and body size

– Severe malnutrition or obesity

– Diseases of skeletal muscle

– Para/quadriplegia

– Vegetarian diet

Proteinuria

• 24 hour collection

– Assure specimen adequacy by creatinine

secretion (varies with gender and age)

• Don’t check 24hr Uprot without a UCr

– Largely being replaced by spot tests

• > 3 gms/day suggests glomerular in origin

– Specifically epithelial cell

• < 1 gm/day suggests tubular origin

Serology

• BMP, phos

• Albumin, total protein

• Cholesterol

• CBC

• Serum immunofixation if > 50yrs

• Intact PTH if GFR < 60

• Further serology may be warranted (for instance if proteinuric)

– ANA, DS DNA, Complement, HIV, Hep

Renal Ultrasound

• R/O obstruction

• Assess kidney size

• Cortical thickness

• Cortical echogenicity

• Evaluate for PCKD

Renal Artery Dopplers

• Asymmetric kidneys

• Cortical thinning

• Hypertension

• PVD, bruits or high suspicion

• Of little utility if pt is not a stent candidate

CT Scan

• Imaging of choice in the setting of nephrolithiasis

• May be beneficial in setting of other diseases to identify more anatomy

• Obvious limitation of contrast

Exposures

• Occupation

– Factory workers etc.

• Cigarette use

• Alcohol, moonshine

• STD’s or IVDA

• NSAIDs

• ACE-I, ARBs, diuretics (reversible)

Exposures

• Complementary and alternative medication use soaring

• Herbal remedies (aristolochic acid, Ma Huang or Ephedra, ayurveda)

• Arsenic, mercury, Cd, Pb all can be present in herbals

CKD

• Family history matters

• Consider bx if etiology is not explained

Clinical Consequences

• Fluid Overload

• Hypertension

• Electrolyte abnormalities

• Metabolic acidosis

• Hyperparathyroidism

• Anemia

• Accelerated CV disease

• Malnutrition

Clinical Action Plan for CKD

Stage GFR (ml/min) Plan

1 >90 Diagnosis and treatment

Slow progression

CVD risk reduction

2 60-89 Estimating progression

3 30-59 Evaluating and treating complications

4 15-29 Preparation for RRT

5 <15 RRT if uremic

Management

• Identify reversible causes of CKD

• Control known factors that lead to progression of CKD

• Many aspects of treatment are not specific to the cause of the renal disease

Slow Progression • Control HTN

• Treat proteinuria

• Avoid nephrotoxins, herbals, offending agents

• Adjust medications for GFR

• Early treatment of obstruction, infections

• Tight sugar control in diabetics?

• Protein restriction?

• Cholesterol control?

• Treat acidosis?

• Treat OSA

• Smoking cessation

Hypertension

• Both a cause and complication of CKD

• Diuretics, fluid mgmt are the cornerstone

– Often mediated by volume retention

• ACE-I or ARBs if no b/l renovascular disease or

very advanced CKD

• BP goal (KDOQI/KDIGO):

– < 130/80 mmHg if proteinuric (> 500mg/day)

– < 140/90 mmHg if not proteinuric

• There is no bang for the buck with hypOtn

ACE/ARB

• Reduced efferent arteriolar resistance

• Lower intraglomerular pressure

= Increase in SCr

• A 25-30% increase in SCr should be expected and

tolerated

• Please recheck SCr and K within a week of initiation

• Titrate up!

When to use ACEi/ARB

• Any patient with CKD

• Any patient with DM and proteinuria

• No specific indication for ACEi or ARB in a normotensive diabetic with no CKD nor proteinuria

Normotensive diabetics with A2 and A3 proteinuria should be started on an ACEi or ARB!

Hyperkalemia

• Body can generally maintain K+ homeostasis until GFR < 30 ml/min

• Potassium in the mid 5s is ok

• ACE-I, ARBs, NSAIDs,

K sparing diuretics,

non-selective BBs

digoxin contribute

• Treat metabolic acidosis

• Dietary restriction – Potato and tomato

• Loop diuretics

• Exchange resins

Metabolic Acidosis

• Once GFR < 25 ml/min

• Impaired renal NH3 production

• Reduced bicarbonate reabsorption

• May be contributing to hyperK

Metabolic Acidosis

• Treat with oral alkali

– Bicarb 650mg pill ~ 8mEq of Nabicarb

– Maintain serum CO2 in normal range

– 1/8tsp baking soda = 650mg PO NaBicarb

• Studies suggest treating may reduce progression

of CKD

• Less fluid overload with NaHCO3 then thought?

• Long term bone protection and Vit D

maintenance

Metabolic Bone Disease

• Hyperphosphatemia

• Hypocalcemia

• Secondary hyperPTH

• Vit D 25 deficiency

Metabolic Bone Disease

• Elevation of PTH may start in Stage 2 CKD

– Secondary hyperparathyroidism (HPTH)

• Many forms of metabolic bone disease

– High (OFC) vs Low (ABD, osteomalacia) bone

turnover

– PTH is normal in adynamic bone disease

• Bone bx is rarely done, unless needed to guide

therapy

Renal osteodystrophy

• Osteitis Fibrosa

– High turnover, high PTH

– subperiosteal bone reabsorption of clavicles, fingers and brown tumors (lytic)

– Dexa of little utility

• Adynamic Bone Disease

– PTH normal, low turnover

– Bisphosphonates are contraindicated!

• Osteomalacia

– Low turnover, a/w Aluminum toxicity, Vit D def, and iron overload

PTH Goal

CKD Stage KDOQI iPTH target (pg/mL)

KDIGO iPTH target (pg/mL)

3 35-70

4 70-110

5 150-300 2-9 X ULN

Calcium and Phosphorous

KDOQI KDIGO

Calcium 8.4-9.5 mg/dL Normal range

Phosphorous 2.7-4.6 mg/dL in CKD stage 3-4

Normal range CKD stage 3-5

Calcium intake < 2000 mg/day including supplements in CKD stage 5

Phosphorous intake 800-1000 mg/day in CKD stage 5

HPTH Treatment Options

• Vitamin D receptor agonists:

– Can use for hyperPTH with nl Vit D

– Calcitriol 0.25mcg/day starting dose (Paricalcitrol and Doxercalciferol also used)

– Repeat iPTH, calcium and phos in one month after

starting therapy

– Watch for hypercalcemia

• Ergo if Vit D deficient

• Do not confuse calcitrol and Cinacalcet

• Parathyroidectomy if refractory to treatment,

calciphylaxis, symptomatic

Vitamin D

• Remember calcitriol is a form of activated Vit D for use in correcting HPTH

• 25-hydroxyvitamin D level should be monitored initially if PTH elevated

• Supplement if < 30 ng/mL with Ergocalciferol (KDOQI guideline) in stages 3-4

• Recommendation based upon opinion

Calcimimetic Therapy

• Cinacalcet (Sensipar)

• Binds to transmembrane domain of the calcium

sensing receptor in the parathyroid gland and renal tubules

• For the treatment of HPTH – generally used in

primary hyperPTH, not FDA approved in CKD 3

and 4

• Ca and Phos levels decline (as opposed to vitamin D therapy)

– Contraindicated in hypocalcemia

Hyperphosphatemia

• Goal <5.5

• Low phosphorous diet, 800-1000mg/day

• Phosphorous binders with meals if dietary intervention ineffective

– Tums, Phoslo 667mg, Renagel 800mg,

Renvela 800mg, Fosrenol 500mg (all with

meals)

– Aluminum and magnesium binders avoided

• Ca x Phos product < 55 mg/dL

Anemia

• Normocytic normochromic anemia

• Reduced erythropoietin production from interstitial cells

• Shortened RBC survival, iron and folate deficiencies contribute

• Clinical manifestations include fatigue, dyspnea, depression, etc.

• HgA1c will be falsely low in late CKD and ESRD

Anemia

• Exclude other causes first

• Treatment with ESAs:

– Essentially all require iron supplementation

• Goal Hgb 10-11 g/dL

• Stop ESA with Hg >12 (higher mortality)

Erythropoeitin Stimulating Agents

Risks

• Exacerbation of HTN

• Thromboembolism

• CV events

Benefits

• Reduction in transfusions (important prior to

transplant)

• Surveys show improved QOL

CV disease

• ESRD patients are at 20x the risk of CV disease as age matched controls

• Every 10ml/min decrease = 7% increased risk of

mortality

• CV disease accounts for ~ 50% of deaths of ESRD patients

• 15% of ESRD patients have normal LVs (by echo)

• Proteinuria and is an independent risk factor for CV

disease

CV disease

• Goal LDL <100, checked annually

• Treat with: Dietary intervention, desirable body

weight, statins

• Statins are agents of choice

– May reduce proteinuria

– Mesangial cell modifications

– No strong data to suggest preservation or

improvement in GFR

Malnutrition

• Multiple serum markers of nutrition: albumin, cholesterol, SGA, nPCR

• Serum albumin correlates with mortality in ESRD patients

• CKD patients benefit from regularly seeing dietitians

Protein Restriction

• Studies vary, controversial

• NIH guidelines suggest:

– GFR 25-55 ml/min 0.8 g/kg/day

– GFR 13-25 ml/min 0.6 g/kg/day

• Proteinuric patients may benefit most

• Must be done under guidance of RD

• Correlation of low albumin with mortality

Tight glycemic control

ACCORD study

– Intense vs. standard glycemic control in DM2

• HbA1c 6.4-6.9 vs 7.3-8.4

– Intense group:

• Increase in hypoglycemia

• No change in doubling of SCr or need for RRT

Take home: No renal benefit from A1c <7

Nephrotoxins

• Contrast dye

• NSAIDs and COX-2 inhibitors

• OTCs (herbals, supplements)

• Select antimicrobial and antifungal agents

– Aminoglycosides, amphotericin B

• Immunomodulators

– Cyclosporine, tacrolimus

Dye/Contrast

• Iodinated Contrast: Risk of Contrast Induced Nephropathy

– Avoid high osmolar agents

– Use lowest volume possible

– Hold concomitant nephrotoxins

– Hold ACEi

– Volume expand (if can tolerate) with saline +/- bicarbonate

– Measure SCr 48-96 hours after contrast exposure

• Gadolinium: Risk of Nephrogenic Systemic Fibrosis

– Avoid use in GFR < 30 unless absolutely necessary

– Prophylactic dialysis? Controversial, no proven benefit

Metformin

• FDA renal impairment contraindication

• Males: Contraindicated if serum creatinine >1.5 mg/dL

• Females: Contraindicated if serum creatinine >1.4 mg/dL

• There is no systematic evidence that metformin increases risk of lactic acidosis in CKD

• Off the record recommendations:

– For eGFR <45, decrease dose by 50% and avoid initiation of metformin

– Stop once eGFR <30

Insulin in CKD

• Increased incidence of hypoglycemia in CKD, whether or not DM is present.

• At low eGFR:

• Insulin, which renally cleared, is not metabolized as fast

• Degradation of insulin in peripheral tissue is reduced

• Uremia, poor appetite = lower caloric intake

• Renal mass is lower therefore renal gluconeogenesis is reduced

• Decreased metabolism of other oral anti-hyperglycemics

Nephrology Referral?

• NIH suggested to refer when SCr > 1.5 mg/dL in women and > 2.0 mg/dL in men

• Clinical practice guidelines suggest referral when GFR < 30 ml/min or stage 4 CKD

• Lower threshold for referral when nephrotic (pathology changes mgmt 86%)

When to refer continued

• Progression of renal dysfunction is quick

• If an ACEi or ARB initiation caused a creatinine increase of over 30%

• Electrolytes abnormalities

Early Referral

• Avoids:

– urgent dialysis

– severe metabolic

abnormalities

– fluid overload

– catheter access

– delay in transplant referral

• Provides:

– lowers initial hospital

cost

– patient choice of modality

– lower 1 year mortality

– Education on modality

– Access placement

Immunizations

• Annual influenza vaccine is recommended

(unless contraindicated)

• CKD is an indication for both PNA 23 and PNA 13 vaccines.

• Consider hepatitis B vaccination series in

patients without preexisting immunity who are

likely to progress to ESRD

Miscellaneous

• Avoid upper extremity PICC lines in patients that have a good chance of requiring dialysis in the future

• If transfusing a potential future renal transplant patient, recommend leukoreduced +/- CMV negative blood

• Treat OSA

Conclusions/Summary

• Qualify & quantify primary renal disease

• Slow the progression

• Identify the clinical consequences

• Prevent and or treat the clinical consequences

• Modify the diet

• Watch medications, avoid nephrotoxins

• Educate the patient

• PLEASE LET THE PATIENT KNOW WHY THEY

ARE REFERRED!

Questions?

Works Cited

• Primer on Kidney Disease, 5th edition

• Up to Date

• AACE Guidelines

• NKF KDOQI/KDIGO Guideline

• NKF

• ASN

• Medscape

• JNC guidelines

• AAFP

• Harrisons

• Comprehensive Clinical Nephrology

• MKSAP