Chronic Kidney DiseaseThe Basics

Kevin Harley, M.D.Assistant Clinical ProfessorDepartment of Medicine

Division of Nephrology & HypertensionUC Irvine Medical Center

Objectives

• Review Definition of CKD and its classification• Discuss Hypertension in CKD• Anemia in CKD• Mineral Bone Disorders in CKD• Nutrition in CKD • Renal replacement therapy prep

A Case76 y/o white female visits clinic. She is distraught. Another MD told her she has stage 3 CKD. She looked it up on the internet and she is afraid she will need dialysis. Has 20 year history of hypertension, on amlodipine. BP 138/72, UA no protein, Cr 1.3 mg/dl

Which of following is the next best step?

a) Repeat blood test to confirm CR and MDRD eGFRb) Repeat blood test for cystatin C level and eGFRc) Repeat labs for CKD-epi CR+cystatin C eGFRd) 24 Hr urine Cr Clearancee) Encourage her to get another doctor

Chronic Kidney DiseaseHow big a problem?

• 10-15% of US population have non-dialysis dependent CKD

• In 2011, there were over 620,000 people receiving ESRD Medicare benefits

Chronic Kidney DiseaseThe Basics

• CKD is defined as either of the following present for 3 months:– Markers of kidney damage

• Pathologic albuminuria• Abnormal urine sediment• Anatomic defect detected by imaging• Histopathologic abnormality

OR

– Decline in GFR < 60ml/min/1.73m2

Chronic Kidney Disease(…Its not good for your health)

Over 1.1 million pts followed > 3 years

New Engl J Med 351:1296, 2004

Classifying CKD: CauseType of Disease Examples of systemic

diseases affecting the kidney

Examples of Primary kidney disease

Glomerular diseases

DM, Autoimmune Disease (eg SLE), infections, neoplasia

FSGS, Primary Membranous, Minimal Change, Proliferative or

crescentic GNs

Tubulointerstitial diseases

Infections, Sarcoid, Drugs, Urate, myeloma, environmental toxins

UTIs, Stones, Obstruction

Vascular Disease Atherosclerosis, HTN, ischemia, cholesterol emboli, systemic

vasculitis, TMAs, scleroderma

ANCA-associated renal limited vasculitides, fibromuscular

dysplasia

Cystic & Congenital

Disease

PKD, Alports, Fabrys Renal dysplasia, medullary cystic kidney disease

Classifying CKD: eGFR

Classifying CKD: Albuminuria

Category Albumin/CR(mg/g)

Terms

A1 <30 Normal

A2 30-300 Moderately Increased

A3 >300 Severely Increased

Albuminuria:Outcomes by eGFR

Pink = ACR > 300 mg/gGreen = ACR 30 – 299 mg/gBlue = ACR < 30 mg/g

Levey, et al, Kidney International (2011) 80, 17–28

Glomerular Filtration

Glomerular Filtration Rate (GFR): 120-130 ml/min

Clearance

Estimating Kidney Function• If 24 hr urine can be collected:

CrCl = (Ucr x Volume) / Pcr

• Time averaged urine urea and Creatinine

• Cockroft-Gault (0.85 for women) – use serum Creatinine

CrCl = 0.85 * ( Wt x [140-age] ) / Scr x 72

• MDRD Equation:eGFR = 170 * Scr

-0.999 * age-0.176 * sex * race *(Female: 0.762)

• CKD-EPI Equation:GFR = 141 X min(Scr/κ,1)α X max(Scr/κ,1)-1.209 X 0.993Age X 1.018 [if female] X 1.159 [if black]

Plasma Creatinine• Creatinine is derived from the metabolism of

creatine in skeletal muscle and from dietary meat intake.

Kidney Handling of Creatinine

• 10-40% Urine Cr is from tubular secretion by the PCT

• IF GFR, tubular creatinine secretion, dietary intake, and muscle mass all remain constant, then the serum [Cr] should remain constant

Every Creatinine is Not the Same

• Patient 1 : 22y/o African American male – Cr = 1.2 mg/dl, MDRD eGFR = 98 ml/min

= normal kidney function, or stage 1 if history of problem

• Patient 2: 50 y/o white male– Cr = 1.2 mg/dl, MDRD eGFR = 68 ml/min

= stage 2 chronic kidney disease

• Patient 3: 80 y/o white female– Cr = 1.2 mg/dl, MDRD eGFR = 46 ml/min

= stage 3 chronic kidney diseaseFrom National Kidney Foundation

Creatinine Caveats

• Decreased Cr secretion (sCr can rise 0.5mg/dl)– Trimethoprim – Dronedarone– Cimetidine – Tenofovir

• Increased Cr production– Large meat intake

• Interference with Cr assay (alkaline picrate method)

– Flucytosine, cefoxitin, acetoacetate

CreatinineNormal Values

Category Male Female

U.S. (all) 1.13 0.93

Mexican-Americans 1.07 0.86

Non-Hispanic Black 1.25 1.01

White (non-Hispanic) 1.16 0.92

NHANES III

Cystatin C(0.53-0.95 mg/L)

• 13 kDa protein produced by all nucleated cells– Freely filtered at glomerulus

– 99% reabsorbed at PCT and catabolized • cant be used to measure clearance

– …its not perfect• Level rises with age

• And w/ inflammation/CRP

Cystatin C to Predict CV DeathShlipak, NEJM 2005;352:2049-60

CR+Cys C eGFRInker, NEJM 2012;367:20-9

Combined creatinine-cystatin C e-GFR performed better than equations based on either of these alone and may be useful as a confirmatory test for CKD.

A Case76 y/o white female visits clinic. She is distraught. Another MD told her she has stage 3 CKD. She looked it up on the internet and she is afraid she will need dialysis. Has 20 year history of hypertension, on amlodipine. BP 138/72, UA no protein, Cr 1.3 mg/dl

Which of following is the next best step?

a) Repeat blood test to confirm CR and MDRD eGFRb) Repeat blood test for cystatin C level and eGFRc) Repeat labs for CKD-epi CR+cystatin C eGFRd) 24 Hr urine Cr Clearancee) Encourage her to get another doctor

Predictable Progression of CKD

Loss of nephrons compensatory hyperfiltration glomerular HTN further loss of nephrons.

GFR

Time

Diabetes45%

Hypertension28%

Glomerulonephritis7%

Cystic Disease3%

Primary Diagnoses for ALL Patients Who Start Dialysis

USRDS 2010 Annual Data Report

Other17%

Management of CKD

Nephrology. A Photographic History

Role of the Nephrologist

Kessler et al (EPIREL Study); Am J Kidney Dis 2003; 42: 474-485Winkelmayer et al. J Am Soc Nephrol 2003; 14: 486-492

Avorn et al. Arch Intern Med 2002; 162: 2002-2006Stack et al. Am J Kidney Dis 2003; 41: 310-318

Kinchen et al. Ann Intern Med 2002; 137: 479-486

• Mortality rate is lower in 1st 3 months of ESRD in CKD pts who were established with a nephrologist prior to reaching ESRD status

– Adjusted HR for Death: 1.60-1.75

– Survival increased with # nephrology encounters

CKD Associated Conditions

• Hypertension• Anemia• Secondary Hyperparathyroidism• Metabolic Acidosis• Hyperkalemia• Malnutrition• Uremia

Question

60 y/o White Male with PMH of DM2 >20 yrs, HTN, Dyslipidemia comes to clinic. Meds = insulinBP 152/90, CR 2.1, urine spot PCR = 1.5g

Which is the next step in managing BP?A) Start HCTZB) Start Losartan C) Start Lisinopril AND LosartanD) Counsel on low NaCl diet, no meds neededE) Start amlodipine

Hypertension in CKD

• 85% CKD patients have hypertension

• Prevalence of HTN increases linearly as GFR falls

• Treating HTN can slow the progression of CKD and reduce the rate of CV complications

What Causes Hypertension in CKD?

• Tend to retain Na+• Increased activity of the RAS • Enhanced sympathetic activity • Impaired nitric oxide synthesis • Secondary hyperparathyroidism • Loss of normal nighttime decline in BP• ESA agents

Hypertension in CKDACEI or ARB use

Placebo or captopril in DM1 with proteinuria and a sCR >= 1.5 Losartan effect on doubling of the sCR and rate of proteinuria in DM2 NEJM 1993; 329:1456

RENAAL, NEJM 2001;345:861-9

Hypertension in CKD

• Ramipril Efficacy In Nephropathy, (No DM)– Ramipril slowed GFR decline (and proteinuria)

• REIN 2– ACEi+/- CCB: no additional benefit

• AASK: ACEi benefit extends to Blacks

• ONTARGET trial enrolled 25,620 pts with PVD or DM to evaluate the effects of ramipril, telmisartan, or both on CV endpoints over 4 yrs

• Of the 5623 patients who had baseline CKD… – ACEi+ARB was associated with significantly

increased composit outcome (ESRD or 50% increase CR)– Higher rates of hyperkalemia

Hypertension in CKDIs combined ACEi+ARB the way to go?

Hypertension in CKDJNC 8

• Expect to use 3+ agents

Question

60 y/o White Male with PMH of DM2 >20 yrs, HTN, Dyslipidemia comes to clinic. Meds = insulin, lisinoprilBP 138/79, CR 2.2, urine spot PCR = 0.7g,Hemoglobin 8.9, T Sat 18%, ferritin is 100

Which is the true regarding anemia management in this CKD pt?A) Colonoscopy is unnecessary – this is Anemia due to CKDB) He is a candidate for darbepoetin with goal Hg 10-11.5C) He is a candidate for darbepoetin with goal Hg 12-14D) He should start oral ferrous sulfate

Etiology of Anemia of CKD• Erythropoietin deficiency• Suppression of RBC synthesis by uremic toxins• Short RBC survival• Iron deficiency

–Blood loss: GI tract, GU tract, etc• Folate or B12 deficiency• Hyperparathyroidism• Chronic inflammation• Infection

• 2006 K/DOQI guidelines suggest administering Fe to:– ≥20% saturation, – serum ferritin > 100 ng/mL

• Erythropoeitin Stimulating Agents considered in pts with Hg < 10, & with repleted Fe stores

– *** Target Hg is 10-12g– *** Do not exceed Hg > 12. (More MIs and Strokes!!)

(CREATE, CHOIR, Normal HCT trials)– *** Beware of pro-malignant effect

Anemia of CKD

Question

60 y/o White Male with PMH of DM2 >20 yrs, HTN, Dyslipidemia comes to clinic. Recent negative colonoscopyMeds = insulin, Lisinopril, occasional ESA and IV IronBP 138/79, CR 2.2, urine spot PCR = 2g, Hg = 10.5CO2 = 19, Phos 4.5, iPTH 130, Albumin 2.7

Which of the following is TRUE?A) Normalization of his CO2 level might delay ESRD onsetB) Persistent metabolic acidosis may lead to malnutritionC) He does not yet need to start phosphorus bindersD) He is a candidate for active vitamin D

Chronic Metabolic Acidosis in CKD• Increase skeletal muscle breakdown • Decreased albumin synthesis • Muscle weakness • Release of Ca++ and PO4 from bone, which can

worsen bone health• Activation of complement pathway promote

tubulo-interstitial injury

• **HCO3 supplementation may slow progression

Brito-Ashurst, et al, JASN, 20: 2075–2084, 2009

Chronic Metabolic AcidosisAlkali Supplementation Slows CKD Progression

in Diabetics and Non-Diabetics

Hyperphosphatemia in CKD

• In CKD there is reduction in the filtered PO4 load.

• Hyperphosphatemia becomes manifest usually as GFR falls < 30 ml/min

• Eventual development of secondary hyperparathyroidism renal bone disease:– osteitis fibrosa, osteomalacia, and adynamic bone disease

Secondary Hyperparathyroidism in CKD

PTH

Bone DiseaseFracturesBone pain

Marrow fibrosisErythropoietin resistance

Serum P¯ 1,25D

Calcitriol

Renal Failure

PTH

Systemic ToxicityCVD

HypertensionInflammationCalcification

Immunological

¯ 25D

Ca++

Decreased Vitamin D Receptors and Ca-Sensing Receptors

FGF-23

Mineral Done Disease in CKDUncontrolled 2nd HPT and HyperPhos

3 years laterAt time of ESRD diagnosis

• CKD 3 (30-60 ml/min)– Measure Ca and Phos yearly– Measure iPTH yearly - goal is 35-70– Use active vitamin D if needed

• CKD 4 (15-30 ml/min)– Measure Ca and Phos every 3 months– Measure iPTH every 3 months – goal is 70-120– Use active vitamin D if needed

Hyperphosphatemia & Bone Disease

Malnutrition in CKDAssociated with incremental mortality risk

Am J Kidney Dis 1992; 20(Suppl 2):32

Relative mortality risk in new starts on chronic HD. Data from 1980s

Modification of Protein Intake in CKD

• Recommended: 0.6-0.8 g protein/kg/day

• Measure 24-hr urine urea nitrogen:Estimated protein intake = = 6.25 * (UUN + 3%(Wt in kg))

(add urine protein if >5 g/d)

Kopple et al. Kidney Int. 2000 Maroni et al. Kidney Int. 1985

Question

60 y/o White Male with PMH of DM2 >20 yrs, HTN, Dyslipidemia comes to clinic. Wt = 100kg, 24 hr urine urea = 8, Urine PCR 2

Est protein intake = 6.25 * (UUN + 3%(Wt in kg))

Estimated dietary protein intake = 6.25 + 0.03(90) = 8.95g/dayIn a 90kg male, 0.8g/kg/day would be 7.2g His goal is less than 7.2 g/day, he is taking ~9/day….he needs nutritional counseling

Hyperkalemia in CKD

• Reduced nephron mass reduced K+ excretion

• Hyporenin, Hypoaldosterone state

• Excessive dietary K+ intake

• Medication effects (ACEi/ARB)

Medications and CKD

• NSAIDs (including COX2 inhibitors)

• Iodinated contrast

• Aminoglycosides

• ***...always do a complete inventory of unprescribed meds and herbal/supplement intake

Question

5 years later…Cr 4.2, BUN 58, K 5.1, Phos 5.6, Urine PCR 4geGFR 20Hg 10 on regular ESA useBP 160/70 on 4 BP meds +Diuretic1+ leg edema

How do we manage CKD pts as they approach ESRD?

Renal Replacement Therapy• Hemodialysis

– Most common RRT – Requires planning for AV fistula once eGFR < 20

• Peritoneal Dialysis– Requires education, dedicated RN- pt training– Requires planning for PD catheter placement

• Kidney Transplant– **the best option– Patients can be listed when GFR < 20– Wait time for deceased donor kidney in Southern California is 8-10 years

Monitoring for Uremiaand Indication to Start RRT

Signs and symptoms + eGFR:– Loss of appetite, nausea, vomiting, fetor– MS, ↓ concentration, seizure, coma– Cramps, pruritus– Uremic pericarditis (rub)– Uremic bleeding tendency, ecchymoses– Volume overload, Anasarca – Acute Neuropathies

Natural Progression of CKD

The rate of progression of GFR is usually predictable...…but can be slowed = longer life and longer time to ESRD.Accurate diagnosis is key.

GFR

Age (years)50 80

HTN control

DM controlTreat 2nd HPT

Alkali Rx

Cardiac Risk ModificationReduce Albuminuria

Managing CKD involves multidisciplinary approach to patient care and education

Thank You