Chronic Kidney Disease Edward Barnes, MD, FACP

Assistant Dean, COMP Chief, Nephrology & Hypertension

Objectives • Background– What’s the Problem?

– Definition and Staging – Epidemiology – Pathogenesis

• Current Management – Goals – Strategies

• To the future – Guideline Medicine Precision Medicine – A peek into New Tech

Filter Erythropoietin

Acid-Base

Sodium-Water

Vitamin D

Definition • Kidney damage for 3 months

– Defined by structural of functional abnormalities of the kidney, with or without decreased GFR, manifest by either:

– Pathological abnormalities – Markers of kidney damage

• Blood or protein in urine • Abnormal Imaging tests

• GFR <60 mL/min/1.73m2 for 3 months, with or without kidney damage

How do we measure Kidney Function?

Estimated GFR (ml/min/1.73m2) MDRD

=186 x (SCr)-1.154x (Age)-0.203x(0.742 if female) x (1.210 if African- American) = exp(5.228-1.154xln(SCr)-0.203xln(Age)-(0.299 if female)+(0.192 if African-American

• Less Accurate in patients with eGFR near or >60mL/min per 1.73m2

• CKD-EPI GFR- Increased accuracy for eGFR >60mL/min per 1.73m2

•26 studies pooled data for validation

Chronic Kidney Disease (CKD)

Stages of CKD

V End-Stage

Renal Disease

IV Severe

III Moderate

II Mild

I Kidney

Damage

Transplant

Dialysis

Hospice

> 90 60-89 30-59 15-29 <15

GFR mL/min/1.73 m2

Causes of ESRD

NKF; Kidney.org/general/new/problem

Growing ESRD Population

USRDS ADR 2010

21%

79%

Cost of CKD to Medicare CKD patient related costsNon CKD patient costs

Economic Burden of CKD in the U.S.

11

Why Do CKD Patients Need Special Care?

eGFR & Mortality

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2

4

6

8

10

12

14

16

>59 45-59 30-44 15-29 <15

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eGFR (ml/min/1.73 m2)

eGFR Adjusted Mortality

No. of Events 25,803 11,603 7,802 4,408 1,842

eGFR < 60 ml/min/m2 Increase Risk of Death

12

ESRD Care is Expensive

Other Medicare

ESRD + Late Stage Chronic Kidney Disease (CKD)

~ $30B per year

~1.5% of Patients ~10% of Federal Healthcare Costs

Other Medicare

Source: USRDS (publicly available comprehensive clinical and financial dataset reported to and used by CMS) ~375,000 ESRD + ~300,000 Stage 4 Chronic Kidney Disease

Pathophysiology

• Susceptibility Factors – Older Age – Health illiteracy – Race and Ethnicity – Family History – Low Renal Mass

• Initiation Factors – Diabetes – Hypertension – Autoimmune – Systemic Infections – Lower Urinary Obstruction – Drug Toxicity

Pathophysiology

• Progression Factors – High Level of Proteinuria – Uncontrolled Hypertension – Poor Glycemic Control – Smoking

• End-Stage Factors (Increasing Mortality) – Low dose Dialysis – Anemia – Low Albumin – Late referral to

Nephrologist

What are the Guidelines?

• KDOQI Guidelines • Therapies for Slowing the Progression of CKD

– RAAS suppression/Albuminuria therapy • ACE inhibitors OR • Angiotensin Receptor Blockers

– Hypertension Control- BP <140/90 mmHg – Diabetes Management- HbA1C <7.0% – Hyperlipidemia Control –LDL <100 mg/dL – Low Protein Diet in Diabetics with macroalbuminuria – no more than 1.3g of

protein/day – Low Sodium diet- <2g/day

Therapy- Slowing the Progression of CKD

• RAAS suppression/Albuminuria therapy

– ACE inhibitors – Angiotensin Receptor Blockers

• Hypertension Control • Diabetes Management • Hyperlipidemia Control

What is Precision Medicine?

Precision Medicine: Medical care designed to optimize efficiency or therapeutic benefit for particular groups of patients, especially by using genetic or molecular profiling.

Guidelines Precision Medicine

Normal Increased Risk Damage Albuminuria GFR ESRD Death

CKD Conceptual Model

Ideal Biomarker

Creatinine

Pavlesky PM, Chief Renal Section VA Pittburgh

Increased GFR

Kidney Markers

Chronic Kidney Disease (CKD)

Stages of CKD

V End-Stage

Renal Disease

IV Severe

III Moderate

II Mild

I Kidney

Damage

Transplant

Dialysis

Hospice

> 90 60-89 30-59 15-29 <15

GFR mL/min/1.73 m2

• Gender Female • Age 67 • eGFR 44 mL/min • UACR 286 mg/g • Serum Ca 9.2 mg/dL • Serum Phos 4.5 mg/dL • Serum Bicarb 20 meq/L • Serum Albumin 3.1 meq/L • Score 10.3% risk of ESRD over 5yrs

ESRD 5 year Risk

• 0-5% Low Risk

• 5-15% Intermediate Risk

• >15% High Risk

Progression and Biomarkers

EGF and CKD progression

Proteomics

Advances in the fields of two-dimensional gel electrophoresis, protein analysis, and computer databases together make proteome analysis

possible.

The study of genetics which refers to all the proteins expressed by a genome; proteomics involves the identification of proteins in the body and the determination of their role in physiological and pathophysiological functions

Proteomics

Pathway driven biomarker discovery

Data Analysis, Validation, & Translation

Profiling biomarker discovery

Proteomics

Traditional Biochemistry

Proteomics

Select Targeted Therapies

• Endothelin Receptor Antagonists

• Advanced Glycosylated End-product (AGE) Inhibitors

• Renal Repair

– Stem Cell Therapy Micro-Chinese Therapies

Endothelin Receptor Antagonists

• Endothelin-1 (ET-1) levels are elevated in urine/plasma in patients with DM

• ET-1 levels correlate with:

– renal function – blood pressure – albuminuria

Avosentan vs. Albuminuria ET-1 inhibitor

Mann et al. J Am Soc Nephrol 21: 527–535, 2010

X

X

AGE Inhibitors

Glucose & Proteins AGEs Cross-linked AGEs RAGE

Glucose Lowering Agents

AGE Formation Inhibitors

Pyridoxamine

AGE Crosslink Breakers

Receptor Blockers

TP Degenhardt et al. KI (2002) 61, 939–950;

Pyridoxamine AGE inhibitor

• Derivative of Vitamin B6

• Inhibits AGE Formation

TP Degenhardt et al. KI (2002) 61, 939–950;

Pyridoxamine

F Zheng et. al. KI (2006) 70, 507–514.

Stem Cells • 1. Micro-Chinese Medicine Osmotherapy

ingredients in the medicines can help patients repair the damaged renal intrinsic cells and prevent the further renal damage. – Also used to manage Hypertension

• 2. Stem Cell Transplant combined application of

Stem Cell Transplant and Micro-Chinese Medicine Osmotherapy. – undifferentiated original cells, which can differentiate new

cells to replace their roles. – Stem Cell Transplant and Micro-Chinese Medicine

Osmotherapy has showed their enormous effect in the treatment of CKD,

Now that is some Sci-Fi S@#!

• Nano-technology

• Renal Assist Device (RAD) – Artificial Kidney

QUESTIONS?