Renal Replacement Therapy – What the Non-Nephrologist Should Know Bernard G. Jaar, MD, MPH,...

Renal Replacement Therapy – What the Non-Nephrologist

Should Know

Bernard G. Jaar, MD, MPH, FASN,FNKF

Johns Hopkins Medical Institutions

Nephrology Center of Maryland

Why is this topic relevant to you?

Kidney Disease is a Public Health Problem

Trends in Kidney Disease Burden …

Coresh, J. et al. JAMA 2007;298:2038-2047

Prevalence of CKD Stages in US Adults Aged 20 Years or Older:

NHANES 1988-1994 and NHANES 1999-2004

ESRD Prevalence – The Forecast Projected growth overall ESRD prevalence (5% / yr)

Gilbertson et al. JASN 2003

Number of patients (millions)

Year

0.4 million

0.7 million

1.3 million

2.2 million (60% diabetic)

2000 2010 2020 20301978

3.0

2.0

1.0

0

618,160 pts (2011)

Objectives

• Describe treatment options for renal replacement therapy

• Understand the general principles of dialysis modalities & compare their outcomes

• Importance of residual renal function

• Describe kidney transplantation process

Case Presentation (I)

• 39 y/o AA man

• PMHx: none

• Routine physical exam: – BP 142 / 100– LE edema– 4+ proteinuria (dipstick)

Case Presentation (II)

• PE:– Unremarkable, except:– Weight 230 lbs (BMI 33) – BP 138 / 85– 2+ LE edema

• Treatment:– ACE inhibitor– Thiazide diuretics

Initial Nephrology Clinic Visit

Case Presentation (III)

• Labs:

Albumin 2.5 T. cholesterol 398 mg/dLSerology w-u (-)UA: protein 4+, 0-2 RBC, 0-2 WBCSpot u. prot. / creat. 413 mg/dL / 41 mg/dL 10

Initial Laboratory Data

12.3

41.0 7490 333

141

3.6

107

28

18

2.495

eGFR 37 cc/min/1.73m2

CKD Progression ESRD

05

10152025303540

Dates

eGF

R c

c/m

in/1

.73m

2

Initial presentation:HTN, CKD, proteinuria

RRT

Kidney Bx: FSGS

“Uremic”ESRD

Indications for Renal Replacement Therapy

• Hyperkalemia• Metabolic acidosis• Fluid overload (recurrent CHF admissions)

• Uremic pericarditis (rub)

• Other non specific uremic symptoms: anorexia and nausea, impaired nutritional status, increased sleepiness, and decreased energy level, attentiveness, and cognitive tasking, …

What are the Treatment Options for Renal Replacement

Therapy for our Patient?

ESRD Treatment Options

ESRD

Hemodialysis

Kidney Transplant

Peritoneal Dialysis

Comfort Care

ESRD Treatment Options

ESRD

Hemodialysis

Kidney Transplant

Peritoneal Dialysis

Comfort Care

Dialysis options

Dialysis

Hemodialysis Peritoneal Dialysis

In-Center HD (3 x week)

Home HD (short daily, nocturnal) CAPD CCPD Home

Incident Patient Counts (USRDS)by 1st Modality

USRDS 2013 ADR

CKD Education

CKD Progression ESRD

05

10152025303540

Dates

eGF

R c

c/m

in/1

.73m

2

Initial presentation:HTN, CKD, proteinuria

RRT

“Uremic”ESRD

CKD Education

Refer patients early, when eGFR < 30 cc/min

Education about types of renal replacement therapy:– Hemodialysis (vascular access +++)– Peritoneal Dialysis (QOL advantage +++)– Kidney Transplantation

• Refer when eGFR <20• Living kidney transplant (family, friends)• Build time on list before dialysis initiation• Even transplant before dialysis initiation (pre-

emptive)

CKD Education

Early Vaccination for Hepatitis B!

Patients with ESRD have response to vaccination

(2ary to general suppression of immune system)

After Hepatitis B vaccination in ESRD patients:– 50 – 60 % develop antibodies, compared to >

90% in patients without renal failure– Have Lower titers– Have protective levels for shorter duration

Stevens CE et al. NEJM 1984; 311: 496

Buti M et al. Am J Nephrol 1992; 112: 144

Too Ofte

n Forg

otten !

Early Vaccination for Hepatitis B!

Patients with ESRD have response to vaccination

(2ary to general suppression of immune system)

After Hepatitis B vaccination in ESRD patients:– 50 – 60 % develop antibodies, compared to >

90% in patients without renal failure– Have Lower titers– Have protective levels for shorter duration

Stevens CE et al. NEJM 1984; 311: 496

Buti M et al. Am J Nephrol 1992; 112: 144

Hemodialysis (HD)

Principle of Hemodialysis

Vein

Artery

Hemodialysis Filter (Dialyzer)

Hemodialysis Filter (Dialyzer)

Hemodialysis Vascular Access

Polytetrafluoroethylene

Arteriovenous (AV) Fistula

Question 1

• Which type of vascular access is associated with better outcomes in hemodialysis patients? (choose one answer):

1.Central venous cuffed catheter

2.Arteriovenous graft

3.Arteriovenous fistula

4.Temporary central venous catheter

Which Vascular Access and When Should It Be Placed?

CKD Progression

05

10152025303540

Dates

eGF

R c

c/m

in/1

.73m

2

Initial presentation:HTN, CKD, proteinuria

HD

Vascular Access (AVF)

Adjusted* Relative Risk of Death by Type of Vascular Access

Diabetes No Diabetes

Cohort: 5,507 patients, followed for 2 years*Adjusted for age, race, gender, BMI, history of smoking, PVD, CAD, CHF, neoplasm, ability to ambulate and education level. Prevalent diabetic pts: CVC vs. AVG (P = 0.42). Incident diabetic pts: CVC vs. AVG (P = 0.48).Prev. nondiabetic pts: CVC vs. AVG (P < 0.0001). Inc. nondiabetic pts: CVC vs. AVG (P = 0.82).

Dhingra RK et al. Kidney Int 2001; 60: 1443–1451

Adjusted* Relative Risk of Death due to Infection by VA Type and Diabetes

Status

Cohort: 5,507 patients, followed for 2 years*Adjusted for age, race, gender, BMI, history of smoking, PVD, CAD, CHF, neoplasm, ability to ambulate and education level. Prevalent diabetic pts: CVC vs. AVG (P = 0.81)Prevalent nondiabetic pts: CVC vs. AVG (P < 0.13)

Dhingra RK et al. Kidney Int 2001; 60: 1443–1451

Astor B. et al. Am J Kidney Dis 2001; 38 (3): 494-501

Patients who started using an AV access by timing of first referral to a nephrologist

N=356 hemodialysis patients

VASCULAR ACCESS GUIDELINES

Arm veins suitable for placement of vascular access should be preserved, regardless of arm dominance. Arm veins, particularly the cephalic veins of the non-dominant arm should not be used.

Dorsum of the hand could be used for IV.

A Medic Alert bracelet should be worn to inform hospital staff to avoid IV cannulation of essential veins.

Subclavian vein catheterization should be avoided for temporary access in all patients with CKD ( stenosis preclude use of ipsilateral arm for vascular access)

SAVE the Non-Dominant ARM for Vascular Access

When GFR < 30 mL/min– No BP measurement – No IV– No Blood Draws

Place vascular access within a year of hemodialysis anticipation …

On Non-Dominant Arm

Peritoneal Dialysis (PD)

Principle of PD Treatment

• Abdominal cavity is lined by peritoneal membrane which acts as a semi-permeable membrane

• Diffusion of solutes (urea, creatinine, …) from blood into the dialysate contained in the abdominal cavity

• Removal of excess water (ultrafiltration) due to osmotic gradient generated by glucose in dialysate

Types of PD Catheters• Overall PD catheter survival : +/- 90% at 1 year• No particular catheter is superior

Placement of Peritoneal Dialysis Catheter

Placement of PD Catheter Exit Site

PD Catheter Exit Site

Peritoneal Dialysis (PD)

PD

Continuous Intermittent

Continuous PD Regimens

Multiple sequential exchanges are performed during the day and night so that dialysis occurs 24 hours a day, 7 days a week

CAPD: Continuous Ambulatory PD

CCPD: Continuous Cyclic PD

Intermittent PD Regimens

PD is performed every day but only during certain hours

DAPD: Daytime Ambulatory PD.

Multiple manual exchanges during waking hours

NPD: Nightly PD.Performed while patient

asleep using an automated cycler machine.

Sometimes,1 or 2 day-time manual exchanges are added to

enhance solute clearances

CCPD Treatment Setup

Question 2

• What is the most common cause of technique failure in peritoneal dialysis? (choose one answer):

1.Ultrafiltration failure

2.Malnutrition

3.Peritonitis

4.Non-adherence to the treatment regimen

Cumulative percentage of PD patients by time from 1st dialysis to

1st switch to HD

Jaar BG et al. BMC Nephrol 2009; 10: 3

25% of PD patients

switched to HD within 5-7 years

Causes of PD Technique Failure (Switching from PD to HD)

47%

19%

15%

15%

4%

Peritonitis

Ultrafiltration Failure

Malnutrition

Abdominal Surgery

Psychological Issues

Jaar BG et al. BMC Nephrol 2009; 10: 3

Which Dialysis Modality Provides the Best Outcomes?

Factors Influencing Dialysis Choice

Dialysis Modality

Contraindications

Survival

Quality of Life

Treatment Satisfaction

Other Factors:Late Referral,

…

Absolute contraindications for PD

• Documented loss of peritoneal function or extensive abdominal adhesions (previous abd. Surgeries) limit dialysate flow

• Uncorrectable mechanical defects (e.g., diaphragmatic hernia)

• In the absence of a suitable assistant, a patient who is physically or mentally incapable of performing PD.

NKF K/DOQI Guidelines 2000

Peritoneal Adhesions

Factors Influencing Dialysis Choice

Dialysis Modality

Contraindications

Survival

Quality of Life

Treatment Satisfaction

Other Factors:Late Referral,

…

Best Study Design to Compare Dialysis Modalities

• Prospective, randomized, clinical trial

• Significant barriers to performing this type of study1

• We are left with the analysis of observational data from well-conducted prospective studies

1Korevaar JC et al. KI 2003; 64(6): 2222-2228

Quinn RR et al. 2011 (I)

Country: Ontario, Canada

Enrollment Years: 7-1-1998 to 3-31-2006

Follow-Up: 8 years

Population Type: Incident – Elective Outpatient (databases @ Institute for Clinical Evaluative Sciences)

Sample Size: HD: 4,538 PD: 2,035

Switching Modality: No

Model(s) Intention-to-Treat (baseline modality)

Quinn RR et al. J Am Soc Nephrol 2011; 22: 1534-1542

Adjusted Survival between PD and HD, (received > 4 months of predialysis care

and Started as outpatient)

Quinn RR et al. J Am Soc Nephrol 2011; 22: 1534-1542

Adjusted HR: 0.96, p = 0.44

Biases

• Residual confounding: limited adjustment for known factors associated with mortality (e.g., comorbidities, lab data [albumin, …])

• Short follow-up (1-2 years) in some studies• Lead-time bias: baseline GFR• Selection bias: patient characteristics• Statistical Methodology:

– Center Effect: confounding by clinic as patient characteristics varied by center and treatment

– How to handle modality switching: As-Treated vs Intention-to-Treat

• No causal relationship, just association!

Other Issues: PD vs HDBeyond Survival

• In considering choice of dialysis technique, other issues must be considered …

Factors Influencing Dialysis Choice

Dialysis Modality

Contraindications

Survival

Quality of Life

Treatment Satisfaction

Other Factors:Cost of Care,Late Referral,

…

CHOICE - Quality of Life: PD vs HD (I)

• PD patients reported better QOL then HD patients in the following domains:– Bodily pain– Travel– Diet restrictions– Dialysis access– Financial well-being– Physical functioning (only at baseline, not at 1

year)

Wu A et al. JASN 2004; 15: 743-753

• At one year,

– HD patients improved more on aspects of general health-related QOL than patients on PD

– HD patients had greater improvement on:• Physical functioning• Sexual functioning• General health perceptions

Wu A et al. JASN 2004; 15: 743-753

CHOICE - Quality of Life: PD vs HD (II)

Factors Influencing Dialysis Choice

Dialysis Modality

Contraindications

Survival

Quality of Life

Treatment Satisfaction

Other Factors:Late Referral,

…

CHOICE - Treatment Satisfaction: PD vs HD

• PD patients were significantly more likely to give excellent ratings of dialysis care overall compared to HD patients (85% vs 56%).

• Also PD patients were more likely to give excellent ratings for specific aspects of care:– information on choosing a dialysis modality– information on fluid removal– staff and nephrologist availability – coordination with other physicians – caring of nurses or staff – …

Rubin HR et al. JAMA 2004; 291: 697-703

Implications• Each modality has distinct advantages or disadvantages

• Physicians should be as explicit as possible in describing specific tradeoffs and attempt to elicit individual preferences at start of dialysis

• Although there is no conclusive evidence that the choice of PD or HD provide a specific survival advantage:– Better selection of PD patients (PD underutilized)– PD patients should be monitored closely after the 2nd or 3rd year of dialysis– Consider a “timely” transfer to HD (if or when PD problems arise)

What is the best long-term treatment?

1. PD

2. HD in-center

3. HD home/ self-care

Ask the nephrology providers which dialysis modality they would select if they had ESRD?

What is the best long-term treatment?Opinion vs Reality

Ledebo I., Ronco C. NDT Plus 2008; 6:403-408

1. PD

2. HD in-center

3. HD home/ self-care

Question 3

• Which one of the following patient’s characteristic or comorbidity is associated with better overall outcome on dialysis (choose one answer):

1.Diabetes Mellitus + end-organ damage

2.BMI > 30

3.Residual urine output of > 500 cc / day

4.Colon cancer

5.Early initiation of dialysis (eGFR > 15)

Is Timing of Dialysis Initiation Important in

ESRD Patients?

(Controversial)

IDEAL Study: K–M Curves for Time to the Initiation of Dialysis & for Time to Death

Cooper BA et al. N Engl J Med 2010;363:609-619

• Between July 2000 & November 2008

• Australia / New Zealand• 828 adults

• Early start: eGFR 10-14 cc/min

• Late start:eGFR 5-7 cc/min

• mean age 60.4 years • 542 men & 286 women • 355 with diabetes • Median follow-up 3.6

years

Implications

• A total of 75.9% of the patients in the late-start group started dialysis when eGFR was > 7.0 cc/minute, owing to the development of symptoms!

• In this study, planned early initiation of dialysis in patients with stage V CKD was not associated with an improvement in survival or clinical outcomes (QOL)

OK to delay initiation of dialysis (eGFR < 7-10 cc/min)

Dialysis initiation should be based upon clinical factors (symptoms) rather than eGFR alone

Cooper BA et al. N Engl J Med 2010;363:609-619

Why is Residual Renal Function Important in

Dialysis Patients?

Why is baseline residual renal function important?

• Remaining GFR at start of dialysis make a significant contribution to the removal of potential uremic toxins

• Also facilitates regulation of fluid, electrolytes, and may enhance nutritional status and QOL

• Offers survival advantage in both HD and PD

Suda T et al. Nephrol Dial Transplant 2000; 15: 396Shemin D et al. Am J Kidney Dis 2001; 38: 85Szeto C et al. Nephrol Dial Transplant 2003; 18: 977

Adjusted Hazard Ratio: 0.70 (0.52-0.93) p = 0.02

Shafi T., Jaar B., et al. Am J Kidney Dis. 2010;56:348-58

Cumulative Incidence of All-Cause Mortality in 579 HD Patients by Urine Status at 1 Year (CHOICE)

Implications

• Try to preserve residual renal function in dialysis patients!

Less dietary restriction Better quality of life Better survival

• Try to avoid nephrotoxins if your dialysis patient still makes urine!

Kidney Transplantation

Principle of Kidney Transplantation

Iliac Fossa

Question 4

• Which one of the following statements is correct? (choose one answer):

1.CKD patients can be referred to a transplant center when their GFR is < 20 cc/min/1.73m2

2.Pre-emptive and live kidney transplants are associated with better graft survival

3.Most common cause of kidney transplant loss is death with a functional transplant

4.All of the above

Trends in Transplantation: patients age 20 years & older

USRDS ADR 2012

Adjusted Relative Risk of Death among 23,275 Recipients of a 1st Cadaveric Transplant

Wolfe RA et al. N Engl J Med 1999;341:1725-1730

Mange K et al. N Engl J Med 2001;344:726-731

K-M Estimates of Allograft Survival According to the Use or Nonuse of Long-Term Dialysis before

Kidney Transplantation from a Living DonorAdjusted Rate Ratio (95% CI): 0.16 (0.07–0.35)

P = 0.009

Acute Rejection within the 1st Year Post-Transplant

Patients age 18 & older with a

functioning graft at

discharge.

USRDS ADR 2012

Cumulative incidence of post-transplant diabetes

Patients receiving a first-time,

kidney-only transplant, 2003–2007 combined.

USRDS ADR 2012

Causes of Death in Kidney Transplant Patients with Functioning Graft

2006–2010

First-time, kidney-only transplant recipients, age 18 &

older, 2006–2010, who died with

functioning graft.

USRDS ADR 2012

Posttransplant Malignancy

• Risk is 4X to 100X compared rates of malignancy in the general population

• No comprehensive reporting system

• Available data suggesting 2- to 3-fold under-reporting

• The precise rate is UNKNOWN

• Accounts for 10% of deaths in kidney recipients with functioning graft

SCREENING is KEY!

Immunization for Kidney Transplant Recipients

Recommended

Influenza types A and B (yearly)

Pneumovax (every 3-5 years)

Diphteria-Pertussis-Tetanus

Haemophilus influenza B Hepatitis A and B Inactivated polio Meningococcus

Not Recommended

Varicella zoster Intranasal influenza BCG Live oral typhoid Measles, Mumps, Rubella Oral polio Yellow fever Smallpox Live Japanese B

encephalitis vaccine

Key Concepts (I)

• Kidney transplantation is the most cost-effective modality of renal replacement

• Transplanted patients have a longer life and better quality of life

• Early transplantation (before [pre-emptive] or within 1 year of dialysis initiation) yields the best results

• Living donor kidney outcomes are superior to deceased donor kidney outcomes

Key Concepts (2)

• Early transplantation is more likely to occur in patients that are referred early to nephrologists

• Refer for transplant evaluation when eGFR < 20 cc/min/1.73m2

• Success of transplantation results from a delicate balance between the suppression of the immune system to prevent rejection and the long-term side-effects of immunosuppression

Key Concepts (3)

• The most common cause of transplant loss is death with a functional transplant due to– Heart disease +++– Infections– Malignancies

• Immunosuppressants are essential to prevent immunological loss of the transplant but side effects can also lead to transplant loss

What are the Costs of the Different Renal Replacement

Therapy Modalities?

Costs (in Billion) of Medicare and ESRD Programs in 2010

488,938 ESRD patients representing less than 1% Medicare population

USRDS ADR 2012

ESRD Cost$32.9 (6.3%)

Total Medicare Costs$522.8

Total Medicare ESRD expenditures per person per year, by modality

USRDS ADR 2012

Period prevalent ESRD patients Patients with Medicare as secondary payor are excluded

$87,561

$66,751

$32,914

What About No Renal Replacement Therapy Option?

Starting Dialysis in the Elderly…Or Not?

• Among patients > 75 yrs with stage 5 CKD who chose NOT to start dialysis:– Overall, more likely to die over next 1-2 years – But if they had ischemic heart disease or other

significant comorbidity NO DIFFERENCE in survival

• Active disease management and supportive care may be appropriate without starting dialysis in the ill elderly

• Must have end-of-life discussions!

Murtagh, et al. Nephrol Dial Transplant. 2007; 22(7): 1955-1962

The Future …

• Regenerative Medicine …

• Stem Cell Therapy …

• Wearable Artificial Kidney

Thank You !

QUESTIONS?