Generalist Care for the Transplant Patient

Aleksandra Kukla, MD Assistant Professor

Renal Division and Hypertension University of Minnesota

Minneapolis, USA

Objectives

Care for transplant recipients begins before the transplant

Risk of cardiovascular disease post transplant is high

Infections and cancers are more common than in general population

Role of primary care physician in post transplant care is crucial

Care for kidney transplant recipients begins..

before transplant !

USRDS 2013 ADR

January 1, 2011 point prevalent ESRD & general Medicare patients age 65 & older. Adj: age/gender/race/ comorbidity; ref: ESRD patients, 2011.

Mortality of ESRD patients on dialysis is higher than those with cancer, diabetes and cardiovascular disease

Kidney Transplant Recipients are a unique subgroup of patients with CKD

Transplant Recipients Live Longer than Dialysis Patients

1411

6

31

22

10

Proj

ecte

d ye

ars o

f life

Waiting list/dialysis Transplant 40

20–39 40–59 60–74 Age group

Wolfe RA, et al. N Engl J Med 1999;341:1725–30

0

20

The Longer Time Spent on Dialysis, the Higher Risk of Death

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

0-6m 6-12m 12-24m 24-36m 36-48m 48+

rela

tive

risk

of d

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Meier-Kriesche et al KI Vol 58 2000 1311-1317

Time on dialysis prior to transplantation

0%

2%

4%

6%

8%

10%

0 6 12 18 24 30 36Months After Wait-Listing / Transplant

Cum

ulat

ive

Inci

denc

e

On the Waiting ListPost-transplant: Deceased DonorPost-transplant: Living Donor

AMI: Waiting List vs. Transplantation

Medicare beneficiaries listed 1995-2002 (N=53,297)

Dialysis Less than 6 Months Translates into Better Kidney Allograft Function

Meier-Kriesche HU, et al. Transplantation. 2002;74:1377-1381.

Risk of Cardiovascular Disease Post Transplant Is High

USRDS 2013 ADR

Causes of death with function, 2007–2011 Figure 7.26 (Volume 2)

First-time, kidney-only transplant recipients, age 18 & older, 2007–2011, who died with functioning graft.

Comorbid factors

Traditional Diabetes HTN Proteinuria

Non-traditional GFR Anemia Dyslipidemia Bone

disorders Other…

Cardiovascular Infections Malignancies

Top 3 causes of death in transplant recipients

Immunosuppression

Risk Factors for Coronary Heart Disease

de Mattos AM , et al. Kidney Int 2006;70:757

N=922 transplants 1993-98 N=111 CHD events (65 AMI, 18 CABG, 16 PTCA, 12 angina)

4.59 3.94 2.89 2.67 2.05 1.790.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

Adj

uste

d H

azar

ds R

atio

>1 Rejection Prior CVD Diabetes Tobacco Obesity Dialysis >1y

Adjusted for (P>0.05): transplant era, DGF, deceased donor, male, age>45, cholesterol, pulse pressure, CsA

Metabolic Syndrome in Kidney Transplant Recipients

Transplant International pages no-no, 30 APR 2012 DOI: 10.1111/j.1432-2277.2012.01488.x http://onlinelibrary.wiley.com/doi/10.1111/j.1432-2277.2012.01488.x/full#f1

Issa N, Reule S, Kukla A Textbook of Organ Transplantation 2014

PTDM

Post Transplant Diabetes

AJT 2014

Class

Principle Mechanism of

Action Example Effect on

HbA1c Adverse Effects Metabolism/ Elimination

Altered Dosing in CKD

Sulfonylureas Insulin secretagogue

Glipizide Glyburide Glimepiride

−1.0 to −2.0%

Hypoglycemia Major: Hepatic No

Meglitinides Insulin secretagogue

Repaglinide Nateglinide

−0.6% Hypoglycemia Major: CYP2C8 and 3A4

CrCl >40 ml/min: No CrCl <40 ml/min: Gradual introduction

Biguanides ↓ hepatic glucose production

Metformin −1.0 to −1.7%

Nausea Lactic acidosis

Major: Renal tubular secretion

Avoid with GFR<30

TZD ↑ insulin sensitivity Pioglitazone −1.0 to −1.9%

Weight gain Fluid retention

Major: CYP2C8 Minor: CYP3A4

No

α-Glucosidase inhibitors

↓intestinal glucose absorption

Acarbose −0.3 to −0.6%

Nausea Flatulence

Major: Fecal Minor: Renal

Not recommended if creatinine >2 mg/dl

GLP-1 receptor agonists

Stimulates glucose mediated insulin secretion; Inhibits glucagon; Induces weight loss

Exenatide −0.4 to −0.8%

Nausea, other gastrointestinal

Major: Renal Not recommended if CrCl ≤30 ml/min

DPP-IV inhibitors

Increases GLP-1 Sitagliptin −0.5% Minimal Major: Renal Minor: CYP3A4, 2C8

Dosage reduction

Kidney International 2014

Theoretically, Metformin has many advantages that should promote it as agent of choice for PTDM, but evidence is limited

It can be safely considered in post transplant recipients with stable allograft function and mGFR >30 ml/min (dose should be adjusted to kidney function)

Cessation of metformin is necessary in the context of acute allograft dysfunction

Dyslipidemia

1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

15

10

5

0

Placebo

Fluvastatin

0.5 0.0

P=0.005 ↓35%

Proportion of patients with event (%)

Cardiac Death or Definite Nonfatal MI

Years after randomization Holdaas H, et al. Lancet 2003; 361: 2024

Assessment of Lescol in Renal Transplantation (ALERT)

Statin Metabolism

Several statins are metabolized by cytochrome P450 (CYP) 3A4 cycle Atorvastatin Lovastatin Simvastatin

Other statins are metabolized by cytochrome P450 (CYP) 2C9 cycle Fluvastatin Rosuvastatin

One statin with non cytochrome P450 metabolism Pravastatin

Statin Interaction with Cyclosporine

Effects of cyclosporine on blood levels of statins in kidney transplant recipients

Statin Increase in statin AUC Atorvastatin 8 fold Simvastatin 3-8 fold Lovastatin 2-20 fold Pravastatin 5 fold Fluvastatin 2 fold Rosuvastatin 7-11 fold

Kasiske B et al. Am J Transplantation 2004; 4 (Suppl 7): 13-53 Simonson SG et al. Clin Pharmacol Ther 2004; 76: 167-77

Inhibitors of Cytochrome P450 Isoenzymes that Potentiate HMG-CoA Reductase

Inhibitors Levels Agent P450 Isoenzyme* Cyclosporine 3A4 Macrolides (erythromycin, clarithromycin) 3A4 Azole antifungals (ketoconazole, fluconazole, itraconazole, voriconazole)

mainly 3A4 and 2C9

Non-dihydropyridine calcium blockers (diltiazem, verapamil)

3A4

Amlodipine 3A4 (mainly with high dose simvastatin)

Gemfibrozil 3A4 Amiodarone 3A4 and 2C9 Omeprazole 2C9 Trimethoprim/sulfamethoxazole 2C9 Protease inhibitors 3A4

*P450 indicates the subfamily of P450 hepatic oxygenase enzyme

Issa N, Reule S, Kukla A Textbook of Organ Transplantation 2014

Dyslipidemia Dyslipidemia Goal Initiate Increase Alternative

TG>500 mg/dL with LDL <100 mg/dL

TG<500 mg/dL TLC TLC + niacin Fibrate or

statin

LDL 100–129 mg/dL

LDL< 100 mg/dL TLC TLC + low-

dose statin Ezetimibe or niacin

LDL>130 mg/dL

LDL<100 mg/dL

TLC + low-dose statin

TLC + 50% max dose statin

Ezetimibe or niacin

TG>200 mg/dL and non-HDL>130 mg/dL

Non-HDL <130 mg/dL

TLC + low-dose statin

TLC + 50% max dose statin

Ezetimibe or niacin

Riella et al. AJT 2012 TLC-therapeutic life style changes

Rhabdomyolysis with Statins Risk in general population ~ 0.44 per 10000 pt yrs Risk is 12x greater when statin is used with a fibrate FDA reports risk for patients on statin combined with CYP3A4

inhibitors ~ 26.0 per 10000 pt yrs (~ 50x higher risk) Average time on statin until rhabdomyolysis presents ~ 1 yr Risk factors for rhabdomyolysis include: advanced age (over 80 yo), women, CKD, DM, liver disease, electrolyte

disturbances, viral infections and concomitant medications 1. Graham DJ et al. JAMA 2004; 292(21): 2585-2590 2. Pasternak RC et al. Stroke 2002; 33: 2337-2341

Hypertension

Etiology of Hypertension after Transplant is Complex

Organ donor characteristics Cadaveric Hypertensive (subarachnoid bleed) Older Renal allograft dysfunction Rejection Delayed graft function Chronic allograft nephropathy (IFTA) Retained native kidneys Renal artery stenosis Medications Calcineurin inhibitors Corticosteroids

Stage eGFR

% of 559

% HTN

% Uncon-trolled

No. of Meds.

1 ≥90 2 60 10 0.7 2 60-89 22 83 36 1.3 3 30-59 60 87 36 1.7 4 15-29 14 89 59 2.2 5 <15 1 100 50 2.3

Karthikeyan V, et al. Am J Transplant 2004;4:262

Prevalence of Hypertension and Its Treatment by CKD Stage in Canadian Transplant Recipients

HTN is a risk factor for allograft loss

11.07

1.13

1.42

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

< 90 90-99 100-109 > 110

1 1.07

1.37

1.57 1.63

2.06

0

0.5

1

1.5

2

2.5

< 140 140-149

150-159

160-169

170-179

> 180

Opelz et al. for the Collaborative Transplant Study, Kidney Int 53:217, 1998

Hypertension Treatment

Should include nonpharmacologic interventions: weight reduction, exercise, dietary sodium restriction

All classes of antihypertensive medications

are acceptable and should be tailored to specific patient needs

Hypertension Dihydropyridine CCB

Commonly used as first line therapy Counteract the vasoconstrictive

effects of cyclosporine Common side effects: edema

Hypertension Nondihydropyridine CCB

Also prevent renal vasoconstriction Can have a synergistic antiproteinuric

effect when used with ACEI Increase cyclosporine levels

Hypertension ACEI/ARB

ACEI/ARB have antiproteinuric, renoprotective and cardioprotective effects

Concerns about use in early post

transplant period Common side effects: hyperkalemia,

anemia, decreased GFR

Diuretics

Can be used in kidney transplant recipients

Thazide diuretics can exacerbate

hyperglycemia, hypertyglicerydemia and hyperuricemia

Hypertension Management

Minimize prednisone & CNI Target BP <140/90 (<130/80?-KDIGO) No agent is contraindicated Most need multiple agents If all else fails consider: Graft artery stenosis Native kidney nephrectomy

Smoking

Corbett et al. Transplantation 2012

Smoking Rates of smoking in kidney transplant candidates range

between 24-30% with 90% continuing to smoke postoperatively

Smoking after transplant is associated with an increased risks

compared with nonsmokers of death-censored allograft loss (HR, 1.43; 95% CI, 1.16–1.76; P=0.001), death (HR, 2.26; 95% CI, 1.91–2.66; P<0.001)

Cancer risk is elevated by 1.12 (1.02–1.21; P=0.016) after a 10

pack-year history and by 2.56 (1.51–4.32; P=0.001) with a 25 pack-year history

Encourage Patients to Stop Smoking

AJT 2010

“Transplant-related risk factors, particularly those linked to graft function like delayed graft function, acute rejection and GFR <40 ml/min/1.73m2, explain much of the variation in CHD after kidney transplantation”

Chronic Allograft Dysfunction Has Multiple Etiologies

DGF

Nankivell et al. Lancet 2011

Approximately ¼ of Recipients Report Poor Adherence to Medications

American Journal of Transplantation Volume 9, Issue 11, pages 2597-2606, 15 OCT 2009 DOI: 10.1111/j.1600-6143.2009.02798.x

Role of Primary Care Physicians in Maintaining Good Allograft

Function

Notify transplant center about acute changes in creatinine/GFR

Treat co-morbidities Monitor for infections and malignancy Stress adherence to medications

Malignancy in Transplant Recipients

.

Chapman, J. R. et al. Nephrol. Dial. Transplant. 2007

Risk of Skin Cancers post Transplant is Very High

Skin Cancers

Encourage sun screen Advice to avoid sun exposure Dermatology referral

Copyright restrictions may apply.

Dantal, J. et al. Nephrol. Dial. Transplant. 2007 22:i4-10i; doi:10.1093/ndt/gfm085

Relative Risk of Cancer in Renal Transplant Recipients Compared with Patients on the Waiting List (all P < 0.05)

Infections

Intensity of exposure to pathogens

Net State of I.S.

•Immunosupp. Rx •Uremia •Diabetes •Neutropenia •Malnutrition •Catheters, etc

•High risk jobs •Antigen load

Infections in Transplant Recipients

Karuthu S , and Blumberg E A CJASN 2012;7:2058-2070

©2012 by American Society of Nephrology

Infections in Solid Organ Transplant Recipients

Infections in Solid Organ Transplant Recipients

Maintain high suspicion for

opportunistic infections Treat infections timely Notify transplant center

Refer to transplant center early Minimize risk of NODAT Treat dyslipidemias Treat hypertension Encourage cigarette abstinence Screen for malignancy Monitor/treat infections Stress adherence to medications

Primary Care Physician Plays a Crucial Role in Care of Kidney Transplant Recipients

Kaplan et al Death After Graft Loss: An Important Late Study Endpoint in Kidney Transplantation. American Journal of Transplantation 2002, 2 (10), 970-974.

Impact of Kidney Transplant Loss on Patient Survival

Thank You!