Post Kidney Transplant Care Management for Graft Survival: Collaboration with Primary Care Providers Dr. Tina Melanson, MD, FNKF March 27, 2014 Interventional Cardiologists.
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Post Kidney Transplant Care Management for Graft Survival: Collaboration with Primary Care Providers Dr. Tina Melanson, MD, FNKF March 27, 2014 Interventional Cardiologists Introduction Kidney transplantation is a treatment option, not a cure. Kidney transplant recipients still have chronic kidney disease (CKD). –per NKF and KDIGO ◦ All kidney transplant recipients require lifelong care due to complications of prior CKD and/or dialysis and anticipated chronic allograft dysfunction over time. ◦ Just as early diagnosis of CKD leads to improved patient outcomes, likewise early recognition of transplant dysfunction decreases morbidity and mortality and improves long term outcomes. Comprehensive care of the kidney transplant recipient should involve a multidisciplinary health care team: ◦ Transplant team providers ◦ Primary nephrologist ◦ Primary care provider Objectives Implications for the PCP include: ◦ Transplant allograft health and wellness. ◦ Awareness of immunosuppression meds: Side effects, critical drug interactions ◦ Management of acute illness in the chronically immunosuppressed patient. ◦ Long term transplant patient health maintenance: Acute or chronic allograft dysfunction Transplant infectious complications Transplant medical complications CVD HTN DM Cancer screening Other Kidney Graft Survival 100 96% 92% 90 80 70 60 59% 1 year 5 years 10 years 42% 50 40 30 20 10 0 Deceased Donor Living Donor OPTN/SRTR Report; Am J Transp Suppl 1:2012 Causes of Kidney Allograft Loss 46% graft loss due to chronic allograft failure 11% graft loss due to primary nonfunction 43% graft loss due to death of patient with functioning allograft 30% CV Disease 20% infection 10% Malignancy •Medical/surgical complications •Acute rejection •Glomerular disease oRecurrent disease oDe novo disease oTransplant Glomerulopathy •Interstitial Fibrosis and Tubular Atrophy (IFTA) oBK virus oRecurrent episodes of rejection oCNI toxicity oHTN •Other or Unknown 40% other or unknown •Arterial or venous thrombosis •Hyperacute rejection •Poor graft quality •Non-recovery of ATN El-Zoghby et al., American Journal of Transplantation 2009; 9: 527–535. Most Common Glomerular Diseases to Recur in Renal Allograft Primary Focal segmental glomerulosclerosis (FSGS) IgA nephropathy (100% after 20 years) Membranoproliferative Glomerulonephritis HUS/TTP Diabetic nephropathy Immunosuppression Nonadherence J. Sellares et al Am J of Transpl 2012:12(2)388-99. 315 transplant recipients followed median of just under three years. Duration of functioning allografts in that window ranged from 6 days to 32 years. Over that time frame 60 allografts failed. All biopsied to identify cause of failure of every graft. Biopsy info available on 56 patients. (36 Patients) J. Sellares et al, Am J of Transpl 2012:12(2)-388-99. Common Post-Transplant Immunosuppression Drug regimens vary from program to program. In general a minimum of two IS drugs, and depending on other factors (HLA matching, DSA’s, donor age, etc.) many patients require three IS drugs: ◦ Prednisone ◦ Calcineurin Inhibitors (CNI’s) (Cyclosporine, Tacrolimus) ◦ Anti-metabolites (Mycophenolate or Myfortic) ◦ mTORi’s (Sirolimus) ◦ Azathioprine Common IS Side Effects Singapuri et al, Soc of CCM, Feb 2012 Post Transplant Infectious Complications Transplant patients are more susceptible to opportunistic infections (early) AND community acquired infections (later). Greater degrees of immunosuppression may decrease rejection risk but may also increase risk and/or severity of infection. The natural inflammatory response is blunted or suppressed by immunosuppression drugs. ◦ Results in atypical presentation of common illnesses. ◦ +/- fever. ◦ S/S may be underwhelming and out of proportion to the true severity of illness. ◦ By the time fever or s/s become “classic” most infectious organism loads are very high. ◦ Remember drug interactions of common antibiotics. Infections Occurring at a Higher Incidence in Kidney Transplant Recipients Can be de novo or reactivation: ◦ ◦ ◦ ◦ ◦ ◦ ◦ BK virus (polyoma) CMV EBV HSV 1 & 2 Hep B Hep C HIV o Tb oCandida oPCP IS in the Infected Transplant Patient Holding IS in an infected patient is a judgment call. ◦ Discuss with transplant team. ◦ If patient appears toxic, or is hemodynamically unstable, it is often safe to hold at least one immunosuppressant if patient is on three drugs. ◦ Unlikely to hold all immunosuppression as revved up immune system increases risk of organ rejection at this time. NPO patients Give meds with sips of water or down NG tube. Stress doses of steroids: ◦ Hydrocortisone 100 mg iv q8h Vaccinating the Transplant Patient Vaccines are recommended in transplant recipients. Most vaccines will result in an antibody response, albeit blunted or diminished. Vaccinate for travel to endemic areas. Annual IM influenza vaccine. Pneumovax every five years post transplant. Live or Attenuated Vaccines are Contraindicated Post Transplant Intranasal influenza Live oral polio or typhoid MMR Yellow fever Small pox BCG VaricellaRecommend given pre-transplant independent of age. If given pre-, should be dosed at least thirty days prior to initiation of immunosuppression. Cytomegalovirus CMV gets special mention because of increased risk of morbidity and mortality. Usually asymptomatic but in a transplant patient can be a FUO. Colitis, esophagitis, gastritis, pneumonitis, iritis, meningitis, encephalitis, hepatitis, viremia. Can occur any time post transplant but risk is highest in the months immediate post transplant. Highest risk of acute disease is CMV + donor into CMV – recipient. Based on US Renal Data Systems, transplanted patients who develop CMV infections have a significant increased incidence of CMV disease, loss of renal transplant function, and overall costs. Even asymptomatic CMV infection is associated with relative risk of overall mortality of 2.9. ◦ One study of transplant patients who were on no CMV prophylaxis reported that CMV was detected in over 60% of patients in the first 100 days post transplant. ◦ If +D/-R the incidence was 70-90%. ◦ Therefore high incidence, high risk, and contributes to overall post transplant morbidity, mortality, and loss of allograft. CMV Prophylaxis Oral antiviral: Valganciclovir for 6-9 months post transplant Renal dosing Periodic CMV monitoring to permit prompt diagnosis and treatment Valganciclovir side effects: ◦ Leukopenia (exacerbated by active viremia and mycophenolate) Recommend decrease drug dose rather than holding or d/c’ing due to resistant disease. ◦ Anemia, Thrombocytopenia ◦ Wallet pain ($$$$) Post Transplant Medical Complications CVD New Onset Diabetes After Transplant (NODAT) HTN Dyslipidemia Malignancy Anemia Neutropenia Others Cardiovascular Disease Patients with CKD and post kidney transplant are higher risk than general population for CVD. Risk factors are inherently increased due to adverse effects of necessary immunosuppression. Pre-existing calcium and phosphorus imbalances due to CKD/ESRD cause irreversible vascular calcification. Annual rate of fatal or non-fatal CV events in kidney transplant patients is 50-fold higher than the general population. CV Mortality Rate by Age Group Jardine et al, Lancet 2011; 378: 1419 Risk Factors for CV Disease in Kidney Transplant Recipients oImmunosuppressive Drugs •Hyperlipidemia •Hypertension •Hyperglycemia oPoor allograft function oProlonged Pre-transplant Dialysis oBone and Mineral Disorders Smoking Aging NODAT Incidence of NODAT is highest in the first three months after transplant. Cumulative incidence of NODAT by the end of the first year is 10-30% in adults on tacrolimus/CsA and corticosteroids. Weight gain post transplant is common due to steroids and general improved sense of well being (compared to dialysis). MOA for corticosteroids: ◦ Aggravation of insulin resistance ◦ Several studies have displayed deleterious effects on insulin secretion and beta-cells ◦ Increased gluconeogenesis MOA for calcineurin inhibitors: ◦ Decreased insulin secretion ◦ Direct toxic effect on the pancreatic beta-cells causing decreased insulin production ◦ Increased apoptosis of beta-cells Prevalence of Transplant-Associated Hyperglycemia 24% 31% NODAT Impaired Glucose Tolerance Normal Glucose Tolerance 45% n = 114 kidney recipients without prior DM 1 year after transplant Nam et al. Transplantation 2001; 71:1417-23. Effect of NODAT on Mortality NODAT/PTDM IGT NGT IFG Valderhaug et al. and Springer Science Business Media; Ref. 21. CV Events and Transplant Associated Hyperglycemia NGT IFG NODAT Cosio et al. Kidney Int 2005; 67:2415-21. Risk Factors for NODAT Cosio et al, 2001. Kasiske et al, 2003. Pham et al, 2007. Post-Transplant HTN Occurs in more than 2/3 of transplanted patients at one year. Pathogenesis: ◦ ◦ ◦ ◦ ◦ ◦ IS drugs (CNI’s, steroids) Allograft dysfunction Pre-existing HTN Obesity Donor Factors: age, sex, h/o HTN Transplant renal artery stenosis Post-Transplant HTN is a risk factor for CVD, but also for renal allograft dysfunction. Graft Survival and HTN Post-Transplant Mahendra et al, Am J Kid Dis 2011: 57(2); 331-41. Dyslipidemia Affects more than 50% of transplant recipients. CsA > tacrolimus; steroids; **sirolimus (hypertriglyceridemia). Recall the FDA warning in 2011: Simvastatin is contraindicated in patients on CsA due to increased risk of rhabdomyolysis. ◦ Less risk with tacrolimus but all statin doses should be considered to be decreased in the presence of CNI’s. *Safer statins: Fluvastatin, Pravastatin, Rosuvastatin (also known to cause proteinuria). Post Transplant Malignancy All chronically immunosuppressed patients are at increased risk of malignancy. Screening for breast, cervical, colon, and prostate cancer are at intervals as recommended by standard guidelines. Non-melanoma skin cancers are especially common and annual dermatology evaluation is recommended. Cancers Occurring at a Higher Incidence in IS Patients Compared to Standard Population Kaposi’s Sarcoma Vaginal NHL Kidney (native & tx) Lip Thyroid Small intestines Penis Oral Esophagus Bladder Leukemia Squamous cell of skin Virus Related Cancers Infectious Agent Viral-Associated Cancers Epstein-Barr Virus Lymphoproliferative Disorders Hep B, Hep C Viruses Hepatocellular Carcinoma Human Herpes Virus 8 Kaposi Sarcoma Human Papillomavirus Cervical, vaginal, penile, anal, tongue, mouth and throat cancers Merkel Cell Polyoma Virus Merkel Cell Carcinoma Engels et al, JAMA 2011. Post Transplant Bone Disease Results in higher fracture risk. Multifactorial etiology: ◦ Pre-existing/residual secondary HPTH due to PT gland hyperplasia (renal osteodystrophy) ◦ Steroids (osteopenia, osteoporosis) ◦ Vitamin D deficiency (rickets) ◦ Calcium and phosphorus imbalances pre-transplant (osteomalacia) Treatment: ◦ Calcium and Vitamin D supplementation ◦ Bisphosphonates when indicated ◦ Cholecalciferol (calcitriol and other vitamin D analogues) Monitoring: ◦ Dexa per guidelinesit is impossible to discern renal bone disease from osteoporosis on bone density testing. ◦ Role of bone biopsy? Do not forget AVN hips secondary to steroids ◦ New onset hip, groin, thigh, or buttock pain Post Transplant Weight Gain 50% of transplant patients are obese or morbidly obese. There is little evidence that decreasing maintenance steroid doses will result in significant weight loss. Herbal treatments for weight loss (St. John’s wort) and Orlistat are contraindicated in transplant patients. Weight gain exacerbated by depression: ◦ Depression and anxiety are more common in kidney transplant patients than the general population. ◦ Depression increases the risk of medication noncompliance. Routine Visits to PCP are Important Opportunities to Re-educate Transplant Patients to: Promptly report wounds, injuries, URI and UTI symptoms. Inform provider well in advance of planned travel. Maintain good hygiene around pets. Frequent hand washing. Avoidance of people with acute contagious illness. Avoidance of secretions from recently live vaccinated children. Review mental health status. DEET containing bug spray in warm months to prevent West Nile Virus. Routine Re-education, cont. Sunscreen application, long sleeves, hats, etc. Review risk of non-adherence to medication therapy, scheduled labs and appointments. Pregnancy/birth control in women of child bearing age. ◦ Incidentally all pregnant women on immunosuppressant should be followed closely by the transplant team and high risk OB. ◦ Mycophenolate is absolutely contraindicated in pregnancy. ◦ Mycophenolate can lower the efficacy of OCP’s. Barrier methods of birth control in sexually active patients with high risk behaviors. Foods to avoid: ◦ ◦ ◦ ◦ ◦ Raw or undercooked eggs and foods that contain them Raw or undercooked meats, poultry, fish and shellfish Raw oysters Unpasteurized milk , cheeses, juices, and cider Raw sprouts, such as alfalfa and bean Summary Post kidney transplant patients are still considered to have CKD, and therefore, like CKD patients, warrant close attention to complications unique to renal failure in addition to chronic immunosuppression. Remember the key drug interactions with immunosuppressants when prescribing antibiotics and antihypertensive agents. CVD, although less common in transplanted patients versus those on dialysis, remains the most common cause of death in this population. Common illnesses may present with uncommon symptoms. Vigilant post transplant health maintenance can decrease morbidity and mortality and improve overall outcomes. Collaboration with the transplant program, primary nephrologist and the PCP enhances post transplant health maintenance delivery.