Medical Complications of Renal Transplantation

1. Medical Complications of Renal Transplantation Thitisak Kitthaweesin,MD.

2. Main topics • Infectious complications • Cardiovascular complications • Lipid abnormalities after KT • Post transplant DM • Parathyroid and mineral metabolism • Post transplant erythrocytosis • Malignancies associated with Tx

3. Infectious complications • General principles of transplant infectious disease • Diagnosis of infection • Management of infection in transplant recipient • Infection of particular importance in transplant recipient

4. General principles • Microorganism causing infection in transplant recipient • True pathogens • Influenza,typhoid,cholera,bubonic plague • Sometime pathogens • S.aureus,normal gut flora • Nonpathogens • Aspergillus fumigatus,cryptococcus neoformans HHV-8

5. General principles • Risk of infection in transplant recipient is determined by 3 factors • Epidemiologic exposure • The net state of immunosuppression • The preventative antimicrobial strategies • Timetable for posttransplant infections • The first rule of transplant infectious disease is that infection is far better prevented than treated

6. Epidemiologic exposure • Exposures within the community • M.tuberculosis • Geographically restricted systemic mycoses • Blastomyces , Histoplasma capsulatum, Coccioides immitis • Strongyloides stercoralis • Community-acquired respiratory dis. • Influenza, Parainfluenza,RSV,Adenovirus • Infections acquired through ingestion of contaminated food/water –Listeria, Salmonella sp. • Community-acquired opportunistic infection • Crypto.neoformans,Aspergillus,Nocardia,PCP. • Viral infections • VZV,HIV,HBV,HCV. • Exposures within the hospital

7. Epidemiologic exposure • Exposures within the community • Exposures within the hospital • Environmental exposures • Aspergillus species • Legionella species • P.aeruginosa and other gram negative bacilli • Person to person spread • Azole-resistant Canidida spp. • MRSA. • VRE. • C.difficile • Highly resistant gram negative bacilli

8. The net state of immunosuppression • Dose,duration,and temporal sequence of immunosuppressive drugs • Host defense defects caused by underlying diseases • Presence of neutropenia,defect in mucocutaneous barrier or indwelling of FB. • Metabolic derangements • PCM,uremia,hyperglycemia • Infection with immunomodulating viruses: • CMV,EBV,HBV,HCV,HIV

9. Timetable for posttransplant infection • Infection in the first month • Infection conveyed with a contaminated allograft • Infection caused by residual infection in the recipients • >95% of the infections are the surgical wound,urinary,pulmonary,vascular access,drain related • Key factors:nature of operation and technical skill

10. Timetable for posttransplant infection • Infection in 1-6 months posttransplant • The immunomodulating viruses • Particular CMV • but also EBV,HHV,HBV,HCV,HIV • opportunistic infection due to • P.carinii • Aspergillus sp. • L.monocytogenes

11. Timetable for posttransplant infection • Infection more than 6 months posttransplant • The >80% of patients with good result (good allograft function,baseline immunosuppression) • Community-acquired resp.viruses • Urinary tract infection • The 5-15% with chronic or progressive infection • HBV,HCV,EBV..chronic hepatitis, progression to end stage liver disease and HCC. • The 10% with poor results (poor allograft function,excessive immunosuppression,chronic viral infection) • PCP,Cryptococcus,Listeria monocytogenes,Aspergillus

12. Usual sequence of infection posttransplant

13. Diagnosis of infection • Radiological diagnosis • CT.chest and brain for early diagnosis and treatment • Pathological diagnosis • Need for biopsy • Microbiological diagnosis • Isolation and identification of microbial species from appropriately obtained specimens • Immunologic methods • Microbial antigen detection • Microbial DNA detection by PCR technique

14. Principle of Antimicrobial Therapy

15. Strategies for antimicrobial therapy • There are three different modes of use • Therapeutic mode • Curative treatment for established infection • Prophylactic mode • Prescribed to entire patients before an event to prevent a form of infection that is important to justify ie. intervention • Preemptive mode • Prescribed to subgroup of patients that high risk for clinical significant disease

16. Strategies for antimicrobial therapy • Prophylactic strategies • Low-dose TMP/SMX • Effective against Pneumocystis,Nocardia,Listeria,urosepsis and perhap,Toxoplasma • Perioperative surgical prophylaxis • Protects against wound infection • Oral gancyclovir,valacyclovir • Effective against CMV disease

17. Strategies for antimicrobial therapy • Preemptive strategies • Appropriate antibacterial or antifungal therapy in ass.with surgical manipulation of an infectedsites…protect against syst.disseminated • Fluconazole therapy of candiduria .. protect against obstructing fungal balls and ascending infection • Intravenous followed by oral ganciclovir in CMV seropositive patient treated with ALG…protect against symptomatic CMV disease • Monitoring bloood for CMV by antigenemia or PCR,with preemptive ganciclovir therapy once a threshold level of viral reached…protect against symptomatic CMV disease

18. Infection of particular importance in transplant recipients

19. Cytomegalovirus • CMV ..evidence of replication 50-75% in transplant recipients • CMV infection • Seroconversion with the appearance of anti-CMV IgMAb • Detection of CMV Ag in infectious cells • Isolation of the virus by C/S of throat,buffy coat or urine

20. CMV disease • Requires clinical signs &symptoms ie. severe leukopenia or organ involvement (hepatitis,pneumonitis,colitis, pancreatitis,menigoencephalitis and rarely myocarditis) • Rare feature is progressive chorioretinitis

21. The manifestation of CMV in transplant recipients • Direct manifestations • Mononucleosis • Leukopenia/thrombocytopenia • Tissue invasive dz. • Indirect manifestation • Depression of host disease • Allergy injury & rejection • Increase the risk of PTLD 7-10 fold

22. Risk of clinical CMV diseaseis determined by 2 factor • Serological status of donor and recipient • Nature of the immunosuppressive therapy

23. Role of CMV infection in transplant recipient

24. Prophylactic therapy • Gancicovir = propylactic therapy of choice • IV • Oral • IV followed by oral • Antiviral therapy • Significant decrease CMV disease and infection • Both antiviral agent asso.with a decrease in disease • Only ganciclovir decrease the risk of infection

25. CMV-positive donorCMV-negative recipient(D+/R-) • 70-90% will develop primary CMV infection • 50-80% will have CMV disease • 30% will develop pneumonitis • Absence of propylactic Rx..mortality rate 15% • Conventional…grade B • Immunosuppression with ALA…grade A • Ganciclovir 1000 mg TID orally 5 mg/kg BID IV. IV. Dose daily x 3 wks. –switch to oral 2-12 wks. With ALA IV. 1 month followed by oral 2 months

26. CMV-negative donor CMV-positive recipient (D-/R+) • Reactivation of latent CMV infection • CMV infection/disease… 20% • Pneumonitis is rare • Antiviral propylaxis recommended for pt. who receive immunosuppression with ALA (grade A) or conventional imm.supp. (grade C)

27. CMV-positive donor CMV-positive recipient(D+/R+) • Risk for reactivation of latent virus and superinfection with new strain • Worst graft and pt.survival at 3 yrs. Post Tx • Antiviral prophylaxis in imm.supp. with ALA (grade A) or conventional Rx (grade C)

28. CMV-negative donor CMV-negative recipient(D-/R-) • Low prevalence of disease • No antiviral prophylaxis therapy was recommended

29. Treatment • Varied with severity of dz. • Mononucleosis-like syndrome • Resolve without antiviral drug • Stop OKT3, AZA & stop if Wbc<4000 • Organ involvement • 2-3 wks. Ganciclovir, +/- hyperimmune globulin • Usual dose 5 mg/kg Q 12 hr.

30. EBV • Possible clinical consequens of EBV replication • Mononucleosis syndrome • Meningoencephalitis • Oral hairy leukoplakia • Malignancies…smooth m.tumor,T-cell lymphoma,PTLD • Active replication …20-30% …of pt.+conventional Rx >80% …of pt.+ALA

31. EBV • Critical effect…its role in pathogenesis of PTLD usually B cell (benign polyclonal to malignant monoclonal lymphoma) • Factors that increase risks of PTLD • High viral load • Primary EBV infection • High dose immunosuppression…ALA, High dose CsA&Tacrolimus, Pulse steroids or in combination • Type of organ Tx • CMV infection

32. EBV • EBV infection • Latent form(great majority) • Not susceptible to antiviral Rx • Replicative form • Susceptible to antiviral Rx • Antiviral therapy alone unlikely to be effective

33. Other viral infections • VZV. • Primary infection with VZV in Tx pt can be severe candidates…screened for AB+Rx with zoster Ig • Reactivation dz…relatively benign typical zoster involve few dermatome in 20-30% pt. , antiviral Rx not always needed

34. HSV • Occur in 50% of pt. • Lesions usually…ulcerative > vesicular • Recurs more often & acyclovir often beneficial • Dual infection with HSV + CMV can be RX with ganciclovir alone • HIV • Tx of organ from HIV-infection donor…transmit virus 100%

35. HHV-6 • Found in blood 30-50% of pt. • Often asso.with CMV viremia • Clinical effects…mononucleosis , allograft dysfunction,prolonged hospital length of stay,inv.pneumonia,encephalitis • Combined infection with HHV-6 & CMV…more severe • Ganciclovir susceptible • HHV-8 • Putative agent of Kaposi’s sarcoma

36. Bacterial infection • UTI • Common after renal Tx • Prevalent within the first post Tx year • Most case inv. Gram negative organisms • Risk factor • Indwelling,trauma to kidney and ureter during Sx • Anatomic abnormalities of native or TX kidneys • Neurogenic bladder • Rejection and immunosuppression

37. Pathogens…similar to general population • E.coli , Enterococci , P.aeruginosa , C.urealyticum • UTI in first few months after Tx …frequently asso. with pyelonephritis or sepsis ,may be asso. with allograft dysfunction and may predispose to develop acute rejection

38. Recommendation… • low-dose TMP/SMX minimum 4 month (most centers prophylasis for 1 year) provides prophylaxis against P.carinii,Nocardia asteroides and L.monocytogenes Pt.with Hx allergy to TMP/SMX…oral quinolones

39. Opportunistic bacterial infections • Three important opportunistic bacterial infection in first year post Tx • L.monocytogenes • N.asteroides • M.tuberculosis

40. Fungal infection • Disseminated infection • Primary infection/reactivation • Dimorrphic fungi(histoplasmosis,blastomycosis,coccidioidomycosis) cause asymptomatic or limited infection in normal host • Invasive infection • Candida sp.,P.carnii,Aspergillus sp. • C.neoformans, Mucor sp.

41. Candida • Mucocutaneous overgrowth can be prevented by Rx of high risk pt. with nystation oral wash • Candiduria should be treated with fluconazole or low-dose IV. Ampho.B with/without flucytosine • Dissemination dz…Ampho-B or fluconazole • Life-threatening infection…Ampho-B probably more effective • Liposomal Ampho-B…less nephrotoxic,similar efficacy

42. Cardiovascular complication of Transplantation

43. Cardiovascular complication of Transplantation • Cardiovascular dzis very common Incidence new IHD events…11.1% (among pt without Hx IHD) during 46+ 36 mo. F/U • Celebrovascular Dz…6.0% (among pt without prior Hx) • CVD 5 fold > pt. similar age &gender • Cumulative incidence • IHD 23% in 15 yrs • CVA 15% in 15 yrs • PVD 15% in 15 yrs

44. Pretransplant CVD • Pre Tx CVD is an important risk factor for post Tx CVD • IHD often asymptomatic in ESRD patients • Asymptomatic CAD pt who underwent revascularization had sig. fewer IHD event after Tx • High risk pt would benefit from screening &Rx asymptomatic IHD as part of preTx evaluation • Recommendation…high risk pt should undergo a cardiac stress test (Dobutamine stress echo/Radionuclude stress test)

45. HT after renal Tx • Major risk factor for graft survival Occur in 60-80% of pt. • Prevalence was low in… • pt.who received LRKT • bilateral nephrectomy • stable Scr < 2 mg/dL

46. Pathogenesis • Acute allograft rejection • Chronic allograft rejection • Cadaveric allografts esp. from a donor with FHx of HT • High renin state from diseased native kidney • Immunosuppressive therapy such as Cyclosporine,Tacrolimus and corticosteroid • Increase BW • Hypercalcemia • New onset essential HT

47. #Suggestive evidences: transplant kidney may have prohypertensive or antihypertensive properties #Experimental models of genetic HT the inherited tendency to HT resides primary in the kidney #Study of 85 pts: BP+antiHT requirement occur more frequently in recipient from normotensive family received a kidney from donor with HT family

48. Role of corticosteroid • Usually not a major risk factor for chronic HT in Tx recipients because of rapid dose reduction

49. Role of cyclosporine • Vasoconstrictive effect HT volume dependent > renin dependent • Increased systemic and renal vascular resist. (primary affecting afferent arteriole) • Increase vascular resistance….inadequate relaxation>active vasoconstriction • Release of vasoconstrictor “endothelin” • Endothelial injury leading to  generation of NO. • Sympathetic activation…additional factor • Mild hypo Mg,affected intracellular Ca-binding protein…increase vascular tone

50. RAS • Functional significant stenosis occur in 12% of recipients with HT • Correctable form of HT • Renal arteriography…procedure of choice for Dx RAS in solitary Tx kidney • Renal allograft Bx prior to angiography to R/O chronic rejection or other renal parenchymal dz