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Medical Complications of Renal Transplantation

Medical Complications of Renal Transplantation. Thitisak Kitthaweesin,MD. Main topics. Infectious complications Cardiovascular complications Lipid abnormalities after KT Post transplant DM Parathyroid and mineral metabolism Post transplant erythrocytosis Malignancies associated with Tx.

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Medical Complications of Renal Transplantation

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  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

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