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
• gt95 of the infections are the surgical
  wound,urinary,pulmonary,vascular access,drain
  related
• Key factorsnature 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 gt80 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,Aspergillu
  s

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,u
  rosepsis 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 infected
  sites 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 reachedprotect 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
• Conventionalgrade B
• Immunosuppression with ALAgrade 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 Wbclt4000
• 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
• Malignanciessmooth m.tumor,T-cell lymphoma,PTLD
• Active replication
  20-30 of pt.conventional Rx gt80 of pt.ALA

31
EBV

• Critical effectits 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 immunosuppressionALA, High dose
  CsATacrolimus, 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
  candidatesscreened for ABRx with zoster Ig
• Reactivation dzrelatively 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 gt 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 donortransmit
  virus 100

35

• HHV-6
• Found in blood 30-50 of pt.
• Often asso.with CMV viremia
• Clinical effectsmononucleosis , allograft
  dysfunction,prolonged hospital length of
  stay,inv.pneumonia,encephalitis
• Combined infection with HHV-6 CMVmore severe
• Ganciclovir susceptible
• HHV-8
• Putative agent of Kaposis 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

• Pathogenssimilar 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/SMXoral 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,coc
  cidioidomycosis)
• 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 dzAmpho-B or fluconazole
• Life-threatening infectionAmpho-B probably more
  effective
• Liposomal Ampho-Bless nephrotoxic,similar
  efficacy

42
Cardiovascular complication of Transplantation
43
Cardiovascular complication of Transplantation

• Cardiovascular dz is very common Incidence new
  IHD events11.1 (among pt without Hx IHD) during
  46 36 mo. F/U
• Celebrovascular Dz 6.0 (among pt without prior
  Hx)
• CVD 5 fold gt 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
• Recommendationhigh 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 lt 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
• ?BPantiHT 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 gt renin dependent
• Increased systemic and renal vascular resist.
  (primary affecting afferent arteriole)
• Increase vascular resistance.inadequate
  relaxationgtactive vasoconstriction
• Release of vasoconstrictor endothelin
• Endothelial injury leading to ? generation of NO.
  
• Sympathetic activationadditional factor
• Mild hypo Mg,affected intracellular Ca-binding
  proteinincrease vascular tone

50
RAS

• Functional significant stenosis occur in 12 of
  recipients with HT
• Correctable form of HT
• Renal arteriographyprocedure 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

51
Treatment

• Patient with CsA
• Reduced CsA dose
• If permanent HTstart CCB,diuretic
• Preventionfish oil 4 gm/day
• Patient without CsA
• Start anti-HTCCB ,ACEI,beta blocker diuretic
• Resistant HT patient should undergo renal
  arteriography to exclude RAS

52
Lipid abnormalities after renal Tx

• Prevalence 16-78 of recipients
• Reported change in serum lipidelevation in both
  cholesterol and triglyceride
• Elevated LDL and apo-B level are common
• Low HDL reported in some studies
• Hypercholesterolemia occurs within 6 months
• Hypertriglyceridemia.. peak incidence at 12 mo
  and correlated with excessive BW, elevated Scr

53
Lipid abnormalities after renal Tx

• Post Tx lipoprotein abnormalities may contribute
  to the development of CVD and PVD
• Expected correlation between high lipid level and
  cardiovascular mortality
• Increased serum triglyceride implicated as
  predictor of chronic renal allograft failure

54
Contributing factors

• Excessive wt.gain
• High fat diets
• Use of diuretic, beta-blockers
• Genetic susceptibility

• High steroid dose
• CsA / FK506
• DM.
• Nephrotic syndrome

55
Pathogenesis

• Multifactorial
• Correlate with corticosteroid dose cyclosporine
• Steroid withdrawal association 17 decreased in
  total chol. Level
• Pt. With CsA ...chol 30-36 mg/dl gt pt. with AZA
  pred.

56
Corticosteroid

• Peripheral insulin resistance
• Hyperinsulinemia
• ?Hepatic VLDL synthesis
• ? ACTH release
• Administration of ACTH 3 weeks
  ? TC,LDL,TG ? HDL
• ACTH may act by upregulate LDL receptor activity
• Steroid may be not benefit to lipid metabolism in
  pt with CsA

57
Cyclosporine

• Dose-dependent
• Correlation between Blood CsA level and degree of
  hypercholesterol
• CsA pt. have higher TG Lp(a) gt AZA
  prednisolone
• CsA induced hypoMg ..contribute to
  hypercholesterol

58
Tacrolimus

• Similar to but less pronounced than CsA
• LDL,Lp(a),fibrinogen levellower in FK506
• may be asso.with lower serum TC
• substitution of tacrolimus for CsA may improved
  lipid profile

59
Treatment

• Dietary modification
• Weight reduction in obesed pt.
• Corticosteroid dose reduction
• Drug therapy
• unclear role
• shoud not be describe early when GCs dose are
  relative high
• drug-induced complications

60
HMG-CoA reductase inhibitor

• More likely to induce rhabdomyolysis in pt with
  CsA
• CsA decreased hepatic met. of drug
• Low dose regimen may allow to be used
• Pravastatin..less muscle toxic,FDA approved
• Fluvastatin..may also have less adverse effects

61

• Low-dose therapy with statin considered in
• stable patient 8 months after Tx
• total chol gt 240 mg/dL
• LDL chol gt 160 mg/dL
• patient with other CV risk factors may be Rx if
  LDL 130-160 mg/dL

62
Benefits of HMG CoA reductase inhibitor

• Lower risk of rejection
• Katznelson et al.Transplantation,1996
• Lower incidence of chronic rejection
• Improved graft survival
• Kobashigawa et al.N Engl J Med,1995

63
Post-transplant DM

• Incidence
• PTDM varied from 2-46
• variation in criterias
• Etiology and Pathogenesis
• onset of PTDM is related to immunosuppressive Rx
• occur mostly in first year
• exogenous glucocorticoid in predisposed
  individuals

64

• Glucocorticoid ..impair both hepatic
  extrahepatic action of insulin
• post receptor insulin resistance
• impaired phase1,2 and glucagon mediated insulin
  secretion
• Cyclosporine..interfere with glucose metabolism
• accum in panc islet cell..?insulin secretion
• FK506..glucose intolerance more often
• unclear mechanism..dampen insulin secretion (
  Filler et al.NDT2000 )

65
Risk factors for PTDM

• Obesity
• black
• age gt 40 years
• first-degree relative with DM
• HLA A28,A30,BW42
• CDKT
• Steroid / FK506

66
Clinical features

• Incidencenot related to renal dz, number of
  rejection or graft function
• peak onsetduring the first year (2-3moths)
• majorityasymptomatic,hyperglycemia on blood test
• 40-50 require insulin therapy

67
Prevention/Management

• Patient education
• dietary management
• exercise
• insulin
• oral hypoglycemic agents

• Screen for and treat microalbuminuria and
  hyperglycemia
• regular ophthalmologic and podiatry exam

68
Go to.. Medical complication of Renal
transplantation Part II
69
Parathyroid and Mineral metabolism after Renal
Transplant
70
Successful KT

• Normalize urinaryP,beta-2 microglobulin excretion
• Normalize renal calcitriol production
• Reverse many abnormalities
• lower P to normal
• lower PTH level
• lower plasma AP
• mobilization of soft tissue calcification
• improvement in Al-bone dz
• prevention of progression of amyloid
  osteodystrophy

71
Primary abnormalities that can persist after KT

• HyperPTH
• Aluminum and beta2-microglobulin accumulation
• Adynamic bone disease
• Osteopenia
• Osteonecrosis

72
HPTH and Hypercalcemia

• 1 in 3 of pt have persistent PTH hypersecretion
• development of hyperCa related to duration of
  dialysis and parathyroid gland size, secondary to
  hyperplasia of gland gt hypersecretion of cells
• other factors
• resorption of soft tissue Ca-P deposits

73
HPTH and Hypercalcemia

• other factors
• resorption of soft tissue Ca-P deposits
• normalization of calcitriol production
• ?PTH effect on bone
• direct enhance GI.calcium absorption
• increased plasma albumin
• ?total plasma Ca via ?binding
• no effect on ionized Ca concentration

74
HPTH and Hypercalcemia

• Plasma Ca begin to rise in first 10 days after Tx
  and can be delayed for 6 months or more
• patients with preexisting severe secondary
  HPTHacute severe hypercalcemia after KT, can
  cause acute allograft dysfunction and rarely
  calciphylaxis

75
Treatment

• Persistent HPTHgenerally asymptomatic
• Hypercalcemiausually resolves spontaneous over 6
  months to as long as 2-3 years
• Conservative Rx with oral P supplement until
  plasma PTH low enough to normalize Ca/P balance

76
Parathyroidectomy

• Severe symptomatic hyperCa
• usually in early period
• Persistent hyperCa
• 4-10 after 1 year
• Elective parathyroidectomy
• if plasma Ca gt 12.5 mg/dL more than 1 year esp.
  if asso.with radiologic evidences of increased
  bone resorption

77
Aluminum toxicity

• KT quickly reverses factors leading to Aluminum
  accumulation
• more effective than desferoxamine therapy in
  lower serum and bone Al level

78
Hypophosphatemia

• Persistent hypo P 20-35
• Induced by P wasting in urine due to HPTH and PTH
  independent pathway
• Treatment
• phosphate supplement
• except in patients with persistent HPTH
  phosphate can exacerbate HPTH by complex with Ca
  and lowering GI calcium absorption

79
Dialysis-related Amyloidosis

• Primarily induced by beta2-microglobulin deposits
• Articular symptoms asso.with disorder rapidly
  improve after KT
• new cystic lesions unusual
• resolution of existing cystsrare

80
Post-transplant Bone disease

• Osteopenia
• Osteonecrosis
• Contributing factors
• persisting uremia-induced abnormal calcium
  homeostasis
• acquired defects in mineral metabolism induced by
  immunosuppressive Rx

81
Osteopenia

• Higher risk for pathologic Fx
• Prevalence of atraumatic Fx in KT may be as high
  as 22
• Primary site High cancellous bone vertebrae and
  ribs
• Bone loss occurs early and rapidly postKT1.6
  per month in first 5 mo
• After early periodbone loss continue at slower
  rate1.7 per year

82
Pathogenesis

• postTx bone loss inv.both HPTH and effect of imm
  supp drugs
• GCs-induced suppression of bone formation most
  important factor
• steroids
• direct toxic to osteoblast
• increase osteoclast activity
• Promote Ca loss by decrease GI
  absorption,gonadal hormone, IGF-1production and
  sensitivity to PTH

83
Monitor

• BMD.of hipspine prior to Tx and 3 mo following
  KT using DEXA
• Rapid bone loss and/or low initial BMD should be
  considered to Rx
• No information regarding the effects of Rx to
  prevent bone loss in KT patients

84
Treatment

• Lowest dose of prednisolone compatible with graft
  survival
• Calcium supplementation 1000 mg/day
• Vit.D analog can improve Ca absorption
• Calcitonin or bisphosphonateif bone loss is
  severe and/or rapid esp. during first 6 months
  after Tx

85
Osteonecrosis

• Non-infectious death of marrow cell and
  asso.trabeculae,osteocytes
• Weight bearing long bonemost often affected esp.
  Femoral head
• Usually multifocal may develop at any time after
  Tx
• Incidence15 within 3 years

86
Osteonecrosis

• Direct asociated with
• glucocorticoid exposure
• cyclosporine
• number of tx
• HPTH
• low bone mass
• fracture

87
Pathogenesis

• GCs
• increase intramarrow pressure
• increase adipocyte hyperplasia
• fat embolism
• microfracture
• compromised vascular supply

88
Diagnosis

• Painpredominant symptom
• Higher risk of Fx
• Arthritis.secondary to joint deformation
• Change in density of necrotic bone
• 10-14 days
• Radiolucent band
• 6-8 weeks
• MRImost sensitive

89
Treatment

• No effective medical Rx
• reduction of steroid dose has little effect once
  osteonecrosis developed
• Surgical Rx
• vascularized bone grafts and core decompression

90
Bone Pain

• Occur only in patients received CsA
• often temporally related to higher level
• Mechanism
• intraosseous vasoconstriction and HT
• Treatment
• CCB..nifedipine SR 30-60 mg,Hs completely
  relieve symptom

91
Erythrocytosis following KT

• PostTx erythrocytosis (PTE)
• Hct gt 51 on two or more consecutive
  determination (Gasten et al.1994)
• affect 10-15 of KT patients
• most often within the first 2 years

92
Etiology and pathogenesis

• Early case reported ..PTE caused by renal
  ischemia from RAS
• Risk factors
• smoking
• DM.
• Rejection-free course
• not RAS
• EPO factorexcess EPO release from native kidney

93
Etiology and pathogenesis

• Non-EPO factors
• enhance sensitivity to EPO
• directly promote erythrocytosis
• IGF-1,IGF-BP,GH..enhance.erythrocytosis
• Angiotensin II
• ACEI,ATRAinhibit erythrocytosis
• activation of AIIreceptor
• may enhance EPO production in the graft or
• increased Rbc precursor sensitivity to EPO

94
Treatment

• ACE inhibitor
• low dose..enalapril 2.5mg twice a day
• lower Hct to normal or near normal level
• effect begin within 6 weeks
• complete effect in 3-6 months
• some pts..asso.ACEI lower Hct and plasma EPO
  level (initially normal or elevated EPO level)

95
Treatment

• AT1receptor antagonists
• Losartan 50 mg/day
• decrease Hct 53 to 48 in 8 wks
• Theophylline
• 8 weeks course,decrease Hct from 58 to 46,as
  much as 10-15
• Act as adenosine antagonist facilitate release
  and BM.response to EPO

96
Recommendation

• ACEI and ATRA
• Losartan 50 mg/day may be increased to 100
  mg/day, if no response within 4 weeks or BP
  remain elevated
• If no adequate lowering of Hct after another 4
  weeks,enalapril 10-20 mg/day or another ACEI
  continue Rx for PTE indefinitely

97
Malignancies associated with Transplantation
98
Malignancies associated with Transplantation

• Cincinnati Transplant Tumor Registry(CTTR)
• Average age 41 years,average time of appearance 5
  years after Tx
• Most striking malignancies
• CA.skinlip,PTLD,Kaposis sarcoma,Renal CA
• CA.uterine cervix,anogenital CA,Hepatobiliary CA
  and Sarcoma
• No increase in the incidences of common tumor in
  general population
• CA.lung,breast,prostate,colon

99
CA. Skin Lips

• Skin cancermost common,38
• Incidence increased with length of F/U
• Appeared on sun-exposed area (light skin,blue
  eyes,blond hair)
• Pt age gt40 yrslesion occurred on the head
• Younger ptslesion mainly on dorsum of
  hand,forearm,chest

100
CA. Skin Lips

• General populationBCC gt SCC
• Renal TxSCC gt BCC
• SCC
• old age in general population
• 30 years younger in Tx pts.
• Aggressive SCC
• Heavy sun exposed area
• Older individual
• Multiple lesions
• Located on the hand
• Histothick tumor involve subcutaneous tissues

101
CA. Skin Lips

• Contributing factors
• Immunosuppressed state
• Exposure to sunlight
• Disagreement about papilloma virus
• HLAA11-protect /B27,DR7-high risk!
• No relation to any immunosupp agents
• Treatment
• Surgical excision
• Retinoids,topical
• Rx solar keratosis,?risk of CA
• Retinoids,systemic
• ?incidence in small group

102
Lymphoma lymphoproliferations

• PTLDPost-Transplant Lymphoproliferative Disorder
• Benign hyperplasia.. to ..malignant lymphoma
• 86B cell in origin
• Classification of PTLD

103
Lymphoma lymphoproliferations

• Predisposing factors
• Intense immunosuppression
• Non renal allograft recipients gt renal recipients
• EBV infection
• 90-95 of PTLDpositive for EBV
• Risk factorSeropositive at time of Tx

104
Lymphoma lymphoproliferations

• Clinical manifestation
• Asymptomatic
• Mononucleosis-like
• Fever,night sweat,URI,weight loss,diarrhea,
  abdominal pain,lymphadenopathy,tonsillitis
• Intestinal perforation,GI bleeding,obstruction
• Lung lesions,renal mass
• Imitating allograft rejection

105
Lymphoma lymphoproliferations

• Treatment
• Localized diseaseexcision,radiation
• Extensive diseasestop all imm supp,minimal
  prednisolone
• Acyclovir,ganciclovir,IFN-alpha
• ChemoRx,anti-B cell monoclonalAb, anti-EBV
  cytotoxic T cell,anti CD22 immunotoxin,etc.

106
Lymphoma lymphoproliferations

• Prevention
• Avoidance of over immunosuppression..
  dose, multiple agents,prolonged,repeated course
  of ALA
• Preemptive antiviral Rx during ALA
• Recurrence
• lt 5 of cases
• Retransplant should be delayed more than 1 year
  after complete remission

107
Kaposis Sarcoma

• HHV-8 (KS asso.herpesvirus)was isolated
• Mainly in renal allograft recipients
• Average age 43 yrs (4.5-67 yrs)
• MaleFemale31
• Average time 21 months after Tx
• Majority of ptsHIV-negative

108
Kaposis Sarcoma

• Non-visceral (60)
• Skin,conjunctiva,oropharynx
• Visceral (40)
• GI.,lung,lymph nodes
• 98 of pt non-visceral had skin lesions
• 38 remission after reduction or cessation of
  immunosuppressive drugs
• Non-visceralremissiongt visceral dz.
• Mortality
• 57 of visceral dz (72 from KS per se)
• 23 of non-visceral KS (infection,rejection)

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Renal carcinoma

• 24 was discovered incidentally
• Related to the underlying kidney dz
• Most cancer developed in own diseased kidney
• 10 in renal allograft
• Average time 75 months after Tx
• Predisposing causes
• Analgesic nephropathy
• Mostly transitional cell CA
• Acquired cystic dz
• Increased 30-40 folds over general pop.

110
Other cancers

• CA cervix
• 10 women with postTx CA
• In situ lesion70 of case
• Incidence ?14-16 fold
• Regular PV Cx smear
• Anogenital CA
• Female gt male
• Invasive dz in younger
• Hepatobiliary CA
• 73hepatoma
• Preceding Hx of HBV infection
• Increased number of hepatoma related to chronic
  hepatitis C

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Preexisting malignancy

• Overall recurrence rate 22,27 with Rx before
  and after Tx
• Recommendation
• No waiting period for Tx in low-risk tumor
• Incidental renal CA,CIS,BCC,low grade CA bladder
• Tx delayed gt 2 yrs in high risk of recurrence
• Malignant melanoma,CA.breast,CA.colon
• Tx delayed 2 yrs with most other tumors

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Thank you

• Happy Valentines Day