Medical Complications of Renal Transplantation Thitisak Kitthaweesin MD

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Medical Complications of Renal Transplantation Thitisak Kitthaweesin, MD.

Medical Complications of Renal Transplantation Thitisak Kitthaweesin, MD.

Main topics Infectious complications Cardiovascular complications Lipid abnormalities after KT Post transplant DM Parathyroid

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

Infectious complications General principles of transplant infectious disease Diagnosis of infection Management of infection

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

General principles Microorganism causing infection in transplant recipient – True pathogens Influenza, typhoid, cholera,

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

General principles Risk of infection in transplant recipient is determined by 3 factors –

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

Epidemiologic exposure Exposures within the community – M. tuberculosis – Geographically restricted systemic mycoses

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

Epidemiologic exposure Exposures within the community Exposures within the hospital – Environmental exposures –

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

The net state of immunosuppression Dose, duration, and temporal sequence of immunosuppressive drugs Host

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, HCV, HIV

Timetable for posttransplant infection Infection in the first month – Infection conveyed with a

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

Timetable for posttransplant infection Infection in 1 -6 months posttransplant – The immunomodulating viruses

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

Timetable for posttransplant infection Infection more than 6 months posttransplant – The >80% of

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

Usual sequence of infection posttransplant

Usual sequence of infection posttransplant

Diagnosis of infection Radiological diagnosis – CT. chest and brain for early diagnosis and

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

Principle of Antimicrobial Therapy

Principle of Antimicrobial Therapy

Strategies for antimicrobial therapy There are three different modes of use Therapeutic mode –

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

Strategies for antimicrobial therapy Prophylactic strategies – Low-dose TMP/SMX – Effective against Pneumocystis, Nocardia,

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

Strategies for antimicrobial therapy Preemptive strategies – Appropriate antibacterial or antifungal therapy in ass.

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 reached…protect against symptomatic CMV disease

Infection of particular importance in transplant recipients

Infection of particular importance in transplant recipients

Cytomegalovirus CMV. . evidence of replication 50 -75% in transplant recipients CMV infection –

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

 CMV disease – Requires clinical signs &symptoms ie. severe leukopenia or organ involvement

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

The manifestation of CMV in transplant recipients Direct manifestations – Mononucleosis – Leukopenia/thrombocytopenia –

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

Risk of clinical CMV disease is determined by 2 factor Serological status of donor

Risk of clinical CMV disease is determined by 2 factor Serological status of donor and recipient Nature of the immunosuppressive therapy

Role of CMV infection in transplant recipient

Role of CMV infection in transplant recipient

Prophylactic therapy Gancicovir = propylactic therapy of choice – IV – Oral – IV

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

CMV-positive donor CMV-negative recipient (D+/R-) 70 -90% will develop primary CMV infection 50 -80%

CMV-positive donor CMV-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. Dose daily x 3 wks. –switch to oral 2 -12 wks. With ALA IV. 1 month followed by oral 2 months

CMV-negative donor CMV-positive recipient (D-/R+) Reactivation of latent CMV infection/disease… 20% Pneumonitis is rare

CMV-negative donor CMV-positive recipient (D-/R+) Reactivation of latent 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)

CMV-positive donor CMV-positive recipient (D+/R+) Risk for reactivation of latent virus and superinfection with

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)

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

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

Treatment Varied with severity of dz. Mononucleosis-like syndrome – Resolve without antiviral drug –

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

EBV Possible clinical consequens of EBV replication – Mononucleosis syndrome – Meningoencephalitis – Oral

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

EBV Critical effect…its role in pathogenesis of PTLD usually B cell (benign polyclonal to

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 Cs. A&Tacrolimus, Pulse steroids or in combination – Type of organ Tx – CMV infection

EBV infection – Latent form (great majority) Not susceptible to antiviral Rx – Replicative

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

Other viral infections VZV. – Primary infection with VZV in Tx pt can be

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

 HSV – Occur in 50% of pt. – Lesions usually… ulcerative > vesicular

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%

 HHV-6 – Found in blood 30 -50% of pt. – Often asso. with

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

Bacterial infection UTI – Common after renal Tx – Prevalent within the first post

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

– Pathogens…similar to general population E. coli , Enterococci , P. aeruginosa , C.

– 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

– Recommendation… Recommendation low-dose TMP/SMX minimum 4 month (most centers prophylasis for 1 year)

– Recommendation… 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

Opportunistic bacterial infections Three important opportunistic bacterial infection in first year post Tx –

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

Fungal infection Disseminated infection – Primary infection/reactivation – Dimorrphic fungi (histoplasmosis, blastomycosis, coccidioidomycosis) cause

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.

 Candida – Mucocutaneous overgrowth can be prevented by Rx of high risk pt.

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

Cardiovascular complication of Transplantation

Cardiovascular complication of Transplantation

Cardiovascular complication of Transplantation – Cardiovascular dz is very common Incidence new IHD events…

Cardiovascular complication of Transplantation – Cardiovascular dz is 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

 Pretransplant CVD – Pre Tx CVD is an important risk factor for post

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 pre. Tx evaluation – Recommendation…high risk pt should Recommendation undergo a cardiac stress test (Dobutamine stress echo/Radionuclude stress test)

HT after renal Tx Major risk factor for graft survival Occur in 60 -80%

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/d. L

Pathogenesis – Acute allograft rejection – Chronic allograft rejection – Cadaveric allografts esp. from

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

#Suggestive evidences: transplant kidney may have prohypertensive or antihypertensive properties #Experimental models of genetic

#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+anti. HT requirement occur more frequently in recipient from normotensive family received a kidney from donor with HT family

 Role of corticosteroid – Usually not a major risk factor for chronic HT

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

 Role of cyclosporine – Vasoconstrictive effect HT volume dependent > renin dependent –

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

RAS Functional significant stenosis occur in 12% of recipients with HT Correctable form of

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

Treatment Patient with Cs. A – Reduced Cs. A dose – If permanent HT…start

Treatment Patient with Cs. A – Reduced Cs. A dose – If permanent HT…start CCB, diuretic – Prevention…fish oil 4 gm/day Patient without Cs. A – Start anti-HT…CCB , ACEI, beta blocker +diuretic – Resistant HT …patient should undergo renal arteriography to exclude RAS

Lipid abnormalities after renal Tx Prevalence 16 -78% of recipients Reported change in serum

Lipid abnormalities after renal Tx Prevalence 16 -78% of recipients Reported change in serum lipid: elevation 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

Lipid abnormalities after renal Tx Post Tx lipoprotein abnormalities may contribute to the development

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

Contributing factors High steroid dose Cs. A / FK 506 DM. Nephrotic syndrome Excessive

Contributing factors High steroid dose Cs. A / FK 506 DM. Nephrotic syndrome Excessive wt. gain High fat diets Use of diuretic, beta -blockers Genetic susceptibility

Pathogenesis Multifactorial Correlate with corticosteroid dose & cyclosporine Steroid withdrawal association 17% decreased in

Pathogenesis Multifactorial Correlate with corticosteroid dose & cyclosporine Steroid withdrawal association 17% decreased in total chol. Level Pt. With Cs. A. . . chol 30 -36 mg/dl > pt. with AZA + pred.

Corticosteroid Peripheral insulin resistance Hyperinsulinemia Hepatic VLDL synthesis ACTH release – Administration of ACTH

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 Cs. A

Cyclosporine – Dose-dependent – Correlation between Blood Cs. A level and degree of hypercholesterol

Cyclosporine – Dose-dependent – Correlation between Blood Cs. A level and degree of hypercholesterol – Cs. A pt. have higher TG + Lp(a) > AZA + prednisolone – Cs. A induced hypo. Mg. . contribute to hypercholesterol

Tacrolimus Similar to but less pronounced than Cs. A LDL, Lp(a), fibrinogen level…lower in

Tacrolimus Similar to but less pronounced than Cs. A LDL, Lp(a), fibrinogen level…lower in FK 506 may be asso. with lower serum TC substitution of tacrolimus for Cs. A may improved lipid profile

Treatment Dietary modification Weight reduction in obesed pt. Corticosteroid dose reduction Drug therapy –

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

HMG-Co. A reductase inhibitor More likely to induce rhabdomyolysis in pt with Cs. A

HMG-Co. A reductase inhibitor More likely to induce rhabdomyolysis in pt with Cs. A 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

 Low-dose therapy with statin considered in – stable patient 8 months after Tx

Low-dose therapy with statin considered in – stable patient 8 months after Tx – total chol > 240 mg/d. L – LDL chol > 160 mg/d. L patient with other CV risk factors may be Rx if LDL 130 -160 mg/d. L

Benefits of HMG Co. A reductase inhibitor Lower risk of rejection – Katznelson et

Benefits of HMG Co. A 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

Post-transplant DM Incidence – PTDM varied from 2 -46% – variation in criterias Etiology

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

 Glucocorticoid. . impair both hepatic & extrahepatic action of insulin – post receptor

Glucocorticoid. . impair both hepatic & extrahepatic action of insulin – post receptor insulin resistance – impaired phase 1, 2 and glucagon mediated insulin secretion Cyclosporine. . interfere with glucose metabolism – accum in panc islet cell. . insulin secretion FK 506. . glucose intolerance more often – unclear mechanism. . dampen insulin secretion ( Filler et al. NDT 2000 )

Risk factors for PTDM Obesity black age > 40 years first-degree relative with DM

Risk factors for PTDM Obesity black age > 40 years first-degree relative with DM HLA A 28, A 30, BW 42 CDKT Steroid / FK 506

Clinical features Incidence…not related to renal dz, number of rejection or graft function peak

Clinical features Incidence…not related to renal dz, number of rejection or graft function peak onset…during the first year (2 -3 moths) majority…asymptomatic, hyperglycemia on blood test 40 -50 % require insulin therapy

Prevention/Management Patient education dietary management exercise insulin oral hypoglycemic agents Screen for and treat

Prevention/Management Patient education dietary management exercise insulin oral hypoglycemic agents Screen for and treat microalbuminuria and hyperglycemia regular ophthalmologic and podiatry exam

Go to. . Medical complication of Renal transplantation Part II

Go to. . Medical complication of Renal transplantation Part II

Parathyroid and Mineral metabolism after Renal Transplant

Parathyroid and Mineral metabolism after Renal Transplant

Successful KT Normalize urinary. P, beta-2 microglobulin excretion Normalize renal calcitriol production Reverse many

Successful KT Normalize urinary. P, 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

Primary abnormalities that can persist after KT Hyper. PTH Aluminum and beta 2 -microglobulin

Primary abnormalities that can persist after KT Hyper. PTH Aluminum and beta 2 -microglobulin accumulation Adynamic bone disease Osteopenia Osteonecrosis

HPTH and Hypercalcemia 1 in 3 of pt have persistent PTH hypersecretion development of

HPTH and Hypercalcemia 1 in 3 of pt have persistent PTH hypersecretion development of hyper. Ca related to duration of dialysis and parathyroid gland size, secondary to hyperplasia of gland > hypersecretion of cells other factors – resorption of soft tissue Ca-P deposits

HPTH and Hypercalcemia other factors – resorption of soft tissue Ca-P deposits – normalization

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

HPTH and Hypercalcemia Plasma Ca begin to rise in first 10 days after Tx

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 HPTH…acute severe hypercalcemia after KT, can cause acute allograft dysfunction and rarely calciphylaxis

Treatment Persistent HPTH…generally asymptomatic Hypercalcemia…usually resolves spontaneous over 6 months to as long as

Treatment Persistent HPTH…generally asymptomatic Hypercalcemia…usually 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

Parathyroidectomy Severe symptomatic hyper. Ca – usually in early period Persistent hyper. Ca –

Parathyroidectomy Severe symptomatic hyper. Ca – usually in early period Persistent hyper. Ca – 4 -10 % after 1 year Elective parathyroidectomy – if plasma Ca > 12. 5 mg/d. L more than 1 year esp. if asso. with radiologic evidences of increased bone resorption

Aluminum toxicity KT quickly reverses factors leading to Aluminum accumulation more effective than desferoxamine

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

Hypophosphatemia Persistent hypo P 20 -35 % Induced by P wasting in urine due

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

Dialysis-related Amyloidosis Primarily induced by beta 2 microglobulin deposits Articular symptoms asso. with disorder

Dialysis-related Amyloidosis Primarily induced by beta 2 microglobulin deposits Articular symptoms asso. with disorder rapidly improve after KT new cystic lesions …unusual resolution of existing cysts…rare

Post-transplant Bone disease Osteopenia Osteonecrosis Contributing factors – persisting uremia-induced abnormal calcium homeostasis –

Post-transplant Bone disease Osteopenia Osteonecrosis Contributing factors – persisting uremia-induced abnormal calcium homeostasis – acquired defects in mineral metabolism induced by immunosuppressive Rx

Osteopenia Higher risk for pathologic Fx Prevalence of atraumatic Fx in KT may be

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 post. KT… 1. 6 % per month in first 5 mo After early period…bone loss continue at slower rate… 1. 7 % per year

Pathogenesis post. Tx bone loss inv. both HPTH and effect of imm supp drugs

Pathogenesis post. Tx 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-1 production and sensitivity to PTH

Monitor BMD. of hip&spine prior to Tx and 3 mo following KT using DEXA

Monitor BMD. of hip&spine 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

Treatment Lowest dose of prednisolone compatible with graft survival Calcium supplementation 1000 mg/day Vit.

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

Osteonecrosis Non-infectious death of marrow cell and asso. trabeculae, osteocytes Weight bearing long bone…most

Osteonecrosis Non-infectious death of marrow cell and asso. trabeculae, osteocytes Weight bearing long bone…most often affected esp. Femoral head Usually multifocal may develop at any time after Tx Incidence… 15 % within 3 years

Osteonecrosis Direct asociated with… – glucocorticoid exposure – cyclosporine – number of tx –

Osteonecrosis Direct asociated with… – glucocorticoid exposure – cyclosporine – number of tx – HPTH – low bone mass – fracture

Pathogenesis GCs – increase intramarrow pressure – increase adipocyte hyperplasia – fat embolism –

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

Diagnosis Pain…predominant symptom Higher risk of Fx Arthritis…. secondary to joint deformation Change in

Diagnosis Pain…predominant symptom Higher risk of Fx Arthritis…. secondary to joint deformation Change in density of necrotic bone – 10 -14 days Radiolucent band – 6 -8 weeks MRI…most sensitive

Treatment No effective medical Rx – reduction of steroid dose has little effect once

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

Bone Pain Occur only in patients received Cs. A often temporally related to higher

Bone Pain Occur only in patients received Cs. A often temporally related to higher level Mechanism – intraosseous vasoconstriction and HT Treatment – CCB. . nifedipine SR 30 -60 mg, Hs …completely relieve symptom

Erythrocytosis following KT Post. Tx erythrocytosis (PTE) – Hct > 51% on two or

Erythrocytosis following KT Post. Tx erythrocytosis (PTE) – Hct > 51% on two or more consecutive determination (Gasten et al. 1994) – affect 10 -15 % of KT patients – most often within the first 2 years

Etiology and pathogenesis Early case reported. . PTE caused by renal ischemia from RAS

Etiology and pathogenesis Early case reported. . PTE caused by renal ischemia from RAS Risk factors – smoking – DM. – Rejection-free course – not RAS EPO factor…excess EPO release from native kidney

Etiology and pathogenesis Non-EPO factors – enhance sensitivity to EPO – directly promote erythrocytosis

Etiology and pathogenesis Non-EPO factors – enhance sensitivity to EPO – directly promote erythrocytosis – IGF-1, IGF-BP, GH. . enhance. erythrocytosis Angiotensin II – ACEI, ATRA…inhibit erythrocytosis – activation of AIIreceptor may enhance EPO production in the graft or increased Rbc precursor sensitivity to EPO

Treatment ACE inhibitor – low dose. . enalapril 2. 5 mg twice a day

Treatment ACE inhibitor – low dose. . enalapril 2. 5 mg 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)

Treatment AT 1 receptor antagonists – Losartan 50 mg/day – decrease Hct 53 to

Treatment AT 1 receptor 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

Recommendation ACEI and ATRA Losartan 50 mg/day may be increased to 100 mg/day, if

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

Malignancies associated with Transplantation

Malignancies associated with Transplantation

Malignancies associated with Transplantation Cincinnati Transplant Tumor Registry(CTTR) Average 41 years, average time of

Malignancies associated with Transplantation Cincinnati Transplant Tumor Registry(CTTR) Average 41 years, average time of appearance 5 years after Tx Most striking malignancies – CA. skin&lip, PTLD, Kaposi’s 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

CA. Skin & Lips Skin cancer…most common, 38% Incidence increased with length of F/U

CA. Skin & Lips Skin cancer…most common, 38% Incidence increased with length of F/U Appeared on sun-exposed area (light skin, blue eyes, blond hair) Pt age >40 yrs…lesion occurred on the head Younger pts…lesion mainly on dorsum of hand, forearm, chest

CA. Skin & Lips General population…BCC > SCC Renal Tx…SCC > BCC SCC –

CA. Skin & Lips General population…BCC > SCC Renal Tx…SCC > 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 Histo: thick tumor involve subcutaneous tissues

CA. Skin & Lips Contributing factors – Immunosuppressed state – Exposure to sunlight –

CA. Skin & Lips Contributing factors – Immunosuppressed state – Exposure to sunlight – Disagreement about papilloma virus – HLA: A 11 -protect /B 27, DR 7 -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

Lymphoma & lymphoproliferations PTLD: Post-Transplant Lymphoproliferative Disorder Benign hyperplasia. . to. . malignant lymphoma

Lymphoma & lymphoproliferations PTLD: Post-Transplant Lymphoproliferative Disorder Benign hyperplasia. . to. . malignant lymphoma 86%…B cell in origin Classification of PTLD

Lymphoma & lymphoproliferations Predisposing factors – Intense immunosuppression Non renal allograft recipients > renal

Lymphoma & lymphoproliferations Predisposing factors – Intense immunosuppression Non renal allograft recipients > renal recipients – EBV infection 90 -95% of PTLD…positive for EBV Risk factor…Seropositive at time of Tx

Lymphoma & lymphoproliferations Clinical manifestation – Asymptomatic – Mononucleosis-like – Fever, night sweat, URI,

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

Lymphoma & lymphoproliferations Treatment – Localized disease…excision, radiation – Extensive disease…stop all imm supp,

Lymphoma & lymphoproliferations Treatment – Localized disease…excision, radiation – Extensive disease…stop all imm supp, minimal prednisolone – Acyclovir, ganciclovir, IFN-alpha – Chemo. Rx, anti-B cell monoclonal. Ab, anti -EBV cytotoxic T cell, anti CD 22 immunotoxin, etc.

Lymphoma & lymphoproliferations Prevention – Avoidance of over immunosuppression. . dose, multiple agents, prolonged,

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

Kaposi’s Sarcoma HHV-8 (KS asso. herpesvirus)was isolated Mainly in renal allograft recipients Average 43

Kaposi’s Sarcoma HHV-8 (KS asso. herpesvirus)was isolated Mainly in renal allograft recipients Average 43 yrs (4. 5 -67 yrs) Male: Female… 3: 1 Average time 21 months after Tx Majority of pts…HIV-negative

Kaposi’s Sarcoma Non-visceral (60%) – Skin, conjunctiva, oropharynx Visceral (40%) – GI. , lung,

Kaposi’s 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-visceral…remission> visceral dz. Mortality – 57% of visceral dz (72% from KS per se) – 23% of non-visceral KS (infection, rejection)

Renal carcinoma 24% was discovered incidentally Related to the underlying kidney dz Most cancer

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.

Other cancers CA cervix – – 10% women with post. Tx CA In situ

Other cancers CA cervix – – 10% women with post. Tx CA In situ lesion… 70% of case Incidence … 14 -16 fold Regular PV & Cx smear Anogenital CA – Female > male – Invasive dz in younger Hepatobiliary CA – 73%…hepatoma – Preceding Hx of HBV infection – Increased number of hepatoma related to chronic hepatitis C

Preexisting malignancy Overall recurrence rate 22%, 27% with Rx before and after Tx Recommendation

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

Thank you & Happy Valentine’s Day

Thank you & Happy Valentine’s Day