Non-infectious medical complications after renal transplant

Non-infectious medical complications after renal transplantPROF COL SOHAIL SABIRHOD NEPHROLOGY MILITARY HOSPITAL RAWALPINDIHOD MEDICAL EDUCATION ARMED FORCES POSTGRDUATE MEDICAL INSTITUTETopicsDelayed graft functionCardiovascular complicationsLipid abnormalities after renal transplantPost transplant DMParathyroid and mineral metabolismPost transplant erythrocytosisMalignancies associated with Tx

Delayed Graft FunctionNeed for >1 haemodialysis post-transplantation weekForm of AKI usually presents with oliguria.Unlikely with living donors (40 ml/min/1.73m2, and urine total protein excretion 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 decreased generation of NO. Sympathetic activation.Mild hypo Mg,affected intracellular Ca-binding proteinincrease vascular tone

33Renal Artery StenosisFunctionally significant stenosis occurs in 12% of recipients with HT Correctable form of HTRenal arteriographyprocedure of choice for diagnosing RAS in solitary Tx kidneyRenal allograft Bx prior to angiography to R/O chronic rejection or other renal parenchymal disease.

Treatment of HypertensionPatient on CsA Reduce CsA dose If permanent Hypertensionstart CCB, diureticPreventionfish oil 4 gm/dayPatient without CsAStart anti-HypertensionCCB , ACEI, beta blocker +diuretic Resistant Hypertension patient should undergo renal arteriography to exclude RAS

Lipid abnormalities after renal TxPrevalence 16-78% of recipientsReported change in serum lipids: elevation in both cholesterol and triglycerideElevated LDL and apo-B level are commonLow HDL reported in some studiesHypercholesterolemia occurs within 6 monthsHypertriglyceridemia.. peak incidence at 12 mo and correlated with excessive BW, elevated Scr

Lipid abnormalitiesPost Tx lipoprotein abnormalities may contribute to the development of CVD and PVDExpected correlation between high lipid level and cardiovascular mortalityIncreased serum triglyceride implicated as predictor of chronic renal allograft failure

Lipid abnormalitiesContributing factorsHigh steroid doseCsA / FK506DM.Nephrotic syndrome

Excessive wt.gainHigh fat dietsUse of diuretic,beta-blockersGenetic susceptibility

Lipid abnormalities PathogenesisMultifactorialCorrelate with corticosteroid dose & cyclosporineSteroid withdrawal association 17% decreased in total chol. LevelPt. With CsA ...cholesterol is 30-36 mg/dl > pt. with AZA + pred.

Steroids: Peripheral insulin resistance, Hyperinsulinemia, Increased Hepatic VLDL synthesis, decreased ACTH release.CsA; dose dependent. CsA induced hypomagnesemia. Tacrolimus: less pronounced than CsA.

39Treatment of dyslipidemiasDietary modificationWeight reduction in obese pt.Corticosteroid dose reductionDrug therapy: unclear roleshould not be prescribed early when steroid dose is relatively highdrug-induced complications

HMG Co A reductase InhibitorsMore likely to induce rhabdomyolysis in pt with CsA CsA decreased hepatic met. of drugLow dose regimen may allow to be usedPravastatin..less muscle toxic,FDA approvedFluvastatin..may also have less adverse effectsLower risk of rejectionKatznelson et al.Transplantation,1996Lower incidence of chronic rejectionImproved graft survivalKobashigawa et al.N Engl J Med,1995

Post-Transplant DMIncidence: 2-46%Glucocorticoids: impair both hepatic & extrahepatic action of insulinpost receptor insulin resistanceimpaired phase1,2 and glucagon mediated insulin secretionCyclosporine:interfere with glucose metabolismaccum in panc islet cells decreasing insulin secretionFK506:glucose intolerance more often unclear mechanism, dampen insulin secretion ( Filler et al.NDT2000 )

Risk factors for PTDMObesityblackage > 40 yearsfirst-degree relative with DMHLA A28,A30,BW42Steroid / FK506

Clinical features of PTDMpeak onsetduring the first year(2-3moths)majorityasymptomatic, hyperglycemia on blood test40-50 % require insulin therapy

Prevention/ManagementPatient educationdietary managementexerciseinsulinoral hypoglycemic agents

Screen for and treat microalbuminuria and hyperglycemiaregular ophthalmologic and podiatry exam

Parathyroid and Mineral metabolism after Renal TransplantPrimary abnormalities that can persist after renal transplantHyperPTHAluminum and beta2-microglobulin accumulationAdynamic bone diseaseOsteopeniaOsteonecrosis

HPTH and hypercalcemia1 in 3 of pt have persistent PTH hypersecretiondevelopment of hyperCa related to duration of dialysis and parathyroid gland size, secondary to hyperplasia of gland > hypersecretion of cellsresorption of soft tissue Ca-P deposits

HPTH and HypercalcemiaPlasma Ca begin to rise in first 10 days after Tx and can be delayed for 6 months or morePatients with pre-existing severe secondary HPT and acute severe hypercalcemia after transplant can cause acute allograft dysfunction and rarely calciphylaxis.

TreatmentPersistent HPTHgenerally asymptomaticHypercalcemiausually resolves spontaneous over 6 months to as long as 2-3 yearsConservative Rx with oral PO4 supplement until plasma PTH low enough to normalize Ca/P balance.Parathyroidectomy:Plasma Ca > 12.5 mg/dL more than 1 year esp. if associated with radiologic evidences of increased bone resorption.

HypophosphatemiaPersistent hypophosphatemia 20-35 %Induced by Phosphate wasting in urine due to HPTH and PTH independent pathwayTreatmentPhosphate supplement except in patients with persistent HPTH. Phosphate can exacerbate HPTH by complexing with Ca and lowering GI calcium absorption.

OsteopeniaPrevalence of atraumatic fracture post-tx may be as high as 22 %.Primary site: High cancellous bone vertebrae and ribsBone loss occurs early and rapidly post-tx1.6 % per month in first 5 mo.After early periodbone loss continue at slower rate1.7 % per year.postTx bone loss due to both HPTH and effect of imm supp drugs esp steroids.

Monitoring/TreatmentBMD of hip & spine prior to Tx and 3 mo following Tx using DEXA.Lowest dose of prednisolone compatible with graft survivalCalcium supplementation 1000 mg/dayVit.D analog can improve Ca absorptionCalcitonin or bisphosphonateif bone loss is severe and/or rapid esp. during first 6 months after Tx

OsteonecrosisNon-infectious death of marrow cell and associated trabeculae, osteocytesWeight bearing long bonemost often affected esp. Femoral headUsually multifocal may develop at any time after TxIncidence15 % within 3 years

ManagementPainpredominant symptom, higher risk of fractureArthritis.secondary to joint deformationChange in density of necrotic bone in 10-14 daysRadiolucent band in 6-8 weeksMRImost sensitiveNo effective medical Rxreduction of steroid dose has little effect once osteonecrosis developedSurgical Rx: vascularized bone grafts and core decompression

Erythrocytosis following Renal TransplantHct > 50% on two or more consecutive determination (Gasten et al.1994)affect 10-15 % of renal transplant patientsmost often within the first 2 years

ErythrocytosisCaused by renal ischemia from RASEPO factorexcess EPO release from native kidney Non-EPO factorsenhance sensitivity to EPOdirectly promote erythrocytosis:IGF-1Treat once Hct >55%.

TreatmentACE Inhibitor:low dose..enalapril 2.5mg twice a daylower Hct to normal or near normal leveleffect begin within 6 weekscomplete effect in 3-6 monthsAT1 Rec Antagonist: Losartan 50mg/day.Theophylline8 weeks course,decrease Hct from 58 to 46%,as much as 10-15%Malignancies associated with TransplantationMalignancies associated with TransplantationCincinnati Transplant Tumor Registry(CTTR)Average age 41 years,average time of appearance 5 years after TxMost striking malignanciesCA.skin&lip,PTLD,Kaposis sarcoma,Renal CACA.uterine cervix,anogenital CA,Hepatobiliary CA and SarcomaNo increase in the incidences of common tumor in general population e.g CA lung,breast,prostate,colon

CA Skin & LipsSkin cancermost common,38%Incidence increased with length of follow up.Appeared on sun-exposed area (light skin, blue eyes,blond hair)General populationBCC > SCCRenal TxSCC > BCC

CA Skin &LipsContributing factorsImmunosuppressed state Exposure to sunlightDisagreement about papilloma virusHLA:A11-protect /B27,DR7-high risk!No relation to any immunosuppresive agentTreatment Surgical excisionRetinoids, topical/systemic

Lymphoma & lymphoproliferationsPTLD:Post-Transplant Lymphoproliferative DisorderAppears in 1st post-transplantation yr.For renal transplant patients, incidence 1-2%.Benign hyperplasia.. to ..malignant lymphoma86%B cell in origin

PTLDPredisposing factorsIntense immunosuppressionNon renal allograft recipients > renal recipientsEBV infection90-95% of PTLDpositive for EBVRisk factorSeropositive at time of Tx

PTLDClinical manifestationsAsymptomatic Mononucleosis-likeFever,night sweat,URTI,weight loss,diarrhea, abdominal pain,lymphadenopathy,tonsillitisIntestinal perforation,GI bleeding,obstructionLung lesions, renal massImitating allograft rejection

PTLDTreatment Localized diseaseexcision,radiationExtensive diseasestop all immunosuppression,minimal prednisoloneAcyclovir,ganciclovir,IFN-alphaAnti CD 20 Rituximab, 65% success rate.

Prevention Avoidance of over immunosuppression, multiple agents.Recurrence < 5% of casesRetransplant should be delayed more than 1 year after complete remission

Kaposis SarcomaHHV-8 (KS asso.herpesvirus)was isolatedMainly in renal allograft recipientsAverage age 43 yrs (4.5-67 yrs)Male:Female3:1Average time 21 months after TxMajority of ptsHIV-negativeMortality 57% of visceral disease (72% from KS per se)23% of non-visceral KS (infection,rejection)

Renal Cell Carcinoma24% was discovered incidentallyRelated to the underlying kidney diseaseMost cancer developed in own diseased kidney10% in renal allograftAverage time 75 months after TxPredisposing causesAnalgesic nephropathy(transitional cell CA)Acquired cystic disease

Other CarcinomasCA cervix10% women with postTx CAIn situ lesion70% of caseIncidence Increases 14-16 foldRegular PV & Cx smearAnogenital CAFemale > maleInvasive disease in youngerHepatobiliary CA73%hepatomaPreceding Hx of HBV infectionIncreased number of hepatoma related to chronic hepatitis C

Pre-existing MalignanciesOverall recurrence rate 22%,27% with Rx before and after TxRecommendations:No waiting period for Tx in low-risk tumor(Incidental renal CA,BCC,low grade CA bladder)Tx delayed > 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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