Final post kt infection

Infections in Kidney Infections in Kidney TransplantationTransplantation

Dr. Sunil Kumar Daksh Dr. Sunil Kumar Daksh PrajapatiPrajapati

LayoutLayout

Risk factors The Timeline of Posttransplant

Infections Viral infections Bacterial infections Fungal infections Parasitic infections

SourceSource

Various articlesVarious articles Handbook of Gabriel M. DanovitchHandbook of Gabriel M. Danovitch Various other standard text booksVarious other standard text books 2010 KDIGO clinical practice 2010 KDIGO clinical practice

guideline for the care of kidney guideline for the care of kidney transplant recipientstransplant recipients

Kidney transplant(KT) infection – Risk factors

Pretranspaltation Comorbid illness (DM, malnutrtion, immunosupression) Immunosuppression for chonic conditons Unrecognized or undertreated infections Colonization by unusual or resistant organism (VRE - stool, MRSA – nares/skin,

Pseudomonas/enterobacteriace – UTI, yeast - skin) Preoperative antibiotic exposure Duration/frequency of hospitalization

Perioperative Complexity of surgery/requirement of re-exploration Prolonged operative time Graft injury or prolonged ischemia Bleeding/multiple BT Infected graft Contaminated preservation fluid Foreign body

Kidney transplant(KT) infection – Risk factors

Post-transplantation Graft failure/dysfunction- needing immunosuppresion Complicated post op management – development or worsening of comorbid

illness Infection with immunomodulating viruse Prolonged hospitalization, catheters,stents, intubation Drains Anastomotic breakdown Leucopenia, thrombocytopenia, acquired hypogammaglobulinemia Prolonged antibiotic therapy Selected occupation/endemic infections Lack of appropriate hand hygiene by caregivers Marijuana abuse

Making clinical decisionMaking clinical decision

Factors that may assist in Factors that may assist in recognizing the causative organismrecognizing the causative organism Timing of infectionTiming of infection Status of donor and recipientStatus of donor and recipient State of immunosuppresionState of immunosuppresion

The Timeline of The Timeline of Posttransplant InfectionsPosttransplant Infections

Common Variables in Immune Suppression

Rejection, antirejection therapy, new agents

Neutropenia, lymphopenia

Viral coinfection (CMV, HCV, EBV)

Transplantation 4 Weeks 6-12 Months Long-term

Nosocomial Technical Common infections

HSV, CMV, HBV, HCV, LISTERIA, PCP, TOXO

Period of most intensiveimmune suppression

Donor-derived infection

Opportunistic, Relapsed, Residual

Nosocomial infection

Fishman J. N Engl J Med 2007;357:2601-2614

Changing Timeline of Infection after Transplantation

Conditions predisposing to early Conditions predisposing to early and nosocomial infectionand nosocomial infection

Intubation (>3 days)Intubation (>3 days)

Catheters (urinary, venous, balloon pumps, dialysis, other Catheters (urinary, venous, balloon pumps, dialysis, other mucosal injuries)mucosal injuries)

Ascites, peritoneal dialysisAscites, peritoneal dialysis

Constipation, endoscopy, Constipation, endoscopy, Clostridium difficileClostridium difficile colitis colitis

Broad-spectrum antimicrobial agentsBroad-spectrum antimicrobial agents

Deep vein thrombosis, atelectasis, decubitus ulcersDeep vein thrombosis, atelectasis, decubitus ulcers

Metabolic (malnutrition/uremia/hyperglycemia)Metabolic (malnutrition/uremia/hyperglycemia)

Latent infections (viral and parasitic) Latent infections (viral and parasitic)

Colonization (bacterial and fungal)Colonization (bacterial and fungal)

Exogenous immune suppressionExogenous immune suppression

Donor derived infectionsDonor derived infectionsPossible infections from the allograft include:Possible infections from the allograft include: TuberculosisTuberculosis Known pathogens (screened): HBV, HCV, HIVKnown pathogens (screened): HBV, HCV, HIV Uncommon pathogens: West Nile virus, Chagas’ disease, Uncommon pathogens: West Nile virus, Chagas’ disease,

Toxoplasma gondiiToxoplasma gondii, rabies, lymphocytic choriomeningitis , rabies, lymphocytic choriomeningitis virusvirus

Common “sticky” bacteria (may be nosocomial colonizers Common “sticky” bacteria (may be nosocomial colonizers of donor): of donor): PneumococcusPneumococcus, , StaphylococcusStaphylococcus, , StreptococcusStreptococcus, , PseudomonasPseudomonas, , SalmonellaSalmonella, , AspergillusAspergillus, , CandidaCandida

Donor-derived InfectionDonor-derived Infection Most are latentMost are latent

CMV, TB, T.cruziCMV, TB, T.cruzi

The majority of these are sub-clinical in The majority of these are sub-clinical in healthy patients, but can be catastrophic healthy patients, but can be catastrophic when transplanted into an immunosuppresed when transplanted into an immunosuppresed patientpatient

Rarely can be acuteRarely can be acute West Nile, rabies, HIV, hepatitisWest Nile, rabies, HIV, hepatitis

At present, routine evaluations of donors for At present, routine evaluations of donors for infectious diseases relies upon serologic infectious diseases relies upon serologic antibody testing, and thus sensitivity is not antibody testing, and thus sensitivity is not 100% for those that may not have had time to 100% for those that may not have had time to seroconvert seroconvert

Donor-derivedDonor-derived Transplantation of organs from deceased donors Transplantation of organs from deceased donors

with viral syndromes is controversialwith viral syndromes is controversial

Livers with known Chagas or Hep B infection may Livers with known Chagas or Hep B infection may be used as there are effective treatments for these be used as there are effective treatments for these infectionsinfections

Hep C infected organs are sometimes transplanted Hep C infected organs are sometimes transplanted into Hep C(+) donorsinto Hep C(+) donors


Recipient-derived Recipient-derived InfectionsInfections

Infections that can be treated or controlled Infections that can be treated or controlled do not necessarily preclude transplantationdo not necessarily preclude transplantation

Most commonly screened for:Most commonly screened for: TBTB Syphilis and other STDSyphilis and other STD Viral: CMV, EBV, VZV, HSV, HIV, HBV, HCVViral: CMV, EBV, VZV, HSV, HIV, HBV, HCV

Other things to think ofOther things to think of T.cruzi, strongyloides, cryptococcusT.cruzi, strongyloides, cryptococcus Endemic fungi: histoplasma, coccidioides, Endemic fungi: histoplasma, coccidioides,

paracoccidioides, aspergillus, blastomycosis paracoccidioides, aspergillus, blastomycosis


ImmunizationsImmunizations Pt’s should be immunized forPt’s should be immunized for

MMRMMR HBVHBV InfluenzaInfluenza Strep pneumoniaeStrep pneumoniae TetanusTetanus DiphtheriaDiphtheria PertussisPertussis PolioPolio VZV – if never infectedVZV – if never infected

Consideration should be given to boosters for any of the Consideration should be given to boosters for any of the above prior to transplantation as live vaccines are above prior to transplantation as live vaccines are generally contraindicated post-transplant, and generally contraindicated post-transplant, and immunologic memory will become impairedimmunologic memory will become impaired

Consider in endemic area•Rabies, (2D)•Tick-borne (2D)•Meningoencephalitis, (2D)•Japanese B encephalitis- inactivated (2D)•Meningococcus, (2D)•Pneumococcus, (2D)•Salmonella typhi-

inactivated. (2D)

Monitoring Monitoring ImmunosuppressionImmunosuppression

There are no specific tests currently There are no specific tests currently available to determine the overall available to determine the overall susceptibility of patients to infection…susceptibility of patients to infection…

……but they are being developedbut they are being developed

Currently, the known determinants Currently, the known determinants contributing to the overall risk of infection contributing to the overall risk of infection are the dose, duration, and sequence of are the dose, duration, and sequence of immunosuppressive therapiesimmunosuppressive therapies

InfectionInfection

TypesTypes ViralViral BacterialBacterial FungalFungal ParasiticParasitic

27

Viral Infection Viral Infection

Copyright ©2008 American Society of Nephrology

Weikert, B. C. et al. Clin J Am Soc Nephrol 2008;3:S76-S86

Figure 1. Time of presentation of common viral illnesses post-transplant

CMVCMV

CMVCMV

• Among all organ transplant KT pt have Among all organ transplant KT pt have lowest risk for CMV disaeselowest risk for CMV disaese

• CMV is still among the most important CMV is still among the most important infectious complications after transplantinfectious complications after transplant

• It is widely distributed in general population It is widely distributed in general population ranging from 40-97%ranging from 40-97%

• Once CMV infection is established, then its Once CMV infection is established, then its replication is highly dynamic with rapid replication is highly dynamic with rapid increases in viral loadincreases in viral load

• Transmitted by Allograft, blood products, Sexual Transmitted by Allograft, blood products, Sexual contactscontacts

24

CMV and Kidney TransplantationCMV and Kidney Transplantation It usually develops during the first few It usually develops during the first few

months of Tx. when patient is months of Tx. when patient is immunosuppressed. immunosuppressed.

In the absence of prophylaxis, CMV In the absence of prophylaxis, CMV reactivation can occur in over 75% of reactivation can occur in over 75% of recipients depending on other risk recipients depending on other risk factorsfactors

It has also been implicated as a cause of It has also been implicated as a cause of acute and chronic allograft injury.acute and chronic allograft injury.

CMV may play a crucial role in chronic CMV may play a crucial role in chronic graft vasculopathy resulting CAN, graft vasculopathy resulting CAN, bronchiolitis and accelerated CADbronchiolitis and accelerated CAD

CMV Infection: Risk Categories in CMV Infection: Risk Categories in Solid Organ Transplant RecipientsSolid Organ Transplant Recipients

Risk CategoryRisk Category Donor (D) or Recipient (R)Donor (D) or Recipient (R)Seropositivity (+/-)Seropositivity (+/-)

High High D+/R-D+/R-

IntermediateIntermediate D+/R+, D-/R+D+/R+, D-/R+

LowLow D-/R-D-/R-

26Fishman JA, Emery V, Freeman R, et al. Cytomegalovirus in transplantation –

challenging the status quo. Clinical Transplantation. 2007;21:149-158.

CMV PathogenesisCMV Pathogenesis

• Viral factorsViral factors– replication dynamicsreplication dynamics– immune evasionimmune evasion– viral heterogeneityviral heterogeneity– viral co-infectionsviral co-infections

• Host factorsHost factors– CD4+, CD8+ T-cellCD4+, CD8+ T-cell– NK cell, B-cell, NK cell, B-cell,

neutropenianeutropenia– exogenous exogenous

immunosuppression/ immunosuppression/ lymphocyte depletion lymphocyte depletion

– D/R immune statusD/R immune status

27

INFLAMMATION(CYTOKINES, NF-B)

LATENTLATENT CMV INFECTIONCMV INFECTION

ANTILYMPHOCYTEANTILYMPHOCYTEANTIBODIESANTIBODIES

OTHER OTHER HERPES VIRUSESHERPES VIRUSES

SEPSIS/SEPSIS/SURGERYSURGERYREJECTIONREJECTION

28

CMV InfectionCMV Infection

Latent CMV infection

Active CMV infection(viral replication)

Direct effects

Indirect effects

29

Direct Effects of CMV InfectionDirect Effects of CMV Infection

CMV Viral SyndromeCMV Viral Syndrome• Fever, malaise, myalgiasFever, malaise, myalgias• Leukopenia, Leukopenia,

thrombocytopenia, and thrombocytopenia, and other laboratory other laboratory abnormalitiesabnormalities

Tissue Invasive Tissue Invasive DiseaseDisease

• HepatitisHepatitis• PneumonitisPneumonitis(most (most

serious)serious)

• ColitisColitis(diagnostic (diagnostic endoscopy)endoscopy)

• CarditisCarditis• Nephritis Nephritis • PancreatitisPancreatitis• RetinitisRetinitis

Direct Effects

30

Indirect Effects of CMV InfectionIndirect Effects of CMV Infection

Altered host immune Altered host immune responseresponse

• Graft rejection; graft dysfunctionGraft rejection; graft dysfunction

• Opportunistic infections: Opportunistic infections: Bacterial fungal superinfectionBacterial fungal superinfection

• Decreased graft and patient Decreased graft and patient survivalsurvival

• Herpesvirus interactions: Herpesvirus interactions: EBV/PTLDEBV/PTLD

Indirect Effects

31

Diagnosis of CMVDiagnosis of CMV

Pretransplantation screeningPretransplantation screening CMV – IgM, IgGCMV – IgM, IgG

DiseaseDisease Culture based – Tissue cultureCulture based – Tissue culture PCR PCR New era for CMV diagnosis by the PP65 New era for CMV diagnosis by the PP65

antigenemia assay. This test is sensitive antigenemia assay. This test is sensitive and specific.and specific.

Quantitative method is used for Quantitative method is used for monitoring responsemonitoring response

Anti-CMV TherapyAnti-CMV Therapy

ValganciclovirValganciclovir:: a prodrug form of ganciclovir with a prodrug form of ganciclovir with improved improved oraloral bioavailability(=Ganciclovir) bioavailability(=Ganciclovir)

GanciclovirGanciclovir: : intravenous or oralintravenous or oral FoscarnetFoscarnet: : is an inhibitor CMV DNA polymerase is an inhibitor CMV DNA polymerase

(UL54)(UL54)‒ Useful for ganciclovir resistant CMVUseful for ganciclovir resistant CMV

‒ Major limitation is nephrotoxicityMajor limitation is nephrotoxicity

CidofovirCidofovir: : inhibits viral DNA polymeraseinhibits viral DNA polymerase‒ Useful for ganciclovir resistant CMVUseful for ganciclovir resistant CMV

MaribavirMaribavir: : is an investigational agent that prevents is an investigational agent that prevents viral encapsidation and nuclear egressviral encapsidation and nuclear egress

33

GanciclovirGanciclovir Adverse effectsAdverse effects: :

– HematologicHematologic: neutropenia, anemia, : neutropenia, anemia, thrombocytopenia(additive with Azathiopurine)thrombocytopenia(additive with Azathiopurine)

– Gastrointestinal: nausea, vomiting, diarrhea, abdominal Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, flatulence, anorexia pain, flatulence, anorexia

– Neurologic: headache, confusion, hallucination, seizuresNeurologic: headache, confusion, hallucination, seizures– OtherOther: pain and phlebitis: pain and phlebitis at injection site (due to high pH), at injection site (due to high pH),

sweating, rash, itchsweating, rash, itch, increased serum creatinine and blood , increased serum creatinine and blood urea concentrationsurea concentrations

ToxicityToxicity: : – Human carcinogen, teratogen, and mutagenHuman carcinogen, teratogen, and mutagen– Inhibits spermatogenesisInhibits spermatogenesis– Increased seizure threhold on use with ImipenemIncreased seizure threhold on use with Imipenem

PharmacokineticsPharmacokinetics::– 90% of plasma ganciclovir is eliminated unchanged in the 90% of plasma ganciclovir is eliminated unchanged in the

urine with a half-life of 2-6 hrs, depending on renal function urine with a half-life of 2-6 hrs, depending on renal function (elimination takes over 24 hours in end-stage renal disease)(elimination takes over 24 hours in end-stage renal disease)

5-10 mg/kg/d in two divided dose for 4-6 weeks for 5-10 mg/kg/d in two divided dose for 4-6 weeks for treatmenttreatment

34

ValganciclovirValganciclovir

Dose :Dose : Oral 900mg BD for mild to moderate CMV disease for 14-21 daysOral 900mg BD for mild to moderate CMV disease for 14-21 days Pt with severe tissue invasive disease, who fail to achieve a reduction in viral load Pt with severe tissue invasive disease, who fail to achieve a reduction in viral load

after 7 days should receive iv ganciclovirafter 7 days should receive iv ganciclovir Weekly monitoring of viral loadWeekly monitoring of viral load

Adverse effectsAdverse effects: : – Similar to ganciclovirSimilar to ganciclovir– Myelosuppression is one of the main side effects that may limit prolonged use of Myelosuppression is one of the main side effects that may limit prolonged use of

valganciclovirvalganciclovir

PharmacokineticsPharmacokinetics::– Oral bioavailability ~ 60%Oral bioavailability ~ 60%

• Fatty foods significantly increase the bioavailabilityFatty foods significantly increase the bioavailability

– Eliminated as ganciclovir in the urine, with a half-life of about Eliminated as ganciclovir in the urine, with a half-life of about 4 hours4 hours

35

CMV PreventionCMV Prevention

• Two strategiesTwo strategies• Universal prophylaxisUniversal prophylaxis

– Therapy from the time of transplant to all patientsTherapy from the time of transplant to all patientsor a subgroup of patients at or a subgroup of patients at high riskhigh risk for CMV disease for CMV disease

• Pre-emptive therapyPre-emptive therapy– Patients are monitored at regular intervals for early evidence of Patients are monitored at regular intervals for early evidence of

CMV replications CMV replications guided by laboratory monitoring guided by laboratory monitoring – Treatment is started when CMV viral load or antigenemia Treatment is started when CMV viral load or antigenemia

reaches a certain thresholdreaches a certain threshold– Useful for low/intermediate riskUseful for low/intermediate risk– In patients with CMV disease, we suggest weekly In patients with CMV disease, we suggest weekly

monitoring of CMV by NAT or pp65 antigenemia.(2D)monitoring of CMV by NAT or pp65 antigenemia.(2D)

36

++ ++ ++ ++ ++ ____ ++ ++ __

00 44 88 12weeks

Initiate pre-emptive therapy to prevent CMV disease

CMV disease

TESTTEST

Pre-emptive TherapyPre-emptive Therapy

____

37

Prophylaxis Pre-emptive

Evidence of efficacy +++ ++

Indirect effects/mortality ++ +

Other viruses + for some ?

Ease ++ +/-

Late onset disease ++ -

Resistance Low Very Low

Prophylaxis vs. Pre-emptive TherapyProphylaxis vs. Pre-emptive Therapy

38

Effects of Anti-CMV ProphylaxisEffects of Anti-CMV Prophylaxison Concomitant Infectionson Concomitant Infections

39Hodson EM, et al. Lancet. 2005;365:2105-2115.

Universal prophylaxisUniversal prophylaxis

Acyclovir, ganciclovir, valacyclovir, valgancilovir Acyclovir, ganciclovir, valacyclovir, valgancilovir and immune- globulin. and immune- globulin.

Acyclovir: Acyclovir: Possesses comparatively poor vitro Possesses comparatively poor vitro activity against CMV at clinically achievable activity against CMV at clinically achievable levels.levels.

Ganciclovir:Ganciclovir: Use in D+ & R-ve patients immediate after Tx.Use in D+ & R-ve patients immediate after Tx.

Valacyclovir:Valacyclovir: Oral 8 gm per day for 3 monthsOral 8 gm per day for 3 months Less effective than gancyclovir.Less effective than gancyclovir.

All prophylaxsis for 3mth or 6 wk after tt with T All prophylaxsis for 3mth or 6 wk after tt with T cell depleting antibodycell depleting antibody

(Dose adjustment necessary for all)(Dose adjustment necessary for all)

Guidelines for CMV prevention Guidelines for CMV prevention in kidney recipientsin kidney recipients

Group:Group: Recommendations:Recommendations:

* * Kidney Kidney * Oral ganciclovir* Oral ganciclovir

D+ve/R-veD+ve/R-ve for 3 months/IV for 3 months/IV ganciclovir 1-3 M ganciclovir 1-3 M

*Kidney*Kidney

R+veR+ve * As above * As above

Start prophylaxis within 10 days post Tx. And continue for 100 Start prophylaxis within 10 days post Tx. And continue for 100 daysdays

Polyvalent I/V ImmunoglobulinPolyvalent I/V Immunoglobulin

The efficacy of I/V Ig in KT has been The efficacy of I/V Ig in KT has been investigated. investigated.

Unclear statusUnclear status

Late Onset CMV Disease DefinitionLate Onset CMV Disease Definition

• CMV disease occurring > 3 months CMV disease occurring > 3 months post transplantpost transplant

• May be primary infection (D+/R-) or May be primary infection (D+/R-) or recurrence (R+)recurrence (R+)

• Incidence 3%-17%Incidence 3%-17%• In IMPACT study 37% with 3 months In IMPACT study 37% with 3 months

of prophylaxis in D+/R-of prophylaxis in D+/R-

43 Limaye, AP, et al. Transplantation. 2004;78(9):1390-1396.

CMV Prophylaxis: Late-Onset DiseaseCMV Prophylaxis: Late-Onset Disease

Prophylaxis period

Patie

nts

With

No

CMV

Dis

ease

(%)

0

10

20

30

40

50

60

70

80

90

100

Time (days)0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200

364 D+/R- patients

Ganciclovir (oral)

Valganciclovir

Paya, et al. Am J Transplant. 2004;4:611-620.44

Herpes Simplex Herpes Simplex Virus and Varicella Virus and Varicella

Zoster Virus Zoster Virus

HSV & HZVHSV & HZV

Seroprevalence for HSV-1 in the adult Seroprevalence for HSV-1 in the adult population is as high as 60 percent, while population is as high as 60 percent, while VZV rates can be as high as 90 percent VZV rates can be as high as 90 percent

Infection in the renal transplant patient is Infection in the renal transplant patient is usually caused by reactivation of latent virus.usually caused by reactivation of latent virus.

Within 6 weeksWithin 6 weeks HSV infection usually presents with oral HSV infection usually presents with oral

or genital lesions, but in some instances can or genital lesions, but in some instances can cause esophagitis,hepatitis, encephalitis or cause esophagitis,hepatitis, encephalitis or pneumonitis pneumonitis

HSV & HZVHSV & HZV

ZV reactivation usually presents as ZV reactivation usually presents as dermatomal zoster, but can disseminatedermatomal zoster, but can disseminate

In the absence of prophylaxis, HSV and In the absence of prophylaxis, HSV and VZV may be seen earlyVZV may be seen early

The incidence of HSV in renal The incidence of HSV in renal transplant recipients is estimated to be transplant recipients is estimated to be approximately 53% and VZV 4 to 12%approximately 53% and VZV 4 to 12%

Due to high seroprevalence in the adult Due to high seroprevalence in the adult population, serologies are rarely helpful in population, serologies are rarely helpful in the setting of active infection. the setting of active infection.

HSV & HZVHSV & HZV Diagnosis Diagnosis

Direct fluorescence antibody for HSV and VZV from Direct fluorescence antibody for HSV and VZV from vesicular lesions or PCR from CSF or visceral tissue vesicular lesions or PCR from CSF or visceral tissue samples. samples.

Treatment Treatment Disseminated infections involves intravenous acyclovir, Disseminated infections involves intravenous acyclovir, Less severe infection ; oral acyclovir, valacyclovir, or Less severe infection ; oral acyclovir, valacyclovir, or

famciclovir famciclovir Acyclovir resistance - foscarnet, cidofovir, and topical Acyclovir resistance - foscarnet, cidofovir, and topical

trifluridine -monitoring of KFTtrifluridine -monitoring of KFT VZV immunoglobulin ASAP but no later than 96 hrVZV immunoglobulin ASAP but no later than 96 hr If immunoglobulin is N/A or more than 96 h have passed, a If immunoglobulin is N/A or more than 96 h have passed, a

7-day course of oral acyclovir begun 7–10 days after 7-day course of oral acyclovir begun 7–10 days after varicella exposure. (2D)varicella exposure. (2D)

Epstein Barr Epstein Barr Virus Virus

Epstein Barr Virus Epstein Barr Virus EBV remains latent in lymphocytes EBV remains latent in lymphocytes

following primary infection. following primary infection. Can cause replication and clonal Can cause replication and clonal

expansion of the B cells that serve as its expansion of the B cells that serve as its primary reservoir and other cell lines as primary reservoir and other cell lines as well. well.

However, a competent immune system, However, a competent immune system, specifically T cell response, specifically T cell response, prevents these cells from propagating. prevents these cells from propagating.

When T cell function is impaired, as is When T cell function is impaired, as is the case in renal transplant patients, this the case in renal transplant patients, this surveillance system can fail and post surveillance system can fail and post transplant lymphoproliferative transplant lymphoproliferative disorder (PTLD)disorder (PTLD) can develop can develop

Epstein Barr Virus & Epstein Barr Virus & PTLDPTLD

Risk of development of PTLD,Risk of development of PTLD, with higher incidence rates observed in with higher incidence rates observed in

patients receiving cytolytic therapies,patients receiving cytolytic therapies, including antithymocyte globulin andincluding antithymocyte globulin and OKT3 OKT3

Occur more commonly in pediatric Occur more commonly in pediatric kidney recipient kidney recipient

EBV seropostive donor and recipient EBV seropostive donor and recipient both are at increased risk of PTLDboth are at increased risk of PTLD

PTLD most commonly occurs in the first PTLD most commonly occurs in the first year post transplant year post transplant

Serologies for EBVSerologies for EBV Serologies for EBV of both donor and recipient should be

obtained before transplant. Allograft recipients who are EBV negative before transplant

and receive an organ from a seropositive donor are at greatest risk for PTLD;

Currently there is no single standard strategy to prevent PTLD.

In some centers, high-risk individuals are screened regularly for the presence of EBV viremia and immunosuppression decreased when viremia is observed.

Effective prevention of CMV may also prevent EBVinfections A recent trial demonstrated that CMV Ig did not prevent the

onset of PTLD in high risk recipients

PTLDPTLD Definitive diagnosis of PTLD requires Definitive diagnosis of PTLD requires

histopathologic confirmation, preferably of histopathologic confirmation, preferably of tissue obtained by excisional biopsy.tissue obtained by excisional biopsy.

In the case of CNS PTLD, analysis of CSF for EBV In the case of CNS PTLD, analysis of CSF for EBV PCR and cytology should be performed. PCR and cytology should be performed.

Although viremia may be noted at the time of Although viremia may be noted at the time of PTLD, its detection cannot be used to confirm or PTLD, its detection cannot be used to confirm or refute the diagnosis. refute the diagnosis.

Staging is performed by histologic type Staging is performed by histologic type (monoclonal (monoclonal versusversus polyclonal, T cell polyclonal, T cell versusversus B cell) B cell) and location (allograft, other organ, metastasis).and location (allograft, other organ, metastasis).

Often the Ann Arbor classification, used for other Often the Ann Arbor classification, used for other non-Hodgkin lymphomas, is utilized non-Hodgkin lymphomas, is utilized

Human Human Herpesvirus-6, Herpesvirus-6,

Human Human Herpesvirus-7, and Herpesvirus-7, and

Human Human Herpesvirus-8 Herpesvirus-8

HHV-6,7,8HHV-6,7,8

HHV-6 is a cofactor for CMV HHV-6 is a cofactor for CMV Human Herpes Virus 8 (HHV8) is a Human Herpes Virus 8 (HHV8) is a

gamma herpes virus that has been gamma herpes virus that has been associated with Kaposi's Sarcoma(30 associated with Kaposi's Sarcoma(30 month), primary effusive lymphoma, and month), primary effusive lymphoma, and Multicentric Castleman's Disease Multicentric Castleman's Disease (lymphoproliferative disorder) (lymphoproliferative disorder)

Routine screening of HHV 6 & 8 are not Routine screening of HHV 6 & 8 are not performedperformed

Hepatitis B and C Hepatitis B and C

Hepatitis BHepatitis B All nonimmune patients with chronic All nonimmune patients with chronic

renal failure should be vaccinated with renal failure should be vaccinated with Hepatitis B vaccine and immunity Hepatitis B vaccine and immunity verified with Hepatitis B surface verified with Hepatitis B surface antibody screening following antibody screening following completion of the vaccination seriescompletion of the vaccination series

HBsAb titer o10 mIU/ml receive booster HBsAb titer o10 mIU/ml receive booster vaccination to raise the titer to X100 mIU/ml.vaccination to raise the titer to X100 mIU/ml.

All HBsAg positive pt should undergo All HBsAg positive pt should undergo live biopsy, because it is difficult on live biopsy, because it is difficult on clinical ground only to estimate severity clinical ground only to estimate severity of liver disease in CKDof liver disease in CKD(AST tend to be spuriously (AST tend to be spuriously low)low)

Decompensated cirrhosis

Biopsy liver

Cirrhosis or Precirrhosis

Replication

Preclude RT

LKT

No replication

RT

Antiviral therapy

Mild Histology

HBsAg +ve

Antiviral therapy

RT

Hepatitis BHepatitis B Risk factor for progression of HBV related liver diseaseRisk factor for progression of HBV related liver disease

AlcoholAlcohol Infection- Infection- ↑ ↑ duration, duration, ↑↑ HBV DNA, genotype C, coinfection HBV DNA, genotype C, coinfection

with hepatitis C & D, HIV, immunosuppresionwith hepatitis C & D, HIV, immunosuppresion Calcineurin inhib & AzathioprineCalcineurin inhib & Azathioprine

All pt with Hep B should receive antiviral therpy after All pt with Hep B should receive antiviral therpy after transplantation transplantation (Only 5% fail to recover)(Only 5% fail to recover)

Tenofovir or entecavir are preferable to lamivudineTenofovir or entecavir are preferable to lamivudine Adefovir or tenofovir for KTRs with lamivudine Adefovir or tenofovir for KTRs with lamivudine

resistance (>5 logresistance (>5 log1010 copies/ml rebound of HBV-DNA).copies/ml rebound of HBV-DNA). Dose reduction is needed – Lamivudine, Adefovir, IFNDose reduction is needed – Lamivudine, Adefovir, IFN During therapy with antivirals, measure HBV DNA and During therapy with antivirals, measure HBV DNA and

ALT levels every 3 months to monitor efficacy and to ALT levels every 3 months to monitor efficacy and to detect drug resistance.detect drug resistance.

Screen for hepatocellular carcinoma every 12 m with Screen for hepatocellular carcinoma every 12 m with liver ultrasound and alpha feto-proteinliver ultrasound and alpha feto-protein

HCVHCV

Graft dysfunction

NODAT(40%)

HCV RNA -ve

Anti HCV +ve

HCV RNA +ve

Cirrhosis or precirrhosisNormal

Defer transplant or consider combined liver-

kidney transplant

Liver Bx

Normal LFT

List for renal transplant

Hepatitis

HCV RNA -ve

Antiviral Rx

HCV RNA +ve

Pt by pt decision

HCVHCV

Cyclosporin inhibit HCV replication, Azathioprine

& Antilymphocye therapy ↑ replication For sustained virological response IFN & For sustained virological response IFN &

ribavirin should be co administered very ribavirin should be co administered very carefully because of risk of hemolytic anemia and carefully because of risk of hemolytic anemia and its metabolites are not cleared by HDits metabolites are not cleared by HD

Dose modification needed - RibavirinDose modification needed - Ribavirin Measure ALT monthly for the first 6 m & every 3–Measure ALT monthly for the first 6 m & every 3–

6 months,thereafter6 months,thereafter Perform imaging annually to lookfor cirrhosis and Perform imaging annually to lookfor cirrhosis and

hepatocellular carcinoma. hepatocellular carcinoma. Test HCV-infected patients at least every 3–6 Test HCV-infected patients at least every 3–6

months for proteinuria. (Not Graded)months for proteinuria. (Not Graded)

West Nile Virus West Nile Virus West Nile Virus is a flavivurus that causes a West Nile Virus is a flavivurus that causes a

febrile illness, associated with encephalitis, febrile illness, associated with encephalitis, and can be fatal and can be fatal

To prevent infection, summer To prevent infection, summer seasonal screening should be considered for seasonal screening should be considered for donors before transplantdonors before transplant

Preventive measures regarding mosquito Preventive measures regarding mosquito bitesbites

Treatment not standardized - reduction in Treatment not standardized - reduction in immunosuppression immunosuppression

AdenovirusAdenovirus CausesCauses

Hemorrhagic cystitisHemorrhagic cystitis FeverFever Renal dysfunctionRenal dysfunction PneumoniaPneumonia HepatitisHepatitis

Definitive diagnosis – renal biopsy Definitive diagnosis – renal biopsy (Granulomatous interstitial nephritis, (Granulomatous interstitial nephritis, ground glass intranuclear inclusion body)ground glass intranuclear inclusion body)

TT –Ribavirin with or without IVIGTT –Ribavirin with or without IVIG

Parvovirus B19Parvovirus B19 CausesCauses

Refractory anemiaRefractory anemia PancytopeniaPancytopenia Thrombotic microangiopathyThrombotic microangiopathy Fibrosing cholestatic hepatitisFibrosing cholestatic hepatitis EncephlitisEncephlitis Graft dysfunctionGraft dysfunction

80% in first three month80% in first three month DiagnosisDiagnosis

Bone marrow – Giant proerythroblastBone marrow – Giant proerythroblast Confirm by detection of B19 in serum by PCRConfirm by detection of B19 in serum by PCR High dose IVIG x 10 daysHigh dose IVIG x 10 days Reduction of immunsuppresionReduction of immunsuppresion

Bacterial Bacterial infectionsinfections

Bacterial infectionsBacterial infections

UTI – Prophylaxsis for 6 m with UTI – Prophylaxsis for 6 m with TMP-SMXTMP-SMX

Even low level of bacteriuria can Even low level of bacteriuria can lead to septicemialead to septicemia 2 set of blood culture should be 2 set of blood culture should be

obtainedobtained Surgical site infection – 2-25%Surgical site infection – 2-25%

Vancomycin-Resistant Vancomycin-Resistant Enterococci Enterococci

in Transplantationin Transplantation Common bacterial pathogen after kidney Common bacterial pathogen after kidney

transplantationtransplantation ““Predictor” of morbidity and mortality Predictor” of morbidity and mortality

that reflects overall “illness” of patientthat reflects overall “illness” of patient VRE may not be detectable from a single VRE may not be detectable from a single

stool culture and 3 samples should be stool culture and 3 samples should be obtained at weekly interval for 3 weeks obtained at weekly interval for 3 weeks before discontinuing search for VREbefore discontinuing search for VRE

Clostridium difficile Clostridium difficile infectioninfection

With in 2 weeks - diarrheaWith in 2 weeks - diarrhea Diarrhea occur in 13% of kidney Diarrhea occur in 13% of kidney

transplanttransplant Infectious agent 41%Infectious agent 41% Medications 34%Medications 34%

Bacterial infection Bacterial infection contd..contd..

Nocardia Nocardia Early rejection, Early rejection, ↑↑imunnosupp, neutropenia, imunnosupp, neutropenia,

uremiauremia 1-6 m after acute or subacute chest presentation1-6 m after acute or subacute chest presentation High dose TMP-SMX 15mg/kg for at least 12 High dose TMP-SMX 15mg/kg for at least 12

monthmonth TBTB

RIF>ETH – neutropeniaRIF>ETH – neutropenia INH increase levels of cyclosporin, tacrolimus. INH increase levels of cyclosporin, tacrolimus.

RIF decrease these levelRIF decrease these level Interactions are predictable occurs in 1-3 days of Interactions are predictable occurs in 1-3 days of

initiating ATT, dose adjustment neededinitiating ATT, dose adjustment needed Consider substituting rifabutin for rifampin to Consider substituting rifabutin for rifampin to

minimize interactions with CNIs and mTORiminimize interactions with CNIs and mTORi

Bacterial infection Bacterial infection contd..contd..

LegionellaLegionella Urinary antigen test 70-100% specificUrinary antigen test 70-100% specific Tt for 21 daysTt for 21 days

RhodococcusRhodococcus Months to years after TxMonths to years after Tx D/d with PTBD/d with PTB

Mixed infectionMixed infection

Fungal infectionsFungal infections

Fungal infectionsFungal infections Incidence of fungal infections in renal transplant recipients is

less than other SOT but mortality high : Limited diagnostic tools Potential for rapid clinical progression

Risk factor for colonization with yeast and molds after KT: Corticosteroid therapy Broad spectrum antibiotic Co morbid disease Domiciliary exposure

Hand book of renal transplant:( Gabriel)

Fungal infectionsFungal infections

Clincal scenario where fungal infection is seen1. Presence of urinary catheter 2. Endotracheal tube3. Immunomodulating viral inf

reactivation4. Ch. Graft dysfunction5. During treatment of post transplant

malignanciesHand book of renal transplant:( Gabriel)

Extent of problemExtent of problem

Incidence of major invasive fungal Incidence of major invasive fungal infection(IFI) among Kidney infection(IFI) among Kidney recipient patient:recipient patient:

1.1. Candida:76-95%Candida:76-95%

2.2. Cryptococcus:0-39%Cryptococcus:0-39%

3.3. Other fungi:0-39%Other fungi:0-39%

4.4. Aspergillus:0-26%Aspergillus:0-26%


Candida Candida

Occurs most Occurs most commonly during commonly during the 1the 1stst month month following following transplant transplant associated withassociated with

Sources:Sources: Endogenous: Endogenous:

Source of Source of colonizationcolonization

Exogenous: lack of Exogenous: lack of hand washing of hand washing of health workershealth workers


Candidal colonizationCandidal colonization

Pulmonary tree

BowelVagina

Esophageal / GI

Disseminated infection: <5%Kidney candidiasis: 0.5-2.2%

PROGNOSTIC FACTORS IN CANDIDEMIAPROGNOSTIC FACTORS IN CANDIDEMIAPROGNOSTIC FACTORS IN CANDIDEMIAPROGNOSTIC FACTORS IN CANDIDEMIA

Associated with death:Associated with death:-more severe clinical symptoms-more severe clinical symptoms-persisting neutropenia-persisting neutropenia-organ involvement-organ involvement--↑↑ age age

Beter survival if:Beter survival if:**catheter is removedcatheter is removed*neutropenic patients given antifungals*neutropenic patients given antifungals

AspergillosisAspergillosis

DEVELOPMENT OF ASPERGILLOSISDEVELOPMENT OF ASPERGILLOSISDEVELOPMENT OF ASPERGILLOSISDEVELOPMENT OF ASPERGILLOSIS

11 22 33

INHALATIONINHALATION INFECTIONINFECTIONCOLONIZATIONCOLONIZATION DisseminationDissemination

Renal aspergillosisRenal aspergillosis

Invasive aspergillosis : Invasive aspergillosis : diagnosisdiagnosis

Radiology: chest X-ray and CTRadiology: chest X-ray and CT MicrobiologyMicrobiology

Respiratory secretions: BAL/biopsyRespiratory secretions: BAL/biopsy Direct microscopyDirect microscopy cultureculture

Serological surveillanceSerological surveillance ELISA for galactomannanELISA for galactomannan

PCRPCR

Invasive aspergillosis: Invasive aspergillosis: TreatmentTreatment

Conventional amphoterin B: 20-83% Conventional amphoterin B: 20-83% responseresponse

?iv itraconazole: limited data?iv itraconazole: limited data Lipid formulations of ampho BLipid formulations of ampho B

5 mg/kg/day liposomal ampho B5 mg/kg/day liposomal ampho B Surgical interventionSurgical intervention

ZygomycosisZygomycosis

Median Median 2 months 2 months post-transplantpost-transplant Most cases occur within 6 months Most cases occur within 6 months

of transplantof transplant Rhinocerebral formRhinocerebral form 76% diabetes and corticosteroids76% diabetes and corticosteroids 56% mortality56% mortality

ProphylaxisProphylaxis

AmBisomeAmBisome ItraconazoleItraconazole Prophylaxsis with systemic antifungal agent Prophylaxsis with systemic antifungal agent

is not recommended after uncomplicated KT, is not recommended after uncomplicated KT, it may be indicated in those with persistent it may be indicated in those with persistent candiduria.candiduria. Azole Ambisome for a period of risk for infectionAzole Ambisome for a period of risk for infection

Those with past history fo endemic mucosis, Those with past history fo endemic mucosis, radiographic e/o healed leison – life long radiographic e/o healed leison – life long azole azole

Successful managementSuccessful management

Prompt recognition of infectionPrompt recognition of infection Adjustment of level of Adjustment of level of

immunosuppressionimmunosuppression Antifungal therapy and surgeryAntifungal therapy and surgery

TreatmentTreatment Conventional amphotericin BConventional amphotericin B

1-1.5 mg/kg/day1-1.5 mg/kg/day Nephrotoxicity big issueNephrotoxicity big issue

18% require haemodialysis18% require haemodialysis

Liposomal amphotericin BLiposomal amphotericin B Much reduced nephrotoxicityMuch reduced nephrotoxicity Superior efficacySuperior efficacy

Itraconazole: iv formulation: little dataItraconazole: iv formulation: little data Voriconazole/caspofungin: little data. Voriconazole/caspofungin: little data.

(apppears to be superior to Amb)(apppears to be superior to Amb)

susceptib

le

Empiricalor

positvetest

AmBisome

Fluconazole

AmBisome

glucan synthesis inhibitor (IV) ornew azole orally

no response

risk of aspergillosis

CULTURE

RESULT

Future Strategy Against Future Strategy Against Probable Probable

Invasive Fungal InfectionInvasive Fungal Infection??

PNEUMOCYSTIS PNEUMOCYSTIS JIROVECII PNEUMONIAJIROVECII PNEUMONIA

PCP prophylaxis with daily TMP-SMX for PCP prophylaxis with daily TMP-SMX for 3–6 months after transplantation. and for 3–6 months after transplantation. and for 6wk after treatment for acute rejection6wk after treatment for acute rejection

Diagnosed by BAL and/or lung biopsy be Diagnosed by BAL and/or lung biopsy be treated with high-dose intravenous TMP-treated with high-dose intravenous TMP-SMX, corticosteroids, and a reduction in SMX, corticosteroids, and a reduction in immunosuppressive medicationimmunosuppressive medication

Treat with corticosteroids for KTRs with Treat with corticosteroids for KTRs with moderate to severe PCP (as defined by moderate to severe PCP (as defined by PaO2 o70mmHg in room air or an PaO2 o70mmHg in room air or an alveolar gradient of 435mmHg)alveolar gradient of 435mmHg)

ParasitesParasites

MalariaMalaria Usually severeUsually severe Pyrexia, which may lack the typical periodicity or rigorsPyrexia, which may lack the typical periodicity or rigors Anemia is severe, being typically hemolytic and occasionally Anemia is severe, being typically hemolytic and occasionally

hemophagocytic, often associated with thrombocytopeniahemophagocytic, often associated with thrombocytopenia Acute graft dysfunction may occur as a consequence of the Acute graft dysfunction may occur as a consequence of the

hemodynamic consequences of falciparum infectionhemodynamic consequences of falciparum infection*. Whether the . Whether the immune response to malarial infection has an impact on immune response to malarial infection has an impact on subsequent rejection is unknownsubsequent rejection is unknown

Antimalarial drugs can be used safelyAntimalarial drugs can be used safely Drug-drug interactions must be taken into consideration as those Drug-drug interactions must be taken into consideration as those

between quinine & chloroquine with cyclosporinebetween quinine & chloroquine with cyclosporine *

*Barsoum RS. Malarial acute renal failure. J Am Soc Nephrol 2000.;11(11):2147-54Tan HW, Ch’ng SL. Drug interaction between cyclosporine A and quinine in a renal transplant patient with malaria. Singapore Med J 1991; 32: 189-190

Nampoory MR, Nessim J, Gupta RK, Johny KV. Drug interaction of chloroquine with ciclosporin. Nephron 1992; 62: 108-109

SchistosomiasisSchistosomiasis Recrudescence of schistosomal

glomerulopathy has been reported in an endemic area in South America, where mesangioproliferative glomerulonephritis with schistosomal antigen deposits developed in a recent kidney transplant recipient who originally had been infected with S. mansoni.

Prophylactically treat patients with such infection

Toxoplasmosis gondiiToxoplasmosis gondii

Lack of T cell immunityLack of T cell immunity Diagnosis by PCRDiagnosis by PCR Protected when given TMP-SMX for Protected when given TMP-SMX for

P. carniiP. carnii

Approach to the kidney Approach to the kidney transplant pt with fevertransplant pt with fever

InfectionInfection Graft rejectionGraft rejection Drug allergyDrug allergy Non infective systemic inflammatory Non infective systemic inflammatory

responseresponse PancreatitisPancreatitis Pulm. EmbolismPulm. Embolism Cytokine release syndrome Cytokine release syndrome

Thank youThank you

Health & Medicine

Final post kt infection