Infectious=20 Complications in Kidney Transplant Patients

Rasika=20 Sirsat, Hinduja=20 National Hospital, Mumbai

Renal=20 transplant is the ideal and practical treatment for rehabilitating End stage kidney Disease = patients. With tissue typing = better donor=20 recipient matching is possible. Meticulous donor evalutation, organ = procurement=20 and preservation, recipient preparation, impecabble surgical technique,=20 individualized and more potent =20 immunosuppression, antimicrobial prophylaxis and pre transplant=20 vaccination, has led to marked =20 improvement in the outcome of renal=20 transplantation.

The=20 first successful kidney transplant was performed in 1954 between = identical=20 twins. Since then, with = the=20 improvement in surgical technique and availability of newer more potent=20 immunosuppressive medications the one year survival has increased from = 88.8% to=20 93.9%. The projected half = life for=20 living donor grafts censored to exclude patients who died with = functioning=20 grafts increased from 16.9 years to 35.9 years and the half life for = deceased=20 donor grafts increased from 11 to 19.5 years¹. Despite this improvement = transplant=20 recipient remains vulnerable to several types of infections. This depends on the net state = of=20 immunosuppression which is determined by several combined factors=20 like:

=D8 =20 Immunosuppressive=20 regimen =96 the dose, duration and the types of drugs = used

=D8 =20 Drug=20 related leukopenia

=D8 =20 Breach=20 of Muco-cutaneous barriers

=D8 =20 Metabolic=20 abnormalities such as protein-caloric malnutrition, uremia,=20 diabetes.

=D8 =20 Underlying=20 immunomodulating viral infections like cytomegalovirus (CMV), = Epstein-Barr Virus=20 (EBV), hepatitis B virus (HBV), Hepatitis C virus (HCV), Human herpes 6 = (HHV-6)=20 and human immunodeficiency virus (HIV). =20 Opportunistic infections (OIs) occur in the context of viral=20 replication.

=D8 =20 Elderly=20 patients have increased infection risk and decreased risk of = rejection, hence a lower dose of immunosuppressive drugs should = be=20 used.²

In a=20 normal host, symptoms=20 increase steadily in proportion to viral load. In the transplant recipient, = however=20 symptoms may remain occult and then suddenly escalate at a point when = there is=20 little available time left for effective antimicrobial treatment. Therefore, constant = monitoring and=20 early diagnosis of infection are essential to initiating treatment = before that=20 point is reached. The = microbial=20 burden increases with time and later the therapy is begun, longer and = more=20 intense treatment may be required. =20 Moreover there is increased possibility of developing resistance = to=20 antimicrobial drugs and also of transmitting the injection to other=20 individual. =20

Infection,=20 rejection and even vaccination can all stimulate production of = cytokines,=20 chemokines and growth factors that, in turn, can create a receptive = environment=20 for both rejection and infection.

Immunosuppressive=20 drugs used in Transplantation

Corticosteroids=20 and azathioprine were the first drugs to be used in=20 transplantation.³ = They=20 exert both immunosuppressive and anti inflammatory effects by inhibiting = proinflammatory cytokine production particularly Interleukin 2=20 (IL-2).

Calcineurin=20 inhibitor (CNI), Cyclosporine was introduced in early 1980 and = dramatically=20 improved renal graft survival while reducing the need for = corticosteroids. Cyclosporine is a selective = inhibitor of=20 IL-2 =96 a T cell growth factor. =20 It exercises dose related inhibition of microbe specific T cell = cytotoxic=20 activity which is the main host defense against many infections eg.=20 herperviruses. = Tacrolimus, also a=20 CNI has a similar effect but is 100 times more potent than=20 cyclosporine.⁴

Mycophenolate=20 mofetil is a highly selective inhibitor of de novo purine = synthesis. It is more potent than=20 azathioprine.⁴

Sirolimus=20 (rapamycin) is a target of rapamycin inhibitor that inhibits growth = factor=20 signaling for both immune and non-immune cells.⁵ This antiproliferative effect = makes it=20 useful for the prevention and treatment of chronic allograft=20 injury.

T cell=20 depleting agents like polyclonal antibodies e.g. antithymocyte globulin = (ATG)=20 and the more specific monoclonal antibodies eg. OKT3 are extremely = effective in=20 reversing acute corticosteroid refractory rejection. They also stimulate the = release of=20 tumour necrosis factor (TNF) thereby =20 increasing the net state of immunosuppression and causing = reactivation of=20 herpesviruses like CMV, EBV.

Monoclonal=20 antibodies to IL-2 receptor eg. daclizumab and basiliximab are more = specific and=20 decrease the incidence of acute rejection without triggering cytokine=20 release. =

Timing=20 of post transplant infections

Dr.=20 Rubin published the time line of infections in transplant patient in=20 1993.⁶ In the = first post=20 transplant month there is a notable absence of opportunistic infections = (OIs)=20 despite higher dosage of immunosuppressive drugs. This indicates that the = duration of=20 sustained immunosuppression is a more significant determinant of the net = state=20 of immunosuppression.

During=20 the first month after = transplant=20 one can expect to see 3 types of infections:

=D8 =20 Infection=20 already present and not eradicated prior to transplant which may worsen = with=20 immunosuppressive regimen.

=D8 =20 Infections=20 as seen in other patients i.e. wound infection, urinary tract infection, = vascular access infection and pneumonia. =20 These are most common.

=D8 =20 Infections=20 transmitted with allograft. =20

The=20 only significant viral infection observed during the early period after=20 transplant is caused by recurrent Herpes Simplex virus (HSV). The incidence has been reduced = by=20 prophylactic anti viral therapy.

In the=20 1 =96 6 month after transplant, is the period of maximum T cell immune=20 dysfunction, immuno = modulating=20 viruses like CMV, EBV, = HHV-6, 7,=20 8; HAV, HBV and HCV are = seen. These infections increase the = net state=20 of immunosuppression resulting in increased incidence of opportunistic=20 infections like = pneumocystis=20 carinii pneumonia (PCP), listeria monocytogenes, cryptococcus neoformans = and=20 Toxoplasma gondii. = Reactivation of=20 Mycobacterium, coccidiomycosis emerge during this = period.

Beyond=20 six months, patients fall into one of 3 = categories.

=D8 =20 Those=20 having good transplant outcome on low dose maintainance = immunosuppression. They usually have community = aquired=20 infections.

=D8 =20 Those=20 with chronic viral infections like CMV, EBV, hepatitis which can lead to = damage=20 of infected organ or malignancy.

=D8 =20 Those=20 with poor allograft function due to recurrent episodes of rejection resulting in greater = exposure=20 to immunosuppression and thus at highest risk for OIs. They need to continue = antimicrobial=20 prophylaxis indefinitely.

Impact=20 of viral infections in renal Transplant = recipient

The=20 effects of viral infection are classified as =93direct=94 and = =93indirect=94. Direct effect is due to = invasive viral=20 infection resulting in fever, leucopenia, pneumonia, enteritis, = meningitis,=20 encephalitis, etc. = Indirect effects=20 are due to the release of cytokines, chemokines or growth factors which = are=20 immunomodulatory and = result in=20 further immunosuppression and hence increase the risk of = opportunististic=20 infections, rejection, oncogenesis and increased replication of other = viruses=20 (eg. CMV and hepatitis C) in a form of =20 =93viral cross talk=94.

With=20 use of more potent immunosuppressive agents like ATG, mycophenolate, = Rapamycin=20 and Tacrolimus a new time line of infection is evolving. Newer virus like BK virus is = appearing=20 not only as opportunistic = infections but also as a = limitation=20 to graft survival. This = risk is=20 seen over an extended period of time.

Herpesvirus=20 group

The=20 herpes viruses are the most important microbial pathogens among renal = transplant=20 recipients. Included in = this group=20 are CMV, EBV, Varicella = =96 Zoster,=20 herpes Simplex and HHV 6, 7 and 8. =20 They all share 3 characteristics, i.e. latency, cell association = and=20 potential for oncogenecity.

=D8 =20 Latency:=20 once an individual is infected, there is always latent intracellular = virus that=20 can be reactivated later, either spontaneously or in reaction to an = exogenous=20 stimulus such as immunosuppression.

=D8 =20 Cell=20 association: These = viruses are=20 transmitted via direct cell to cell contact as in transplantation, blood = transfusion. Once = infected cells=20 are in contact with susceptible cells the host=92s humoral immunity is = not=20 effective in eradicating the infected cells. A key host defense is major=20 histocompatibility complex =96 restricted, virus specific cytotoxic T = cells. The degree to which = immunosuppression=20 affects the cytotoxic T cell response affects the infection. In the presence of MHC = disparity=20 the host may have increased difficulty in eliminating the=20 virus.

=D8 =20 Potential=20 of oncogenicity: EBV is = the primary=20 etiologic factor for post transplant lymphoproliferative = (PTLD)⁷ and=20 the presence of CMV further increases the incidence of PTLD, most likely = because=20 of cytokines, chemokines and growth factors that are upregulated in the = presence=20 of CMV.

HHV-8=20 is responsible for Kaposi=92s sarcoma.⁸

CMV

CMV is=20 the single most important pathogen in transplant recipients due to both = direct=20 and indirect effects . = =93CMV=20 Infection=94 is defined as isolation of the CMV virus or detection of = viral=20 proteins or nucleic acids in body fluids or tissue specimen.

=93CMV=20 disease=94 is defined by the presence of signs and symptoms of tissue = injury=20 combined with virus isolation and or histopathologic or = immunohistochemical=20 evidence of CMV in tissue samples. Infection presents as asymptomatic = viremia,=20 fever and neutropenia often with myalgias and fatigue. Choreoretinitis and colitis = are often=20 seen later in the post transplant course.

Indirect=20 effects can be significant. = CMV=20 infection suppresses host defenses predisposing to secondary invasion by = pneumocystis, candida, aspergillus species, etc. CMV can also contribute to the = risk of graft=20 rejection, EBV mediated - post transplant lymphoproliferative disorder = (PTLD),=20 HHV-6 and HHV-7 infections.⁹

In=20 seronegative individual primary CMV infection can occur through blood=20 transfusions, sexual contact or allograft. =20

In=20 seropositive individuals reactivation of CMV infection can occur in 10 = to 15% of=20 patients on conventional immunosuppressive treatment but the rate = increases with=20 the use of biological agents either as induction or anti rejection=20 treatment.¹⁰ =20

There=20 is a close link between CMV and cytokines. =20 Tumor necrosis factor (TNF) is the key mediator in the = pathogenesis of=20 CMV disease. TNF combines = with TNF=20 receptor on latently infected cells, initiating activation of protein = kinase C=20 and nuclear factor Kappa B (NFkB) which translocates into the nucleus = and binds=20 to CMV =96 immediate early enhancer region, initiating viral = replication. Infected cells produce IL-I = activating=20 destructive activity in the surrounding cells.

Serologic=20 tests are useful before transplantation to predict risk for disease but = are of=20 little value after transplantation in defining acute clinical disease as = seroconversion may not occur until well after the resolution of = symptoms. Quantitation of intensity of = CMV=20 infection is related to the risk for infection in transplant recipients = and is=20 essential for the management of acute infections. The antigenemia assay is a=20 semiquantitative fluorescence assay in which circulating neutrophils are = stained=20 for CMV early antigen (PP65 or PP67). The molecular assays = (DNA PCR,=20 hybrid capture, amplification assays) are highly specific and sensitive = for the=20 detection of viremia.

Quantitative=20 CMV assays have 2 prominent gaps: neurologic disease including = chorioretinitis=20 and gastro intestinal disease including invasive colitis and = gastritis. In these syndromes the CMV = assays are=20 often negative and biopsy diagnoses is necessary.

CMV=20 Prevention

Patients=20 at risk for primary infection (D+/R-) are given valganciclovir = prophylaxis for 3=20 =96 6 months after transplantation.¹¹ Patients at lower risk (R+) = may be=20 followed up using quantitative assays at weekly intervals to detect and = treat=20 pre emptively.¹²

Treatment

Intravenous=20 Ganciclovir 5 mg/kg twice daily (dose adjusted for renal dysfunction) for 2 = to 3=20 weeks. In seronegative = patients and=20 those slow to respond to treatment, addition of CMV hyperimmune globulin = (100 to=20 150 mg/kg per dose intravenously given monthly). Intravenous treatment should = be=20 continued till viremia has cleared, =20 followed by oral valganciclovir for 3 to 6 months. Alternative therapies include=20 forscarnet, cidofovir and leflunomide. =20

VZV

VZV can=20 present as localized dermatomal zoster to multi dermatomal or or = disseminated=20 zoster¹³ with = or without=20 visceral involvement. =20 Pediatric patients taking MMF have more generalized vesicular=20 lesion,¹⁴disseminated intravascular coagulation and hepatitis occur in up to = half of=20 these patients. Over all = mortality=20 is more than 30%. =20 Disseminated VZV must be treated with high dose acyclovir with = reduction=20 in immunosuppression.

Varicella=20 vaccination in pre transplant period may help to protect vulnerable=20 population. After = transplant use of=20 live vaccines is avoided. = Varicella=20 zoster immunoglobulin is recommended for immunocompromised individual = with=20 exposure to Varicella / Zoster.

EBV/PTLD:

Primary=20 EBV infection presents as a mononucleosis type syndrome, with = lymphocytosis with=20 or without lymphadenopathy and pharyngitis. Meningitis, hepatitis and = pancreatitis=20 may also occur.

Primary=20 EBV infection increases the risk of PTLD by 10 to 76 fold.¹⁵ The incidence of PTLD among = kidney=20 transplant recipient ranges from 1 to 3%. =20 The spectrum of diseases ranges from benign polyclonal B cell = infectious=20 mononucleosis like disease to malignant monoclonal lymphoma. The majority is of B cell = origin=20 although T cell, NK cell and Null cell tumours have been described. Primary EBV infection, EBV=92 = load,=20 presence of HCV, CMV, use = of CNI=20 and OKT3 increases the risk of developing PTLD.

Lymphomas=20 comprise up to 15% of tumours among adult transplant recipients (51% in=20 children) with mortality of 40 =96 60%.

Compared=20 with lymphoma in the general population, PTLD has increased extranodal = involvement,=20 poorer response to conventional therapies and poorer=20 outcomes.

PTLD=20 may present as

=D8 =20 Unexplained=20 fever

=D8 =20 Lymphocytosis

=D8 =20 Gastrointestinal=20 bleeding, obstruction, perforation

=D8 =20 Back=20 pain

=D8 =20 Infiltrative=20 disease of allograft

=D8 =20 Hepatic=20 or pancreatic dysfunction

=D8 =20 Headache=20 or CNS involvement

=D8 =20 Chest=20 nodules on XRay.

Quantitative=20 EBV viral load may be helpful for the diagnosis and management of = PTLD. The first step in the = treatment is=20 reduction of immunusuppression as much as feasible. In polyclonal form especially = in=20 children reduction of immunosuppression may cause regression of = PTLD. Antivirals may affect the = continuing=20 lytic infection that triggers the proliferative process. Antiviral treatment also = impacts=20 possible co infection with CMV.

EBV=20 negative PTLD may occur later after transplantation and may be more = severe. =

In=20 extranodal disease and or monoclonal malignant form alternate therapies = may be=20 required. Combination of = anti-CD20=20 (Rituximab) plus chemotherapy = with=20 cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone = (CHOP), irradiation for central = nervous system=20 disease may be used. =20

HHV-6=20 can present as fever, mononucleosis, interstitial pneumonitis, hepatitis = and=20 encephalitis. = Co-infection with=20 HHV-6 and CMV promotes development of symptomatic CMV disease and = susceptibility=20 to other OIs.

HHV-8=20 is associated with Kaposi sarcoma (KS),^8,17 castleman disease = and=20 primary effusion lymphoma. = In renal=20 transplant recipients KS occurs in 0.2% to 5% of the patients. KS progenitor cells may be = transmitted=20 from donor to recipient at the time of transplant. HHV-8 has also = been linked=20 with hemophagocytic syndrome, a combination of febrile = hepatosplenomegaly,=20 pancytopenia, hypofibrinogenemia and liver = dysfunction.

Treatment=20 usually involves reducing the immunosuppressive medication and treatment = with=20 chemotherapy or foscarnet.

BK=20 Polyomavirus

Treatment=20 of cellular rejection, = use of high=20 dose immunosuppression particularly tacrolimus and MMF, use of = biological=20 agents, severe ischemia =96 reperfusion are some of the risk factors for = developing BK nephropathy.¹⁸ =20 BK virus infections may be asymptomatic or present with Ureteral=20 ulceration, stenosis and hemorrhagic cystitis. Active infections may be = associated with=20 progressive loss of graft function (BK Nephropathy). Presentation is usually a = sterile=20 pyuria, shedding of infected tubular and ureteral epithelial cells which = are=20 detected by urine cytology as =93decoy Cells=94. Patients with BK nephropathy = treated as=20 acute rejection have a high incidence of graft = loss.

Renal=20 biopsies demonstrate cytopathic changes in renal epithelial cells = without=20 cellular infiltration with the gradual evolution of cellular = infiltration=20 consistent with diagnosis of interstitial = nephritis.

There=20 is no accepted treatment for BK nephropathy other than reduction of=20 immunosuppression. = Low dose cidofovir has been used = but may=20 result in renal toxicity. =20 Leflunomide and derivatives and fluroquinolone antimicrobials are = under=20 investigation for treatment of BK nephropathy.

JC=20 Virus

Presents=20 as both nephropathy and or progressive multifocal=20 encephalopathy.

HBV

With=20 institution of specific infection control practices and HBV vaccination = the=20 prevalance of HBV infection is <5%.¹⁹ HBV infection is associated = with=20 increased morbidity and mortality after renal=20 transplantation.²⁰

IFN=20 a is not=20 recommended for HBV in renal transplant recipients. Lamivudine is effective in = normalizing=20 aminotransferases and eliminating HBV-DNA. =20 However, = resistance to=20 Lamivudine can develop in up to 46% of patients. Adefovir dipivoxil and = entecavir are=20 effective in treating lamivudine resistant disease. Adefovir can be=20 nephrotoxic.

Vaccination=20 against HBV in non immune renal transplant candidates is essential = however the=20 efficacy of vaccination is reduced when administered after=20 transplantation.

HCV

Many=20 recipients are infected before renal transplantation. HCV infection is associated = with=20 increased morbidity and mortality in renal transplant=20 recipients.²⁰

HCV=20 infection is diagnosed serologically, although some patients with active = disease=20 and positive HCV viral load remains antibody negative. A smaller group remains HCV = serum RNA=20 negative and HCV liver RNA positive.

IFN=20 treatment carries a risk for graft rejection.²¹ However, low dose IFN = & plus=20 ribavirin 600 mg/day has been tried as also ribavirin=20 monotherapy.

Parvo=20 virus 19

Parvovirus=20 B19 can cause erythropoietin resistant anemia, myocarditis, pneumonitis, = Pancytopenia, allograft dysfunction with = glomerulopathy.

Fungal=20 Infections

Prolonged=20 dialysis prior to transplantation, diabetes, immunosuppression with = tacrolimus,=20 episodes of rejection, prolonged antibiotic usage, IV lines, indwelling foley catheter are = risk=20 factors for fungal infection.^22,23 However, reduction in the = dosage of=20 cortico steroids, improved surgical technique and the development of = effective=20 treatments have reduced the incidence of invasive fungal infection. Candida is the most common = fungal=20 infection accounting for 90 to 95% of all invasive fungal infections in = renal=20 transplant recipients.

Cryptococcus=20 neoformans occurs in approximately 2.8% of renal transplant = recipients. Portal of entry is through the = lungs. It is = disseminated rapidly to the central nervous = system,=20 skin, bones and soft tissue.

Aspergillus=20 spp is an angioinvasive fungus, the portal of entry being the = lungs. Once blood vessels are = infected, tissue=20 infarction, hemorrhage and metastases often follow. Mortality is greater than 75% = for=20 invasive pulmonary disease and approaches 100% with disseminated disease = and=20 central nervous system involvement.

The=20 incidence of Zygomycosis = has=20 decreased considerably. = Most cases=20 occur within 6 months of transplantation. =20 These fungi are ubiquitous in nature and associated with decaying = material inhalation is the most common portal of entry. Risk factors for disease = include=20 augmented immunosuppressive treatment for rejection, diabetes mellitus,=20 metabolic acidosis and neutropenia. =20 Rhino cerebral disease is the most common presentation. Mortality is significant = without early=20 diagnosis and prompt initiation of antifungal therapy and surgical=20 debridement.

Pneumocystis=20 Carini Pneumonia (PCP)

=B7 =20 There=20 is a dramatic decline in the incidence of PCP with prophylaxis with=20 TMP/SMX. Usually occurs = within=20 first 6 months but can occur beyond 12 months in patients receiving = augmented=20 immunosuppression.

Most=20 patients with PCP present with shortness of breath, non productive cough = and=20 fever. Significant = hypoxemia may be=20 present. Trimethoprim =96 = sulfa=20 methoxazole is the drug of choice for treatment of PCP. Other agents like pentamidine, = atovaquone, clindamycin =96 primaquine and dapsone can also be used in = patients=20 who are intolerant, allergic or =20 resistant to TMP =96 SMX.

Tuberculosis

Tuberculosis=20 is a serious complicating factor in renal transplantation, with an incidence of 0.35 to = 15%=20 ²⁴depending on the geographic region. It usually involves the lung = and is=20 disseminated in one third of the cases. =20 Those at risk of developing active tuberculosis should be given = isoniazid=20 prophylaxis for one year.

With=20 the introduction and usage of newer immunosuppressive agents the = incidence of=20 acute rejections has decreased significantly. More potent immunosuppression = however=20 have made these patients vulnerable to various infections. Infection is far better = prevented=20 than treated. =20

Prevention

=B7 =20 Pre=20 transplant screening of oral cavity, urine, Xray chest for infections = and if=20 present appropriate treatment.

=B7 =20 Post=20 transplant prophylaxis with TMP/SMX =96 reduces the risk of developing = PCP,=20 listeria, toxoplasmosis, nocardiosis & UTI.

=B7 =20 Valgancyclovir decreases risk of developing=20 CMV

=B7 =20 Isoniazid=20 prophylaxis reduces the risk of developing = tuberculosis

=B7 =20 Nystatin=20 mouth paint to reduce fungal infections.

=B7 =20 Good=20 hygiene and environment

=B7 =20 Vaccination

Vaccination=20 for vaccine preventable diseases should be advocated prior to = transplantation=20 especially in case of live attenuated vaccines like varicella. Pre transplant = evaluation of=20 pre-existing infections and their treatment and post transplant = prophylaxis for pnuemocystis carini, = tuberculosis=20 and CMV as and when indicated should be given. The goal for treatment = should be=20 to prevent both graft rejection as well as = infection.

References

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