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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 12  |  Issue : 4  |  Page : 236-242

Modulation of maintenance immunosuppression during infection in renal transplant recipients


Department of Nephrology, Government Stanley Medical College and Hospital, Chennai, Tamil Nadu, India

Date of Web Publication18-Dec-2018

Correspondence Address:
Dr. R Vivek Praveen
Department of Nephrology, Government Stanley Medical College and Hospital, Chennai - 600 001, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_25_18

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  Abstract 


Infection occurs commonly after renal transplantation, and it is associated with significant morbidity and mortality. Infections are commonly associated with changes in the white blood cell count; however, it may be masked in the background of immunosuppression. Immunosuppression modulation during infection is crucial, keeping in mind, the risk of rejection on the one hand and risk of severe infection and mortality on the other hand. Idea about timeline of infection after renal transplantation in a particular geographical area is helpful in management of infection. The approach to modulate immunosuppressive agents will vary depending on the severity of infection. Many infections require specific anti-infective agents which may have significant drug interaction with immunosuppressive agents. It may also necessitate stoppage of immunosuppression either temporarily or permanently in severe infections to salvage the life of the patient.

Keywords: Anti-infective agent, immunosuppression, infection, renal transplantation, white blood cell count


How to cite this article:
Fernando M E, Praveen R V, Ishwarya A. Modulation of maintenance immunosuppression during infection in renal transplant recipients. Indian J Transplant 2018;12:236-42

How to cite this URL:
Fernando M E, Praveen R V, Ishwarya A. Modulation of maintenance immunosuppression during infection in renal transplant recipients. Indian J Transplant [serial online] 2018 [cited 2019 Jan 20];12:236-42. Available from: http://www.ijtonline.in/text.asp?2018/12/4/236/247790




  Introduction Top


Infection occurs in two-third of the renal transplant recipients in the 1st year after transplantation, and it is associated with morbidity, mortality, and graft loss after transplantation.[1] Constitutional symptoms of infection include fever, chills, sweat, rigor, fatigue, malaise, and weight loss. However, in the background of immunosuppression, these symptoms may be masked. Bacterial infections tend to be associated with increase in total white blood cell (WBC) count, particularly the polymorphonuclear (PMN) count. Viral infections are often associated with a decrement in the WBC count, particularly in the lymphocyte count. Viral infections may be associated with relative monocytosis. Parasite infections may be manifested by a relative eosinophilia. Fungal infections may be associated with altered WBC count, particularly PMN count.[2]

Too little immunosuppression is associated with rejection and graft loss, and too much immunosuppression is associated with infection and malignancy. Thus, a delicate and immeasurable balance exists between these two extremes. The subject of this review deals with immunosuppression modulation during various infections in renal transplant recipients.

We shall discuss the common infections that happen in India, after renal transplantation and how to deal with immunosuppression in such situations.


[Table 1]">  Timeline of Infection after Renal Transplantation-Global: [Table 1] Top
Table 1: Timeline of infection after renal transplantion - global 3

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Timeline of infection after renal transplantation – across India: [Figure 1]
Figure 1: Timeline of infection after renal transplantion – Across India[4]

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Viral infections

Human BK polyomavirus

Polyomavirus-associated nephropathy (PyVAN) is seen in 1%–10% of kidney transplant patients.[5]

Infection with BK virus (BKV) occurs in the first decade of life, as evidenced by increase in BKV seroprevalence to 90% and more.[6] Nature of BKV transmission is not resolved, but likely occurs through the respiratory or oral route.[7] Subsequently, BKV colonizes the renourinary tract as the principal site of latent infection, most likely through a primary viremia.[8] In kidney transplant recipients (KTRs), however, approximately one-third of the patients with high-level viruria (>7 log10 geq/ml) develop BKV viremia and in the absence of any intervention progress to histologically proven PyVAN.[9] This progressively affects the graft function and increase the risk of graft loss from 10% to >90%.[10]

The mainstay of therapy for PyVAN in kidney transplantation patients, without concurrent acute rejection, is reducing or discontinuing immunosuppressive drugs. Although there are no randomized-controlled trials, a number of observational studies have reported successful clearance of BKV viremia in >85% of patients.[11] More advanced disease may require more interventional steps, a longer time for recovery and result in a permanent loss of renal function.

Tacrolimus trough levels are commonly targeted to <6 ng/ml, cyclosporine trough levels to <150 ng/ml, sirolimus trough levels to <6 ng/ml, and mycophenolate mofetil (MMF) daily dose equivalent of ≤1 g[12] with low-dose steroids.

Additional strategies have been switching from tacrolimus to low-dose cyclosporine or switching from calcineurin inhibitors (CNIs) to low-dose sirolimus or switching from MMF to low-dose sirolimus.[13]

In patients with sustained high-level plasma BKV load, despite adequately reduced immunosuppression, the adjunctive use of antiviral agents may be considered.[13] Adjunctive agents include cidofovir, leflunomide, fluoroquinolones, and intravenous immunoglobulin preparations.

Kidney disease initiative global outcomes (KDIGO) suggest reducing immunosuppressive medications when BKV plasma nucleic acid testing is persistently >10,000 copies/ml. Acute rejection after reduced the immunosuppression for PyVAN should be treated according to the standard protocols.

Cytomegalovirus

Cytomegalovirus (CMV) is a ubiquitous viral infection in humans. The seroprevalence of CMV is 30%–97%.[14] Primary infection manifests as an asymptomatic or self-limited febrile illness in immunocompetent individuals, after which CMV establishes lifelong latency in various cells,[15] which serve as reservoirs for reactivation and as carriers of infection to susceptible individuals.[16]

Cautious reduction in the degree of immunosuppression should be considered in solid-organ transplant patients presenting with CMV disease, especially if the disease is moderate-to-severe stopping, the antimetabolite is advocated when treating CMV disease. It is unusual to restart it at the end of CMV. However, occasionally among the patients who are at increased risk of rejection, it can be reintroduced at a lower dose. If CMV recurs, the antimetabolite is discontinued indefinitely or else it can be continued at a lower dose.[17]

KDIGO suggests the reducing immunosuppressive medication in life-threatening CMV disease and CMV disease that persists in the face of treatment, until CMV disease has resolved.

The definitive treatment includes oral valganciclovir or intravenous (IV) ganciclovir. The adjuvant therapy includes IVIG.

Epstein–Barr virus

Epstein–Barr virus (EBV) has the seroprevalence of >89% in adults. Viral transmission occurs through saliva and sexual intercourse.[18] After primary infection, the virus persists within B-lymphocytes for life, with the majority of hosts demonstrating no evidence of active infection.

However, in KTRs, both acute infection and reactivation may lead to nonneoplastic viral replication on the one hand and EBV-medicated posttransplant lymphoproliferative disorder (PTLD) on the other hand.[19] Forms of PTLD include early, polymorphic, monomorphic, and Hodgkin lymphoma-like lesion.

Once PTLD has been diagnosed, the immunosuppressive agents are reduced. Decreasing CNI exposure, stopping the antimetabolite, and continuing lowest possible steroid dose is advocated.

Early PTLD responds to immunosuppression reduction alone, whereas other lesions in PTLD, in addition requires rituximab, chemotherapy, radiation, or a combination of these treatment modalities.[20]

KDIGO recommends that patients with EBV disease including PTLD have a reduction or cessation of immunosuppressive medication.

Other herpes viral infections

Herpes Simplex Virus

Incidence of herpes simplex virus (HSV) (superficial and invasive) is higher in KTRs than in the general population,[21] with the greatest risk occurring during the 1st month following transplantation.[22]

KDIGO recommends that KTRs who develop a superficial HSV 1, 2 infection be treated with an appropriate oral antiviral agent (acyclovir, valacyclovir, or famciclovir), until all lesions have resolved. KDIGO recommend that KTRs with systemic HSV 1, 2 infection be treated with IV acyclovir and a reduction in immunosuppressive medication.

Herpes Zoster

Primary herpes zoster (HZ) infection can be life-threatening in KTRs.[23] Immunosuppression increases the risk for the development of both uncomplicated and complicated HZ infection.

KDIGO recommends that primary HZ infection in KTRs be treated with either IV or oral acyclovir or valacyclovir and a temporary reduction in amount of immunosuppressive medication until all lesions have scabbed. Furthermore, it recommends that disseminated or invasive HZ be treated with IV acyclovir, and a temporary reduction in the amount of immunosuppressive medication, at least until all lesions have scabbed.

Hepatitis infection

Hepatitis B

The prevalence of hepatitis B among the KTRs in endemic area is as high as 15%.[24]

The specific immunosuppressive regimen varies among the centers. For patients who are at the risk of rejection to use dose of prednisolone ≤5 mg/d. Some clinicians may attempt to discontinue steroids completely in patients treated with tacrolimus and MMF. The length of the time for the steroid taper to the designed target dose is variable.[25]

Hepatitis C

The reported prevalence of hepatitis C virus (HCV) infection among renal transplant recipients is approximately 1.8%–8%.[26]

There are scarce data on the influence of steroid in kidney transplant patients with HCV infection. In the setting of liver transplantation, the steroid discontinuation after liver transplantation was associated with a reduced rate of posttransplant diabetes mellitus (PTDM).[27] It is thus reasonable to think that steroid withdrawal after kidney transplantation in HCV-positive selected patients could be beneficial to reduce PTDM.

Concerning CNIs, there are no significant differences in outcomes with cyclosporine versus tacrolimus therapy, in HCV-infected transplant recipients. However, it should be noted that the risk of PTDM is higher in HCV-positive patients, treated with tacrolimus and cyclosporine inhibits the HCV replication on cultured hepatocytes.[28]

Increased HCV viremia has been reported in patients, who received MMF in the place of azathioprine. In spite of this MMF as a part of maintenance, the immunosuppressive regimen was associated with better survival using induction, steroids, CNI, and MMF.[29]

Published information on clinical use of mammalian target of rapamycin (mTOR) inhibitors in kidney transplant patients with HCV are scarce, and therefore, the influence of mTOR inhibitors in HCV patients on patient survival after kidney transplant is unknown.

Few significant drug interaction include

Elbasvir–Grazoprevir

Coadministration with cyclosporine is contraindicated because OATB1B1/3 inhibition could result in elevated grazoprevir plasma concentration which in turn increases the risk of alanine aminotransferase elevation.

Coadministration with tacrolimus increases the concentration of tacrolimus, thus the frequent monitoring of tacrolimus whole-blood concentration is recommended.

Ritonavir-based Regimen

Ritonavir is a potent inhibitor of CYP3A4, and its use with tacrolimus, everolimus, and sirolimus is contraindicated. Ritonavir-based regimen can be used with cyclosporine (to reduce the cyclosporine dose to one-fifth).

Simeprevir

Simeprevir is avoided among the patients who are on cyclosporine since cyclosporine-induced inhibitors of OATB1B1, P-gp, and CYP3A will increase the simeprevir concentration.

Simeprevir may be used among the patients who are on tacrolimus or sirolimus, and no dose adjustments are required. However, close monitoring of the whole-blood concentration of tacrolimus or sirolimus is recommended.

Sofosbuvir

No interactions found between sofosbuvir with CNIs and mycophenolate.

HIV

In the anti retroviral therapy era, the renal transplant graft survival at 1 and 3 years is 95% and 88%, respectively.[30] Although the cyclosporine may have some antiviral effects in vitro, tacrolimus is the preferred CNI in HIV-infected transplant recipients. Sirolimus was associated with significantly higher the risk of acute rejection.[31] Although the use of steroid-sparing regimens has been reported,[32] it is not routinely followed.

Few significant drug interactions

CYP3A4 Inhibitors

Protease inhibitors and cobicistat are potent CYP3A4 antagonists. For patients on cyclosporine, a typical dose would be 25 mg every 24–48 h, while those on tacrolimus-based regimens may require 0.5–1 mg every 5 to 8 days.[33]

CYP3A4 inducers

Nonnucleoside reverse transcriptase inhibitors are inducers of CYP3A4 and can lead to low levels of CNIs when the drugs are coadministered to patients taking a NNRTI and CNI together usually require a 1.5–2-fold increase in CNI dose to achieve target trough levels.[34]

Mycobacterium tuberculosis

The incidence of tuberculosis (TB) among KTRs varies between 5% and 15% in India and Pakistan.[35] The incidence of TB among KTRs is 50–100-fold high compared to the general population. Thirty percent of active infection involves disseminated disease or extrapulmonary sites.

Drug interactions

Rifampin and calcineurin inhibitors

Rifampin by activating the CYP3A4 pathway markedly reduces the levels of CNI and mTOR inhibitors to increase the potential risk for rejection.

Rifampin and mycophenolate mofetil

Rifampin induces the intestinal hepatic and renal enzymes involved in the conversion of MMF into active MPA leading on to marked decrease in active drug.

One potential alternative is to substitute rifabutin for rifampin. Rifabutin has activity against Mycobacterium tuberculosis that is similar to rifampin, but rifabutin is not as strong as rifampin to induce CYP3A4. However, there is little-published experience with rifabutin in KTRs.

Experts agree that rifampins are indicated in patients with severe or disseminated TB or suspicion of isoniazid resistance.[36] If rifampin is used, the dose of the CNI or mTOR inhibitors should be increased, approximately three- to five-fold and serum concentration should be monitored. CYP3A4 induction by rifampin takes several days to occur, usually peaks with a week and lasts for days to weeks.[37] Rifamycins also reduce the levels of glucocorticoids, although this has been less well characterized.[38] Caution is advised against the overzealous reduction in immunosuppressive while treating posttransplant TB given the challenge of immune reconstitution inflammatory syndrome.[39]


  Severe Pneumonia Top


In an important study in KTRs,[40] 60 patients classified according to the time of pneumonia onset as early-onset severe pneumonia (E-SP) <1 year after transplant and late-onset severe pneumonia (L-SP)- >1 year after transplant. In the E-SP patients – fungi (42.1%) and viruses (31.6%) were the most common pathogens. In the L-SP patients, bacteria (42.1%) and viruses (26.3%) were the predominant pathogens.

Immunosuppressive medications were completely withdrawn in all. Methylprednisolone (1 mg/kg every 12 h) was initiated followed by gradual tapering. Total duration of the immunosuppressant withdrawal was 10 ± 3 days in the patients in the E-SP group and 8 ± 3 days in the patients on the L-SP group.

Renal function at intensive care unit (ICU) discharge was comparable to baseline and none experienced the acute allograft rejection within a mean duration of 6-month follow-up after ICU discharge.


  Parasitic Infestations Top


Malaria

Malaria is potentially fatal in the transplant recipients. Recipient traveling to endemic areas should be given appropriate chemoprophylaxis to prevent infection. Chloroquine can inhibit CYP3A4 and increase the CNI levels. Quinine may interfere with cyclosporine metabolism thereby decreasing its blood levels.[41] Artemisinin group of drugs interferes with tacrolimus metabolism therapy decreasing its blood levels, so frequent monitoring of whole blood CNI level is required. Although there is a paucity of information regarding immunosuppressive agent modulation during malaria, it is reasonable to decrease the immunosuppression during serious infections.

Entamoeba histolytica

Entamoeba histolytica infection can result in asymptomatic carriage, amoebic colitis, liver abscess, and rarely other organ involvement as well. It is unknown if the clinical presentations are altered in transplant recipients. It is reasonable to decrease immunosuppression during active infection.

Drug interactions

Azoles

Metronidazole and tinidazole can inhibit CPY3A4 therapy increasing therapeutic levels of CNIs.

Paromomycin

Tacrolimus will increase the level or effect of paromomycin by affecting multidrug resistance protein 1 (MDR1) efflux transporter. Tacrolimus and paromomycin both increase the nephrotoxicity and/or ototoxicity.

Strongyloides

Strongyloides hyperinfection syndrome (HIS) characterized by an overwhelming parasitic burden in immunocompromised individuals.[42] HIS typically occurs in the first 3 months after transplantation and 50%–70% mortality rates were reported in KTRs.

Tacrolimus may be changed to cyclosporine due to possible antihelminthic properties.[43]

Tacrolimus will increase the level or effect of ivermectin by affecting the MDR1 efflux transporter.


  Fungal Infections Top


Pneumocystis jirovecii

Pneumocystis jirovecii pneumonia (PCP) is rare, following the universal prophylaxis during the first 6–12 months. PCP is associated with 29%–50% mortality rate in KTRs.

KDIGO recommends that KTRs with PCP diagnosed by bronchoalveolar lavage and/or lung biopsy be treated with high-dose IV trimethoprim–sulfamethoxazole, corticosteroids, and a reduction in immunosuppressive agents.

Crytococcus neoformans

During cryptococcal meningoencephalitis or disseminated infection reducing the immunosuppressive therapy may be beneficial for control of cryptococcal infection. Although this immunomodulation must be weighed between rejection and immune reconstitution.[44] Reducing immunosuppressants over time in a step-wise fashion following initiation of antifungal therapy is appropriate.[45] It may be helpful to reduce the corticosteroids before CNIs since the latter class has direct anticryptococcal activity in vitro.[46] Fluconazole may increase the serum concentration of tacrolimus and reduced doses of tacrolimus will likely be required with administration of fluconazole.

Aspergillosis and mucormycosis

Dose reduction of immunosuppressive agents is advised in pulmonary or disseminated disease. An important consideration when giving voriconazole to solid-organ transplant recipients is its significant interaction with CNIs and mTOR inhibitors, which lead to increased levels of these immunosuppressants. Thus, dose reduction (reduce tacrolimus dose to one-third of the original dose)[47] and careful monitoring of serum concentrations of these immunosuppressant agents are necessary.

Candidiasis

Decreasing dose of immunosuppressive agents is considered in candidemia or invasive disease caspofungin may decrease levels of tacrolimus and frequent monitoring of tacrolimus is recommended when both are given together.

Stress-dose steroids

Inability of host to mount an appropriate hypothalamic–pituitary–adrenal (HPA) axis response is seen in severe infections. Steroids may significantly reduce the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse effects.[48]

HPA suppression was defected in 60% of the kidney or kidney–pancreas transplant patients using low-dose (1 μg) ACTH test.[49] Therefore, it is reasonable to empirically begin the stress dose of steroids (e.g., IV hydrocortisone <400 mg/d for ≥3 days)[50] and a festered approach to withdrawal that is guided by the clinical response.


  Conclusion Top


The approach to modulate the immunosuppressive agents will vary depending on the severity of the infection. If it is a life-threatening infection, stop the immunosuppressive agents except steroids, which can be hiked and changed to IV form if needed. For severe infections (e.g., CMV, varicella, pneumonia, severe urinary tract infection [UTI]), the first step is to stop the antimetabolite and if needed reduce the dose of calcineurin inhibitors. For mild infection (e, g., upper respiratory infection, mild UTI), change or dose reduction of immunosuppressive agents is generally not required. Importantly, set an alarm so that immunosuppressive agent is added or dose is increased once the infection is settled completely. Finally, to note that the life of the patient takes precedence over the graft.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Introduction
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