optimal immunosuppression to prevent infection

1. Dr. M. Ranjanee
M.D.(Gen Med) D.M. Nephrology (SGPGIMS ), FIMSA ,CHS
Senior Consultant Nephrologist & Transplant Physician
Apollo Hospitals , Chennai
Post Renal Transplant –
Optimizing Immunosuppression
to Reduce Infection Risk

2. Introduction
• Kidney transplant rates has increased world-wide since first
successful transplant in 19541
• With improved immunosuppressive regimens,
o Main barriers to disease-free survival - infection & malignancy 2
• Infections:
o 2nd cause of death in patients with allograft function
o 70% of all KTRs  at least one infection episode by 3 years
o Estimated rate: 45* per 100 patient-years of follow-up in initial 3 years
2
•1. Fishman JA; Infection in the solid organ transplant recipient 2018 . Available at
https://www.uptodate.com/contents/infection-in-the-solid-organ-transplant-recipient
• 2. Shamila et al Clin J Am Soc Nephrol 7: 2058–2070, 2012

3. Infections in Immunosuppression
• Fever: Neither sensitive nor a specific predictor of infection2
o ~40% infections  No fever (especially fungal infections)
o ~22% of fevers  Non-infectious in origin
o Allograft rejection, may develop fever in transplant recipients
3
Fishman JA; Infection in the solid organ transplant recipient. Available at
https://www.uptodate.com/contents/infection-in-the-solid-organ-transplant-recipient#H3;
accessed in 05 Nov 2018;
Immuno-
suppression
Therapy
Increased
susceptibility
to microbial
invasion
Susceptibility
Impaired inflammatory
responses associated
microbial invasion
Immune
response
• Diminished
symptoms
• Muted clinical /
radiologic finding
• Different
presentation
Diagnosis

4. Current Transplantation Era
4
. Fishman JA; Infection in the solid organ transplant recipient.
Available at https://www.uptodate.com/contents/infection-in-the-solid-organ-transplant-recipient#H3; accessed
in 05 Nov 2018; 2.Sawyer RG etal Clin Transplant 1999; 13:260.
Risk of Rejection
(Under-
Suppression)
Risk of infection
(Over-suppression)

5. Determinants of infections
5
Fishman JA; Infection in the solid organ transplant recipient. Available at https://www.uptodate.com/contents/infection-in-the-solid-
organ-transplant-recipient#H3; accessed in 05 Nov 2018; 2.Fishman JA. N Engl J Med 2007; 357:2601.
Causative
Organism
& its virulence
Net State of
Immuno-
suppression
Current level
of Protection
(Vaccine /
Prophylaxis)
Infectious
complication
Infection risk post transplant changes over time
No assays for accurate measurement
Etiology of
Infection

6. Etiologies of Infection
6
Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007; 357:2601
Epidemiologic
Exposures
Community
acquired
Nosocomial
Surgery
related
Reactivation
Opportunistic
Donor
Derived

7. Net State of Immunosuppression
Though none of the association are consistent
the notable association would be:
7
Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007; 357:2601
Immunosuppresive Agent Infection Risk
Plasma pheresis Encapsulated bacteria ,line infections
Corticosteroids Bacteria , fungi (PCP),Hep B , wound healing
Mycophenolate mofetil Overall increase in infections, especially viral
ATG CMV and BKV reactivation, ARDS
Tacrolimus and MMF BKV nephropathy , SAR-CoV2
Alemtuzumab Viral , invasive fungal ,PML
Rituximab Nesseria infection ,PML
Belatacept UTI, EBV/PTLD
Basiliximab Reduced risk of CMV
Everolimus Reduced incidence of CMV & BKV

8. Risk Factors for Infection
8
Infection
Recipient
Extremes of age
Female gender
Pre transplant
SLE as primary cause
Pre-transplant DM
Time on dialysis
Arteriovenous graft
Transplant related
Higher HLA
mismatches
Delayed Graft Function
Donor
Deceased donor
Older donor age
CMV positive
donor

9. Timeline of infections in KTRs
Business Use Only
9
Jha V. Indian J Nephrol. 2010 Oct;20(4):171-8.

10. Immunosuppressive Strategies

11. Risk stratification
11
Cippà PE, Schiesser M, Ekberg H, et al. Clin J Am Soc Nephrol. 2015;10(12):2213-20.
Integrated risk
stratification
approach
Risk of
rejection &
infection
vary
KTRs are highly
heterogeneous
population
Rejection (Immunological)
Risk stratification
• Mild risk
• Moderate Risk
• High Risk
Infection Risk?
• No established approach

12. Risk stratification
Rejections and severe infections have similar incidences in the first year after transplantation
The curves for infection (red) and rejection (purple) end points intersect at day 139 after
transplantation.
12
Cippà PE et al . Risk Stratification for Rejection and Infection after Kidney Transplantation. Clin J Am
Soc Nephrol. 2015;10(12):2213-20.

13. Risk stratification
An attempt of integrated risk stratification basis Symphony1
13
Cippà PE, Schiesser M, Ekberg H, et al. Risk Stratification for Rejection and Infection after Kidney Transplantation. Clin J Am Soc Nephrol. 2015;10(12):2213-20.

14. Risk stratification- Recommended Model1
• Model based on parameters at
the time point of Tx in ELITE-
Symphony
• Strategy broadly useful
• Personalized target levels of IS
• determining duration of
prophylaxis
• Identification of patients who
might benefit from
immunosuppression
minimization or tolerance
induction protocols
Business Use Only
14
Cippà PE, et al. Risk Stratification for Rejection and Infection after Kidney Transplantation. Clin J Am
Soc Nephrol. 2015;10(12):2213-20.

15. Ways of Prevention
Business Use Only
15
Fishman JA; Infection in the solid organ transplant recipient. Available at https://www.uptodate.com/contents/infection-in-the-solid-organ-transplant-recipient#H3; accessed in 05 Nov 2018
Pre-Transplant
Measures
Screening of Donor
Screening &
treatment of
recipient
Vaccination
Peri-Transplant
Measures
Pre-Surgical
prophylaxis
Technical Measures
Induction Regimen
Post transplant
Measures
Immuno-
suppressive
regimen
Dynamic
Surveillance
Post Transplant
Prophylaxis

16. Selection of induction therapy
16
Transplant International, Volume: 26, Issue: 7, Pages: 662-672, First published: 31 December 2012,
DOI: (10.1111/tri.12043)

17. Immunosuppression
17
Nicolas C. Issa, etal Clinical Infectious Diseases, Volume 48, Issue 6, 15 March 2009, Pages 772–786
Induction Therapy Maintenance Therapy Antirejection therapy
Fungal
Viral
Bacterial
• Most common form
• UTIs, Wound,sepsis
bacteremia, and
pneumonia
• E.Coli, Enterococcus
 most isolated
uropathogens
• Role in CMV
promotion and
activation
• Increased risk of EBV
& PTLD (higher with
CMV co-infection)
• BKV viremia  BKV
nephropathy (esp at
higher doses)
• HCV replication 
mortality in KTRs
(not in HCV +ve)
• Pneumocystis
Pneumonia and
other invasive
fungal infections,
in absence of
prophylaxis
• False-positive
assay results for
Histoplasma
antigens
r ATG

18. Immunosuppression to alter infection risk
18
Nicolas C. Issa, etal Clinical Infectious Diseases, Volume 48, Issue 6, 15 March 2009, Pages 772–786
Induction
Therapy
Maintenance Therapy
Antirejection
therapy
Basiliximab (low-mod immunological risk)
Active / History of viral
infections
Elderly (>65yrs )donor/
recipients
Deceased donor with
mod-high infection risk
(donor derived)
Low dose ATG (High immunological risk)
Higher number of HLA
mismatches
Higher risk of infection
ATG (High
immunological risk)
Minimal infection risk
on adequate screening
of recipient & donor
Universal anti CMV
prophylaxis+ PCP prophylaxis

19. Immunosuppression
19
Kirk AD et al. Transpl Int 2005 Jan; 18 (1): 2–14 Nicolas C. Issa, etal Clinical Infectious Diseases,
Volume 48, Issue 6, 15 March 2009, Pages 772–786; http://www.antimicrobe.org/t34.asp#t2
Induction Therapy
Maintenance
Therapy
Antirejection
therapy
Infection CNIs MMF mTORi Belatacept Steroids
Bacterial + ++ + ++
URTI + (CsA) ++ ++ (Siro)
UTI + (CsA) +++ ? +
Sepsis + (CsA) +++ ?
Viral infection + (Tac>CsA) ++ + (Siro) +(PTLD) +
BKV 
Nephropathy
+++ (Tac) +++ - ++ (Maintenance)
CMV ++ (Tac) +++ - ?
Fungal Infection + + + ++
PCP + + ++ (Siro) ++
Other effects impacting infection risk
Leukopenia - ++ ++ (Siro)
Diabetes
+++ (Tac)/+
(CsA)
- - +++
Antifungal
properties
++ - - -

20. Immunosuppression to alter infection risk
20
Kirk AD etal. Transpl Int 2005 Jan; 18 (1): 2-14
Induction Therapy
Maintenance
Therapy
Antirejection
therapy
IS reduction based on clinical over-suppression
• CNI or MMF reduction as per IS status
Immunosuppression reduction / elimination in clinical stability
• Steroid reduction /withdrawal
• Steroid avoidance
• CNI switching /reduction
• Alternative regimens
• Compensatory immunosuppressant elimination

21. Immunosuppression to alter infection risk
IS reduction for clinical over-suppression
o Viral replication  Biological surrogate for over-immunosuppression
 Non rejection of Viral replicating cells indicate inability to reject organs
 Eg: BK polyoma virus, CMV, EBV
Prophylactic anti-infective regimens  counters infection risk
 Limited to CMV, PCP, and urinary tract infections
Viral load monitoring as guide to immunosuppressive reduction
21
Nicolas C. Issa, etal Clinical Infectious Diseases, Volume 48, Issue 6, 15 March 2009, Pages 772–786
Induction Therapy Maintenance Therapy Antirejection therapy
Active viral disease need less immunosuppression & comprise a category
of individuals in whom reduction should be considered strongly

22. Immunosuppression to alter infection risk
IS reduction/elimination in clinical stability
Reduction in clinically stable may seem less intuitive, reasons include
o Chronic immunosuppression  graft survival worsened
o Regimen may not be precisely right  any error can be minimized by
judicious drug withdrawal
All agents commonly used in triple drug regimens have been reduced in
prospective trials with reasonable degrees of success
22
Kirk AD etal. Transpl Int 2005 Jan; 18 (1): 2–14 Nicolas C. Issa, etal Clinical Infectious Diseases,
Volume 48, Issue 6, 15 March 2009, Pages 772–786; http://www.antimicrobe.org/t34.asp#t2
Induction Therapy Maintenance Therapy Antirejection therapy
Steroids
reduction /
withdrawal
Steroid
avoidance
CNI
switching /
Reduction
Alternative
regimen
Compen-
satory IS
elimination

23. Immunosuppression to alter infection risk
Business Use Only
23
Kirk AD etal. Transpl Int 2005 Jan; 18 (1): 2–14 Nicolas C. Issa, etal Clinical Infectious Diseases, Volume 48, Issue 6, 15 March 2009, Pages 772–786; http://www.antimicrobe.org/t34.asp#t2
Induction Therapy Maintenance Therapy
Steroids
reduction /
withdrawal
Steroids
avoidance

24. CNI reduction in combination with mTORi
24
TRANSFORM: Significant fall in infection rate at 12 & 24 months1
1.J. Pascual, TTS 2018
52.0
34.8
17.2
4.3 3.6 6.8
14.4
59.8
37.6
29.2
8.0
13.3
4.5
14.9
0
20
40
60
80
100
Any… Bacterial Viral BKV CMV Fungal Unknown
Proportion
of
patients
(%)
EVR+rCNI (N = 1014)
MPA+sCNI (N = 1012)
57.6
37.9
20.5
4.5 4.3 7.9
20.0
65.6
40.6
35.3
8.6
15.6
5.3
19.4
0
20
40
60
80
100
Any
infection
Bacterial Viral BKV CMV Fungal Unknown
Proportion
of
patients
(%)
P < 0.001
P < 0.001
P < 0.001
P = 0.0004
M12
M24
P < 0.001
P < 0.001
P < 0.001 P < 0.001

25. Immunosuppression to alter infection risk
Elimination of any IS drug  Two drug / one drug
 Steroids > MMF = Everolimus > CNIs
• Late post-transplant period
o Immunosuppression need lesser
o No trial with compensatory IS elimination has been shown to actually
improve patient outcome in terms of rejection risk
o However, reduce of drug often improve the effects of that drug & can
improve infection risk
25
Kirk AD etal. Transpl Int 2005 Jan; 18 (1): 2–14
Induction Therapy
Maintenance
Therapy
Compensatory
IS elimination
Evidently, Most patients do not need triple immunosuppression for
life. Considering fundamental causes of allograft rejection, a potential
elimination regimen can be explored

26. Immunosuppression to alter infection risk
• Infection risk with anti-rejection therapy  critical as any infection
predisposes to rejection
o Owing to altered pro-inflammatory & anti-inflammatory milieu
26
Kirk AD etal. Transpl Int 2005 Jan; 18 (1): 2–14
Induction Therapy
Maintenance
Therapy
Antirejection
therapy
Appropriate prophylaxis regimen to be adopted to contain infection risk
ATG High Dose Steroids Bortezomib
Pseudomonal sepsis BKV reactivation Varicella zoster
Viral and invasive fungal

27. BKV Infection & Immunosuppressive agents
• Tacrolimus or MMF therapy & Recurrent rejection episodes  increase the
risk of persistent BKV replication in KTRs
• Routine screening for BK viremia monthly for 9 months, then 3 monthly until
2 years’ post-transplant
Currently no established antiviral treatment is available
control of viral infection via reduction in immunosuppression
27
Shamila et al Clin J Am Soc Nephrol 7: 2058–2070, 2012

28. Immunosuppressive strategies in BKV
Business Use Only
28
Barten et al . (2018). BK Virus: A Cause for Concern in Thoracic Transplantation?. Annals of
Transplantation. 23. 310-321. 10.12659/AOT.908429.

29. CMV infection in KTRs  Impaired survival
29
John Wiley and Sons: Sagedal S, et al. Clinical Transplantation. 2007;21:309 13
2000 3000
1000
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Days post-transplantation
Long-term
patient
survival
Low-risk* group/CMV 
Low-risk* group/CMV +
High-risk† group/CMV 
High-risk† group/CMV +
Kaplan–Meier analysis of overall recipient survival
beyond 100 days post-transplantation
CMV infection during the first 100 days post kidney transplantation is associated
with overall long-term mortality both in patients with high- or low-risk of
mortality
High mortality risk : Transplanted
patients with NS ,DKD , amyloidosis.
*Low risk of mortality: All others

30. CMV infection with reduced CNI &mTORi regimen
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30
4.3
15.6
0
20
CMV
Proportion
of
patients
(%)
P < 0.001
TRANSFORM 24 month Safety analysis1
CMV events, n (%) EVR+rCNI
(N = 1014)
MPA+sCNI
(N = 1012)
P-value
Clinical signs of CMV infection 53 ( 5.2) 132 (13.0) <0.001
CMV syndrome 18 (1.8) 59 (5.8) <0.001
With prophylaxis Without prophylaxis
9.1 9.7
26.1
9.9
1.0
18.2
27.0
36.4
41.7
16.2
2.9
39.1
0
20
40
60
80
100
Total D+/R+ D+/R− D−/R+ D−/R− Other
Incidence
(%)
EVR+rCNI (N = 484)
MPA+sCNI (N = 492)
8.3 5.4
18.8
5.6 3.0 4.5
17.7
12.8
43.7
10.1 7.8 5.9
0
20
40
60
80
100
Total D+/R+ D+/R− D−/R+ D−/R− Other
Incidence
(%)
EVR+rCNI (N = 530)
MPA+sCNI (N = 520)
P <0.001
P = 0.004
P<0.001
P = 0.312
P = 0.219 P = 0.849
1.J. Pascual, TTS 2018 – Novartis Symposium, 4 Jul 2018
P <0.001
P <0.001
P = 0.222
P = 0.267
P = 0.327
P = 0.208

31. Business Use Only
31

32. SARS-CoV 2 Infection & Immunosuppression
• 20-30% increased mortality in infected KTR as compared to gen population
(India 11.6%)45
• Impaired immunity secondary to IS
• ARDS triggered as state of dysregulate inflammation and cytokine release
• Pre Tx Covid : post recovery can proceed to renal Tx with
asymptomatic period of at least 28 days,
 social distancing between donor and recipient for 14 days
 no residual radiological abnormality,
 at least 2 negative PCR SARS-CoV-2 tests done 24 hrs apart
 defer COVID-19 vaccination for 2 weeks post symptom resolution (MH&FW)
• no tailoring of induction or maintenance immunosuppression irrespective
of the time gap from infection to transplant or severity of COVID-19 infection.
32
Vivek B. Kute et al/Experimental and Clinical Transplantation (2022) Suppl 4: 32-42

33. SARS-CoV 2 Infection & Immunosuppression
• Degree of IS – no major impact on disease severity and outcome
• IS reduction logical to unleash anti viral T cell response to
control infection
• Also baseline IS maintenance reasonable to avoid over
activation of immune response leading to ARDS
• donors – deceased recently with lung damage 69
live donation post covid recovery successful
Business Use Only
33
Vivek B. Kute et al/Experimental and Clinical Transplantation (2022) Suppl 4: 32-42

34. Immunosuppressive strategies
34
Ahmadian E et . Immunosuppressant Management in Renal Transplant Patients with COVID-19.
Biomed Res Int. 2021 Oct 14;2021:9318725

35. 35
Devresse et al Transplantation Direct 2022;8: e1292;
Stop
MMF/AZA
mTORi
Rtx
Belatacept

36. Pharmacological interactions of anti virals with
immunosuppressants
36

37. Risk factors for covid associated mucormycosis
• Incidence 4.4 % (61/1382 COVID-19 KTRs from 18 centres)
• Mortality rate of 26.2%, with obesity and high-flow oxygen need¹
• Uncontrolled diabetes, high neutrophil-to-lymphocyte ratio,
lymphopenia
• overuse of steroids, iron therapy, broad-spectrum antibiotics, zinc
in multivitamins and reuse of masks²
37
1. Georgery H et al . Disappointing immunization rate after 2 doses of the BNT162b2 vaccine in a
Belgian cohort of kidney transplant recipients. Transplantation2021;105:e283–e284.
2. Georgery H , et al. High response rate to BNT162b2 mRNA COVID-19 vaccine among self-care
dialysis patients. Clin Kidney J. 2021;14:2129–2131.

38. Covid 19 mRNA vaccine
Decreased humoral and cellular response
 50% after 2 doses and 68 % after 3 rd dose
Poor response due to
1) IS –MPA, RTX , Belatacept, steroid
2) Old age
3) Impaired kidney function , TLC < 1500 /microL
4) Tx period < 4 yrs
 Pre Tx vaccine mandatory for donors and recipients but unvaccinated
potential recipients not withdrawn from waitlist for Tx
 Vaccination deferred for atleast 3 months if received convalescent plasma
as part of COVID-19 treatment.
38
Devresse et al Transplantation Direct 2022;8: e1292;
Post transplant
Covid vaccination
deferred for atleast
6 months

39. Requisites as we go ahead
39
Jha V. Indian J Nephrol. 2010 Oct;20(4):171-8.
• Dynamic Surveillance for Infections
• Multidisciplinary approach
• Increase covid vaccine immunogenicity to
improve vaccine efficacy –adjuvant use
,intradermal injection and high antigen dose
• Early & accurate diagnosis require
o Imaging
o Invasive techniques

40. Immune monitoring in conjunction with BKV
qPCR in establishing treatment guidelines
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40

41. Conclusion
• Although infections remain a significant cause of morbidity and
mortality after transplantation, improved prophylactic,
diagnostic, and treatment strategies have decreased the
negative effect of infection on transplant outcomes.
• Customized delicate immunosuppressive balance necessary
based on individual risk profile
• Alternatives regimens show promising results with infection
control
• Fundamental causes of allograft rejection should be considered
to plot a new course on the road toward true
immunosuppressive minimization
41

42. Thank You
Business Use Only
42