A guide to the management

1. Neutropenia in kidney transplant
recipient
Dr. Buddhika Illeperuma
Senior Registrar in Nephrology

2. Neutropenia
Mild ANC ≥1000 and <1500 cells/microL
Moderate ANC ≥500 and <1000 cells/microL
Severe ANC <500 cells/microL
Agranulocytosis ANC <200 cells/microL

3. Epidemiology
• About 5-40% of kidney recipients will experience at least one
episode of neutropenia.*
• Typically occurs around day 100 after transplantation and can last
from 1 to 4 weeks**
• Published data are scarce
* Rerolle JP, Szelag JC, Le Meur Y. Unexpected rate of severe leucopenia with the association of
mycophenolate mofetil and valganciclovir in kidney transplant recipients. Nephrol Dial Transplant 2007; 22:
671–672.
** Luan, F. L., Kommareddi, M., and Ojo, A. O. (2011). Impact of cytomegalovirus disease in D+/R- kidney
transplant patients receiving 6 months low-dose valganciclovir prophylaxis. Am. J. Transplant. 11, 1936–1942.

4. Sparse evidence !
• RCT evidence are not available for investigation and
management.
• Largest study to date is a single-center, retrospective, cohort
study done by Zafrani et al* published in 2009 in American
Journal of Transplantation
• Neutropenia was experienced by 112/395 patients (28%)
during the first year post-transplant.
1. * Zafrani et al, Incidence, Risk Factors and Clinical Consequences of Neutropenia Following
Kidney Transplantation: A Retrospective Study. American Journal of Transplantation 2009; 9:
1816–1825

5. Causes of neutropenia in kidney
transplant recipient
• Etiology of neutropenia is often multifactorial
• Common culprits are drugs and viral infections
1. Antimetabolites – MMF, EC-MPS, AZA
2. Valganciclovir
3. Co-trimoxazole
4. CMV disease

6. Causes of neutropenia in kidney
transplant recipient
Uncommon causes
1. Induction agents and additional immunosuppressives
ATG, Rituximab
2. mTOR inhibitors - Sirolimus
3. Calcineurin inhibitors – Tacrolimus
4. Post-transplant lympho-proliferative disorders
LGL leukemia
5. Parvovirus B19, HHV-6
6. Hemophagocytic syndrome due to infections
Usually
causes
pancytopenia

7. Drug induced neutropenia
• Almost always reversible after dose reduction or temporary
cessation apart from severe cases associated with AZA
• Mild-moderate neutropenic cases will respond to dose
reduction and may need cessation in severe neutropenia
• MMF is the most potential culprit
• Valganciclovir associated neutropenia has been reported in
various studies from 4.9% to 37.5% and more common with
450mg bid dose than 450mg/d dose.

8. Drug induced neutropenia
• Co-trimoxazole usually potentiates neutropenic effects of
other drugs.
• Tacrolimus is the least possible culprit for neutropenia and the
postulated mechanism is increased bioavailability of MMF by
tacrolimus.
• Complete cessation of MMF beyond 6 days is associated with
greatly increased risk of acute rejection.
• Once the acute episode is managed can usually recommence
the drug with a low dose with careful monitoring of ANC

9. CMV disease and neutropenia
• Usually associated with other cytopenias
• Can present with isolated neutropenia
• Usually associated with constitutional symptoms (CMV
syndrome) or typical tissue invasive CMV disease symptoms,
compared to drug induced neutropenia
• Diagnostic cut-offs of CMV PCR have not been standardized
and need to correlate with clinical manifestations

10. Neutropenic sepsis
• Bacteria are the most frequent infectious causes of
neutropenic fever
• Gram-negative bacteria (eg, P. aeruginosa) are generally
associated with the most serious infections.
• S. epidermidis is the most common gram-positive pathogen,
and it is much less virulent than other bacterial pathogens
• Among gram-positive bacteria, S. aureus (particularly
methicillin-resistant strains), some viridans streptococci, and
enterococci (particularly vancomycin-resistant strains) can
cause serious infections

11. Neutropenic sepsis
• Although anaerobic bacteria are abundant in the alimentary
tract, they are infrequent pathogens isolated from patients
with neutropenic fever.
• Fungal pathogens are common in high-risk patients with
neutropenic fever especially ANC<500 more than 7days
• Candida spp and Aspergillus spp account for most invasive
fungal infections during neutropenia.
• Reactivation of herpes infections and tuberculosis are known
to occur.

12. Decisions to be made in neutropenic
transplant recipient
• Patients with very low neutrophil counts are at very high risk for
severe infections
• Prompt diagnostic and treatment strategies to prevent the death
from neutropenic sepsis.
• Balancing neutropenia and the risk of infection versus
immunosuppression reduction and risk of graft rejection.
• Where the risk of rejection and the consequences of rejection are
extreme, need to decide on therapeutic boosting of neutrophil
count
• Wise usage of G-CSF to prevent overshooting of neutrophil count.

13. Approach to neutropenic renal transplant
recipient
Source : Zafrani et al, Incidence, Risk Factors and Clinical Consequences of Neutropenia Following Kidney
Transplantation: A Retrospective Study. American Journal of Transplantation 2009; 9: 1816–1825
Mild Neutropenia without fever
1 32
MMF Co-trimoxazoleValganciclovir
50% dose reduction Dose adapted to renal function?
Yes No
Duration
> 4/12
Duration
< 4/12
Stop Dose
reduction
Dose adaptation
Duration
> 3/12
Duration
< 3/12
Stop Continue

14. Approach to neutropenic renal transplant
recipient
Moderate – Severe neutropenia

15. G-CSF in neutropenic renal transplant recipient
• G-CSF leads to proliferation of neutrophils and reduced production of
inflammatory cytokines including tumor necrosis factor, interleukin-1,
interleukin-12, and interferon.*
• Analysis of various studies showed that G-CSF improves white cell count,
reduces infections, and does not provoke rejections *
* Khalil MAM, Khalil MAU, Khan TFT, Tan J, Drug-Induced Hematological Cytopenia in Kidney
Transplantation and the Challenges it poses for Kidney Transplant Physicians, Journal of
Transplantation,vol.2018,ArticleID9429265, 22 pages, 2018. https://doi.org/10.1155/2018/9429265.