Neutropenia in transplant recipients

* How common is neutropenia after kidney transplantation and when does it usually occur?

About 20-50% of kidney recipients will experience at least one episode of neutropenia. It typically occurs around day 100 after transplantation and it can last from 1-4 weeks.

* What is the etiology of neutropenia in those patients?

The cause is usually multifactorial, but the leading culprit is the use of MMF. Valgancyclovir and bactrim can also contribute directly to neutropenia with their myelotoxicity profile. In one study, tacrolimus was also strongly associated with neutropenia. CNI-induced neutropenia is rare and the most plausible explanation for this association is due to its pharmacokinetic interaction with MMF – FK inhibits MPA glucuronidation, which increases the availability of the active form of MMF. Induction therapy may also contribute to neutropenia, especially antithymocyte antibody (ATG). Interestingly, neutropenia is usually not associated with lymphopenia, anemia or thrombocytopenia. Finally, neutropenia may occur as a consequence of a viral or bacterial infection.

* What is the consequence of neutropenia in transplant patients?

Infections. As in oncological patients, neutrophil count is inversely correlated with frequency and severity of infectious complications. The most common infection is UTI followed by intraabdominal infections.

* How should neutropenia be managed in these patients?

There are no guidelines in transplantation but the most effective way to improve neutropenia is to cut down the MMF dose. Depending on the severity, some patients may even require complete interruption of this drug. The caveat is that longer interruptions (>6 days) have been linked to increase risk of rejection Some centers also stop the bactrim and valgancyclovir. The latter when given at full dose 900mg/day may contribute significantly to neutropenia. In our center for example where ATG induction is commonly used in combination with MMF and FK, the prophylaxis dose of valgancyclovir was adjusted down to a maximum of 450mg/day due to very high incidence of neutropenia with the higher dose.

* If neutropenia does not improve, should we consider G-CSF?

G-CSF has been shown to shorten the duration of neutropenia in cancer patients, but had no effect on the number of culture-positive infections or the rate of hospitalization. In the transplant setting, there has been one report of rejection after G-CSF, but in general is well tolerated. My personal opinion is that G-CSF should be considered a second-line of therapy after adjustment of the other medications.

Prospective trials are needed to validate this approach and careful monitoring for infection/rejection on these patients is essential.

Figure: Stimulated neutrophil with extracellular traps and some trapped Shigella (orange). Colored scanning electron micrograph. Provided by Max Planck Institute.