Management of a post-transplant patient with a rising creatinine and C4d positive biopsy

A rising creatinine and C4d positive biopsy is suggestive of antibody mediated rejection if DSA are present. A new sample would be requested for follow up antibody investigation if the last sample was more than 3 months ago. All the HLA antibody tests since the transplant and including the transplant sample itself will be reviewed and the DSA levels tabulated and graphed to show changes in the DSA level over time.

The clinicians will be advised to consider intervention if DSA levels are over 5000 MFI. Interventions to consider include starting on rituximab and IVIg and monitoring antibody levels. If antibody levels do not come down or graft dysfunction is detected, then plasmapheresis or immunoadsorption and possibly Bortezimab would be considered.

The H&I laboratory would undertake Luminex SAB titre tests to predict the number of plasmapheresis or immunoadsorption rounds that may be required and if these proceed, pre and post plasmapheresis/immunoadsorption Luminex SAB testing to determine if DSA MFI levels are reducing.

BK virus Post-Transplant

Renal failure from BK virus (BKV) infection is a relatively common challenge in kidney transplant recipients and is associated with the potent immunosuppression used to reduce rejection. If left untreated, BKV infections can lead to kidney allograft dysfunction or loss.

BKV replication typically begins early after transplantation and/or after treatment for rejection when immunosuppression levels are at their greatest. The primary treatment for BKV nephropathy is a reduction in immunosuppression. This however runs the risk of increasing rejection. It is therefore vital that screening is undertaken early to detect and prevent BKV nephropathy. Reduction in immunosuppression results in a significant increase in BKV-specific IgG antibodies, the emergence of BKV-specific cellular immunity, clearance of the BKV and increase in graft function as measured by a reduction in creatinine levels.

From the laboratory perspective, a kidney biopsy remains the gold standard for diagnosing BKV nephropathy. Luminex DSA levels should also be monitored closely during any period of reduction in immunosuppression.

Post-Transplant Lymphoproliferative Disorder

A post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of kidney and other solid organ transplantation. PTLD after solid organ transplantation almost always derives from recipient lymphoid cells. The majority of cases are associated with EBV infection or reactivation as a result of the patient being in an immunocompromised state.

Laboratory diagnosis of PTLD is mainly based on histology rather than H&I tests, though screening for an increase in EBV DNA levels may give an early indication. First line treatment mainly involves a reduction in immunosuppression. More recently use of Rituximab has shown some promise.

As the first line treatment is a reduction in immunosuppression, Luminex SAB DSA levels should be monitored closely during any period of reduction in immunosuppression.

Pancreas After Kidney

Patients listed for pancreas after kidney (PAK). A note will be made of all mismatches with the kidney and these will be listed as unacceptable if the patient has DSA directed against them of if there are gaps in the antibody history. A limited study in heart patients has shown that in the absence of detectable HLA-antibodies, repeat mismatches are not associated with worse graft or patient survival. Therefore if a full antibody history is available mismatches to which the patient has not developed HLA antibodies will not be listed as unacceptable. However if the offered organ has a repeat mismatch this will be highlighted to the transplant team.

One key consideration for PAK is the type and level of immunosuppression required. This needs to be discussed between the two transplant teams.

Kidney After Stem Cell Transplantation

• Acute kidney injury (AKI) is a common post HSCT complication with an incidence ranging from 20% to 73%
• Contributory risk factors to the development of AKI post HSCT include use of development of sepsis, use of cyclosporine and other nephrotoxic drugs, myeloablative induction and development of graft-versus-host disease (GVHD)
• The main management approach for the avoidance of AKI in stem cell transplant patients is the avoidance of risk factors which contribute to AKI
• Involvement of a nephrologist in the post-transplant management of HSCT patient may be desirable. HSCT patients should be periodically monitored for Creatinine levels
• For completeness, it may be desirable to screen for BK virus
• Where AKI is suspected, depending on the rate of loss of renal function, pre-emptive listing prior to dialysis may be desirable for such patient
• A kidney transplant from the stem cell donor may be undertaken with minimal or no maintenance immunosuppression if 100% donor chimerism is confirmed
• Initial immunosuppression is still required to avoid memory T and B cells which have potentially survived
• If it is not possible to obtain a kidney from the stem cell donor then discussions are required between the stem cell and kidney transplant teams to agree an induction and immunosuppression strategy for any kidney transplant

Pregnancy After Kidney Transplantation

Many patients, male and female, have their fertility affected by kidney disease and pregnancy after transplant is not uncommon. For females who are thinking of having children post-transplant, an important consideration is the choice of immunosuppression. Many of the drugs used for induction and immunosuppression pose a risk to the unborn child. For this reason, females of child bearing age who are about to undergo transplantation have a pregnancy test to confirm they are not pregnant before starting treatment.

An ideal profile of the potential kidney transplant mother includes “normal” or “good” kidney function (usually defined as glomerular filtration rate, GFR ≥ 60 ml/min), scant or no proteinuria (usually defined as below 500 mg/dl), normal or well controlled blood pressure (one drug only and no sign of end-organ damage), no recent acute rejection, good compliance and low-dose immunosuppression, without the use of potentially teratogen drugs (mycophenolic acid and m-Tor inhibitors) and an interval of at least 1–2 years after transplantation.

In pregnancy post-transplant there are risks to the unborn child, risks to the kidney graft and risk to the health of the mother.

There are risks to the child associated with the length of the gestation, maternal health, risk of disease transmission and importantly, risks from the immunosuppression in use. In addition, there are risks associated with the original kidney disease for which the mother underwent transplantation. The original kidney disease is an independent risk factor for preeclampsia, prematurity, low birth weight and neonatal death. The impact of these on the pregnancy is influenced by the degree of renal dysfunction, any pre-existing hypertension and the extent of proteinuria.

The mean gestational age for pregnancy after transplant tends to be shorter (34 weeks) than for other pregnancies and so plans should be made to manage early delivery. The risk posed by calcineurin inhibitors such as cyclosporin and tacrolimus is unknown though there are some concerns. Mycophenolate mofetil (MMF) and Sirolimus (rapamycin) are considered harmful and current recommendations are to avoid their use for 6week before pregnancy.

Risks to the graft include risk to long term graft function and risk of rejection. A rising serum creatinine level, associated with proteinuria, significantly increases the risk for irreversible graft loss as a result of the pregnancy. Achieving the correct blood immunosuppression maintenance levels in pregnancy can be a challenge as a result of changes in blood volume, thus increasing the risk of rejection. Rejection can be treated with corticosteroids.

Risks to the mother include hypertension which must be treated to maintain normal blood pressures to reduce the risk of preeclampsia. Preeclampsia can cause severe maternal and foetal complications such as renal failure, HELLP syndrome (haemolysis, elevated liver enzymes, and thrombocytopenia), seizures, liver failure, stroke and potentially death for the mother. Other comorbidities which can be present in maternal transplant patients include gestational diabetes, anaemia and infections such as urinary tract infections.

It is noted from several small studies that women who become pregnant after donating a kidney have little cause for concern.

From the point of view of the H&I laboratory, the key contribution that is made is to help monitor HLA donor specific antibody levels as immunosuppression is changed and tailored for pregnancy and also at the time of biopsy to help interpret the biopsy results.