Hematopoietic Stem Cell Transplantation–Related Kidney Injury

Hematopoietic stem cell transplantation (HSCT) exposes the kidney to a multitude of injuries, including acute kidney injury (AKI), hypertension, glomerular disease, and chronic kidney disease (CKD). A common pathology noted in most of these patients is a renal-limited thrombotic microangiopathy (TMA). A recent review article in the American Journal of Kidney Diseases discusses this in more detail. Dr. Neeraj Singh (NS), corresponding author of the manuscript, discusses this topic with Dr. Kenar Jhaveri, eAJKD Blog Editor (eAJKD).

eAJKD: Besides veno-occlusive disease in the HSCT, what other risk factors do you think contribute to the development of AKI?

NS: The key risk factor is the chemotherapy used for induction; risk of AKI increases with dose escalation. Besides that, total-body irradiation can lead to endothelial injury. Other causes such as infections, drugs, and hemodynamic alterations can predispose to AKI in this setting.

eAJKD: Do you think that veno-occlusive disease might be an endothelial injury in the liver similar to the TMA we see in the kidney?

NS: Exactly, I think it is. It is endothelial injury of the small hepatic venules.

eAJKD: So, in other words, therapy for TMA may be effective for veno-occlusive disease, hence the use of defibrotide in both conditions?

NS: Yes, defibrotide is one therapy which has been tried successfully in both veno-occlusive disease and for the treatment of the transplant-associated TMA (TA-TMA).

eAJKD: Have you noticed a good response to defibrotide in both veno-occlusive disease and TMA?

NS: I’ve not personally used defibrotide for veno-occlusive disease, but we have had a couple of patients who had favorable outcomes within weeks of starting defibrotide for TA-TMA. We noticed the decrease in proteinuria and in the progression of CKD.

eAJKD: In terms of the glomerular disease associated with stem cell transplantation, we understand 75% of it is membranous nephropathy and the remaining 25% is a mix of minimal change disease, membranoproliferative glomerulonephritis, and other pathology. When you have relapse of minimal change disease after stem cell transplantation, what is the likelihood that then there’s recurrence of the primary hematologic malignancy and how aggressive should a nephrologist be in pursuing that primary cause?

NS: Yes, screening for relapse of primary hematologic malignancy when minimal change disease is diagnosed is crucial. However, I have also seen cases where no malignancy is found in the setting of minimal change disease after stem cell transplantation.

eAJKD: Do you see any correlation between transplant glomerulopathy after solid organ transplants and the glomerular findings after stem cell transplantations? In other words, have you seen CD4 positivity and duplication of the basement membrane following stem cell transplantation?

NS: I think the histology of membranoproliferative glomerulonephritis is very similar in transplant glomerulopathy following solid organ transplantation and stem cell transplantation, because in both these conditions, we see duplication of the glomerular basement membrane. We also see C4d positivity. So, histologically I would say the conditions are similar, just the clinical context is different.

eAJKD: How significant a role dose radiation play in TA-TMA?

NS: The conditioning regimens in stem cell transplantation are mixed, with some using only chemotherapy and some using a combination of total-body irradiation and chemotherapy. There are conditioning regimens which only use high dose chemotherapy, and we have seen cases of TA-TMA in those patients, so it is not just radiation. When Luxton first described radiation nephropathy, the pathology was very similar to TMA on the kidney biopsy. Classic cases of radiation nephropathy can be seen with radiation that is more directed to the pelvic area in cases of seminomas and bladder cancers. In stem cell transplantation, it might play a role, but it’s not the only risk factor for TA-TMA.

eAJKD: Calcineurin inhibitors (CNIs) are a mainstay of graft-versus-host disease (GVHD) prophylaxis in these patients, and may cause CNI-TMA as you point out in the manuscript. We looked at T cell depleted stem cell transplantation cases where GVHD prophylaxis is not needed, and still found cases of TA-TMA, suggesting radiation dosing played a major factor. What do you think about TA-TMA in that scenario?

NS: I was not aware of these T-cell depleted transplantations. I think this is an option to reduce the incidence of GVHD and to minimize the CNI nephrotoxicity in the long term. It also begs the question of the risk factors for TMA in those cases. Besides CNI, chemotherapy induction, and age, radiation might play a role in causing TA-TMA.

eAJKD: How do you differentiate CNI-TMA from TA-TMA?

NS: CNI-TMA is an idiosyncratic reaction that can cause both AKI and CKD, and occurs any time post transplantation. TA-TMA happens typically six months to one year after patient receive a HSCT. While CNI-TMA is an idiosyncratic reaction, TA-TMA is the result of many other factors. Lactate dehydrogenase levels are in much higher range in TA-TMA compared to CNI-TMA. Finally, withdrawal of CNI would improve the TMA in CNI-TMA, but not in TA-TMA. Histology of TA-TMA will show C4D positivity, whereas CNI-TMA does not.

eAJKD: What is the role of empiric plasma exchange or plasmapheresis for treatment of TA-TMA?

NS: The current evidence suggests that the response rate with the plasma exchange in the patients with TA-TMA is less than 50%. Although I’ve seen patients get better, there is no evidence that one approach is better than another. What factors predict response to plasma exchange is not known. I think this would be a good area for further research.

eAJKD: Why does CKD following stem cell transplantation take 6 months to surface?

NS: Radiation and chemotherapy disrupt the DNA, and cells with damaged DNA may continue to function well for months as long as they do not have to divide. Once they start dividing, injury may appear. I think that’s why we are seeing the 6 month lag time. The initial endothelial injury that could be from total-body irradiation, chemotherapy, or other factors progresses slowly in the setting of CNI and leads to ongoing endothelial damage surfacing as TMA and CKD eventually.

To view the article abstract or full-text (subscription required), please visit AJKD.org.

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