Topic Discussion: New Glomerular diseases cases with targeted therapies

Targeted therapies can lead to a glomerular disease. Previously, two reviews didn’t find any glomerular diseases associated with BRAF inhibitors and PD-1 inhibitors.  In the last 6 months, 3 recent papers have highlighted interesting cases of both BRAF-MEK combination and PD-1 inhibitors leading to glomerular diseases.

Encorafenib, a new BRAF inhibitor, and binimetinib, MEK inhibitor—Proliferative GN
Pembrolizumab ( PD-1 inhibitor)- Minimal Change Disease
Dabrafenib, BRAF inhibitor and tramitinib( MEK inhibitor)- Podocytopathy- like MCD

  

While the PD-1 inhibitor case is the first of it’s kind, we must be mindful of GN in these patients as well. In terms of the BRAF+MEK combo, both authors of the above listed papers. Showed that it was the BRAF inhibition that decreased PLCε1 expression in podocytes, accompanied by a reduction in nephrin expression and an increase in permeability to albumin. Additionally, these drugs inhibited the podocyte–vascular endothelial growth factor (VEGF) system leading to perhaps a component of TMA as well.

IN THE NEWS: Preventing rejection while using immunotherapy in organ transplants

Use of immunotherapy such as CTLA-4 and PD-1 inhibitors have been sparingly used in renal transplant patients due to the concern for rejection.  Several cases and one recently published in NEJM last year showed severe acute cellular and antibody mediated rejection with use of PD-1 inhibitor therapy. In the limited number of patients who have received these agents, it appears that PD-1 inhibitors could be more prone than CTLA-4 antagonists to cause rejection in the transplanted kidney. This is especially true when the patients receive anti–CTLA-4 agents before PD-1 inhibitor treatment. 

We reported now in NEJM a creative solution of preventing rejection in a patient getting nivolumab (PD-1 inhibitor). By using a prophylactic approach of higher doses of steroids and mTOR inhibitors, we were able to successfully prevent rejection along with successful treatment of the cancer as noted in the supplementary files of the letter. Immune check point inhibitors have revolutionized the treatment of many types of cancers.With this approach, it is possible that these agents can be perhaps safely be used in the organ transplant patient.

We recently reviewed entire literature on the use of immunotherapy in the organ transplant world. As stated above, the rejections were mostly seen in PD-1 inhibitor based therapy compared to CTLA-4 therapy. In addition, the 2 cases of liver transplant where these agent were used and 1 case of heart transplant didn’t lead to a rejection episode.  But in the renal transplant patients, 5 cases have now been reported of leading to acute cellular and antibody mediated rejection when PD-1 inhibitor was administered. The above NEJM case suggests a potential treatment strategy.

Renal effects of immunotherapy are not minor.  AIN, podocytopathy and electrolyte disorders have been reported. It is important for the general nephrologists to know about these effects.Two recent reviews discuss this elegantly.

http://www.karger.com/Article/FullText/455014
http://ndt.oxfordjournals.org/content/early/2016/12/23/ndt.gfw382.abstract

Targeted therapies and tumor lysis syndrome

Novel targeted therapies are being approved in clinical trials for many hematologic malignancies. Tumor lysis syndrome (TLS) is being noticed as a novel side effect of many of these agents. A recent review in AJH summarizes the various drugs that have led to TLS as a potential side effect of targeted therapies.

TLS was most common in drug trials dealing with patients with acute leukemias, high grade non Hodgkin’s lymphomas, mantle cell lymphomas, CLL and myeloma. Some of the risk might be tumor related rather than the drug but below are the drugs that could be potential TLS promoting.

Incidence of TLS based on clinical trials for novel targeted therapies

Alvocidib (cyclin dependent kinase inhibitor) – 42% in poor risk AML patients, 13% in CLL patients

Venetoclax( ABT-199)( small molecule B cell lymphoma/leukemia 2 inhibitor)- 2.7-8.9% in CLL

Dinaciclib( cyclin dependent kinase inhibitor)- 15% in patients with AML or ALL and another 15% in CLL

Ibrutinib( Bruton kinase inhibitor)- 6.7% in CLL patients

Dasatinib( BCR-ABL tyrosine kinase inhibitors)- 4.2% in patients with ALL

Lenalidomide( immunomodulatory agent)- 3-4% in CLL patients

Obinutuzumab( anti CD20 agent)- 3-4.8% in CLL patients

Oprozomib( proteasome inhibitor)- 2.4% in various hematologic malignancies

Brentuximab vedotin( anti cd30 antibody)- 1.7% in anaplastic large cell lymphoma patients

Carfilzomib( proteasome inhibitor)- 1% in myeloma patients

Not much found in the two listed below

Idelasib( phosphatidylinositol 3-kinase inhibitor)- No TLS in CLL patients

Ofatumumab( anti CD20 agent)-No TLS in CLL patients

Clinical Case 88: Answers and Summary

Which one of these immune check point inhibitors leads to loss of transplanted kidney?

The correct answer is nivolumab or PD-1 inhibitors.  Several cases of kidney injury have now been reported when the immune check point inhibitor use in kidney transplant patients. While Lipson et al had initially reported successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma without any rejection, they recently reported a case of tumor regression but allograft rejection after administration of   pembrolizumab.  In addition, three cases of rejection were reported with use of nivolumab  in renal transplant patients with melanoma. 

https://www.ncbi.nlm.nih.gov/pubmed/26752406

https://www.ncbi.nlm.nih.gov/pubmed/26951628
https://www.ncbi.nlm.nih.gov/pubmed/26988410
Based on the 6 cases, it appears that PD-1 inhibitors are more prone to causing rejection in the transplanted kidney compared to CTLA-4 antagonists , especially when the  patients  have received anti CTLA-4 agents prior to PD-1 inhibitor treatment.  Graft tolerance might be minimized and hence rejection ensues.