Symposium 3.4 – Onconephrology

Symposium Summary

Written by Jasna Trbojevic-Stankovic
All the speakers reviewed and approved the contents

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High cut-off filters and multiple myeloma

Paul Cockwell, United Kingdom

Onco-nephrology is an emerging subspecialty that focuses on the complex relationships between the kidney and cancer. With the steadily increasing number of cancer patients, the aging population, improved cancer diagnostic tools, and survival, this field has been constantly evolving in the last years.

Multiple myeloma (MM) is typically characterized by the neoplastic proliferation of clonal plasma cells producing a monoclonal immunoglobulin. Although it is still considered a single disease, in reality, MM is a collection of several different plasma cell malignancies resulting in the accumulation of paraproteins in blood. Survival of MM patients has improved significantly in the last decade with the development of new treatment regimens. Nevertheless, the disease is commonly complicated with acute kidney injury (AKI) due to myeloma cast nephropathy, sometimes requiring haemodialysis (HD) treatment. Biopsy findings in these patients typically show cast formation, direct tubular injury, and interstitial inflammation caused by nephrotoxic monoclonal free light chains (FLC). Although most of them do not recover renal function, an improvement in survival rate has been observed in recent years, driven by the introduction of novel chemotherapeutic regimens. The latest recommendations by the International Myeloma Working Group acknowledge the significance of renal involvement in MM by emphasizing the importance of determining serum creatinine, electrolytes and FLC, estimating glomerular filtration rate (GFR), and performing urine electrophoresis at diagnosis and disease assessment.

The current standard of care for MM-related AKI includes disease-specific and supportive measures. These include the rapid introduction of dexamethasone and bortezomib, adequate hydration to maintain a urine output of 3L/day, avoidance of renin-angiotensin-system (RAS) blockade, and diuretics, and hypercalcemia treatment with pamidronate. The single predictor of good renal prognosis in MM patients is sufficient early reduction in serum FLC. One possible intervention to achieve this is performing high cut-off (HCO) HD using a dialyzer membrane that provides significant clearance of molecules up to a molecular weight of albumin.

Figure 1. Effect of HCO-HD vs high-flux HD on survival of MM patients

Several open-label retrospective studies evaluated the efficacy of this approach from 2007 to 2015 highlighting the benefits achieved regarding renal function recovery. Nevertheless, more recent prospective randomized controlled trials did not fully corroborate these findings. Even though they confirmed an improved renal recovery among patients with myeloma cast nephropathy treated with a bortezomib-based chemotherapy regimen, no significant difference was observed in survival. One possible explanation for these disappointing results is the high early infection rate in patients treated with HCO-HD, and another is that a significant drop in FLC levels has already been achieved by chemotherapy, thus precluding an exceptional effect of the dialytic intervention. More studies are expected to further elucidate this topic.

Cancer immunotherapies (checkpoint inhibitors, CAR-T cells, IL-2) and the kidney

Laura Cosmai, Italy

Many anticancer agents may directly or indirectly affect renal function. The recent development of multiple molecularly targeted agents and their introduction in clinical practice has substantially widened the spectrum of possible adverse events. These include recombinant IL-2 (rIL-2), immune checkpoint inhibitors (ICIs), and the evolving CAR-T cells.

IL-2 stimulates the growth and differentiation of B cells, NK cells, lymphokine-activated killer cells, monocytes, macrophages, and oligodendrocytes. As a potent lymphocyte activator rIL-2 has mainly been used in the treatment of melanoma and metastatic renal cell carcinoma. However, in recent years it has been nearly abandoned as it does not selectively activate cytotoxic lymphocytes but extends its effect on T regulatory cells as well, thus ultimately extinguishing the anticancer immune response. Furthermore, it requires high doses to achieve efficiency, thus causing cardiotoxicity and renal adverse events. ICIs are humanized or human IgG monoclonal antibodies that inhibit the immune system through various mechanisms. Their discovery was a breakthrough in cancer immunotherapy since they specifically target the key regulators of the immune system. Currently in use are programmed cell death receptor 1 (PD-1) inhibitors, programmed cell death ligand 1 (PD-L1) inhibitors, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors. PD-1 blockade prevents PD-1 mediated signalling and restores the antitumor activity of T cells. CTLA-4 blockade prevents CTLA-4-induced inhibition of T cells. CAR-T cells are human T-cells genetically modified to express chimeric antigen receptors (CARs). So far, they have been approved for the treatment of certain types of lymphoma and acute lymphoblastic leukaemia, but are also being investigated in various solid cancers.

Nephrological management of cancer immunotherapies is focused on the prevention and treatment of renal toxicities of these agents and avoiding unnecessary treatment interruptions and dose reductions that could hinder the therapeutic effects. The most common manifestation of renal toxicity of these agents is acute interstitial nephritis, but a wide spectrum of glomerular diseases may also develop. The risk factors for the progression to AKI include low baseline eGFR, use of proton pump inhibitors, and combination therapy with anti-PD-1 and anti-CTLA-4. The underlying mechanisms of kidney damage encompass re-activation of drug-specific T-cells, loss of tolerance versus self-antigen, and release of pro-inflammatory cytokines. The usual therapeutic intervention in the case of AKI is corticosteroid treatment which elicits complete or partial recovery of renal function in 85% of the patients. Alternatives include infliximab, rituximab, eculizumab, mycophenolate-mofetil, and cyclophosphamides, which have been evaluated in small studies. Fortunately, the event rate of recurrent AKI is low.

Figure 2. The scope of nephrology-related considerations in patients treated with ICIs

Recent studies have challenged the role of ICIs in AKI development based on the fact that PD-L1-related AKI incidence is <1%, suggesting that other drugs may be involved in the pathogenesis of renal impairment. Thus, kidney biopsy might be warranted in some cases.

Patients on renal replacement therapies represent challenging populations requiring special considerations concerning ICIs use. In HD patients these therapeutics seem to be safe to use, require no dose adjustment and are not dialyzable. Transplant patients, on the other hand, may experience acute rejection in over 40% of the cases, thus requiring strategies to minimize allograft dysfunction while maintaining antitumor response. In conclusion, even though ICIs and CAR-T cells exhibit promising results in oncology, additional larger studies are needed to more precisely define the incidence and outcomes of immune-related adverse events in patients with impaired renal function receiving these agents.

Hematological disorders in transplant recipients

Jolanta Malyszko, Poland

Renal transplantation is associated with a risk of developing various blood disorders. These can be typically divided into two main categories: common disorders, including posttransplant anaemia (PTA), posttransplant cytopenias (PTC) and posttransplant lymphoproliferative disorder (PTLD); and uncommon but serious disorders, including therapy-related myelodysplasia (t-MDS) and therapy-related acute myeloid leukaemia (t-AML), hemophagocytic syndrome (HPS), and thrombotic microangiopathy (TMA).

Post transplantation anaemia is common and generally benign among kidney transplant recipients. The typical risk factors for its development include older donor/recipient age, surgical and/or chronic blood losses, hyperparathyroidism, iron deficiency, infection, inflammation, graft dysfunction, and chronic exposure to immunosuppressive agents. PTA increases the risk of allograft loss and is associated with increased mortality. The optimal treatment approach to PTA remains elusive. Randomized controlled trials found no difference between oral and parenteral iron supplementation in restoring haemoglobin levels. Studies on the correction of anaemia with erythropoiesis-stimulating agents in the immediate post-transplant period are underpowered and therefore not suited to give definitive answers.

Several immunosuppressive drugs (e. g. azathioprine, mycophenolate mofetil, calcineurin inhibitors, alemtuzumab), anti-viral agents (e. g. valganciclovir), antibiotics (e. g. trimethoprim-sulfamethoxazole), and the nutritional deficiency (e. g. folic acid, B12) have all been linked to post-transplant leukopenia or neutropenia. Neutropenia is present in nearly one-third of kidney transplant recipients and linked to a greater incidence of infection (mainly bacterial). Optimal treatment of this condition has not been established so far. Granulocyte colony-stimulating factors were effective and safe, albeit not benign, in short-term studies. Nevertheless, milder cases warrant a cautious approach. Posttransplant thrombocytopenia can be treated with transfusions, corticosteroids to enhance platelet production and thrombopoietin receptor agonists as second-line therapy.

PTLD is a well-recognized complication of solid organ transplantation. Polymorphic lesions are either monoclonal or polyclonal lymphoid proliferations, showing evidence of malignant transformation, but not meeting criteria for lymphomas as specified by WHO classification. Monomorphic PTLDs are equivalent to lymphomas in immunocompetent hosts. The most frequent monomorphic PTLD is diffuse large B-cell lymphoma. PTLD is usually caused by Epstein-Barr virus (EBV) infection due to therapeutic immunosuppression after renal transplantation. The diagnosis should rely on histopathological examination and staging should be performed with contrast CT or PET. Treatment options include tapering immunosuppression, discontinuing antimetabolic drugs, introducing rituximab monotherapy, immunochemotherapy, chemotherapy, EBV-specific cytotoxic lymphocytes, and local surgical or radiological interventions.

Therapy-related neoplasms, t-MDS and t-AML, are clonal disorders occurring following exposure to genotoxic agents and radiation. The pathogenesis of these disorders is vague and likely multifactorial, probably related to immunosuppression, antigenic stimulation by graft, opportunistic infections with oncogenic potential and direct mutagenicity of medications. Tapering of immunosuppressive medication is mandatory, although not sufficient, to achieve a complete response, and chemotherapy is also needed. Several promising new agents, including liposomal formulations of cytarabine and daunorubicin, venetoclax, glasdegib, midostaurin, endasidenib, and gemtuzumabozogamicin have emerged in the recent trials.

The hemophagocytic syndrome is a life-threatening, hyper-inflammatory clinicopathologic entity characterized by the uncontrolled proliferation of hematophagic monocytes/macrophages/histiocytes that are actively ingesting other blood cells. Diagnostic criteria for HPS may include fever, cytopenia of two lines, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia (>500 μg/L), hemophagocytosis, elevated soluble IL-2 receptor (CD25), decreased NK-cell activity, and hepato-splenomegaly. Renal symptoms include AKI and sometimes nephrotic syndrome as a manifestation of focal segmental glomerulosclerosis or minimal change disease. The range of associated infections is wide and includes viral and protozoal agents. The condition is associated with a high mortality rate and graft loss. Treatment relies on reduction or cessation of immunosuppression and treatment of underlying infection or malignancy. High-dose immunoglobulin may be beneficial.

Figure 3. Pathogenesis of hemophagocytic syndrome following transplantation

Thrombotic microangiopathy is a rare and fatal condition characterized by thrombocytopenia, Coombs negative haemolysis with microvascular occlusion, AKI, neurological symptoms, fever, and involvement of other organs. In renal transplant recipients, TMA may occur de novo or recur in patients with a previous history of the haemolytic uremic syndrome. Reduction or withdrawal of calcineurin inhibitors is the first step in the management of TMA and may be accompanied by plasma exchange, eculizumab, or rituximab treatment.

Further reading

Basnayake K, Cheung CK, Sheaff M, et al. Differential progression of renal scarring and determinants of late renal recovery in sustained dialysis dependent acute kidney injury secondary to myeloma kidney. J Clin Pathol. 2010;63(10):884-7. doi: 10.1136/jcp.2010.079236.

Dimopoulos MA, Sonneveld P, Leung N, et al. International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment. J Clin Oncol. 2016;34(13):1544-57. doi: 10.1200/JCO.2015.65.0044.

Hutchison CA, Cockwell P, Stringer S, et al. Early reduction of serum-free light chains associates with renal recovery in myeloma kidney. J Am Soc Nephrol. 2011;22(6):1129-36. doi: 10.1681/ASN.2010080857.

Yadav P, Cook M, Cockwell P. Current Trends of Renal Impairment in Multiple Myeloma. Kidney Dis (Basel). 2016;1(4):241-57. doi: 10.1159/000442511.

Bridoux F, Carron PL, Pegourie B; MYRE Study Group. Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis Independence Among Patients With Myeloma Cast Nephropathy: A Randomized Clinical Trial. JAMA. 2017;318(21):2099-2110. doi: 10.1001/jama.2017.17924.

Hutchison CA, Cockwell P, Moroz V, et al. High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial. Lancet Haematol. 2019;6(4):e217-e228. doi: 10.1016/S2352-3026(19)30014-6.

Cortazar FB, Kibbelaar ZA, Glezerman IG, et al. Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study. J Am Soc Nephrol. 2020;31(2):435-446. doi: 10.1681/ASN.2019070676.

Seethapathy H, Zhao S, Strohbehn IA, et al. Incidence and Clinical Features of Immune-Related Acute Kidney Injury in Patients Receiving Programmed Cell Death Ligand-1 Inhibitors. Kidney Int Rep. 2020 Jul 21;5(10):1700-1705. doi: 10.1016/j.ekir.2020.07.011.

Strohbehn IA, Lee M, Seethapathy H, et al. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients on Dialysis: A Retrospective Case Series. Am J Kidney Dis. 2020;76(2):299-302. doi: 10.1053/j.ajkd.2020.02.451.

Perazella MA, Shirali AC. Immune checkpoint inhibitor nephrotoxicity: what do we know and what should we do? Kidney Int. 2020;97(1):62-74. doi: 10.1016/j.kint.2019.07.022.

Malyszko J, Oberbauer R, Watschinger B. Anemia and erythrocytosis in patients after kidney transplantation. Transpl Int. 2012 Oct;25(10):1013-23. doi: 10.1111/j.1432-2277.2012.01513.x.

Małyszko J, Watschinger B, Przybyłowski P, Durlik M. Anemia in solid organ transplantation. Ann Transplant. 2012;17(2):86-100. doi: 10.12659/aot.883227.

Malyszko J, Głowińska I, Malyszko JS, Levin-Iaina N, Koc-Zorawska E, Mysliwiec M. Iron metabolism in kidney allograft recipients: still a mystery? Transplant Proc. 2011t;43(8):2973-5. doi: 10.1016/j.transproceed.2011.08.055. PMID: 21996204.

Yang Y, Yu B, Chen Y. Blood disorders typically associated with renal transplantation. Front Cell Dev Biol. 2015;3:18. doi:10.3389/fcell.2015.00018