The amyloidoses constitute a large group of diseases in which misfolding of extracellular protein has a prominent role. This dynamic process generates insoluble, toxic protein aggregates that are deposited in tissues (1). The kidney is one of the most common sites of amyloid deposition, with clinically evident renal involvement occurring in more than half of the patients (2). The natural history of amyloidosis-associated renal disease is progressive decline of glomerular filtration rate up to end-stage organ failure requiring renal replacement therapy (3). High-dose melphalan followed by peripheral blood autologous stem cell transplantation (SCT) is presently considered the most effective treatment for AL (or primary) amyloidosis. Because of the toxicity associated with such therapy, there has been concern about its utility in patients with end-stage renal disease (ESRD) and it has been suggested that AL amyloidosis patients with renal insufficiency are not ideal candidates for myeloablative chemotherapy regimens because of high morbidity and mortality rates (4).
In this issue of the American Journal of Transplantation, Leung and coworkers propose a new treatment approach for patients with AL amyloidosis and ESRD (5). Sequential living donor kidney transplant followed by autologous SCT after conditioning with melphalan was developed. Eight patients underwent kidney transplantation with immediate graft function, but only five of these, subsequently received successful autologous SCT, with satisfactory tri-lineage engraftment. However, the new kidney did not prevent complications. Indeed, Leung et al. found that medical complications occurred in all five patients during post-SCT follow-up (5). Most common were neutropenic fever or bacteremia, and gastrointestinal disturbances. One patient suffered CMV colitis. Renal function remained stable following SCT in four and declined in one due to infections and bleeding complications.
An alternative, opposite strategy of first high-dose i.v. melphalan with autologous SCT and then a living or cadaveric donor kidney transplantation has already proven a tolerable and effective treatment in selected patients with AL amyloidosis-associated ESRD (6). A complete hematologic response was achieved in 8 of 15 patients. Two patients died during the peritransplant period, a treatment-related mortality (13%), comparable to that observed in the general AL patient population undergoing high-dose melphalan and SCT alone (7). Six of the eight patients with a complete hematologic response were still alive at a median follow-up of 4.5 years. Four of them received melphalan at a dose of 200 mg/m2. Two of these patients underwent successful living-related renal transplantation with functioning grafts for more than 5 years; one had successful cadaver donor transplant still functioning 6 years later. Other two patients were on waiting list for transplantation. One was alive but not on waiting list for kidney transplantation.
The two above proposed strategies underline different rationales: The Leung's approach of first step kidney transplant (5) is intended to provide the patient with enough renal function to give the highest possible chance of an adequate high-dose chemotherapy to be associated with autologous SCT. This might (but not data are available so far) theoretically enhance the chance of hematologic remission. On the other hand, the other strategy of first step SCT followed by renal transplant is aimed to better protect the subsequent transplanted kidney. It remains to be clarified whether adopting a regimen that includes kidney transplantation actually would improve outcomes such as hematologic response, toxicity and overall survival compared with front-line high-dose chemotherapy and autologous SCT alone. Given the rarity of AL amyloidosis and its heterogeneity, it is unlikely that a randomized trial will ever be performed to nail down these uncertainties. These treatment approaches, however, merit continued application on carefully select AL patients and the choice between these two proposed therapeutic strategies should be mainly based on the clinical experience of the center.