Managing light chain deposition disease

In this issue of Leukemia and Lymphoma, Minarik and colleagues report three patients with renal biopsy-proven light chain deposition disease [1]. All three were treated with bortezomib and achieved hematologic responses with normalization of the free light ratio in all, a > 50% reduction in proteinuria in all, and 50% reduction in creatinine in two of the three. Significant neurotoxicity was seen requiring discontinuation of bortezomib in two.

The renal manifestations associated with monoclonal immunoglobulin light chains are many. The most common occurs when an immunoglobulin light chain binds to a common site on Tamm-Horsfall protein, a glycoprotein secreted by the thick ascending limb of Henle loop. Aggregation of these protein complexes produces casts that obstruct tubule fluid flow resulting in renal failure, so-called myeloma cast nephropathy [2].

IgM monoclonal proteins can bind to polyclonal IgG immunoglobulin resulting in immune complexes that can deposit in the kidney leading to proteinuria and an active urinary sediment. When immune complexes precipitate in the cold they are type II cryoglobulins. Occasionally, monoclonal immunoglobulin ĸ chains can form crystalline deposits in the proximal renal tubule leading to the disruption of transport of glucose, uric acid, phosphorus and amino acids. The characteristic laboratory finding is amino aciduria and the complex is referred to as Fanconi syndrome. The loss of phosphorus in the urine and the resulting rise in parathyroid hormone leads to vitamin D-resistant rickets. Microscopic bone fractures are the presenting clinical manifestation [3].

There are two renal disorders associated with monoclonal immunoglobulin light chains that result from protein misfolding. One is light chain amyloidosis where fragments of immunoglobulin light chain, usually λ or heavy chain, misfold into a β-pleated sheet configuration. These misfolded light chains are insoluble and deposit as fibrils in any tissue, with the kidney being the most frequently affected. The clinical manifestation is nephrotic range proteinuria. The other form of monoclonal immunoglobulin light chain deposition is usually associated with ĸ light chains. This syndrome was first described by Randall [4] and is referred to as light chain deposition disease, Randall type, in order to distinguish light chain deposition from light chain cast nephropathy. On renal biopsy, the characteristic glomerular lesion is nodular glomerulosclerosis, the lesions seen resemble diabetes mellitus. Free ĸ light chains are found in the urine and serum. In contrast to amyloidosis which frequently presents with multi-organ involvement, most patients with ĸ light chain deposition disease present with isolated renal involvement; although, there is some risk of cardiac or hepatic involvement. There is always a monoclonal bone marrow plasma cell population which does not fulfill criteria for multiple myeloma. The deposits are granular and non-organized compared to the β-pleated sheets of amyloidosis [5]. Monoclonal immunoglobulin deposition disease occurs at a median age 15 years younger than patients with multiple myeloma and amyloidosis. There is a preponderance of males. Treatment has focused on cytotoxic chemotherapy to suppress ĸ light chain synthesis eliminating the precursor protein that damages the kidney. The use of melphalan-based chemotherapy prior to the year 2000 was effective but the low frequency of complete responses often resulted in further renal deposition [6].

Subsequent to the year 2000, new techniques were introduced that increased the frequency of complete responses. Stem cell transplantation is uniquely suited to the management of ĸ immunoglobulin deposition disease. Unlike multiple myeloma, the plasma cell burden is usually low (5% plasma cells or less). The cells do not have a high proliferative rate and frequently lack the genetic abnormalities that are associated with an adverse prognosis in multiple myeloma. A single course of high-dose chemotherapy can, therefore, result in long-term suppression of the plasma cell clone, producing durable responses. A series of five patients with light chain deposition disease who received high-dose melphalan and autologous stem cell transplant has been reported [7]. Five of the six patients had renal light chain deposition disease; one patient had additional deposits in the heart. All were alive, and five of the six achieved a complete hematologic remission at a median follow-up of 12 months after stem cell transplant. Recently, eight patients have been reported who received high-dose melphalan followed by stem cell transplantation [8]. The median age of the patients was 48 years, and seven of the eight had ĸ light chains. Of the five evaluable for a hematologic response, all responded with one complete response. A renal response was seen in seven of the eight patients; two of the eight relapsed at 16 and 17 months. The remaining six were in continuous response from 2 to 40 months. We have reported on six patients who received stem cell transplantation; four were male with a median serum creatinine of 2.4 mg/dL. One patient died on day + 26. Of the five survivors, all achieved a hematologic response; but two subsequently relapsed and required further chemotherapy. There was one patient on hemodialysis prior to transplant who received a renal transplant. The median reduction in proteinuria was 92%, and the median improvement in GFR was 95%. Of four evaluable patients, all achieved a renal response. Stem cell transplantation is an effective therapy, and those patients who achieve a complete hematologic response become candidates for renal transplantation [9].

Bortezomib is a highly active agent in the treatment of multiple myeloma. It has the advantage that no dose modification is required for renal insufficiency. In myeloma cast nephropathy, multiple reports of its ability to reverse renal failure have been published. Phase I and II studies have also shown it to be highly active in producing hematologic and organ responses in amyloidosis. One patient with light chain deposition was reported who failed two chemotherapy regimens and a stem cell transplant, and was on dialysis, post renal transplant, when bortezomib was initiated. Bortezomib therapy led to recovery of renal function [10]. Four patients were reported, with ĸ light chain deposition in three and λ in one, all of whom had elevations of their involved immunoglobulin free light chain. All had renal insufficiency and proteinuria. Two of the patients achieved a complete response, and two achieved a partial response. Three of the patients achieved their response within 21 days. The fourth patient met response criteria at 84 days. A complete response, seen in two, was recorded on days 63 and 84. In these patients, bortezomib was used as an induction in anticipation of stem cell transplantation, which was performed in three who are free of progression at 12 +, 15 + and 16 + months [11]. Bortezomib was combined with stem cell transplant attempting to capitalize on the advantages of both therapies.

A significant number of patients with light chain deposition disease present with renal failure. If the patient is not a candidate for a renal transplant, it is unclear that chemotherapy is justified unless there is evidence of hepatic or cardiac infiltration. For those patients that are candidates for renal allografting, control of light chain production is required lest rapid recurrence of the disease occur in the transplanted kidney [12]. We have reported on renal allografts in seven patients with light chain deposition disease. Renal insufficiency, hypertension and proteinuria were present in all seven. Three had proteinuria in excess of 3.5 g/day. A monoclonal protein was detectable in the urine in five. The renal biopsy showed ĸ light chains in all seven, and five were on dialysis prior to renal allografting. Light chain deposition recurred after a median of 33 months in five of the seven patients. One remains on dialysis and the other four have died. Only one patient was recurrence free with normal function. Kidney transplantation without aggressive chemotherapy to eliminate light chain production should not be considered [13].

ĸ immunoglobulin light chain deposition disease, Randall type, is a distinct clinicopathologic entity involving granular deposition of light chains in the kidney. It should be distinguished from Fanconi syndrome; myeloma cast nephropathy, cryoglobulinemia and amyloidosis, all of which are also associated with monoclonal proteins. Therapy to achieve complete suppression of light chain production is indicated. Disease control appears to be most easily achieved using bortezomib chemotherapy, autologous stem cell transplantation or both. Renal transplantation for these patients is justified if light chain synthesis can be abrogated.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.