|Year : 2015 | Volume
| Issue : 3 | Page : 437-442
|Light chain nephropathy
Sihem Darouich1, Ilhem Bettaieb2, Raja Aouadia3, Hafedh Hedri3, Ezzeddine Abderrahim3, Rym Goucha3, Adel Khedher3
1 Foetopathology Unit, Habib Bougatfa Hospital, Bizerte, Tunisia
2 Department of Immunohistocytology, Salah Azaiez Institute, Tunis, Tunisia
3 Department of Nephrology and Internal Medicine, Charles Nicolle Hospital, Tunis, Tunisia
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|Date of Web Publication||20-May-2015|
| Abstract|| |
Light chain deposition disease (LCDD) is characterized by the tissue deposition of monotypic immunoglobulin light chains of either kappa or lambda isotype. It is the archetypal systemic disease that is most frequently diagnosed on a kidney biopsy, although the deposits may involve several other organs. This brief review focuses on the clinicopathological features of LCDD-associated nephropathy with an emphasis on the diagnostic and therapeutic difficulties related to this elusive condition.
|How to cite this article:|
Darouich S, Bettaieb I, Aouadia R, Hedri H, Abderrahim E, Goucha R, Khedher A. Light chain nephropathy. Saudi J Kidney Dis Transpl 2015;26:437-42
|How to cite this URL:|
Darouich S, Bettaieb I, Aouadia R, Hedri H, Abderrahim E, Goucha R, Khedher A. Light chain nephropathy. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Jun 23];26:437-42. Available from: https://www.sjkdt.org/text.asp?2015/26/3/437/157296
| Introduction|| |
The early studies of light chain (LC) nephropathy, initially described as non-amyloid glomerulopathy, in myeloma patients in the late 1950s and 1960s were based on light and electron microscopy. The identification of monotypic LC deposits by immunofluorescence (IF) at the same location of ultrastructurally-characterized finely granular deposits did not occur until 1974 (reviewed in reference)  This specific clinicopathological entity, coined the light chain deposition disease (LCDD), was first extensively documented and described by Randall et al.  Subsequently, with the advent of routine staining of renal biopsies for κ and λ-LC using IF or immunoelectron microscopy, single case reports and small case series of the LCDD of the kidney have expanded dramatically, especially in the 1980s. ,,,,,,,,, However, the relatively large clinicopathological studies are uncommon due to the rarity and difficulty in the diagnosis of this condition. , This brief review focuses on the clinicopathological features of LCDD-associated nephropathy with an emphasis on the diagnostic salient immunohistological and ultrastructural features. Prognostic factors and therapeutic options are also outlined.
| Clinical and Pathological Features of LCDD-Related Nephropathy|| |
On review of the previously published series of LCDD, the disease seems to frequently occur in the fifth to seventh decades of life, ,,,, but a wide range of affected ages ranging from 28 - 94 years are reported in a significant series of patients.  Furthermore, the pure LCDD mainly occurs in patients with a mean age of 56 - 58 years, , while the combined LCDD and myeloma cast nephropathy (MCN) tend to affect older patients with a mean age of 67 years.  Both genders may be equally affected, although male predominance is observed in some case series. ,, Proteinuria, which is usually in the nephrotic range, and renal insufficiency are the most common renal manifestations. ,,,, Renal failure is characterized by its high prevalence, early appearance and high severity. ,,,, The renal function declines rapidly in most cases, suggesting a rapidly progressive glomerulonephritis. Besides, acute renal failure resulting from the LC-mediated acute tubulointerstitial nephritis may be observed.  It typically occurs in LCDD with a coexistent MCN that is usually associated with more severe renal impairment and less impressive proteinuria than the pure LCDD.  Hypertension is frequently noted and could be severe.
The demonstration of monoclonal LC in the serum and/or urine is important to corroborate the diagnosis of LCDD. The LCs were not detected in both blood and urine in up to 20% of the patients. ,, It was postulated that the lack of detection of circulating monoclonal protein is related to the unusual structure of the pathogenic LC (presence of hydrophobic residues, glycosylation) that increases their propensity to precipitate in tissues.  Thus, monoclonal LC may appear intermittently at low concentrations in serum and/or urine. The traditional electrophoretic methods lack the requisite sensitivity and specificity to serve as screening tests for plasma cell dyscrasia (PCD). , More sensitive assays including immunofixation and high-resolution electrophoresis provide high detection rates.  In addition, the measurement of free κ and λ LC in the serum and urine using the Freelight immunoassay was demonstrated to be an interesting tool in both the diagnosis and the monitoring of therapy response. , However, in the presence of severe renal insufficiency, the κ/λ ratio is more useful than the absolute serum levels because renal clearance of the LC is impaired.
LCDD usually occurs in patients with lymphoproliferative disorders, primarily multiple myeloma (MM).  It is often the presenting disease that leads to the discovery of the MM at an early stage. Renal involvement can, however, manifest in a fair proportion of cases without detection of a circulating monotypical LC or a clinically patent hematological disease despite an extended follow-up period. ,,,,, With bone marrow aspiration and biopsy, the diagnosis of PCD depends on cell morphological evaluation by IF and immunophenotyping with monoclonal anti-κ and anti-λ antisera  due to the alteration of the ratio of κ/λ-positive cells. 
The nodular glomerulosclerosis (NG) with features that mimic diabetic nephropathy is the characteristic, easily recognized and the best described glomerular pattern of the LCDD in the kidney. , Nevertheless, the NG is far from being a constant feature. ,,,,, The histological spectrum of glomerular abnormalities ranges from the minimal to the proliferative glomerular changes. ,,, Of note, the NG was found to be more prevalent in the pure LCDD than in the LCDD associated with MCN. , In cases mimicking MCN, the glomeruli appeared essentially unremarkable by LM, contrasting with severe tubulointerstitial lesions. The severity of the tubulointerstitial lesions usually results in a form of acute tubulointerstitial nephritis that explains the acute renal failure at onset of the disease.  Typical myeloma casts consistent with overlapping features of the MCN were frequently demonstrated in these cases, yet the MM could not be identified. The diagnosis of the LCDD would be unrecognized in such cases, mimicking the minimal change disease, without the immunostaining and/or ultrastructural evaluation. The uncommon occurrence of the NG in the LCDD associated with the MCN is possibly due to the early presentation of the MCN-induced acute renal failure with insufficient time for the development of the nodular sclerosing glomerulopathy. Alternatively, the pathogenic LC proteins in this entity may have a weak sclerogenic potential, as suggested by their variable ability to upregulate mesangial synthesis of the transforming growth factor beta (TGFβ). 
IF can localize the LC in the various renal compartments and frequently confirm the monoclonal deposits, predominantly of the κ isotype. ,,,, The deposits peculiarly outline the basement membranes of the kidney.  Although IF is a more sensitive method to demonstrate renal LC deposits even at the early stages of the disease, it may be weak or may lack immunereactivity in biopsies where electron-dense deposits are present. ,, It is noteworthy that the antibodies, which are routinely used, do not necessarily label the abnormal LC. Hence, a negative IF workup does not rule out the LC nephropathy.
The contribution of EM to the diagnosis of LCDD-related renal disease has been highlighted. , It typically displays non-organized granular osmiophilic deposits along the glomerular and tubular basement membranes. ,,, Deposits can also be marked in Bowman's capsules and in the wall of the small arteries between the myocytes.  The use of ultrastructural immunolabeling may be necessary to address the diagnostic challenge, especially in cases with inconspicuous LC deposits that cannot be confirmed by the routine workup of renal biopsy. ,,
| Prognosis and Treatment|| |
The main risk factors associated with a worse renal prognosis and patient survival include advanced age, associated MM, combined LCDD and MCN, severe renal insufficiency at the time of renal biopsy and symptomatic extra-renal involvement, especially heart or liver failure. , The LCDD carries a uniformly poor long-term prognosis owing to the frequent occurrence of renal failure even in the absence of dire extra-renal involvement. Reported median survival rates from the time of diagnosis can range from 18 months to more than five years.  Although the patient and renal survival rates remain poor, stable or improved renal function may be achieved with early detection and treatment of the disease.  Conventional chemotherapy (Melphalan/thalidomide dexamethasone) has been applied for this condition. Such therapy aims at eliminating the abnormal clone of plasma cells and reducing the synthesis and secretion of the LC. It is needed on account of the systemic involvement and high recurrence rate of disease at end-stage renal failure or after transplantation, even in the absence of overt myeloma.  According to the literature data, chemotherapy can significantly slow the progression of chronic renal failure and improve mortality rate, provided it is initiated early before the occurrence of severe renal function impairment. , The resolution of the nodular lesions and the LC deposits was previously reported in two patients who presented with the nephrotic syndrome and mild renal failure, and were treated with prolonged chemotherapy. ,
The use of plasmapheresis is supported in treating patients with biopsy-proven cast nephropathy as it allows rapid reduction of the toxic free LC and recovery of renal function, although the beneficial effects are controversial. ,
As ascertained before, dialysis does not worsen the survival of patients.  Renal transplantation has been seriously debated because the recurrence of disease in the allograft is quite common.  It is considered in patients who are free of extra-renal manifestations at presentation or show disease stability for more than one year without evidence of clinically significant extra-renal deposition. Thus, the renal transplantation is not indicated unless the complete hematologic remission is achieved. The most interesting therapeutic approach is the use of high-dose chemotherapy, especially myeloablative doses of melphalan, followed by autologous blood stem-cell transplantation (ASCT). Such aggressive therapeutic intervention was found to stabilize renal function and improve patient and renal survivals. ,,,,, Biopsy-proven resolution of the LCDD-associated NG with significant and long-lasting improvement of the kidney function was previously reported in one patient following highdose melphalan and ASCT. 
Apart from the eradication of the abnormal plasma cell clone, further elucidation of the molecular mechanisms involved in the pathogenesis of renal damage is required to design new and more effective therapeutic strategies. 
| Conclusion|| |
LC nephropathy should be considered in adult patients, regardless of age, presenting with unexplained proteinuria and/or renal failure. A number of significant challenges remain in the diagnosis and treatment of this condition. Although nodular glomerulosclerosis is commonly observed on light microscopy, less characteristic glomerular morphologic expressions may be seen, including minimal change disease and mesangial and membranoproliferative patterns. IF evaluation with specific stains for κ and λ LCs is a key for the diagnosis. Electron microscopy study and/or ultrastructural immunolabeling of renal biopsy may be essential, especially when IF is not conclusive. Unless therapeutic measures are taken to eliminate the abnormal plasma cell clone and suppress LC secretion, the patients inexorably progress to end-stage kidney failure and the disease recurs after transplantation. The early performance of renal biopsy and timely application of effective therapy are of critical importance in the stabilization or improvement of renal function. Myeloablative high-dose chemotherapy combined with autologous stem cell transplantation seems to be the most efficient therapeutic option as it can induce hematologic remission and reverse the deterioration of renal function.
Our understanding of the molecular mechanisms involved in the pathogenesis of LC deposition-related renal lesions has substantially increased. The next step is to design new therapeutic interventions that aim at both suppressing the toxic LC secretion and inhibiting the LC-induced signaling pathways involved in the production of TGF-β. The development of specific drugs may improve the dismal prognosis that is currently associated with LCDD.
Conflict of interest: None declared
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Dr. Sihem Darouich
Foetopathology Unit, Habib Bougatfa Hospital, Bizerte
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