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Published ahead of print on April 4, 2007
Clin J Am Soc Nephrol 2: 440-444, 2007
© 2007 American Society of Nephrology
doi: 10.2215/CJN.02450706
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Clinical Nephrology

Severity of Baseline Proteinuria Predicts Renal Response in Immunoglobulin Light Chain–Associated Amyloidosis after Autologous Stem Cell Transplantation

Nelson Leung*, Angela Dispenzieri{dagger}, Martha Q. Lacy{dagger}, Shaji K. Kumar{dagger}, Suzanne R. Hayman{dagger}, Fernando C. Fervenza*, Stephen S. Cha{ddagger}, and Morie A. Gertz{dagger}

Divisions of * Nephrology and Hypertension, {dagger} Hematology, and {ddagger} Biostatistics, Mayo Clinic Rochester, Rochester, Minnesota

Address correspondence to: Dr. Nelson Leung, 200 First Street, SW, Rochester MN 55905. Phone: 507-266-7083; Fax: 507-266-7891; E-mail: leung.nelson{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Ig light chain–associated amyloidosis is a fatal plasma cell proliferative disorder that is characterized by fibril deposition in various organs. High-dose melphalan followed by autologous stem cell transplantation has been shown to improve organ dysfunction and survival. This study was undertaken to investigate factors that influence renal response. Patients who had AL amyloidosis with ≥1 g/d proteinuria and a minimum follow-up of 12 mo were recruited. Renal response was defined by >50% reduction in proteinuria with <25% decline in renal function. Hematologic response was defined as a 50% reduction in serum monoclonal protein or free light chains. Baseline characteristics were examined for relationship to renal response. Thirteen of the 135 patients were excluded for various reasons. Median follow-up was 45.4 mo. Hematologic and renal response was noted in 73 and 43.4% of the patients, respectively. Median response time for the kidney was 10 mo (1 to 40 mo). In univariate analysis, low cardiac troponin T (cTnT), higher albumin, lower proteinuria, and hematologic response were associated with renal response. In multivariate analysis, cTnT and proteinuria were predictive of renal response. Renal response was associated with a longer survival than hematologic response alone. This study showed that severe proteinuria and high cTnT negatively affected renal response after autologous stem cell transplantation. Achievement of renal response was associated with improved survival. These results suggest that early intervention with aggressive therapy is not only justified but recommended to achieve optimal response.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Amyloidosis is a group of diseases that are characterized by fibril deposition in various tissues. More than 20 proteins have been identified to be capable of forming amyloid fibrils (1). Although these precursor proteins share little similarity in size or structure, the amyloid fibrils formed are morphologically indistinguishable from one another. The most common form of systemic amyloidosis in developed nations is Ig light chain–associated (AL) amyloidosis, formerly known as primary systemic amyloidosis. It has an incidence of 8 per million per year in the United States (2). AL amyloidosis is the result of a clonal plasma cell dyscrasia, but the majority of the patients do not have multiple myeloma. Only 18% of cases have >20% marrow plasma cells (3). Both groups were historically referred to as primary systemic amyloidosis because distinguishing between myeloma and a clonal plasma cell proliferative disorder is often difficult and somewhat arbitrary. More important, the first-year survival is determined by the presence of amyloidosis, which makes the distinction between the two groups unnecessary (4).

AL amyloidosis is fatal because the relentless amyloid deposition results in progressive multiorgan failure. Before the introduction of high-dose therapy, the prognosis was extremely poor. A number of studies using conventional chemotherapy all showed the median survival to be between 13 and 18 mo (5–7). Patients with symptomatic heart involvement had the worst prognosis, often succumbing to the disease within 6 mo of diagnosis. Fortunately, recent advances have changed the outlook of this disease. Long-term remission and survival can be achieved with high-dose melphalan followed by autologous stem cell transplantation (ASCT) (8). The largest study to date demonstrated an overall median survival of 4.6 yr. Even more encouraging were the results of those who did not have cardiac involvement. They had not reached their median survival. Treatment-related mortality was 13% in this population.

The advantage of ASCT stems from its high rates of hematologic response and more rapid onset of organ response. Skinner et al. (8) showed that 40% of their patients achieved complete hematologic response. These patients were more likely to achieve other organ response. In the kidney, response is characterized by improvement in proteinuria and preservation of renal function and is associated with better long-term survival (9,10). The major drawback to ASCT is the treatment-related mortality, which can reach as high as 25 to 40% (11,12). Unfortunately, those who have severe organ dysfunction and need definitive therapy most are also the ones with the highest risk. Therefore, it is important to understand factors that influence renal response after ASCT so that better patient selection can be made. This study was undertaken to investigate these baseline characteristics in patients with AL amyloidosis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Patients
Patients who underwent ASCT for AL amyloidosis at our institution from March 1996 to December 2004 were recruited for this study. Patients were eligible for ASCT when they had documented systemic involvement with AL amyloidosis. Full inclusion criteria were previously described elsewhere (13). The diagnosis of AL amyloidosis was made histologically by Congo red stain and confirmed by immunohistochemistry. Diagnosis was also supported by evidence of a circulating monoclonal gammopathy, a monoclonal population of plasma cells, and typing of the amyloid by immunohistochemistry or immunofluorescence. Patients with localized and amyloid other than AL were not eligible for ASCT. This study was approved by the institutional review board at the Mayo Foundation in accordance with the Declaration of Helsinki and the Health Insurance Portability and Accountability Act guidelines.

Demographic and laboratory data were obtained from electronic records. Baseline GFR was measured by nonradioactive iothalamate clearance (14). Proteinuria was assessed by 24-h urine collection. Serum free light chains were measured by nephelometry using the BN II nephelometer (Dade Behring, Deerfield, IL) and Freelite Serum Free Light Chain Assays (The Binding Site, San Diego, CA). Septal thickness was measured by echocardiography. Measurement of cardiac troponin T (cTnT) in this population was started in late 2002. cTnT was not available for those who received a transplant before this date.

Inclusion and Exclusion Criteria
Patients must have had a baseline proteinuria >1 g/d to be classified as having renal amyloidosis. A minimum follow-up of 12 mo was also required for inclusion into this study; this was to allow sufficient time for the recognition of renal organ response. Patients were excluded when a baseline laboratory measurement was not available or when treatment response could not be determined because of a lack of laboratory data. Patients who received renal replacement therapy before ASCT were excluded. Those who underwent a kidney transplant after ASCT or second SCT were also excluded from this study.

Mobilization and Conditioning
Stem cells were mobilized by either G-CSF (5 µg/kg per d) alone or GM-CSF (250 mcg/m2) with cyclophosphamide (3 g/m2) before July 2001. After July 2001, the practice of cyclophosphamide pulsing was discontinued. A minimum of 2 x 106 CD34+ cells/kg were collected for transplantation. Conditioning was performed with melphalan (140 mg/m2) with total body irradiation (12 Gy) or melphalan 200 mg/m2 until January 1999. After January 1999, melphalan alone was used in dosages of 200 mg/m2. Reduced-dosage melphalan at 140 or 100 mg/m2 was used in patients with more severe organ dysfunction or poor performance status at the discretion of the primary hematologist.

Definitions
Renal response was defined as a reduction in proteinuria by 50% or more with <25% decrease in renal function. Renal function after transplantation was assessed by serum creatinine (Scr). Patients who had a >25% decline in renal function after transplant regardless of proteinuria reduction, became dialysis dependent, or died before achieving renal response were considered nonresponders. Hematologic response was defined by a 50% reduction of Ig free light chains when the level was >100 mg/L or a complete eradication when the monoclonal (M) protein was too small to be quantified (15). Treatment-related mortality is defined as death from any cause before day 100 after autologous stem cell infusion in those who received a transplant.

Statistical Analyses
The following clinical parameters were evaluated for theirs association with renal response and overall survival: Age, gender, conditioning, septal thickness, ejection fraction, Scr, GFR, proteinuria, serum albumin, and cTnT. Hematologic response, which is a posttransplantation variable, is analyzed separately. Values are presented as median (range) unless stated otherwise. Wilcoxon rank sum test was used for continuous variables, and Pearson {chi}2 test was used for categorical variables. Univariate analysis was performed with pretransplantation and posttransplantation variable with renal response as dependent variable. Variables that were found to have an association at a significance level of ≤0.20 were used in the multivariate analysis using a logistic regression model. Predictors of survival were determined using parametric survival calculation. Survival was also analyzed using the Kaplan-Meier method from day 0 of ASCT.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
Of the 174 patients who received a transplant and had a minimum of 12 mo of follow-up, 135 met criteria for renal involvement and were selected for this study. Thirteen patients were excluded for the following reasons: Kidney transplant after ASCT (n = 4), second SCT (n = 4), dialysis dependent before transplantation (n = 2), response could not be determined at the time of study because of insufficient data (n = 2), and baseline GFR measurement was not performed (n = 1). No patient was lost to follow-up. The median age of the remaining 122 patients at the time of transplantation was 57.7 yr (32.6 to 75.2 yr), and 52.9% of the patients were male. Median follow-up was 45.4 mo: 53.4 (15.2 to 117.4) for renal responders and 43.4 (15.3 to 122.0) for nonresponders (P = 0.31). No differences were noted in the duration of follow-up for patients with > or <10 g/d proteinuria (median 44.0 versus 45.4 mo, respectively; P = 0.74).

Hematologic response was achieved in 72.1% of the patients in this study. Hematologic response was highly associated with renal response (P = 0.003). Hematologic response was noted in 96.2% of the renal responders versus 53.6% of the renal nonresponders (odds ratio 22.1; P < 0.0001; Table 1). Renal response was noted in 43.4% of the patients in this study. Patient demographics are listed according to renal response (Table 2). Median time for detection of renal response was 10 mo (1 to 40 mo). No differences were noted in terms of cardiac involvement (ejection fraction or septal thickness), conditioning regimen, or overall renal function (GFR) between the renal responders and nonresponders.


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  		Table 1. Distribution of hematologic and renal response for the 122 patients after ASCTa

 

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  		Table 2. Characteristics of renal responders and nonrespondersa

 
Significant differences were noted in baseline proteinuria and serum albumin between renal responders and nonresponders. Renal responders had lower baseline proteinuria (4.7 g/d [1.1 to 14.6 g/d] versus 6.6 g/d [1.1 to 26.2 g/d]; P = 0.02) and higher serum albumin (2.7 g/dl [1.1 to 4.0 g/dl] versus 2.1 g/dl [0.8 to 3.8 g/dl]; P = 001) than nonresponders. cTnT was measured in 52 patients before ASCT. No renal responder had a cTnT level >0.01 µg/L, but higher levels were noted in 35.3% of the nonresponders (P = 0.0005). On the basis of the univariate analysis, the following variables were introduced into the multivariate model: Albumin, proteinuria, cTnT, and age (Table 3). After adjustment for age, the multivariate analysis showed that lower proteinuria (P = 0.04) and lower cTnT (P = 0.0002) were independent predictors of renal response.


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  		Table 3. Age-adjusted independent predictors of renal response in the multivariate analysisa

 
Treatment-related mortality (death before day 100) in this study was 13.9%. Several baseline characteristics were predictive of survival after ASCT. These include septal thickness <14 mm (P = 0.03), cTnT ≤0.01 µg/L (P = 0.0007), conditioning with melphalan 200 mg/m2 (P = 0.002), and Scr <0.9 mg/dl (P = 0.01). Multivariate analysis revealed that only cTnT (P = 0.05) and melphalan 200 mg/m2 (P = 0.05) were independent predictors of survival after transplantation.

Both hematologic response (P < 0.0001) and renal response (P < 0.004) were highly associated with survival after ASCT. Median survival of patients without renal response was 57.3 mo but had not been reached by renal responders. To eliminate survivor bias, the Kaplan-Meier analysis excluded those who died before 100 d (landmark) and the significance of renal response remained (Figure 1). The impact of renal response alone could not be determined because only two patients had renal response without hematologic response in this cohort, but the survival benefit of renal response was clearly independent and additive to that of hematologic response. Dual responders had not reached their median survival; median survival was 66.0 mo in patients with hematologic but not renal response. Patients with neither renal nor hematologic response had a median survival of 4.7 mo.


Figure 1
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  		Figure 1. Landmark survival of 122 patients who were assessed from day 100 of autologous stem cell transplantation. Survival was significantly longer in patients who achieved both renal and hematologic response (A) as compared with patients with single (either hematologic or renal) response (B) or those without any response (C) (P = 0.007, A versus B; P < 0.001, A versus C). Borderline differences in survival was noted between the single-organ responders and nonresponders (P = 0.06, B versus C).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
High-dosage melphalan followed by ASCT is increasingly used to treat AL amyloidosis. Patient survival after ASCT seems to be better when compared with historical control subjects that were treated with conventional chemotherapy (6–8,10). The better long-term survival is credited to the higher rates of hematologic response and ultimately organ response (8,10). The importance of organ response in these patients highlights the major difference between AL amyloidosis and other hematologic malignancies. The bone marrow is usually the only organ that is diseased in patients with other hematologic disorders. In contrast, patients with AL amyloidosis usually have relatively normal bone marrow, but it is the progressive multiorgan damage that eventually leads to their death (3). This explains why although hematologic response is important, it is the organ response that is ultimately responsible for long-term survival in these patients.

In this study, we examined factors that influenced renal response in patients with AL amyloidosis after ASCT. The severity of proteinuria was found to be an independent predictor of renal response after ASCT. One possible explanation is that the damage caused by amyloidosis becomes irreversible at a certain point. This is seen in other glomerular diseases, including IgA nephropathy, ANCA-associated glomerulonephritis, membranous glomerulopathy, and membranoproliferative glomerulonephritis, in which patients with more severe renal insufficiency and proteinuria are less likely to respond to therapy (16–18). A window of opportunity exists after which organ response will not occur despite adequate treatment.

It is interesting that cTnT was found to be an independent predictor of renal response. Unfortunately, baseline cTnT was not measured in the majority of the patients, leaving unanswered the question of whether the results would be the same if cTnT were available in all patients. It is also unclear what cTnT actually predicts. One possibility is that it is associated with longer survival after transplantation, thereby allowing more time for renal response to occur. Another possibility is that it represents the severity of disease and therefore higher levels are associated with the less reversible disease. N-terminal pro-brain natriuretic peptide (NT-pro-BNP) has been found to have prognostic ability in patients with AL amyloidosis (19). Like cTnT, NT-pro-BNP was not routinely ordered on patients until after 2003, and only 36 patients in this group had NT-pro-BNP measured before transplantation. As a result, it was not included in these analyses, but in a separate analysis, NT-pro-BNP was not associated with renal response in the univariate analysis (data not shown).

In this study, neither GFR nor Scr levels correlated with renal response. At first, this seems odd that baseline renal function did not influence renal response while proteinuria did. It is one reason that both GFR and Scr were used to eliminate the possibility that Scr did not truly represent renal function. One possibility is that GFR may not be a sensitive marker of reversible renal damage in AL amyloidosis. Indeed, patients with GFR as high as 132 ml/min per 1.73 m2 did not achieve renal response. Another possibility may be in the way that renal response is defined. Because it is defined by reduction of proteinuria and not improvement in renal function, baseline GFR seems less important.

Patient survival seems to be superior in those who achieved renal response. The effect was cumulative to the benefits of hematologic response. Although the results support our feeling that organ response should be the goal of therapy, it is possible that the difference in survival is due to the definition of hematologic response that was used in this study. A different outcome may result if complete hematologic response in which no evidence of a circulating monoclonal protein or plasma cell is used instead. However, the debate over the definition (50% reduction, 90% reduction, or complete) of hematologic response remains unsettled, and the most appropriate definition has yet to be defined. In addition, renal response is almost definitely a marker of other organ response. Enhancement in survival is unlikely to be due to renal improvement alone but the overall improvement in all of the organs.

There were several limitations in this study. First, although conditioning did not seem to play a role in determining hematologic or organ response, the retrospective nature of this study cannot completely exclude it as a possibility. In addition, patients who developed ESRD from causes other than progression of amyloid were considered renal nonresponders. This may explain why some long-term survivors never achieved renal response.

The results of this study support the use of ASCT as a treatment of AL amyloidosis. Although no head-to-head controlled trial comparing ASCT with conventional chemotherapy or the newer AL amyloidosis treatments exists, the results from our studies and others have demonstrated benefits with this intensive treatment (8,10). The recovery of renal function and prevention of ESRD after ASCT depended on the achievement of hematologic response and the degree of preexisting damage to the kidney. Patients with less renal injury (lower proteinuria and higher serum albumin) were more likely to experience a successful renal response. This suggests that early intervention with aggressive therapy is not only warranted but essential if optimal organ response is to occur. It is not uncommon that we encounter patients who are referred with advanced disease and had been observed for some time without definitive treatment. Possible reasons include lack of understanding of the benefits of ASCT and intimidation by the treatment mortality rate. We hope that the results presented will reverse this trend, because it clearly shows that the treatment mortality for this fatal disease is acceptable and the early intervention produces better outcome.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
None.


   Acknowledgments
 
This study was presented as an abstract at the 47th annual meeting of the American Society of Hematology; December 9 to 12, 2006; Atlanta, GA.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received July 13, 2006. Accepted February 26, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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