Late Onset Renal Failure and Nephrotic Syndrome after Autologous Stem Cell Transplant for AL Amyloidosis

Abstract

We present a patient with AL amyloidosis who had an autologous stem cell transplant (ASCT) over 9 years ago. She has since then developed slowly progressive renal insufficiency and the nephrotic syndrome. Hematologic evaluation has failed to identify recurrent disease and a renal biopsy demonstrated extensive amyloid deposition and substantial glomerulosclerosis. We suggest that the patient has chronic glomerulosclerosis as a consequence of renal damage associated with her disease process and her treatment.

• acute kidney injury
• AL amyloidosis
• nephrotic syndrome
• autologous stem cell transplant
• chronic glomerulosclerosis

INTRODUCTION

AL or primary amyloidosis is a disease caused by overproduction of monoclonal immunoglobulin light chains by clonal plasma cells in the bone marrow. These light chains or light chain fragments combine with glycosaminoglycan moieties of proteoglycans and serum amyloid P (SAP) component to form deposits characterized by a β-pleated sheet configuration that produces apple-green birefringence under polarized light when stained with Congo red dye. These amyloid deposits have been described as stable and insoluble.¹

In the past decade, substantial progress has been made in treating this disease. A variety of chemotherapeutic interventions and stem cell transplant techniques have proven to be highly effective in prolonging the life expectancy and achieving clinical remission in some patients. Because of this success, complications associated with long-term survival are now being observed. This report describes a patient who is 9 years post stem cell transplant for AL amyloidosis, is in clinical remission, and has developed slowly progressive renal dysfunction and the nephrotic syndrome. The issues raised by her clinical course are described and discussed.

CASE REPORT

The patient is a 46-year-old female who presented in 2001 with nephrotic syndrome with proteinuria of >15 g/24 h. She had well-preserved renal function. A renal biopsy revealed extensive amyloid deposition and a bone marrow biopsy confirmed the diagnosis of AL amyloidosis. She had some restrictive physiology on echocardiogram. Her AL amyloid was of the lambda type. She underwent a successful autologous stem cell transplant (ASCT) in January 2002. Her serum creatinine about 2 years post-ASCT was approximately 1.05 mg%. In October 2006 her serum creatinine was 1.2 mg%. Thereafter, the serum creatinine gradually began to increase to the present level of about 3.8 mg%. Her proteinuria decreased to a nadir of about 1.3 g/24 h in March 2005. Proteinuria then remained relatively stable in the 1.4–2.5 g/day range until March 2009 when she was noted to have nephrotic syndrome with proteinuria of over 7 g/24 h. The nephrotic syndrome has persisted to the present time. Because of the slowly progressive renal insufficiency and nephrotic syndrome, a renal biopsy was done in February 2011. The biopsy showed extensive glomerular, interstitial, and vascular deposition of amorphous material which stained positive for Congo red and showed apple-green birefringence upon polarization. Thioflavin T staining was also positive. Immunofluorescence showed positive staining for lambda light chains and fibrils were seen on electron microscopy. In addition, there was also substantial glomerulosclerosis with 20 out of 33 glomeruli being globally sclerotic. The biopsy was complicated by an 8 unit bleed and an acute kidney injury resulting in the brief need for hemodialysis. Evaluations for recurrent disease have included bone marrow biopsies in November 2010 and March 2011. They showed persistent, extensive amyloid deposition, but no evidence for a plasma cell dyscrasia. Repeated free light-chain assays continue to have normal kappa/lambda ratios. She also has no evidence of a monoclonal gammopathy by serum and urine immunofixation electrophoresis. Her most recent serum creatinine was 3.8 mg% and she has about 7.5 g/day of proteinuria. The patient does have hypertension which is controlled with an angiotensin-receptor inhibitor and a diuretic.

DISCUSSION

The main clinical issue concerning this patient is whether recurrent disease is causing her progressive renal dysfunction and nephrotic syndrome. Extensive evaluation on multiple occasions has failed to find evidence of such recurrent disease. These evaluations have included several bone marrow biopsies which did not show evidence of a plasma cell dyscrasia and numerous free light-chain studies that were unremarkable. The patient could have a subclinical recurrence but this would be, by definition, undetectable. The possibility of retreatment for AL amyloidosis has been raised and rejected at this time because of the lack of firm evidence of disease activity.

If the patient does not have recurrent disease then the discussion shifts to address the issues of (1) the presence of extensive renal amyloid deposition 9 years after achieving hematologic remission, (2) the lack of correlation between biopsy findings and clinical course, and (3) the cause of her progressive renal dysfunction and nephrotic syndrome.

The natural history of amyloid deposition is not well defined in the literature. Light chains, along with SAP, are constituents of the amyloid deposits. In the light-chain deposition disease, several authors have reported resolution of nonamyloid light-chain deposits years after ASCT or prolonged chemotherapy.^2–4 Royer et al.⁵ reported a patient with both light-chain deposition disease (LCDD) and AL amyloidosis in whom post-ASCT skin immunofluorescence became negative while Congo red staining persisted, suggesting that resolution of amyloid deposits might not readily occur.

AA amyloidosis is a disease process in which chronic inflammation or chronic infection triggers the hepatic production of the acute phase reactant serum amyloid A (SAA). The N-terminal fragment of SAA associates with other moieties such as glycosaminoglycans and SAP to form amyloid deposits. A patient with heroin-associated AA amyloidosis was found to have persistent AA amyloid deposits in the kidney 5 years after the discontinuation of drug use even though renal function had remained stable and the nephrotic syndrome had resolved.⁶ In a patient with tumor necrosis factor receptor-associated periodic syndrome, treatment with etanercept resulted in remission of the nephrotic syndrome, but amyloid mass was noted to be more pronounced on a follow-up renal biopsy performed after 30 months of treatment.⁷ A patient with AA amyloidosis secondary to Castleman’s disease had disappearance of proteinuria 18 months after resection of her abdominal mass. A repeat renal biopsy 30 months after surgery showed persistence of the amyloid deposits in the same extent although subtle reparative phenomena at the epithelial site of the basement membrane were noted.⁸ On the other hand, in a large study of patients treated in a variety of different fashions for AA amyloidosis, Lachmann et al.⁹ followed 374 patients for a median of 86 months and estimated the amyloid burden using whole-body SAP component scintigraphy in 221 patients. They found that amyloid deposits regressed in about 60% of patients whose median SAA protein concentration was <10 mg/L. In addition, Bodin et al.¹⁰ demonstrated rapid resorption of visceral amyloid using antibodies to SAP in a human SAP transgenic mice model of reactive amyloidosis (AA amyloidosis). Thus, it seems clear that in patients with AA amyloid, regression of the amyloid deposits with treatment of the underlying disease process is possible.

Zeier et al.¹¹ reported, by quantitative measurement using a computer-aided device, no reduction in amyloid deposits in two patients more than 3 years after successful ASCT. Sanada et al.¹² presented a patient who had a renal biopsy 2 years after ASCT for AL amyloidosis. They found that, while the amount of amyloid deposition in the mesangial areas were quite similar to that in the biopsy done prior to the ASCT, the deposits staining the capillary walls appeared to be reduced and this finding was confirmed by quantitative image analysis. In terms of other organ involvement, normalization of hepatomegaly and improvement in macroglossia after ASCT have been reported.¹³ In addition, Van Buren et al.¹⁴ noted, using ¹²³I-labeled serum amyloid precursor scintigraphy, a strong decrease in serum amyloid precursor accumulation in the spleen and a minor decrease in the liver 2 years after syngeneic SCT. Consistent with the suggestion that AL amyloid deposits regress slowly if at all, Qian et al.¹⁵ from the Mayo Clinic stated that in their experience AL amyloid kidney biopsies done after stem cell transplant show no decrease in amyloid load 2–3 years after the transplant, although by 4 years there may be a small decrease in amyloid load. However, their experience is otherwise unpublished. Assuming that she does not have recurrent disease, our patient demonstrates that amyloid deposits can persist in a patient with AL amyloidosis and hematologic remission for at least 9 years post-ASCT-induced remission.

In patients with AL amyloidosis, there appears to be a lack of correlation between the extent of amyloid deposition evident by kidney biopsy and the severity of clinical manifestations including urinary protein excretion and rate of GFR decline. It is usual, however, for successful treatment of AL amyloidosis to result in improvement in renal function and improvement in proteinuria with ultimate normalization of proteinuria in a substantial proportion of patients.¹⁶ In patients who achieved a complete hematologic response, Dember et al.¹⁷ observed a 19% renal response at 3 months and a 71% response at 12 months. However, in this group, the median urinary protein excretion at 24 months was still 1.4 g/24 h. Qian et al.¹⁵ speculate that the proteinuria is likely due to podocyte injury from the light chains and not from the amyloid-associated proteins. Zeier et al.¹¹ also speculated that it is the disappearance of the amyloidogenic light chains that results in the observed clinical improvement post-ASCT. In support of this hypothesis, there is accumulating evidence linking amyloidogenic precursor proteins to amyloidosis-associated organ dysfunction independent of mature amyloid fibrils.¹⁸

Recently, there have been a number of reports demonstrating an association between acute kidney injury and progression to chronic kidney disease.^19,20 Acute kidney injury appears to be commonly associated with ASCT for AL amyloidosis. An incidence of acute renal failure of about 20% has been reported by two groups.^21,22 Our patient’s clinical course is similar to that of Petrakis et al.² in terms of the development of late onset nephrotic syndrome after ASCT. Their patient initially presented with renal failure, serum creatinine as high as 619 μmol/L, and up to 2 g/day of proteinuria. She was diagnosed with LCDD and had an ASCT. Post-ASCT her serum creatinine stabilized at 238 μmol/L and her proteinuria decreased to 0.5 g/day. Four years later, she developed nephrotic syndrome. Renal biopsy at that time showed not only resolution of the light-chain deposition, but extensive glomerulosclerosis (80% of glomeruli were totally sclerotic).We hypothesize that our patient’s progressive renal insufficiency and nephrotic syndrome is most likely a manifestation of this phenomenon of progression to chronic renal disease after an episode of renal damage. Clinicians should be aware of this possibility, even as a very late event, when evaluating a patient post-ASCT.

Declaration of interest:The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.