Overt Multiple Myeloma Acquired Fanconi Syndrome Is an Indolent ...

From bloodjournal.hematologylibrary.org by guest on June 6, 2013. For personal use only.

Prepublished online March 9, 2004; doi:10.1182/blood-2003-10-3400

Acquired Fanconi Syndrome Is an Indolent Disorder in the Absence of Overt Multiple Myeloma Cynthia X Ma, Martha Q Lacy, John J Rompala, Angela Dispenzieri, S V Rajkumar, Philip R Greipp, Rafael Fonseca, Robert A Kyle and Morie A Gertz

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From bloodjournal.hematologylibrary.org by guestMarch on June9,6,2004; 2013. For personal use only. Blood First Edition Paper, prepublished online DOI 10.1182/blood-2003-10-3400

-1[Category: Brief Report] Revised Ms. 2003-10-3400.R2 Scientific Heading: Clinical Observations, Intervention, & Therapeutic Trials Acquired Fanconi Syndrome Is an Indolent Disorder in the Absence of Overt Multiple Myeloma Cynthia X. Ma, MD Martha Q. Lacy, MD John F. Rompala, MD Angela Dispenzieri, MD S. Vincent Rajkumar, MD Philip R. Greipp, MD Rafael Fonseca, MD Robert A. Kyle, MD Morie A. Gertz, MD

From the Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota. Address reprint requests to Martha Q. Lacy, MD, Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected]. Supported in part by NIH-funded Program Project Grant # CA62242. Running Head: Acquired Fanconi Syndrome Word count for abstract: 145 Word count for text: 1184

Copyright (c) 2004 American Society of Hematology


MA et al

ACQUIRED FANCONI SYNDROME -2-

Abstract Adult-acquired Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. We retrospectively reviewed 32 patients diagnosed with adult-acquired FS between April 1968 and June 2002 at Mayo Clinic (Rochester, Minnesota). At diagnosis, most patients had monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), with a median creatinine level of 2.0 mg/dL (range, 0.9-3.7 mg/dL) and evidence of osteomalacia. During the average 65 months (range, 2-238 months) of follow-up, 5 patients developed end-stage renal disease (ESRD) and only 1 of 14 patients with MGUS transformed to MM. Fourteen deaths occurred, with only 1 from ESRD but 4 from alkylator-related leukemia or myelodysplastic syndrome. Chemotherapy offered little benefit on renal functions of MGUS or SMM patients. In conclusion, FS associated with monoclonal gammopathy does not appear to confer an additional risk of subsequent evolution to MM. ESRD occurs late in the disease process.

Key words: end-stage renal disease; MGUS; monoclonal gammopathy; outcome; retrospective study


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Introduction Adult-acquired Fanconi syndrome (FS) is a rare condition characterized by generalized wasting of amino acids, glucose, phosphate, uric acid, and various ions from the proximal renal tubules. It is complicated by metabolic changes, bone disease, and renal failure. Most cases of adultacquired FS are associated with monoclonal gammopathy. Literature on this identity is generally isolated case reports and small case series.1-9 The largest series reported so far included 11 patients.10 To better characterize the clinical presentation of these patients, we studied all 32 patients who were evaluated at Mayo Clinic (Rochester, Minnesota) over a 34-year period. Materials and Methods Patients in whom FS was diagnosed between April 1968 and June 2002 were identified through the Mayo Clinic Dysproteinemia Database, which includes more than 28,000 patients with dysproteinemia, dating from 1960. Charts were reviewed for history; laboratory results of serum potassium, phosphorus, uric acid, alkaline phosphatase, creatinine, parathyroid hormone, vitamin D, protein electrophoresis and urine phosphorus, glucose, amino acids, uric acid, and urine protein electrophoresis; bone marrow biopsy; bone survey; and kidney biopsy. The diagnosis of FS was based on the presence of a generalized proximal renal tubular defect. This study was conducted with the approval of the Mayo Clinic Institutional Review Board in accordance with US federal regulations and the principles of the Declaration of Helsinki for research on human subjects.


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Results and Discussion Thirty-two patients (22 men, 10 women) were identified with FS diagnosed between April 1968 and June 2002 (Table 1) at Mayo Clinic (Rochester, Minnesota). The median age at diagnosis was 58 years (range, 31-81 years). The average length of follow-up was 65 months (range, 2-238 months). At diagnosis, 10 patients (31%) had multiple myeloma (MM), 2 (6%) had Waldenström macroglobulinemia (WM), 6 (19%) had smoldering MM (SMM), and 14 (44%) had monoclonal gammopathy of undetermined significance (MGUS). A monoclonal light chain was detected in the urine of all patients at diagnosis. Of the 32 patients, 29 (91%) had the other 3 (9%) had

light chains and

light chain Bence Jones proteinuria. A serum

monoclonal protein was found at the time of diagnosis in 22 patients (69%). The types of monoclonal protein in the serum are as follows: IgG (9 patients), IgA (3 patients), IgM (2 patients), IgG (3 patients), and free (5 patients). Of the 32 patients studied, 15 presented with bone pain as their main complaint, 7 with fatigue, and 10 with asymptomatic renal insufficiency, proteinuria, or glycosuria. Although some patients were already taking supplements of potassium and phosphate at the time of diagnosis, a significant number had low levels of potassium and phosphorus: 14 patients (44%) had hypokalemia, 16 (50%) had hypophosphatemia, and 21 (66%) had hypouricemia. A significant proportion of patients, including 6 of the 9 with normal findings on a bone survey, had an increased level of alkaline phosphatase. The level of 1,25-hydroxyvitamin D was normal in all 5 patients tested. The parathyroid hormone level was normal in 10 of the 12 patients tested. The other 2 patients had secondary hyperparathyroidism due


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to end-stage renal disease (ESRD). All 30 patients tested had aminoaciduria. Glucosuria was detected in all 27 patients tested. Of 17 the patients tested, 6 (35%) had increased excretion of urine phosphorus. Most of the patients with MM had lytic bone lesions, whereas most patients with MGUS had negative findings on a bone survey. Seventeen patients had renal biopsy performed, and 8 (47%) had characteristic crystal structures in the cytoplasm of the epithelial cells of the proximal renal tubules. Interstitial fibrosis was seen in 4 patients, acute tubular necrosis in 1, and nonspecific changes in 4. Fourteen patients (44%) died during follow-up. The causes of death included pneumonia in 2 patients, sepsis in 1, alkylator-induced acute leukemia in 3, alkylator-induced myelodysplastic syndrome in 1, arrhythmia in 1, bleeding complication after kidney biopsy in 1, and unknown in 5. The Kaplan-Meier survival plot for overall survival is shown in Figure 1. As expected, patients with MM had a shorter survival time than those with MGUS (P=.013). Of the 10 patients with MM, 7 (70%) died after a median survival of 34 months. Five patients (36%) with MGUS died after a median survival of 165 months, and 2 patients (33%) with SMM died. Only 1 patient with MGUS developed MM. At the time of diagnosis of FS, the median creatinine level was 2.0 mg/dL (range, 0.9-3.7 mg/dL). At the end of follow-up, ESRD had developed in 5 patients (1 with MM and 4 with MGUS), all of which occurred more than 7 years after FS was diagnosed. The median time from the diagnosis of FS to the development of ESRD was 196 months (range, 90-238 months). Twenty-two patients, including all with MM and WM, received chemotherapy during the course of the disease. A significant number of


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patients without overt MM, including 4 with SMM and 6 with MGUS, also received chemotherapy because of progressive renal dysfunction or a progressive increase in monoclonal protein in the urine. Four patients (19%) (1 MGUS, 1 SMM, and 2 MM) developed secondary myelodysplastic syndrome or acute leukemia and died. All 4 patients received a melphalancontaining regimen for at least a year (range, 12 months-7 years). No significant change in renal function was observed after 4 to 26 months of treatment in patients with MGUS or SMM (data not shown), including the 2 patients whose 24-hour urine light chain excretions were more than 1 g (1.6 and 1.2 g). We believe that adult-acquired FS represents a complication of monoclonal immunoglobulin. Consistent with previous studies, we detected crystalloid inclusions in kidney biopsy specimens in a significant number of patients. Recent investigations into the nature of these crystals have shown that they are composed of a portion of a variable region of either the or light chain.9-12 Furthermore, the -variable domains from patients with adult-acquired FS have been shown to be highly resistant to protease degradation and to have unusual self-reactivity to form crystals.10,11 This observation has led to the hypothesis that the light chains in these patients cannot undergo complete proteolysis and, thus, accumulate in the lysosomal compartment of the cells in the proximal renal tubules. This provided a possible mechanism to explain the dysfunction of proximal renal tubules observed in FS. Consistent with previous data, the 32 patients studied showed evidence of osteomalacia and marked heterogeneity in regard to the associated monoclonal gammopathy.10,13-16 The longer follow-up and


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larger sample size also allowed us to study the long-term outcome and treatment effects of these patients. Our study showed that the likelihood of transformation to MM in patients with FS and MGUS is rare and probably not higher than it would be for patients with MGUS alone.17 Our data indicated that the progression to ESRD and metabolic bone disease is a slow process, with most patients dying of other causes. It appears that chemotherapy, especially with alkylating agents, carries a significant risk of complications but without much benefit on kidney function. Because of the relatively benign course of FS in patients who do not have an overt malignancy, the risks and benefits of chemotherapy should be weighed carefully.


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References 1. Chan KW, Ho FC, Chan MK. Adult Fanconi syndrome in kappa light chain myeloma. Arch Pathol Lab Med. 1987;111:139-142. 2. Orfila C, Lepert JC, Modesto A, Bernadet P, Suc JM. Fanconi’s syndrome, kappa light-chain myeloma, non-amyloid fibrils and cytoplasmic crystals in renal tubular epithelium. Am J Nephrol. 1991;11:345-349. 3. Sewell RL, Doreen MS. Adult Fanconi syndrome progressing to multiple myeloma. J Clin Pathol. 1984;37:1256-1258. 4. Thorner PS, Bedard YC, Fernandes BJ. Lambda-light-chain nephropathy with Fanconi’s syndrome. Arch Pathol Lab Med. 1983;107:654-657. 5. Truong LD, Mawad J, Cagle P, Mattioli C. Cytoplasmic crystals in multiple myeloma-associated Fanconi’s syndrome: a morphological study including immunoelectron microscopy. Arch Pathol Lab Med. 1989;113:781-785. 6. Uchida S, Matsuda O, Yokota T, et al. Adult Fanconi syndrome secondary to kappa-light chain myeloma: improvement of tubular functions after treatment for myeloma. Nephron. 1990;55:332-335. 7. Yonemura K, Matsushima H, Kato A, Isozaki T, Hishida A. Acquired Fanconi syndrome associated with IgG kappa multiple myeloma: observations on the mechanisms of impaired renal acid excretion. Nephrol Dial Transplant. 1997;12:1251-1253. 8. Maldonado JE, Velosa JA, Kyle RA, Wagoner RD, Holley KE, Salassa RM. Fanconi syndrome in adults: a manifestation of a latent form of myeloma. Am J Med. 1975;58:354-364.


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9. Isobe T, Kametani F, Shinoda T. V-domain deposition of lambda Bence Jones protein in the renal tubular epithelial cells in a patient with the adult Fanconi syndrome with myeloma. Amyloid. 1998;5:117-120. 10. Messiaen T, Deret S, Mougenot B, et al. Adult Fanconi syndrome secondary to light chain gammopathy: clinicopathologic heterogeneity and unusual features in 11 patients. Medicine (Baltimore). 2000;79:135-154. 11. Aucouturier P, Bauwens M, Khamlichi AA, et al. Monoclonal Ig L chain and L chain V domain fragment crystallization in myelomaassociated Fanconi’s syndrome. J Immunol. 1993;150:3561-3568. 12. Rocca A, Khamlichi AA, Touchard G, et al. Sequences of V kappa L subgroup light chains in Fanconi’s syndrome: light chain V region gene usage restriction and peculiarities in myeloma-associated Fanconi’s syndrome. J Immunol. 1995;155:3245-3252. 13. Clarke BL, Wynne AG, Wilson DM, Fitzpatrick LA. Osteomalacia associated with adult Fanconi’s syndrome: clinical and diagnostic features. Clin Endocrinol (Oxf). 1995;43:479-490. 14. Bate KL, Clouston D, Packham D, Ratnaike S, Ebeling PR. Lambda light chain induced nephropathy: a rare cause of the Fanconi syndrome and severe osteomalacia. Am J Kidney Dis. 1998;32 (6):E3. Retrieved June 6, 2003, from the World Wide Web: http://www.ajkd.org/ 15. Harrison NA, Bateman JM, Ledingham JG, Smith R. Renal failure in adult onset hypophosphatemic osteomalacia with Fanconi syndrome: a family study and review of the literature. Clin Nephrol. 1991;35:148150.


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16. Rao DS, Parfitt AM, Villanueva AR, Dorman PJ, Kleerekoper M. Hypophosphatemic osteomalacia and adult Fanconi syndrome due to light-chain nephropathy: another form of oncogenous osteomalacia. Am J Med. 1987;82:333-338. 17. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564-569.

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Table 1. Characteristics of the 32 Study Patients With Fanconi Syndrome and Monoclonal Gammopathy

Characteristic Female, no.

Value 10

From bloodjournal.hematologylibrary.org by guest on June 6, 2013. For personal use only. Male, no. 22

Age, y, median (range)

58 (31-81)

Length of follow-up, mo, mean (range)

65 (2-238)

Urine protein electrophoresis, no. of patients Light chain

29

Light chain

3

Serum protein electrophoresis, no. of patients Light chain IgA

3

IgG

9

IgM

2

Free

5

Light chain IgG Negative

3 10

Serum studies Hypokalemia, no. of patients (%)

14 (44)

Hypophosphatemia, no. of patients (%)

16 (50)

Hypouricemia, no. of patients (%)

21 (66)

Initial creatinine, mg/dL, median (range) Normal 1,25-hydroxyvitamin D

2.0 (0.9-3.7) 5 of 5 tested

Normal PTH

10 of 12 tested

Elevated alkaline phosphatase

15 of 25 tested

Urine studies Aminoaciduria

30 of 30 tested

Glucosuria

27 of 27 tested

Phosphaturia

6 of 17 tested

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Table 1 (continued)

Characteristic Kidney biopsy, no. of patients

Value 17

Cytoplasmic crystals

8

From bloodjournal.hematologylibrary.org by guest on June 6, 2013. For personal use only. Acute tubular necrosis 1

Interstitial fibrosis

4

Nonspecific

4

Diagnosis of dysproteinemia MM

10

WM

2

SMM

6

MGUS

14

Outcome ESRD

5

Transformation from MGUS to MM

1

Death

14

Alkylator-induced AML or MDS

4

AML, acute myeloid leukemia; ESRD, end-stage renal disease; MDS, myelodysplastic syndrome; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; PTH, parathyroid hormone; SMM, smoldering multiple myeloma; WM, Waldenström macroglobulinemia.


MA et al Fig. 1


Legend Fig. 1. Kaplan-Meier survival plot for overall survival. MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; SMM, smoldering MM.


MA et al Fig. 1
