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, MN). At diagnosis, most patients had monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), with a median creatinine level of 176.8 μM (2.0 mg/dL; range, 79.56-327.08 μM [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 multiple myeloma (MM). Also, 14 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.

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 adult-acquired FS are associated with monoclonal gammopathy. Literature on this identity consists of 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, MN) over a 34-year period.

Study design

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.

Results and discussion

At Mayo Clinic, 32 patients (22 men, 10 women) were identified with FS (Table 1) diagnosed between April 1968 and June 2002. 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 κ light chains and the other 3 (9%) had λ 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: immunoglobulin Gκ (IgGκ, 9 patients), IgAκ (3 patients), IgMκ (2 patients), IgGλ (3 patients), and free κ (5 patients).

Table 1.

Characteristics of the 32 study patients with Fanconi syndrome and monoclonal gammopathy


Characteristic

Value
Female, no.   10  
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  
    κ light chain   29  
    λ light chain   3  
Serum protein electrophoresis, no. of patients  
    κ light chain   
        IgA κ   3  
        IgG κ   9  
        IgM κ   2  
        Free κ   5  
    λ light chain   
        IgG λ   3  
    Negative   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)   176.8 μM (79.56-327.08)  
    Normal 1,25-hydroxyvitamin D   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  
Kidney biopsy, no. of patients  17  
    Cytoplasmic crystals   8  
    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
 

Characteristic

Value
Female, no.   10  
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  
    κ light chain   29  
    λ light chain   3  
Serum protein electrophoresis, no. of patients  
    κ light chain   
        IgA κ   3  
        IgG κ   9  
        IgM κ   2  
        Free κ   5  
    λ light chain   
        IgG λ   3  
    Negative   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)   176.8 μM (79.56-327.08)  
    Normal 1,25-hydroxyvitamin D   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  
Kidney biopsy, no. of patients  17  
    Cytoplasmic crystals   8  
    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
 

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

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 to end-stage renal disease (ESRD). All 30 patients tested had aminoaciduria. Glucosuria was detected in all 27 patients tested. Of the 17 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. Of the patients, 17 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.

During follow-up, 14 patients (44%) died. 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. Of the 14 MGUS patients, 5 (36%) died after a median survival of 165 months, and 2 (33%) with SMM died. Only 1 patient with MGUS developed MM.

Figure 1.

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

Figure 1.

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

At the time of diagnosis of FS, the median creatinine level was 176.8 μM (2.0 mg/dL; range, 79.56-327.08 μM [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).

There were 22 patients, including all with MM and WM, who received chemotherapy during the course of the disease. A significant number of 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. There were 4 patients (19%; 1 MGUS, 1 SMM, and 2 MM) who developed secondary myelodysplastic syndrome or acute leukemia and died. All 4 patients received a melphalan-containing regimen for at least a year (range, 12 months to 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 κ or λ light chain.9-12  Furthermore, the κ-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  These observations have 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 theory 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 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.

Prepublished online as Blood First Edition Paper, March 9, 2004; DOI 10.1182/blood-2003-10-3400.

Supported in part by National Institutes of Health (NIH)–funded Program Project Grant no. CA-62242.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

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.
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 myeloma-associated 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
:
E3
.
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
:
148
-150.
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.