Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma

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.

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.

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).

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.

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.