ACQUIRED FANCONI'S SYNDROME ASSOCIATED WITH MONOCLONAL GAMMOPATHIES

  • View
    218

  • Download
    2

Embed Size (px)

Text of ACQUIRED FANCONI'S SYNDROME ASSOCIATED WITH MONOCLONAL GAMMOPATHIES

  • MONOCLONAL GAMMOPATHIES AND RELATED DISORDERS 0889-8588/99 $8.00 + .OO

    ACQUIRED FANCONI'S SYNDROME ASSOCIATED WITH

    MONOCLONAL GAMMOPATHIES Martha Q. Lacy, MD, and Morie A. Gertz, MD

    Guido Fanconi first described a syndrome in children characterized by renal glycosuria, generalized aminoaciduria, hypophosphatemia, polyuria, and rickets in the absence of azotemia. He postulated deficient renal tubular reabsorption of glucose, amino acids, calcium, and phosphate associated with normal rates of glomerular filtration.z8 At least two forms of inherited Fanconi's syndrome (FS) have been described.'O Subsequently, acquired forms of Fanconi's syndrome were described in adults.28 The differential diagnosis of acquired FS includes monoclonal gammopathies including multiple myeloma and primary systemic amyloidosis, Sjogren's syndrome, inherited enzyme disorders, heavy metal poi- sonings, and toxic drug reactions. This article reviews acquired FS associated with plasma cell dyscrasias.

    RENAL COMPLICATIONS OF MONOCLONAL GAMMOPATHIES

    Renal dysfunction is commonly associated with monoclonal gammopathies. Fanconi's syndrome is characterized by crystalline cytoplasmic inclusions in the plasma cells of the bone marrow and the renal tubular cells,2* in contrast with multiple myeloma (MM), which often causes renal failure through myeloma cast nephropathy or hypercalcemia. Myeloma casts are large, dense, and waxy and are found in the distal and collecting tubules. They are composed of monoclonal light chains with small amounts of albumin and Tamm-Horsfall protein (THP).l8

    Supported in part by NIH Grant CA62242.

    From the Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Founda- tion, and Mayo Medical School, Rochester, Minnesota

    HEMATOLOGY / ONCOLOGY CLINICS OF NORTH AMERICA ~~ ~

    VOLUME 13 * NUMBER 6 DECEMBER 1999 1273

  • 1274 LACY & GERTZ

    Nephrotic syndrome is the most common renal manifestation of primary sys- temic amyloidosis. Amyloid deposition is found in mesangial or glomerular basement membranes.18 Light-chain deposition disease is characterized by depo- sition of monoclonal light chains in the renal glomerulus, leading to renal insufficiency and nephrotic syndrome.'*

    PATHOLOGY AND PATHOGENESIS OF ACQUIRED FANCONI'S SYNDROME

    Kidney biopsies viewed by light microscopy may reveal cytoplasmic crystals in proximal tubule cells7, 11, u, 3o or tubulointerstitial nephritis without glomerular lesions. Immunofluorescence studies have shown that the crystals stain strongly for monoclonal light chain. These findings have been confirmed by electron microscopy and by immunoelectron microscopic techniques.=, 30 Similar cyto- plasmic crystalline inclusions are also seen in bone marrow plasma cells and macrophages.7, 26

    The critical role of the proximal renal tubule in the catabolism of light chains was shown in a rat model? Investigators were able to induce proximal tubular lesions in rats by the intraperitoneal injection of human K-type Bence Jones proteins. They found that approximately 80% of injected K-chains were reabsorbed by the proximal tubular cells, where they formed crystal-like struc- tures with phagolysosomes.

    In an elegant series of investigations,l, 19, 24 Aucouturier et a1 showed that light-chain toxicity in FS is related to the resistance of the V domain to degrada- tion in lysosomes of the proximal tubular epithelial cells. Initially, they investi- gated light chains from a single patient with FS.' The sequence of the patient's monoclonal K-chain was determined by cloning the K complementary DNA (cDNA) sequences from bone marrow plasma cells. Analysis of tubular crystals by N-terminal sequencing and mass spectrometry showed that the crystals were composed primarily of the V domain of the K light chain together with small proportions of the entire light chain, suggesting posttranscriptional degradation in the lysosomes. Protease treatment of the K light chain yielded a fragment of the V domain that, in contrast with other K light chains, was completely resistant to further proteolytic degradation. In addition, the patient's light chain displayed an unusual self-avidity.

    These studies prompted further investigations by the same group. They studied light chains from 4 patients with FS, 12 patients with cast nephropathy, and 4 control patients.19 All the light chains from patients with FS were of the K type. Kinetic studies of light-chain digestion by pepsin and cathepsin B showed generation of a protease-resistant 12-kDa fragment corresponding to the V do- main of the light chain. In contrast, digestion studies of the light chains obtained from patients with cast nephropathy had a variable pattern of protease resistance (Fig. 1). All the light chains from myeloma patients without cast nephropathies were completely digestible. In addition, light chains from patients with FS showed avidity for light chains but no reactivity with THP. The majority of the light chains from cast nephropathy patients bound to THP. Finally, the group demonstrated a preponderance of sequences of the V K ~ subgroup among patients with FS.24

    These studies suggest that complete proteolysis of the K light chain cannot occur in vivo after endocytosis by the proximal tubule cells. As a result, the V fragment accumulates in the lysosomal compartment of the cells. Reactivity with light chains from normal polyclonal immunoglobulin G (IgG), which is

  • Fig

    ure

    1. K

    appa

    ligh

    t cha

    ins

    are

    endo

    cyto

    sed

    by ly

    soso

    mes

    . Und

    er n

    orm

    al c

    ondi

    tions

    , the

    y ar

    e co

    mpl

    etel

    y deg

    rade

    d by

    pro

    teas

    es in

    clud

    ing

    peps

    in a

    nd c

    athe

    psin

    D.

    In p

    atie

    nts

    with

    Fan

    coni

    s s

    yndr

    ome,

    pro

    teas

    e-re

    sist

    ant 1

    2 kD

    a fra

    gmen

    ts c

    orre

    spon

    ding

    to t

    he V

    dom

    ain

    are

    gene

    rate

    d. T

    hese

    frag

    men

    ts a

    vidl

    y bi

    nd to

    oth

    er l

    ight

    cha

    ins

    and

    serv

    e as

    a n

    idus

    for

    crys

    tal f

    orm

    atio

    n.

  • 1276 LACY & GERTZ

    Tubule lumen

    Crystal-laden lysosomes

    Peritubule space

    Figure 2. Crystal-laden lysosomes interfere with a broad range of apical membrane trans- porters.

    continuously filtered by the glomerulus and reabsorbed in the proximal tubules, may serve as a nidus for crystal formation. The crystals interfere with a broad range of apical membrane transporters, including the sodium-hydrogen (Na-H) exchangers and sodium-linked symporters for glucose, phosphate, urate, and amino acids (Fig. 2).'QI9

    CLINICAL MANIFESTATIONS OF ACQUIRED FANCONI'S SYNDROME

    Patients with FS most often seek medical attention for back or bone pain, fatigue, or myalgias.zl, 25 Proximal muscle weakness is not uncommon. Symptoms are frequently confused with myeloma bone pain. Many patients with FS are asymptomatic, and the finding of glycosuria, proteinuria, electrolyte abnormali- ties, or renal insufficiency triggers the work-up. Unexplained hypouricemia may be the only clue to a diagnosis of FS.

    Electrolyte and Renal Abnormalities

    Mild and slowly progressive renal insufficiency is commonly seen in FS.21, 25 Renal failure often stabilizes or improves with ~hemotherapy.'~, 31, 32 Electrolyte abnormalities typically include hypokalemia, hypophosphatemia, and hypouri- cemia. The diagnosis is confirmed by the demonstration of aminoaciduria and

  • ACQUIRED FANCONI'S SYNDROME WITH MONOCLONAL GAMMOPATHIES 1277

    glycosuria. The renal dysfunction is a constellation of proximal tubule transport defects resulting in broad failure of tubule reabsorption. The kaliuresis is not a direct effect but rather is a consequence of the delivery of large amounts of bicarbonate past the distal nephron under conditions that favor aldosterone secretion.'O

    Bone Findings

    Osteomalacia, with or without 1,25-dihydroxyvitamin D deficiency, has been seen in patients with acquired FS and is a result of prolonged hypophos- phatemia.5, 20, 23 Roentgenograms are often normal but may show demineraliza- tion, fractures, or pseudofractures." 21 Lytic lesions suggest fully developed multi- ple myeloma. When roentgenograms are normal, the presence of osteomalacia may be suggested by an elevated serum alkaline phosphatase?, 21, In the absence of overt myeloma, bone pain may be dramatically relieved by treatment with phosphorus (NeutraPhos), with or without calcitriol. Complete reversal of the osteomalacia has been demonstrated by repeat bone biopsies after treatment with phosphoru~.~~ Noninvasive methods of assessing treatment efficacy include following serum alkaline phosphatase and phosphate levels and 24-hour urine calcium excretion.

    The primary cause of osteomalacia in FS is proximal renal tubular phosphate wasting? The degree of osteomalacia correlates with the duration and severity of the hypophosphatemia.2 Osteomalacia, however, may develop even in the face of normal serum phosphorus levels, because these patients invariably have high fractional excretions of phosphorus? This can eventually lead to secondary hyperparathyroidism. Parathyroid hormone levels (PTH) were elevated in two of nine FS patients with osteomalacia in one series? Low levels of 1,25-dihydroxy- vitamin D levels may be seen and are presumed to be caused by low serum phosphorus, which is a potent stimulus of renal la-hydroxylase. C