A 58 year-old Caucasian man is referred to a nephrologist by his hematologist for work-up of progressive renal insufficiency. The patient was recently diagnosed with multiple myeloma and received a 1 month course of dexamethasone and thalidomide as induction therapy approximately 2 months ago. There is no past medical history of hypertension, diabetes or NSAID use. Approximately 1 year ago, the patient had a baseline serum creatinine of 0.9 mg/dl which has slowly increased over the last year to 1.3 mg/dl (creatinine was 1.2 mg/dl prior to chemotherapy). Additional laboratory work-up is significant for hematocrit 42%, 24 hour urine protein of 1.28 g/day, urinalysis with 2+ protein, 1+ glucose and bland sediment, UPEP with a free kappa light chain and albumin of 4.0 g/dl. Serum electrolytes and serum glucose are normal. Serologic work-up is negative or normal for ANA, anti-DNA, C3, C4, RF and ASLO. Physical exam reveals blood pressure of 130/50 with no evidence of edema or rash.
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Light Chain Proximal Tubulopathy, kappa type (a.k.a. Light Chain Fanconi Syndrome)
Light chain proximal tubulopathy, more commonly referred to as light chain Fanconi syndrome (LCFS), is an uncommon renal disease that occurs in the setting of dysproteinemia. Clinically, the presentation is often indolent with slowly progressive renal insufficiency. Evidence of proximal tubular dysfunction including normoglycemic glycosuria, aminoaciduria, uricosuria, hyperphosphaturia (with hypophosphatemia), or type II renal tubular acidosis is present in most cases, but often only some of the above listed features are found in any single patient. In the case presented here, testing for Fanconi syndrome was not performed although the patient was noted to have glycosuria in the setting of normal serum glucose.
New-onset Fanconi syndrome is extremely uncommon in adults and is most often seen in the setting of plasma cell dyscrasias (though may be seen with certain medication toxicities). Pathologically, LCFS shares similarities with the more common entity of myeloma cast nephropathy (MCN) in that both conditions are characterized by tubular injury with crystalline deposits of monoclonal light chains. In LCFS, the crystalline deposits are intracellular and confined to proximal tubules, as opposed to the intraluminal, distal tubular casts seen in MCN. As a result of crystal accumulation in proximal tubules, patients with LCFS exhibit features of proximal tubular dysfunction. LCFS can be a difficult diagnosis to make because (unlike this case) light microscopic findings may be very subtle. Despite the fact that the tubular crystals are composed of light chain they often fail to stain with kappa or lambda using standard techniques of immunofluorescence (IF) on frozen tissue and special techniques such as pronase digestion are required. Often the diagnosis is not made until electron microscopy reveals crystals inside tubules.
The propensity for the light chains in LCFS to form crystals that precipitate within the cytoplasm of proximal tubules appears to be determined by their amino acid sequences and the resultant physical and chemical properties. In the normal state, light chains pass through the GBM and are reabsorbed by the proximal tubule where they are broken down to amino acids by lysosomal enzymes. Certain light chain subtypes, most frequently the V-kappa-1 subtype, display resistance to proteolysis and a propensity to crystallize.
Because of the rarity of the disease, prognosis and optimal therapy for LCFS remain largely unknown. Most patients have relatively indolent renal dysfunction and do not quickly progress to ESRD. In 2004, Ma et al. reported the Mayo Clinic experience with adult-acquired Fanconi syndrome (FS). Over a 35 year period, 32 patients were seen including 10 with multiple myeloma (MM), 6 with smoldering MM, 2 with Waldenstrom’s macroglobulinemia (WMG), and 14 with monoclonal gammopathy of undetermined significance (MGUS). Importantly, only 17 patients underwent renal biopsy, among which only 8 had crystals in proximal tubular cells characteristic of LCFS. Thus, the data from this cohort is reflective of a heterogeneous group that is not limited to individuals with LCFS. Nonetheless, the findings are interesting. Over the period of follow-up (mean 65 months), 5 patients progressed to ESRD, which in each instance was more than 7 years following the initial diagnosis of FS. The median time from diagnosis of FS to ESRD was 196 months, and only 1 of 10 patients with MGUS evolved to MM. Chemotherapy was given to all patients with MM or WMG, 4 of 6 patients with smoldering MM, and 6 of 14 patients with MGUS. Among the 10 patients with smoldering MM or MGUS who received chemotherapy, no significant improvement in renal function was seen over 4-26 months of treatment. Importantly, 4 patients (1 MGUS, 1 smoldering MM, 2 MM) developed treatment-related myelodysplastic syndrome or acute leukemia and died. The authors concluded the adult-acquired FS has a slow progression to ESRD and that the risk of chemotherapy with alkylating agents appears unjustified in patients who lack evidence of overt malignancy.
In summary, LCFS is a rare disease characterized by slowly progressive renal dysfunction associated with FS. The diagnosis of LCFS requires pathologic evaluation, where the distinctive finding is accumulation of crystalline inclusions composed of light chains within the cytoplasm of proximal tubules. Patients with LCFS typically have evidence of MM, “smoldering MM”, or MGUS. Although limited data are available, renal prognosis appears to be closely tied to the prognosis of the underlying malignancy. Patients meeting criteria for multiple myeloma should be treated appropriately for their myeloma; however, in patients who lack evidence of overt malignancy, aggressive treatment with alkylating agents in an attempt to treat renal manifestations of disease does not appear justified.
Markowitz GS. Dysproteinemia and the kidney. Adv Anat Pathol 2004; 11:49-63.
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.
Ma CX, Lacy MQ, Rompala JF et.al. Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma. Blood, 2004; 104: 40-42.
Leal C. Herlitz M.D.
Columbia University Medical Center, New York, NY