69 year old male presents with acute renal failure and nephrotic range proteinuria. Past medical history is significant for severe coronary artery disease and hypertension. He presented to the emergency room complaining of lethargy and abdominal pain. On initial laboratory work-up he was found to have a serum creatinine of 15 mg/dL, BUN 130 mg/dL and urinalysis with 2+ protein, >5 RBCs/hpf, >5 WBCs/hpf and numerous granular casts. Hematocrit was 31%, WBC 3.9 and platelets 150 K. Prior to biopsy, a 24 hour urine collection showed 5.5 grams of protein and serologic work-up revealed negative or normal ANA, anti-DNA, ANCA, anti-GBM, HCVab, HBsAg, HIV, C3 and C4. Kidney size was normal by ultrasound and SPEP/UPEP were pending at the time of biopsy.
RENAL BIOPSY DIAGNOSIS:
Light chain cast nephropathy, lambda type.
SPEP revealed a small monoclonal lambda spike and bone marrow biopsy showed 30% plasmacytosis, consistent with multiple myeloma.
Light chain cast nephropathy (LCCN) is the most common pattern of renal involvement by monoclonal light chains and the vast majority of patients with LCCN meet criteria for multiple myeloma (hence the alternate names for LCCN are “myeloma cast nephropathy” and “myeloma kidney”). Clinical presentations range from chronic progressive renal insufficiency to acute renal failure with nephrotic range proteinuria (as in this case). Discordance between the urine dipstick protein measurement (which predominantly detects albuminuria) and the 24-hour collection (which detects all protein fractions) is often a clue to the presence of significant light chain in the urine.
The renal biopsy diagnosis of LCCN is generally straightforward. Classically, the glomerular and vascular compartments are preserved while the tubulointerstitial compartment shows marked abnormalities. Often there is widespread and severe acute tubular injury involving both proximal and distal tubules. This diffuse tubular injury may be associated with interstitial edema and interstitial inflammation. Distal tubules will contain “atypical” tubular casts. These casts have a classic appearance with the standard array of stains used to evaluate renal biopsies. The casts are hypereosinophilic on H&E stain, appear pale with the PAS stain and are often polychromatic with the trichrome stain (see figures 3-5 above). Benign proteinaceous casts by contrast are usually moderately eosinophilc, stongly PAS positive and do not display significant polychromasia. Myeloma casts come in a variety of shapes and textures ranging from hard angular crystals to more irregular granular casts (as in the case above). The casts may also be associated with “cellular reaction” where giant cells attempt to surround and digest the casts. The diagnosis of LCCN is confirmed by immunofluorescence or immunohistochemistry showing strong positivity for either kappa or lambda and minimal or absent staining for the other.
Multiple factors likely contribute to the formation of clinically significant light chain casts. The physical and chemical characteristics of the particular light chain that is produced are important. The relative affinity of the light chain for Tamm-Horsfall protein is thought to be a significant determinant in the propensity of light chains to form casts in distal tubules. High concentrations of free light chains are likely to have a direct toxic effect on tubules and also increase the chance of significant precipitation in distal tubules. Additional factors noted to precipitate LCCN include dehydration, hypercalcemia, hyperuricemia, low urine pH and NSAID use.
Optimal therapy for LCCN remains a hotly debated issue. There is general agreement that chemotherapy must be used to decrease the production of circulating light chains. Attempts to inhibit further cast formation, including hydration and the avoidance of NSAIDS and other nephrotoxic agents are also standard. Currently debated is the potential role for plasmapheresis as a means of decreasing the concentration of circulating light chain. Small retrospective trials have come to differing conclusions on the utility of plasmapheresis. The largest prospective trial currently available (see reference 2 – Clark et. al. Ann Intern Med 2005) failed to show significant benefits of plasma exchange in LCCN patients. This trial involved 14 apheresis units in Canada and entry criteria were: 1) newly diagnosed myeloma, 2) acute renal failure (with an absence of another likely cause of ARF) and 3) normal sized kidneys. Biopsy diagnosis of LCCN was not required. All patients received melphan/prednisone or VAD and were randomized to the control arm with standard supportive therapy or to the plasmapheresis arm which included standard supportive therapy plus 5 to 7 plasma exchanges over 10 days, concurrent with initiation of chemotherapy. Plasma exchange showed no significant clinical effect on death, dialysis dependence or GFR <30 cc/min at 6 months. A small retrospective trial of plasma exchange in biopsy proven LCCN was published in 2008 (see reference 3 – Leung et al in Kidney International) which appeared to show a benefit of plasma exchange in patients who had biopsy proven LCCN and achieved at least a 50% reduction in serum free-light chains with plasma exchange. Importantly, this study was severely limited due to its retrospective nature, lack of a control group and marked heterogeneity in treatment. Notably, 12 different chemotherapy regiments were used and plasma exchanges ranged from 1 to 19 treatments. The superior outcome seen in patients who had a 50% or greater reduction in free light chains could as easily be attributed to variable response to chemotherapy regimens, rather than an actual benefit of plasma exchange. Larger randomized trials of plasma exchange are being undertaken and will hopefully provide a more definitive answer regarding the benefit of apheresis in LCCN.
1. Markowitz G.S. Dysproteinemia and the kidney. Adv Anat Pathol 2003; 11: 49-63.
2. Clark WF et.al. Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial. Ann Intern Med 2005; 143: 776-784.
3. Leung N et.al. Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains. Kidney Int 2008; 73: 1282-1288.
What is your diagnosis?
Light chain cast nephropathy, lambda type.
Myoglobinuric acute tubular necrosis
Amyloidosis, AL-lambda type
Light chain deposition disease, lambda type