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We read with interest the article by Abadie et al¹ and would like to add our observations that largely corroborate their findings. Abadie et al¹ provide confirmatory data that renal reference intervals are required when interpreting the serum free light chain (FLC) ratio in patients suspected of having plasma cell dyscrasias. Because borderline ratios cause significant diagnostic confusion, we were interested to further characterize the clinical characteristics of patients who had borderline abnormal serum FLC ratios and no evidence of plasma cell dyscrasias or lymphoproliferative disorders.

We performed a retrospective audit of FLC assays performed between January 1, 2006, and September 13, 2008, at 3 tertiary referral hospitals and correlated cases with borderline abnormal ratios (arbitrarily defined as 0.13–0.25 and 1.66–3.2, ie, 2 times below or above the lower and upper ranges of normal, respectively) with their renal function, laboratory measurements of inflammatory parameters (C-reactive protein, ferritin, erythrocyte sedimentation rate, and albumin values), serum and urine protein electrophoresis results, clinical features, and final clinical diagnosis. During the study period, 2,524 FLC assays were requested for 955 patients. Of these, 374 tests in 214 patients had a borderline FLC ratio, of which 324 tests were from 167 patients known to have a plasma cell dyscrasia or lymphoproliferative disease.

Thus, 47 patients (4.9% of all patients tested) had a borderline abnormal ratio and no known plasma cell disorder, including 3 patients in whom a monoclonal gammopathy was not definitively excluded. Their median age was 71 years; median creatinine level, 164 mmol/L (range, 62–1,070 mmol/L); and median estimated glomerular filtration rate, 34 mL/min/1.73 m² (range, 5–90 mL/min/1.73 m²), with a median clinical follow-up after the FLC assay of 264 days. All 47 patients had a borderline high κ/λ FLC ratio ranging from 1.67 to 3.2 (median κ FLC, 110 mg/L [range, 12–580 mg/L]; median λ FLC, 49 mg/L [range, 7–300 mg/L]). No patient without clonal disease had a borderline low ratio. Of the 47 patients, 33 (70%) had an estimated glomerular filtration rate of less than 50 mL/min/1.73 m², 6 being dialysis-dependent. Other diagnoses besides renal impairment included infection or gangrene (n = 9), chronic liver disease (n = 7), malignancy (n = 3), colitis (n = 2), vasculitis (n = 1), and rheumatoid arthritis (n = 1). There was 1 patient with lung cancer who had a ratio of 3.2 with no evidence of clonal plasma cell disease; this ratio was just outside the recommended renal reference interval.² Of the patients, 26 (55%) had serum protein electrophoresis features suggestive of an inflammatory process.

Our analysis confirms the findings of Abadie et al¹ and Hutchison et al² that renal reference intervals are required when interpreting the FLC assay results. We also highlight that such borderline high FLC ratios are also seen in non–dialysis-dependent renal failure and in patients with a polyclonal inflammatory response even in the absence of renal impairment. The practical difficulty, of course, is how to determine if such borderline high ratios are due solely to a polyclonal inflammatory response or to an underlying monoclonal gammopathy with superimposed infection or inflammation. In addition, patients with AL amyloidosis and monoclonal κ FLC may have marginally elevated ratios that fall within this extended range. Clinical judgment and judicious application of appropriate investigations are required to diagnose this small but diagnostically challenging population. Occasionally, patients without plasma cell disorders may also have elevated FLC ratios outside the suggested renal reference intervals, and further study is required to determine the appropriate reference intervals for patients with renal impairment and inflammatory states. Finally, we confirm that borderline low FLC ratios are uncommonly due to inflammatory states or renal impairment and that borderline low ratios should provoke a thorough search for plasma cell dyscrasias and lymphoproliferative disease.

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