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Correlation Between Urine ACR and 24-H Proteinuria in a Real-World Cohort of Systemic AL Amyloidosis Patients Alissa Visram1,2, Abdullah S

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Correlation Between Urine ACR and 24-H Proteinuria in a Real-World Cohort of Systemic AL Amyloidosis Patients Alissa Visram1,2, Abdullah S Visram et al. Blood Cancer Journal (2020) 10:124 https://doi.org/10.1038/s41408-020-00391-2 Blood Cancer Journal ARTICLE Open Access Correlation between urine ACR and 24-h proteinuria in a real-world cohort of systemic AL amyloidosis patients Alissa Visram1,2, Abdullah S. Al Saleh1,3,HarshParmar4, Jennifer S. McDonald5,JohnC.Lieske 6, Iuliana Vaxman1,7,8, Eli Muchtar1, Miriam Hobbs1, Amie Fonder1,YiL.Hwa1, Francis K. Buadi1, David Dingli1,MarthaQ.Lacy1, Angela Dispenzieri 1,PrashantKapoor1, Suzanne R. Hayman1, Rahma Warsame1, Taxiarchis V. Kourelis1, Mustaqeem Siddiqui 1, Wilson I. Gonsalves1,JohnA.Lust1,RobertA.Kyle1,S.VincentRajkumar 1,MorieA.Gertz 1, Shaji K. Kumar 1 and Nelson Leung 9 Abstract A 24-h urine protein collection (24hUP), the gold standard for measuring albuminuria in systemic AL amyloidosis, is cumbersome and inaccurate. We retrospectively reviewed 575 patients with systemic AL amyloidosis to assess the correlation between a urine albumin to creatinine ratio (uACR) and the 24hUP. The uACR correlated strongly with 24hUP at diagnosis (Pearson’s r = 0.87, 95% CI 0.83–0.90) and during the disease course (Pearson’s r = 0.88, 95% CI 0.86–0.90). A uACR ≥300 mg/g estimated a 24hUP ≥ 500 mg with a sensitivity of 92% and specificity of 97% (area under the receiver operating curve = 0.938, 95% CI 0.919–0.957). A uACR cutoff of 3600 mg/g best predicted a 24hUP > 5000 g (sensitivity 93%, specificity 94%), and renal stage at diagnosis was strongly concordant using either 24hUP or uACR as the proteinuria measure (k = 0.823, 95% CI 0.728–0.919). In patients with serial urine collections, a > 30% 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; decrease in uACR predicted a > 30% decrease in 24hUP with a sensitivity of 94%. In conclusion, the uACR is a reliable and convenient method for ruling out proteinuria >500 mg per day, prognosticating renal outcomes, and assessing renal response to therapy. Further studies are needed to validate the uACR cutoffs proposed in this study. Introduction ~50–70% of systemic AL amyloid patients at diagnosis5,6, Systemic light chain (AL) amyloidosis is a rare clinical and is defined as 24-h urine protein (24hUP) >0.5 grams entity, with an estimated incidence of 10–14 cases per per day, that is predominantly albumin7. In patients with million people in the United States1,2. The pathogenic renal AL amyloidosis, the degree of renal insufficiency and immunoglobulin light chain in systemic AL amyloidosis is proteinuria at diagnosis is predictive of the risk of pro- most often produced by a small clonal plasma cell gression to end stage renal disease (ESRD) requiring population, and misfolded light chains aggregate and dialysis8. The reduction in proteinuria with plasma cell deposit in organs as amyloid fibrils, leading to organ directed therapy has also been shown to correlate with toxicity and dysfunction3. Renal AL amyloid deposition prevention of end stage kidney disease and improved predominantly involves the glomerulus, and therefore survival in systemic AL amyloidosis patients8,9. Therefore, patients typically develop albuminuria, renal insufficiency, the assessment of proteinuria in amyloidosis remains or nephrotic syndrome4. Renal involvement is seen in clinically relevant for prognostication at diagnosis, and for monitoring disease response. Currently, the gold standard for assessment of protei- Correspondence: Nelson Leung ([email protected]) nuria is a timed 24-hour urine collection that measures 1Division of Hematology, Mayo Clinic, Rochester, MI, USA 2University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada the total protein. However, a 24-hour protein (24hUP) Full list of author information is available at the end of the article © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Blood Cancer Journal Visram et al. Blood Cancer Journal (2020) 10:124 Page 2 of 8 collection is cumbersome for patients and is unreliable 24hUP was assessed using the Pearson’s test. Linear due to under or over collection and laboratory processing regression analysis was used to construct a model to – methods10 14. Therefore, the urine albumin to urine predict the 24hUP using uACR as the primary predictor, creatinine ratio (uACR) has been proposed as a con- along with other variables that could affect the prediction venient way to estimate 24hUP, and has been reported to of 24hUP (sex, body mass index, morning [AM] versus be predictive in multiple diseases associated with albu- afternoon [PM] spot urine collection, serum creatinine at – minuria15 18. The uACR has also been shown to correlate time of urine collection, and age at urine collection). A with 24hUP when collected in systemic AL amyloidosis univariable analysis was conducted and significant vari- patients enrolled in clinical trials at diagnosis; however, ables (defined as a p value < 0.15) were included in a this association has not been validated in a real-world multivariable analysis. A final model to predict 24hUP was setting19. constructed based on the multivariable analysis. Receiver operating characteristic (ROC) analysis was Methods used to identify the best uACR cutoff to predict the fol- We identified patients with systemic AL amyloidosis lowing 24hUP cutoffs: ≥500 mg (to establish renal invol- who were evaluated during their disease course at Mayo vement7,20), ≥1000 mg (to establish progressive renal Clinic Rochester, between January 1, 2010 and September disease7,20), 24hUP > 5000 mg (for amyloid renal staging8), 30, 2019. Patients with a paired random spot urine (for and <200 mg (as a reduction in proteinuria to this level uACR evaluation) and a 24hUP sample collected less than has been associated with improved overall survival in 7 days apart were included. Baseline characteristics and amyloid patients). ROC curves were compared with a correlation analysis were performed only on the first concordance statistic, using the Delong method. Cohen’s paired samples available. Medical records were reviewed kappa statistic was used to assess the reliability of renal to verify that included patients had biopsy proven sys- staging based on 24hUP versus uACR. temic AL amyloidosis. Patients on dialysis at the time of The Kaplan–Meier method was used to determine renal urine collection were excluded from this study. All survival, defined as time from diagnosis to ESRD requiring patients had a serum creatinine tested within 1 day of dialysis. Patients who died without requiring dialysis were random urine collection. At our center the Roche censored for the renal survival analysis. Univariable Cox ® COBAS 6000 Analyzer is used to measure the urine proportional models were used to assess the hazard ratios albumin (Tina-quant Albumin Gen.2 reagent) and urine and 95% confidence intervals for progression to dialysis. creatinine (CREP Gen.2 reagent) in order to obtain All statistical analyses were performed using JMP Pro the uACR. v14.1 (SAS Institute, Cary, NC) and R (R Core Team, Demographic data, baseline disease characteristics, 2020). All p values were two sided and a level of <0.05 was progression to dialysis, and follow-up dates were extrac- considered significant. This study was approved by the ted through a chart review. The primary objective of this Mayo Clinic Institutional Review Board. study was to assess the degree of correlation between uACR and 24hUP in systemic AL amyloid patients during Results the course of their disease. Our secondary objective was to A total of 575 patients with systemic AL amyloidosis validate the renal staging system for systemic AL patients had a paired 24hUP and uACR samples collected at Mayo using the uACR as a substitute for 24hUP. Lastly, we Clinic within 7 days, and were included in this retro- tested the relationship between uACR and a spot urine spective study. The median time between diagnosis and protein to creatinine ratio (uPCR) to a 24hUP collection. uACR collection was 24 months (IQR 0.9–77). Of the 575 For this analysis we included systemic AL amyloidosis patients, 155 had paired uACR and 24hUP samples col- patients with both a urinalysis and random uACR col- lected within 30 days of diagnosis. lection on the same day, and a 24hUP collection within The median 24hUP at diagnosis was 2168 mg (inter- 7 days of the random urine collections. The protein to quartile range [IQR] 808–5795), with a median serum creatinine ratio was calculated using the total protein creatinine of 1.1 (IQR 0.9–1.5) mg/dL. Renal involvement from the urinalysis, and the urine creatinine measurement at diagnosis was seen in 394 (69%) of included patients. At from the uACR. diagnosis, 54 out of 534 patients (10%) with a urine pro- tein electrophoresis (UPEP) performed on a 24-hour urine Statistical analysis collection had a monoclonal protein (MCP), and only 23 Descriptive statistics were used to quantitate baseline (4%) had >200 mg of urine MCP. Similarly, at the time of characteristics. A Wilcoxon rank sum test was used to 24hUP collection 455 patients had a UPEP performed and assess data that was not normally distributed. A Chi- 39 (9%) had a quantifiable MCP.
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