Cystatin C-Based Equations Detect Hidden Kidney Disease And Poor Prognosis in Newly Diagnosed Patients With Multiple Myeloma

4. Discussion

Renal disease is a common complication associated with poor prognosis in MM. sCr and CrCl are classically used to detect eGFR decline, but they may underestimate their prevalence, particularly in patients with MM [12]. Measurement of GFR using inulin infusion or radiotracers is one of the most accurate methods to evaluate renal function, but it is time-consuming, expensive, and not available in most hospitals [5]. Alternatively, eGFR CysC-based equations are more sensitive, cheaper, and easy to implement [12–14]. ,e FDA (Food and Drug Administration) and EMA (European Medicines Agency) recommend these equations for drug dose adjustment and for renal disease evaluation [15]. Despite their clinical impact, there are no clear indications about which equation must be used [15]. ,e criteria for diagnosis of RI may have a significant impact in the use of nephrotoxic drugs, such as some antibiotics, chemotherapeutic drugs, or nonsteroidal anti-inflammatory drugs (NSAIDs), the adjustment of the dose of bisphosphonates, or the use of intravenous contrasts, which may quickly impair renal disease in undiagnosed patients with MM.

In this study, we compare different equations based on CysC (CKD-EPI-CysC and CAPA) and sCr (CKD-EPI-sCr) to estimate the occurrence of renal disease in 61 newly diagnosed patients with MM. Our findings show that the equations based on CysC are more sensitive than sCr, duplicating the number of patients with renal disease detected (39% vs. 19%). ,e equations based on CysC were also more sensitive in detecting chronic renal disease (stage 3) than CKD-EPI-sCr (35 vs. 28 patients detected). Of note, the CAPA equation showed the least bias and imprecision compared to the reference method [16]. ,is equation uses an international calibrator, it is easy to implement (it only requires the age and CysC levels of the patient without race or sex), and our study is the first that shows a 100% concordance with CKD-EPI-CysC (eGFR <60 mL/min/1.73 m2 ) in newly diagnosed MM patients. Furthermore, our study brings to light that sCr-based methods are particularly inaccurate in detecting renal disease in female patients. Using sCr, we only detected 1 woman with renal disease, whereas CKD-EPI-sCr (<40 mL/min/1.73 m2 ), the most frequently used equation in most hospitals, detected 3 women. Contrasting these data, 7 female patients with RI were identified using the CKD-EPI-CysC equation. sCr levels highly depend on the muscle mass, and thus, it might not be adequate to use the same cutoff for both male and female patients. , The fact that CysC values are not affected by muscle mass, sex, or age may explain the higher accuracy of CysC compared to sCr to diagnose renal disease, particularly, in female patients. In addition, Jaffe’s method, despite not being specific to sCr, is still the most widely employed to determine this value. Nevertheless, Jaffe’s reaction may also occur with other chromogenic substances (such as cephalosporins or bilirubin), and monoclonal proteins may also interfere with this analysis in patients with MM [17–19]. In contrast, CysC analysis may be altered by thyroid disease or high-dose corticosteroid treatment, a scenario we cannot evaluate in this study since none of the newly diagnosed patients included had these features.

Equations based on CysC may be useful for the early detection of patients with renal disease. In MM, eGFR <40 ml/ min/1.73 m2 has been established for RI, but eGFR <60 mL/ min/1.73 m2 for more than 3 months is used for the general population because it detects patients with increased risk of mortality in a more accurate way [11]. In this study, we used a stricter cutoff (60 mL/min/1.73 m2 ) for the analysis of patients with MM. ,is allowed the detection of a group of patients with MM with low levels of serum albumin, which is well known to be associated with poor nutritional status and higher liver alteration. It may also reflect higher inflammation since serum albumin has been associated with interleukin 6 (IL-6), a potent inflammatory mediator and promoter of myeloma cell growth. Likewise, it has been associated with poor prognosis of patients with MM [20]. Furthermore, there is also increasing evidence that CysC may be associated with bone disease in MM, and it has been proposed as a biomarker and, further, as a potential therapeutic target in this type of cancer [13, 21]. CysC has also been shown to identify a subset of ISS-3 score patients with worse outcomes [13]. In agreement, univariate and multivariate analyses showed that the worse outcome for CKD-EPI-CysC reduction (<60 mL/min/1.73 m2 ) is an independent prognosis factor according to the R-ISS-3 score in our study.

Figure 2: Comparison of CKD-EPI-creatinine, CKD-EPI-cystatin C, and CAPA equations with CKD-EPI-crea-CysC equation (using with reference method according to KDIGO guidelines) in newly diagnosed multiple myeloma patients.

Our study has limitations of the small number of patients included in the cohort and the lack of an invasive reference method to measure GFR, but we are working to expand the number of patients in a larger study to confirm the results. Overall, our study shows that the criteria proposed by IMWG may underestimate renal disease, particularly in female patients with MM. ,e equations based on CysC (CKD-EPI-CysC and CAPA) are easier to implement and more sensitive than those based on sCr for the identification of renal impairment in patients with MM. CysC-based equations may also identify patients with MM with more risk factors, which could lead to early detection and personalized treatment of these patients.

Data Availability 

The data used to support the findings of this study are included within the article. Other data are restricted in order to protect patient privacy. 

Conflicts of Interest 

The authors declare that they have no conflicts of interest. 

References

[1] A. Palumbo and K. Anderson, “Multiple myeloma,” New England Journal of Medicine, vol. 364, no. 11, pp. 1046–1060, 2011. 

[2] S. V. Rajkumar and S. Kumar, “Multiple myeloma: diagnosis and treatment,” Mayo Clinic Proceedings, vol. 91, no. 1, pp. 101–119, 2016. 

[3] S. V. Rajkumar, M. A. Dimopoulos, A. Palumbo et al., “International myeloma working group updated criteria for the diagnosis of multiple myeloma,” Lancet Oncology, vol. 15, no. 12, pp. e538–e548, 2014. 

[4] P. Moreau, J. San Miguel, P. Sonneveld et al., “Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up,” Annals of Oncology, vol. 28, pp. iv52–iv61, 2017. 

[5] S. A. Padala, A. Barsouk, A. Barsouk et al., “Epidemiology, staging, and management of multiple myeloma,” Medical Science, vol. 9, no. 1, p. 3, 2021.

[6] H. Ludwig, J. Drach, H. Graf, A. Lang, and J. G. Meran, “Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma,” Haematologica, vol. 92, no. 10, pp. 1411–1414, 2007.

[7] L. Duncan, J. Heathcote, O. Djurdjev, and A. Levin, “Screening for renal disease using serum creatinine: who are we missing?” Nephrology Dialysis Transplantation, vol. 16, no. 5, pp. 1042–1046, 2001. 

[8] A. C. Baxmann, M. S. Ahmed, N. C. Marques et al., “Influence of muscle mass and physical activity on serum and urinary creatinine and serum cystatin C,” Clinical Journal of the American Society of Nephrology, vol. 3, no. 2, pp. 348–354, 2008.

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