Discussion.
The present study suggests the relationship between high NLR and PLR with all-cause mortality in patients with CKD. Thus, those patients who had a high NLR or PLR showed twice the risk of dying compared to those who had these ratios within normal limits. Our results are similar to a study conducted in 350 Japanese patients with CKD in stages 1 to 4, in which a high NLR was associated with a higher probability of requiring dialysis and death(15). Likewise, they are similar to a study done in 165 Turkish patients with CKD in stages 1 to 3 that found that a high NLR was associated with higher mortality from all causes(21). In contrast, Chinese patients with CKD in stages 1 to 4, did not find an association between NLR and cardiovascular mortality or of any cause(20). Methodological differences can explain these discrepancies. Although the study included a more significant number of patients (938) and was multicenter, it also had a smaller number of diabetic patients (23.8%) compared to the Japanese (37%), Turkish (41.4%) or in our study (30%), and could explain these differences, due to the higher mortality in diabetic patients(28). Similarly, the mean age of the Chinese patients was comparatively lower (52.8) than that of the patients in the Japanese (68), Turkish (73.8) and our studies (78.3), which is essential because older age is associated with higher mortality in CKD(29).
The association of NLR and survival is justified in that is a marker of inflammation that predicts complications and mortality in patients with chronic diseases. This biomarker indicates an imbalance between effector cells (neutrophils), which reflect oxidative stress and regulatory cells (lymphocytes), which decrease the pro-inflammatory state(30). This relationship between neutrophil count and lymphocyte count is a new measure of inflammation in different diseases with systemic inflammation such as CKD(31) Uncontrolled inflammation causes glomerular, tubular and interstitial damage that leads to renal hemodynamic imbalance and failure to control blood pressure(30).
Regarding PLR and mortality, we have similar findings to a study in patients with rapidly progressive glomerulonephritis in which both NLR and PRL were associated with mortality(32). However, a Turkish study no found association between PRL and mortality or the need of dialysis, but, the PRL group that died was a mean of 112 ± 267, while in our study a high PLR was considered as cut-off > 232.5(21). In that sense, another study found that relationship between PRL and mortality is not a linear relationship and that it can follow a curve in J-shaped that differs according to ethnicity (PLR≥83.18) and albumin (PLR ≥ 113.89)(42). It is likely that, as with NLR, systemic inflammation may play a fundamental role. Increase in platelets or an increase in lymphocytes is typical to find in patients with inflammatory states(33). Platelet release can be modulated by inflammatory cytokines as a mechanism for rapid recovery, while decreased lymphocytes may be due to increased lymphocyte apoptosis and suppressed lymphocyte production caused by high levels of cortisol in response to inflammation(33,34).
Although the association between NLR, PLR and mortality may be related to more significant inflammation, it would also be mediated by CKD progression, because in the advanced stages of the disease, there is higher mortality (34). However, after sensitivity analysis, removing stage 4 and 5 participants, lymphocyte ratios remained as an independent risk marker for mortality. This finding could suppose other additional routes to the progression of the disease to explain this association in our population. Moreover, several studies reported NLR and PLR associated with albuminuria (regardless of GFR) and decrease in GFR.(19,35). So, this finding becomes relevant due to the association between albuminuria, CKD progression, and mortality(32,33).
Our study has limitations. First, being a retrospective study, the data obtained could have deficiencies in its registration. Second, there is the possible inclusion of patients with subclinical inflammatory and infectious diseases, which are not registered in the SSCKD or RESULAB database. Third, no other possible factors that could potentially influence mortality, such as nutritional status, albuminuria, cardiovascular disease, obesity, smoking, and acute renal injury, have been evaluated. Fourth, by the design of our study, we can only assume that lymphocyte ratios are biomarkers of risk and not of causality. Finally, the measurement of the ratios has only been carried out at the beginning of the follow-up; therefore, we not evaluated variations in time and influence in the mortality.
In conclusion, our study suggests the relationship between high NLR and PLR with all-cause mortality in patients with CKD. The patients who had a high NLR or PLR showed twice the risk of dying compared to those who had these ratios within normal limits. These ratios are constructed with values usually collected in hemograms commonly used for patient follow-up. Being constructed based on a cheap and common exam and, due to our results, we believe that it could be considered within the usual practice in resource countries limited.