The lack of tools to assess prognosis in patients with kidney injury is one of the reasons for the slow progress in developing new management strategies. Biomarkers close to the ideal standards can help design and interpret new studies that facilitate patient stratification. There is evidence that protein electrophoresis results are associated with ARF prognosis, especially in patients with several diseases [1, 21]. The results in such diseases often demonstrate extreme variation from reference values and it is unclear if relatively lower alterations can also be diagnostic or prognostic. Owing to the direct relationship between FLCs and renal function, we sought to investigate whether blood and urine protein electrophoresis findings could be associated with 1-year mortality in ARF. The current study revealed that 1-year all-cause mortality rate was 22.03% in our cohort, consistent with previous studies [22–24]. However, despite some observable changes in particularly urine κ and λ levels, our results showed that none of the electrophoresis-related parameters were associated with mortality. Notably, older age and low albumin were the only two factors that were clarified as independent risk factors.
Despite progress in diagnosing and treating ARF, the mortality associated with it remains elevated. Consequently, the KDIGO guidelines recommend the monitoring of all ARF patients [25] and the UK guidelines recommend 2 to 3 years of post-ARF surveillance [4]. In addition to the traditional mortality risk factors in ARF, which will be discussed below, systemic inflammation is also thought to play an important role in the pathogenesis and prognosis of AKI [15, 26–28]. Immunoglobulin FLC level is a potential nonspecific marker of immune system activation [15] and it is well established that systemic inflammation can affect the concentration of numerous proteins including acute phase reactants and those involved in other processes [29–31]. Therefore, it is possible that the distribution of protein fractions might be associated with ARF prognosis [11, 32]. Moreover, prior research indicating a potential link between serum protein distribution and the severity of kidney diseases has motivated our investigation into the utility of these protein fraction concentrations for predicting ARF prognosis [16]. For instance, in patients with multiple myeloma, a prevalent plasma cell dyscrasia, the primary cause of AKI involves tubular accumulation of cylinders composed of Tamm-Horsfall protein and FLCs [1]. Indeed, a prior study including Turkish patients reported a significant relationship between serum λ light chain concentration and GFR value, suggesting a potential for predicting and perhaps stratifying renal function and risks [21]. In the context of IgD multiple myeloma, which is a rare form of multiple myeloma (1–2% of cases), there is a production of gamma globulin light chain forms (Bence Jones protein) and patients suffer from acute renal failure despite lack of a monoclonal peak in serum protein electrophoresis. Studies have shown that 20–40% of patients present with ARF—cast nephropathy, even at initial diagnosis, caused by intratubular precipitation of FLCs [16–18]. It is therefore conceivable that ARF may be associated with FLCs; however, it appears that if such a relationship is true, the relationship could be true for only a select subset of patients.
In a study investigating the impact of monoclonal gammopathy on renal failure and death in patients with chronic renal disease, monoclonal gammopathies (undetermined significance or renal significance) were unassociated renal failure risks [8]. Moreover, proteomics data has substantiated claims that renal injury and creatinine elevation are closely-knitted factors in ARF, potentially with links to the need for renal replacement therapy [2]. Furthermore, studies examining patients with plasma cell dyscrasia have demonstrated that kidney injury develops due to the renal toxicity of FLCs. This relationship is apparently not unidirectional, as patients presenting with renal disease later demonstrate elevated FLC concentrations in serum [21]. It is clear however, that serum protein electrophoresis patterns specific to ARF and their role in the prediction of ARF prognosis have not been studied extensively. In our present study, none of the characteristics derived from serum protein electrophoresis were found to be linked to 1-year mortality in ARF patients without malignancy. In a recent prospective investigation by Wang et al., the utility of serum combined FLC concentrations at the onset of AKI was assessed as an independent predictor of mortality in individuals experiencing AKI post-cardiovascular surgery. The primary finding was that combined FLC (cFLC) concentrations independently predicted overall mortality in AKI patients [15]. A high cFLC level was notably associated with a five-fold increase in the risk of mortality compared to a low cFLC level. FLC levels were positively correlated with an increased requirement for dialysis and worse kidney function, reflected in higher levels of serum creatinine and urea nitrogen. Both FLC κ and FLC λ concentrations in individuals with stage 3 AKI surpassed those in stages 1 and 2, and levels were also higher among individuals with chronic kidney disease compared to those with only AKI [15], indicating some prognostic promise. Some other previous studies have also shown that serum FLC concentration is associated with increasing stage in patients with chronic renal failure [9–11]. Nonetheless, the absence of large-scale longitudinal studies with homogeneous patient populations and long follow-up periods makes it difficult to draw definitive conclusions.
AKI commonly stems from damage to renal structures, triggered by factors such as sepsis, hypotension, drug toxicity, and cardiopulmonary events [33]. Although decreased urine output and increased serum creatinine are the most important distinguishing features of AKI, there is insufficient evidence regarding the levels of proteins in urine and their direct relationship with AKI severity. FLCs can emerge as a result of excessive immunoglobulin synthesis and they are normally removed from the circulation by the kidneys. They are filtered through the glomeruli but are reabsorbed in the proximal tubules and subsequently metabolized, and therefore the concentration of light chains in the urine is expected to be low. Therefore, under normal conditions, decreased GFR should result in increased serum FLC, while restricted reabsorption should increase urine concentration [21]. Interestingly, urine protein electrophoresis has been suggested to be diagnostic in the identification of glomerular or tubular origin of AKI. This has been based on the finding that glomerular proteinuria may serve as a predictor for long-term progression to chronic renal failure [33]. A study employed 2-D gel electrophoresis to assess urinary proteins in AKI patients with acute tubular necrosis. Unlike serum creatinine, which was unreliable for predicting renal replacement therapy, urine protein analysis showed 78% accuracy in forecasting renal failure progression, with 75% sensitivity for identifying those needing renal replacement therapy and 80% specificity for those who did not [2]. In another study, urinary peptide signatures of patients with subclinical tubular injury resembled those of patients with overt disease, and furthermore, 1-year mortality was deemed to be predictable with these data [34]. In a general sense, the literature supports the assertion that urine protein patterns can be prognostic in patients with ARF. However, despite relatively greater variations in urine values (compared to serum values), we found that neither urine FLC κ and λ nor FLC κ-to-λ ratio were associated with mortality after ARF. Although urine protein patterns have the potential for ARF prognostication, ARF is a disease that has unforecastable characteristics and numerous etiologies. These biases could impact the alteration of urinary proteins, especially with respect to the longitudinal properties of kidney injury.
The variability in the properties and etiologies of ARF make it difficult to create homogeneous patient groups and determine generalizable prognostic factors [1]. Research has sought to identify patient risk stratification markers in order to be able to generate strategies for treatment early in the course of the disease [3, 5–7]. However, prognosis predictors for the medium and long term are rather weak. In our study, advanced age and low albumin levels were found to be independent risk factors for 1-year mortality. Risk factors reported in previous publications on mortality after ARF include previous AKI history, AKI severity, baseline renal function levels, and subsequent recovery of renal function [3, 5–7]. In a large population-based cohort study, in patients who developed AKI in the hospital, the factors most associated with mortality in the mid- and long-term after discharge were reported to be initial renal function, AKI severity, and previous AKI history [3]. In the study of Wang et al., age, aortic surgery, high creatinine, high CRP, and decreased albumin were determined to be risk factors associated with 90-day mortality among subjects suffering from AKI following cardiac operations [15]. Also there are a number of parameters worthy of mention in this respect, including cystatin C [35], neutrophil gelatinase associated lipocalin [36] and urinary liver-type fatty acid-binding protein [37].
In general, ARF poses a significant clinical challenge with a notable mortality rate, and effective prognostic markers for medium to long-term mortality are currently lacking. While some studies have shown promising results regarding the predictive value of blood and urine protein patterns for ARF prognosis, our study did not yield significant findings in this context. Notably, advanced age and low albumin levels emerged as potential prognostic markers for ARF. We must also record the fact that urine levels of FLC markers suggested considerable variations in some patients; however, prospectively desgined studies that can leverage the heteregenous inclusion of patients in order to characterized potential subgroups are necessary to clarify whether there exist distinct subgroups in which these markers can be utilized. This, in turn, may aid in differentiating high-risk patients in terms of post-ARF mortality, ultimately contributing to the prevention of mortality associated with the condition.
The study under consideration presents several limitations that warrant careful interpretation of its findings. The foremost limitation lies in its retrospective design and the restriction to a single center, which may limit the generalizability of the results to a broader population. Beyond these primary constraints, additional possible limitations should be acknowledged, which may influence the comprehensive understanding of the study's outcomes.
Limitations
As mentioned previously, one notable limitation of our study is the heterogeneous etiology of ARF. Unfortunately, this study did not differentiate patients based on the specific etiologies of ARF, and consequently, potential prognostic markers were not investigated within the context of different causal factors. This lack of categorization hinders comparative analysis of data based on ARF etiology. Secondly, while the study reported comorbidities causes of death were not examined, and ultimately, the analysis of all-cause mortality could have obscured significant relationships in patients who died due to reasons more closely impacted by ARF. Thirdly, the time elapsed until death was not assessed as this data was not available for a large proportion of patients, which prevents temporal analyses. Furthermore, the study solely relied on hospital records for mortality information, which were kept in a detailed and up-to-date fashion, but it is possible that some post-discharge deaths were not recorded.