The findings of the present study showed a non-linear progression of CKD over the four years. During follow-up, there was a reduction of 1.3 mL/min/1.73m² in GFR. In the progression group, there was an average reduction of 13 mL/min/1.73m², which characterizes rapid progression. On the other hand, in the non-progression group, there was an increase of 2 mL/min/1.73m² in GFR, contrary to what is traditionally expected, which is a GFR reduction (slow or fast) or maintenance.
Xie et al. [15] characterized three different GFR trajectory classes of people entering CKD stage 4 (2008–2013): consistent slow decline with absolute GFR change of − 2.45 mL/min/1.73 m2 per year; consistent fast decline and GFR change of − 8.60 mL/min/1.73 m2 per year; and early nondecline and late fast decline with GFR change of − 0.4 mL/min/1.73 m2 per year in years 1 to 3 and − 7.98 and − 21.36 mL/min/1.73 m2 per year in years 4 and 5, respectively. The study Prevention of Renal and Vascular End-Stage Disease, carried out with 6,894 people during four years, found an estimated GFR loss of 0.2 mL/min/1.73m² in the impaired renal function group [21], similar to the study by Inaguma et al. [22] that showed an annual average decrease of 0.36 mL/min/1.73 m2 in GFR. Another study with a median follow-up of 31 months (2.5 years) with patients with estimated GFR less than 30 mL/min/1.73m² showed a decline in GFR of 2.65 mL/min/1.73m² per year [23]. Therefore, different situations are observed in relation to GFR over time, and it is not possible to establish a pattern. In the present study, we can establish two situations: a group that progressed rapidly (3.25 mL/min/1.73m² per year) and another group that maintained a similar GFR and/or increased the GFR in relation to the baseline (non-progression).
Thus, an important finding of this study was the non-linear variation in the values of GFR throughout time, with increased or decreased GFR. The traditional paradigm of GFR progression among patients with CKD shows a steady and almost linear decline over time [3, 14]. In contrast to the traditional paradigm, many patients with CKD have a fast and/or slow progression of the disease or an extended period of non-progression. In the Modification of Diet in Renal Disease study, approximately 19% of patients with GFR between 25 and 55 mL/min/1.73m² experienced improvement or stabilization of renal function during the study period of two years [24], which corroborates other studies of great relevance [3, 4, 14, 15, 25].
In addition to the individual biological variation, the analytical variation inherent to the estimation of the GFR from serum creatinine measurements should be considered. Some problems related to determining the serum creatinine are inconstant production of serum creatinine, increasing with intake of meat, creatine, or with excessive muscular effort; the Jaffé creatinine analysis method suffers interference, in vitro, positively from cephalosporins and ketone bodies and negatively from bilirubin; enzymatic methods suffer interference, in vitro, from n-acetylcysteine and dipyrone; and creatinine values vary with the presence of simple infections, dehydration, and use of nephrotoxic drugs [26]. Thus, one of the challenges in the use of routine analyses of creatinine to estimate changes in GFR over a long period is to ensure the stability of the test. Although the strict quality control routines protect against major fluctuations, variation in the long term cannot be completely excluded [14].
This study also associated the progression of CKD with sociodemographic, economic, lifestyle, clinical, anthropometric, and biochemical variables. Knowing the associated factors may contribute to the correct identification of CKD and implementation of actions to slow its progression [27]. In the multivariate analyses, age ≥ 75 years, DM, and urea were independently associated with CKD progression.
In the present study, individuals aged ≥ 75 years were eight times more likely to have CKD progression than individuals aged ≤ 68 years. Age is recognized as an independent risk factor for CKD, and the findings of association of this disease with aging are consistent with previous studies [28, 29]. However, in an analysis of a large cohort, older age was associated with slower loss of GFR, although this seemed to be true only at GFR levels < 45 ml/min per 1.73 m² [30]. Conway et al. [31] described similar results in an elderly population with stage 4 CKD. Thus, it appears that there is some other pathological process, likely vascular in etiology, that plays a role in pathogenesis of GFR decline in the elderly [32]. Considering that all individuals in this study have AH, this factor may also be contributing to the progression of CKD. Data from the Boston Longitudinal Study of Ageing suggest that the decline in GFR with increasing age is largely attributable to AH or the presence of comorbidities, such as heart failure and other cardiovascular diseases [33].
Another important factor is DM, which is the leading cause of CKD in the developed world, and people with diabetes and CKD have a greatly increased risk of all-cause mortality, cardiovascular mortality, and kidney failure [34]. In individuals with diabetes, both GFR and albuminuria are important predictors of kidney outcomes. In a recent meta-analysis, compared to the nondiabetic participants, those with diabetes showed a borderline increased hazard for the progression from late-stage CKD to end-stage renal disease (HR 1.16, 95% CI 0.98–1.38) [35]. On the other hand, the study by Levin et al. [23] had the largest study population and enrolled stage 4 to 5 CKD patients, for whom diabetes was reported as a nonsignificant factor (HR 0.82, 95% CI 0.56–1.20; P = 0.30). Previous studies have demonstrated large variation in GFR progression in persons with diabetes [36]. In the present study, individuals with diabetes were 8.74 times more likely to have CKD progression than individuals without diabetes.
In relation to urea, individuals with higher urea levels were 8% more likely to have CKD progression. Its elevation indicates inability of the renal system to purify the blood of nitrogenous products. Fehrman-Ekholm and Skeppholm [37] found a significantly positive correlation between age and urea (p = 0.0019); that is, urea increased with age, which probably reflects the decrease in GFR, which corroborates the data from the present study. Levey [38] highlights that urea is the first used endogenous marker, but it is not completely reliable, as its levels are more vulnerable to changes for reasons unrelated to GFR.
Finally, in individuals who are progressing, the subsequent risk of morbidity and mortality increases exponentially, as well as the costs associated to health. A reduced GFR also associates with a wide range of complications and reduced quality of life. Therefore, it is important to clarify which factors are associated with the CKD progression and are potentially modifiable, in order to intervene early and improve the associated adverse results [25].
There are limitations to this study. There are medications that may be more commonly taken by hypertensive patients that may have an effect on renal function. We were unable to include these in our analysis. Another limitation of the study was the difficulty maintaining consistent calibration of the serum creatinine test over time, and the results are highly sensitive to progression adrift in the assay of creatinine. Despite this, the findings of this study have implications for future researches on CKD. Identifying non-linearity in the progression of the disease suggests a new approach to other studies that investigate the association of risk factors that vary in time with changes in renal function. Thus, a more accurate understanding of the CKD trajectory can help to guide clinical decision making, develop actions of prevention of disease progression, and seek to improve patients’ quality of life.