Contemporary rates and predictors of fast progression of chronic kidney disease in adults with and without diabetes mellitus

The population burden of chronic kidney disease (CKD) is high, with an estimated prevalence of 15% of U.S. adults in 2007–2012 [1] and 3.3–17.3% in 13 European populations [2]. CKD is independently associated with excess cardiovascular events, death, hospitalization and other adverse outcomes [3]. Stage 3 CKD, defined as an eGFR 30 to 59 ml/min/1.73 m², makes up the largest fraction of CKD patients [1] and carries the highest potential to intervene early and affect the natural history of the disease.

Despite being relatively common, only a small fraction of patients with eGFR 30 to 59 ml/min/1.73 m² progress to end-stage renal disease (ESRD) over their lifetime, with diabetes mellitus being one of the commonly attributed factors [4]. Previous research has focused primarily on the outcome of receipt of renal replacement therapy (chronic dialysis or receipt of renal transplant) that occurs often many years in the future [5‐8] and is subject to important biases given that the definition of ESRD is currently based on receiving a procedure [9]. More rapid progression of CKD is associated with worse clinical outcomes (e.g., cardiovascular events and death) independent of current level of eGFR [10‐14]. However, predicting which subset of patients are at high risk for progression of their CKD in the short-term is challenging but more clinically and policy relevant when prioritizing resources targeting the highest risk patients to potentially avoid or significantly delay the need for renal replacement therapy and potentially preventing cardiovascular and other adverse outcomes [15]. Prior research on fast progression of CKD has been limited by modest-sized samples, under-representation of racial/ethnic minorities, or being conducted during older eras not reflecting contemporary therapy and management [16‐20]. Relatively little is known about whether predictors of the fast CKD progression of CKD varies by diabetes mellitus status, and this could have further clinical and population management implications.

Within a large, diverse cohort of adults with mild-to-moderate CKD, we evaluated contemporary two-year rates and predictors of fast progression of CKD. We hypothesized that there would be higher rates of fast progression in the presence of diabetes and that risk factors may differ based on the presence or absence of diabetes.

There has been a growing appreciation that a significant proportion of patients with mild-to-moderate CKD do not progress in a predictable, slow linear pattern, with some patients either not progressing and others having a much faster decline in kidney function [31]. Identifying the subset of mild-to-moderate CKD patients who will subsequently experience fast CKD progression in the short-term has important clinical implications as they may benefit from more intensive monitoring and intervention. To address this, we examined a large, diverse community-based cohort with eGFR 30 to 59 ml/min/1.73 m² and found that 23% of these patients with diabetes and 15% of those without experienced fast CKD progression, and that the significant multivariable factors regardless of diabetes status included age ≥ 80 years, proteinuria, higher systolic blood pressure, lower hemoglobin level, and known heart failure, even after accounting for initial level of eGFR and receipt of cardiovascular and renal-related medications.

While CKD “progression” has been investigated in various ways, the large majority of studies focused on the end point of ESRD defined as the receipt of chronic dialysis or renal transplantation [5‐8]. Other studies have used varying definitions in the absolute or relative amount of drop in eGFR or reaching a particular level of eGFR [32]. While these are all potentially relevant outcomes, existing studies frequently use long time horizons and do not necessarily address the rate of change, which may be more important clinically to identify the subset of patients who are losing kidney function quickly in the short-term and may benefit from earlier, more frequent surveillance and intervention. Toward that end, our cohort of patients with Stage 3 CKD who had annual outpatient measurements of eGFR during 2 years of follow-up provides important insights into the rate of fast CKD progression and associated patient characteristics.

Our finding that documented proteinuria, a reflection of underlying structural kidney damage, is a strong predictor of short-term, fast CKD progression is consistent with other studies that have examined the development of ESRD or significant reductions in the absolute level of eGFR over a longer period of follow-up [5‐8, 32].

In patients with diabetes, the youngest patients with CKD were also more likely to experience fast progression after accounting for other potential risk factors and use of cardioprotective and renoprotective therapies, which is consistent with other studies [32] and may reflect a difference in underlying cause(s) of CKD. In contrast, among patients without diabetes, those aged 50–69 years old were less likely than those aged 70–79 years old to have fast CKD progression. Patients ≥80 years were more likely to experience fast progression regardless of diabetes status. We found that current or former cigarette smoking was associated with fast CKD progression in the short-term among patients without diabetes, which is consistent with results from the Cardiovascular Health Study cohort that showed a 31% relative increase in the likelihood of a serum creatinine increase ≥0.3 mg/dL over 3 years [33]. Furthermore, among 1906 participants in the Italian Longitudinal Study on Aging (ISA) cohort, current smoking > 20 cigarettes/day was associated with a more than twofold higher odds (adjusted odds ratio 2.29, 95% CI:1.00–5.27) of an increase in serum creatinine > 0.3 mg/dL during mean 3.6-year follow-up [34]. However, conflicting results exist about the relationship between smoking history and longer-term endpoints such as the need for renal replacement therapy [35, 36].

Higher systolic blood pressure is a well-documented risk factor of development of ESRD [35, 37] or a 50% reduction in baseline eGFR in patients with CKD [38], but fewer studies have examined the influence of blood pressure on rate of change of eGFR. Among 220 participants with eGFR 30–59 ml/min/1.73 m² enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA), having a systolic blood pressure ≥ 130 mmHg was associated with a more than twofold higher adjusted odds (odds ratio 2.29, 95% CI:1.20–4.37) of CKD progression, defined as > 2.5 ml/min/1.73 m² decline in eGFR over 5 years of follow-up when estimating GFR using combined serum creatinine and cystatin C data [39]. Our study supports and extends these findings in a much larger cohort showing a graded increased risk of fast CKD progression with systolic blood pressure > 120 mmHg even after additional adjustment for receipt of different antihypertensive agents.

Lower hemoglobin levels below 13.0 g/dL were also associated with a higher risk of fast progression. These results are consistent with an analysis of 6100 adults with systolic heart failure showing that a hematocrit < 36% (hemoglobin of approximately < 12.0 g/dL) was associated with a higher adjusted odds (odds ratio 1.30, 95% CI:1.18–1.45) of rapid decline in kidney function (defined as ≥6 ml/min/1.73 m² decrease in eGFR per year) and was more prominent in those with CKD (adjusted odds ratio 1.71, 95% CI:1.43–2.05) [20]. In addition, hemoglobin levels were lower among 117 Stage 3 CKD patients who progressed (eGFR decline > 3 ml/min/1.73 m² per year over 4 years) compared with 364 Stage 3 CKD patients considered non-progressors (< 1 ml/min/1.73 m² per year over 4 years) [40].

There have been conflicting data about the association between different lipoproteins and the risks of ESRD or significant loss of kidney function in adults with CKD. For example, in the Chronic Renal Insufficiency Cohort (CRIC) Study, none of the lipoproteins studied (total, LDL, HDL, VLDL, Lp(a), apoA-I, apoB) were independently associated with development of ESRD or > 50% reduction in baseline eGFR [41]. In contrast, among a Japanese population with CKD [42], the highest two quartiles of triglyceride-to-HDL cholesterol ratio were associated with rapid decline (defined as > 5 ml/min/1.73 m² reduction per year) compared with the lowest quartile, which supports our observation that a lower HDL level was associated with a graded, increased risk of fast CKD progression in the subset of patients without diabetes.

Despite evaluating a wide range of candidate predictors of fast progression of CKD, our model discrimination was moderate for models in patients with (c statistic 0.66) or without (c statistic 0.64) diabetes which is in contrast to models of initiation of renal replacement therapy which achieve much higher c statistics (0.84–0.90) [5, 8], depending on the severity of the CKD population studied and time horizon used. This highlights the challenge of accurately discriminating which subset of patients starting at an eGFR 30 to 59 ml/min/1.73 m² will experience fast progression of CKD and the need for investigation of additional factors influencing this risk to potentially intervene earlier in the process to delay the progression to ESRD. Importantly, however, model calibration (i.e., the ability to correctly estimate absolute risk of fast CKD progression over 2 years) was outstanding in patients with and without diabetes at entry, which highlights the potential clinical value in providing prognostic information to patients with stage 3 CKD (Figs. 2 and 3).

The study was strengthened by inclusion of a large, racially/ethnically diverse sample of adults with mild-to-moderate CKD who had approximately annual outpatient, non-emergency department measurements of serum creatinine from baseline through the first 2 years of follow-up. This allowed us to examine annual rate of eGFR decline and to identify the subgroup of patients who experienced fast CKD progression. All relevant diagnoses, procedures, test results and treatments were comprehensively captured through a state-of-the-art electronic medical record system that facilitated assessment of relevant patient characteristics which may predict fast CKD progression. Our study also had some limitations. For each patient, we calculated an average annual rate of eGFR decline estimated using linear regression, but patients may experience non-linear patterns of change in kidney function not reflected using this approach. Since this was a retrospective study of patients receiving clinically obtained measures of eGFR (rather than a structured research protocol with annual assessment of kidney function), the findings may not apply to all patients with eGFR 30–59 ml/min/1.73 m². We also used estimated GFR rather than measured GFR which may lead to some misclassification [43]. Similarly, results may not be completely generalizable to other clinical practice settings or to uninsured patients who may experience a different intensity of treatment or follow-up. Even though we examined a wide range of patient characteristics, we cannot rule out residual confounding affecting our model results. We were unable to comprehensively identify exposure to nephrotoxic insults or episodes of acute kidney injury from available data. Systematic information on other selected biomarkers that have been associated with different measures of CKD progression were also not available (e.g., urinary phosphorus excretion [44], serum calcium and phosphorus [40], serum bicarbonate [40, 45], NT-proBNP [19], or troponin T [19]).

In sum, within a large, contemporary population of adults with mild-to-moderate CKD, accelerated progression of kidney dysfunction within 2 years affected ~ 1 in 4 patients with diabetes and ~ 1 in 7 without diabetes. Regardless of diabetes status, the independent predictors of fast CKD progression included proteinuria, elevated systolic blood pressure, heart failure, anemia, and age ≥ 80 years. Age 18–49 years was also a predictor in those with diabetes, while additional predictors in patients without diabetes included smoking history, prior ischemic stroke, prior pacemaker implantation, and HDL cholesterol < 60 mg/dL. These findings may help in identifying the subset of patients who may benefit from more frequent monitoring of eGFR to identify fast CKD progression or proteinuria and subsequent intervention to potentially retard further loss of kidney function and other potentially associated adverse clinical outcomes such as cardiovascular events.