The main function of kidney is to remove excess water and waste products from blood. It also helps to regulate the levels of minerals such as sodium, calcium, and potassium in blood. One suffers from chronic kidney disease (CKD), also known as renal disease, when kidney losses its function gradually and usually permanently. CKD, defined by reduced glomerular filtration rate (GFR), proteinuria, or structural kidney disease, is a worldwide growing public health problem ¹ . Many subjects with renal disease of most etiologies progress to severe renal failure and/or end stage renal disease (ESRD), requiring renal replacement therapy, which may involve a form of dialysis or renal transplantation (Lewis et al., 1993; Klahr et al., 1994; DCCT, 1995; Brenner et al., 2001; Lewis et al., 2001; Wright et al., 2002; Niki et al., 2015). However, progression rate of CKD is very heterogeneous (Lindeman et al., 1985; Lindeman, 1990; Hallan et al., 2006). While a few predictive factors for progression such as proteinuria have been detected, identification of those at risk to progress remains a significant problem. It has also been established that there are several therapies that can ameliorate the progression of renal disease including ACE inhibitors, blood pressure control, tight diabetes control and perhaps low protein diets; however, in trials examining these therapeutic modalities there remains a very significant risk of progression of renal disease in the subjects receiving optimal therapy (Lewis et al., 1993; Klahr et al., 1994; DCCT, 1995; Brenner et al., 2001; Lewis et al., 2001; Wright et al., 2002; Niki et al., 2015).

African-American Study of Chronic Kidney disease with Hypertension (AASK) was motivated by the high rate of hypertension-related chronic kidney disease in the African-American population and the scarcity of effective therapies. The study involved 21-center randomized double-blinded treatment trial of 1,094 African-American patients with hypertension at ages ranging from 18 to 70 years. Patients had renal failure with GFR between 20 and 65 ml/min/1.73m². Patients were randomized to the angiotensinogen converting enzyme inhibitor (ACEi) ramipril, the β-blocker (BB) metoprolol or the dihydropyridine calcium channel blocker (CCB) amlodipine, and to usual (mean arterial pressure (MAP 102–107) or low (MAP < 92 ) blood pressure (BP) goals. The rationale for the treatment arms was that there was human and animal data suggesting that ACEi and CCB might slow progression of renal disease independent of their BP effects (Lewis et al., 1993; Hallan, 1998), and there was data from observational and treatment studies that a lower BP might have beneficial effects (Klahr et al., 1994; Klag et al., 1997). Although other studies had attempted to achieve a 10   m m H g MAP separation (Hansson et al., 1998; Lewis et al., 2001), AASK is the first major trial to actually achieve this goal. The primary outcome was rate of decline of GFR (GFR slope) based on iothalamate GFR studies at 6 months intervals, with a secondary clinical composite outcome of end stage renal disease (ESRD), a 25   m l / m i n or 50% drop in GFR from baseline (GFR event), or death (Subasi et al., 2017).

The initial AASK results were not conclusive (Wright et al., 2002). While the adopted therapy was shown to slow the progression of renal disease, there was still high rate of progression to renal failure. The CCB arm of the study was stopped early when interim analysis indicated that CCB was inferior to both BB and ACEi in patients with > 0.22 urine protein/creatinine ratio (about 300 m g proteinuria/24 h) (Agodoa et al., 2001). The low BP goal of the study did not improve outcomes: there was no beneficial effect of low MAP on rate of progression of renal disease as defined by GFR slope or clinical composite outcomes (GFR events, end stage renal disease (ESRD) or death). Subsequently, a similar result was found in the REIN trial (Ruggenenti et al., 1999). Studies in Type 2 diabetes have demonstrated a linear relation of achieved BP to renal outcomes (Bakris et al., 2003; Pohl et al., 2005); however, it should be noted that all the patients in these studies were treated to the same goal BP, so that rather than low BP being protective, the ability to achieve lower BPs may have defined a sub-population in these studies with low risks of disease progression. Despite the lack of effect on renal outcomes in AASK, proteinuria was diminished by the lower BP goal. This finding is similar to that previously reported for diabetics (Lewis et al., 2001). Finally, a subgroup analysis in AASK did suggest that patients on a non-protective regimen (CCB) may have benefited from the low BP goal (Contreras et al., 2005). Most importantly in AASK, ACEi decreased the number of events as compared to both BB and CCB (Wright et al., 2002). These data for ACEi vs. CCB are tabulated in Table 1 (risk reduction adjusted for baseline covariates) and were most dramatic for the hard outcomes, especially ESRD.

Several possible interventions such as blood pressure control (Wright et al., 2002), diabetes treatment (DCCT, 1995), controlling dietary protein intake (Klahr et al., 1994) and medications with possible renoprotective effects (Ruggenenti et al., 1999; Agodoa et al., 2001; Wright et al., 2002) have been tested in clinical trials. In all cases, the residual rate of progression of chronic kidney disease has remained significant. To date, there are few prediction models to identify which patients are likely to progress significantly. Subasi et al. (2017) (Subasi et al., 2017) identified serum proteomic patterns that can accurately distinguish rapid progression and slow progression among AASK patients. Recently, Lipkowitz et al. (2013) (Parsa et al., 2013) examined effects of variants in gene encoding apolipoprotein L1 (APOL1) on the disease progression and observed that renal risk variants in APOL1 were associated with the higher rates of ESRD and progression of chronic kidney disease in African-American patients as compared to white patients. Other recent studies include Rahman et al. (2013), where the effects of two antihypertensive drug dose (PM dose and add-on dose) schedules on nocturnal blood pressure vs. usual therapy (AM dose) in former participants were determined and Chen et al. (2016), where the longitudinal changes in hematocrit in hypertensive renal disease were studied.

The goal of our current study is to apply a pattern-based classification method to identify clinical and genomic features that may serve as prognostic markers for the progression of renal disease among AASK patients. Clinical and genomic features identified in our analysis shall be used in a future study to obtain comparison of the disease progression in white patients and African-American patients, both of those with and those without apolipoprotein L1 (APOL1) high-risk variants. The ultimate goal of our AASK data analysis, started in (Subasi et al., 2017) and continued in this current work, is to identify new targets and provide basis for new therapeutic interventions for chronic kidney disease.

Closer inspection of the data highlights the current dilemma: although there is a 30 − 60 % decrease in the number of events with ACEi still a residual event rate of > 6 % / y r in the trial as a whole and > 11 % / y r in subjects with urine protein/creatinine > 0.22 , a mild degree of proteinuria of 200 − 300 m g / d a y (Figures 1 and 2). In addition it can be seen that the event rate is essentially constant throughout the 5 years of the trial, indicating that remaining patients are still at risk to progress. This finding is similar to that of other trials such as MDRD (Klahr et al., 1994; Hebert et al., 1997), the Collaborative Study Group Trial (Lewis et al., 1993), RENAAL (Brenner et al., 2001) and IDNT (Lewis et al., 2001).

Figure 3 indicates the significant heterogeneity of progression rate of renal disease in the AASK Trial, where the rate of decline of GFR after 6 months in the trial (chronic GFR slope) is depicted in blue for each patient from most rapid decline (negative slope) on the left, to the least rapid decline (positive slope) on the right. The expected rate of decline of GFR with aging is generally assumed to be − 1 m l / m i n / y r (Berg, 2006; Murussi et al., 2006), although longitudinal studies have raised questions about this assumption (Lindeman et al., 1985; Lindeman, 1990). Based on this estimate, approximately 30 % of the AASK patients in Figure 3 did not progress (right side, slope > − 1 m l / m i n / y r ) while approximately 30 % progressed rapidly (left side, slope < − 3 m l / m i n / y r ). The figure also shows that proteinuria, the strongest predictor of progression rate reported in literature, is not an ideal predictor in that there are a number of slow progressors with significant proteinuria (red spikes, right), while a significant number of rapid progressors had no or minimal proteinuria (absence of red bars, left) (Subasi et al., 2017). This data is supported by the observation in genetics studies that proteinuria and progression of renal disease may be disparate phenotypes (Fogarty et al., 2000; Krolewski et al., 2006).

The datasets generated for this study can be found in the African American Study of Kidney Disease and Hypertension Study (Clinical Trial) (AASK Trial) https://repository.niddk.nih.gov/studies/aask-trial/.

ES, ML, and MMS are senior co-authors who designed and supervised the entire project and participated in writing the manuscript. MMM, TB, and MSM participated in the study design and performed the combinatorial analysis and participated in writing the manuscript. KC, EC, ZA, and RP were involved in various steps of the combinatorial analysis.

ML, ES, and MMS’s work was supported by National Institutes of Health—Grant number: 5R21DK67468. KC and EC’s work was supported by National Science Foundation (NSF) Research Experience for Undergraduates (REU) Grant—Award number: 1,359,341.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.