A perspective on chronic kidney disease progression

Abstract

Chronic kidney disease (CKD) will progress to end stage without treatment, but the decline of renal function may not be linear. Compared with glomerular filtration rate and proteinuria, new surrogate markers, such as kidney injury molecule-1, neutrophil gelatinase-associated protein, apolipoprotein A-IV, and soluble urokinase receptor, may allow potential intervention and treatment in the earlier stages of CKD, which could be useful for clinical trials. New omic-based technologies reveal potential new genomic and epigenomic mechanisms that appear different from those causing the initial disease. Various clinical studies also suggest that acute kidney injury is a major risk for progressive CKD. To ameliorate the progression of CKD, the first step is optimizing renin-angiotensin-aldosterone system blockade. New drugs targeting endothelin, transforming growth factor-β, oxidative stress, and inflammatory- and cell-based regenerative therapy may have add-on benefit.

the prevalence of chronic kidney disease (CKD) is estimated to be 8–16% worldwide (38). In patients over 64 yr old, the prevalence increases to 23.4–35.8%, suggesting increasing age contributes to increased CKD (104). The yearly economic costs of care for CKD and end-stage renal disease (ESRD) in patients over age 65 are $60 billion, representing 24% of total Medicare expenditures in 2011 in the United States of America. The diagnostic criteria for CKD are: a glomerular filtration rate (GFR) threshold <60 ml·min⁻¹·1.73 m⁻² or the presence of kidney damage ≥3 mo. Kidney damage refers to pathological abnormalities documented by biopsy or imaging, alterations in urinary sediment or proteinuria (urine protein-to-creatinine ratio >200 mg/g or urine albumin-to-creatinine >30 mg/g), genetic disorders, or a history of renal transplantation (47). In 2002, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative classified CKD into five stages according to estimated GFR (eGFR) (60). These guidelines in 2012 recommended classification of CKD based not only on the cause and GFR category but also albuminuria category because of the graded relationship between increasing proteinuria and a variety of important outcomes, including all-cause mortality, cardiovascular disease, and kidney failure (35). The overall awareness of CKD is remarkably low: 90% of individuals with two to four CKD markers and 84% of people with more than five CKD markers were reported to be unaware of their kidney disease (87). Although it is still debated whether early screening for CKD should be done in the population, early stage intervention treatment is important to improve the quality of life and survival (50). Numerous experimental models attempt to model the human disease conditions, but none completely capture the mechanisms and phenotypes of human CKD. In this regard, we quote Pickering et al. who eloquently stated: “We would make a plea that so far as any conclusions are drawn as to the mechanism of human disease, the evidence derived from man should at least be considered” (68). This review will therefore focus on new findings from human studies related to detection, mechanism, and treatment of progressive CKD.

Definition of Progressive CKD

Progress rate of CKD.

The progression rate of CKD varies among individuals. Some CKD patients maintain stable eGFR levels over several years, so-called “stable CKD,” or even improve eGFR, so-called “reversal CKD.” In contrast, other CKD patients lose eGFR over time, so-called “progressive CKD.” Progressive CKD is observed in the majority of CKD patients while reversal CKD is uncommon. Follow-up for 12 yr in the African American Study of Kidney Disease and Hypertension (AASK) trial showed that 3.3% patients improved eGFR with a mean slope of +1.06 ml·min⁻¹·1.73 m⁻²·yr⁻¹ per year compared with −2.45 (0.07) ml·min⁻¹·1.73 m⁻²·yr⁻¹ among the remaining patients (32). In another small 10-yr follow-up study, 167 of 347 (48.1%) CKD III patients did not progress while 60 (17.3%) progressed to stage 4 and 120 (34.6%) progressed to stage 5 (4). Another study from France showed improved eGFR in 15.3% of patients with a median slope +1.88 ml·min⁻¹·yr⁻¹ even in CKD stage 4–5 (96). Similar results were observed in the Modification of Diet in Renal Disease Study. Stable eGFR was observed in 19% and reversal of CKD in 11% over 2 yr follow-up (33). Significantly improved eGFR slope was detected in 48.2% of CKD stage 2 patients, 29.3% of CKD stage 3 patients, and only 14.7% of CKD stage 4 patients (86). Clearly, whether CKD progresses or not is related to the CKD stage at enrollment and beginning of intervention.

Nonlinear pattern for progressive CKD.

The progression of CKD may not be linear. CKD progression, especially GFR decline, has been assumed to follow a linear or possibly a loglinear trajectory. Physicians have used the linear decline model to counsel patients on when they might reach ESRD and need renal replacement therapy (33, 58). Newer data suggest that the natural pattern of progression from CKD to ESRD followed a more staccato and unpredictable course (74, 103). In a study of individual GFR progression trajectories over 12 yr of follow-up, Li et al. demonstrated that 41.6% of CKD patients showed a >0.9 probability of having either a nonlinear trajectory or a prolonged nonprogression period while in 66.1% of patients the probability of these nonlinear courses was >0.5 (51).

Markers for progressive CKD.

To predict and define progressive CKD is still difficult, especially with short follow-up time. This is related to a lack of a consensus definition for CKD progression and lack of sensitive and specific biomarkers for the early prediction of CKD progression. True end points for CKD, such as development of ESRD, which is often defined as a new initiation of renal replacement therapy, may not be reached for decades. Surrogate end points have potential advantages over true clinical end points, which could reduce the cost and offer more opportunities for clinical trials (Table 1). The most popular surrogate markers for CKD are albuminuria, serum creatinine, and GFR. As an early marker of renal damage, microalbuminuria may allow earlier interventions for CKD (48). However, it is unclear whether reducing microalbuminuria is necessary for inhibiting CKD progression and improving clinical outcomes (26). Another accepted surrogate end point for progression of CKD to ESRD is doubling of serum creatinine and/or 50% reduction of GFR. Doubling of serum creatinine corresponds to a 57% change in eGFR. In acute kidney injury (AKI), serum creatinine has been found as a late and often insensitive marker of underlying injury. Among CKD patients with baseline eGFR <60 ml·min⁻¹·1.73 m⁻², the adjusted hazard ratios for ESRD were 32.1 for changes of −57% in eGFR and 5.4 for changes of −30%. Average adjusted 10-yr risk of ESRD was 99% for eGFR change of −57%, was 83% for eGFR change of −40%, and was 64% for eGFR change of −30% vs. 18% for eGFR change of 0%. Corresponding mortality risks were 77, 60, and 50% vs. 32%, showing a similar but weaker pattern (17). This and other studies suggested using eGFR declines of 30 and 40% as alternative surrogate end points of progression, which may offer the advantage of being earlier and more common markers of deteriorating kidney function, potentially allowing shorter clinical trial duration.

Table 1.

Surrogate markers for progressive CKD

	Marker	CKD Stages	Advantage	Disadvantage	Ref. No.
Standard markers	Albuminuria	1–3	Sensitive	Not correlated to CKD progression	(26, 48)
	Doubling of serum creatinine	2–4	Correlated to CKD progression	Insensitive	(17)
	50% reduction of GFR	2–4	Correlated to CKD progression	Insensitive	(17)
Novel Biomarkers	KIM-1	1–3	Sensitive, correlated with eGFR decline	Need to validate threshold	(72)
	NGAL	1–3	Sensitive, correlated with eGFR decline	Need to validate threshold	(6, 8, 78)
	ApoA-IV	1–3	Sensitive, correlated with eGFR decline	Need to validate for threshold	(7)
	suPAR	1–3	Sensitive, correlated with eGFR decline	Need to validate for threshold	(29)

CKD, chronic kidney disease; GFR, glomerular filtration rate; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase-associated protein; ApoA-IV, apolipoprotein A-IV; suPAR, soluble urokinase receptor; eGFR, estimated GFR.

Some biomarkers can be considered to be intermediate end points. Currently, the use of biomarkers for clinical decision making is not defined, but some markers, such as kidney injury molecule (KIM-1), neutrophil gelatinase-associated protein (NGAL), apolipoprotein A-IV (apoA-IV), and soluble urokinase receptor (suPAR), appear to be good candidates. In a retrospective analysis of 107 diabetic type 1 with CKD stages 1–3 followed for 5–15 yr, 63% of those subjects with higher KIM-1 levels (>97 pg/ml) progressed to ESRD, whereas only 20% of patients with lower levels progressed. In addition, baseline plasma KIM-1 levels correlated with rate of eGFR decline after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and HbA_1c (72). As an established marker for AKI, NGAL has also been associated with CKD incidence and progression in adults. In a community-based study, NGAL was evaluated as an independent risk factor for incident CKD. Participants with NGAL concentrations in the highest quartile had more than twofold higher odds of incident CKD stage 3 compared with those with NGAL in the lowest quartile after multivariable adjustment. Adjustment for urinary creatinine and albumin concentration attenuated this association (6). In a cohort of 158 elderly Caucasian predialysis CKD patients with low-grade proteinuria, urinary NGAL-to-creatinine ratio was associated with mortality and renal replacement therapy, and this risk was independent of kidney and cardiovascular risk factors (78). Similar results were found in a cohort of 96 CKD patients followed for 18.5 mo, where urinary NGAL and sNGAL predicted CKD progression independently of other potential confounders, including eGFR and age (8). Human apoA-IV is a 46-kDa glycoprotein synthesized in intestinal enterocytes during fat absorption and incorporated on the surface of chylomicrons. Increased baseline ApoA-IV levels were found in those mild to moderate CKD patients who progressed over 7 yr follow-up in a small study of 177 patients. Serum ApoA-IV increase by 1 mg/dl predicted progression, with 11 ml/min decrease in GFR, with an area under the curve of 0.792 (P < 0.001) and a hazard ratio of 1.062 (P = 0.006) (7). In the Emory Cardiovascular Biobank cohort and the Women’s Interagency HIV Study cohort, a higher suPAR level at baseline was associated with a greater decline in the eGFR. The participants with a normal eGFR at baseline had the largest suPAR-related decline in the eGFR (29). The above biomarkers need to be validated to identify thresholds and cut-offs for prediction of CKD progression and adverse events by additional large multicenter prospective studies. Additional studies are also required to determine whether the biomarkers continue to predict CKD progression longitudinally, in addition to merely associating with the baseline levels of GFR that correlate with progression. It is likely that a panel of CKD biomarkers will provide more information than any one alone. Such a panel may need to be context-specific based on pathophysiological considerations. For example, distinct panels may emerge for prediction of CKD due to etiology, such as diabetes and primary glomerulonephritis vs. reflecting the major underlying pathological feature such as tubulointerstitial fibrosis and inflammation. Ongoing discoveries using techniques such as proteomics, peptidomics, urinary transcriptomics, and micro-RNA analysis are continuing to reveal novel biomarkers and therapeutic targets. The CKD Biomarkers Consortium has 15 ongoing studies with the aim to develop and validate novel biomarkers for CKD.

New Insights into Mechanisms of CKD Progression

Progressive CKD may be viewed as having three phases. First, there is cause-specific injury and acute response to that injury. In the second phase, misdirected repair generates fibrosis and dysfunction. At this phase, although fibrosis is a pathological and destructive event, it is essentially a self-limiting repair process to restrict the injury. The third and final stage is that of relatively steady progressive loss of remnant nephrons, which requires multiple nascent injury to each nephron or cluster of nephrons. Thus, the causes of CKD incidence appear different from those driving CKD progression, since progression rates of CKD differ dramatically among patients with apparent identical primary diseases (71).

Genetic and epigenetic variants.

Genome-wide association studies (GWAS) focus on the most common genetic variations in the human genome. Single nucleotide polymorphisms (SNPs) are common substitutions of a single base with another, which occur with high frequency in the human genome (1 per 300–500 base pairs) (36). Although most SNPs have no functional outcome, some might result in biological changes, which could play a role in disease susceptibility. Compared with some rare diseases that are caused by single locus mutations, the genetic component of common polygenic diseases, such as CKD, is thought to involve many common genetic variants (34). Because a single SNP explains only a small proportion of a trait’s variance, multiple genetic variants are required to account for the total genetic risk of a disease. GWAS identified several genes, in which variants are associated with decline of renal function in CKD, including uromodulin (UMOD), nonmuscle myosin heavy chain type 2 isoform A, methenyltetrahydrofolate synthetase, eyes absent homolog 1, and transcription factor-7-like 2 (43, 45, 67). In a follow-up analysis, the presence of the UMOD SNP rs4293393 was found to be associated with uromodulin levels, and elevated uromodulin levels preceded the development of CKD (44). Apolipoprotein L1 (APOL1)-mediated risk for CKD progression was also reported by the AASK and Chronic Renal Insufficiency Cohort (CRIC) studies (52, 65). These longitudinal studies observed that the presence of two APOL1 risk variants was associated with more rapid loss of kidney function in the nondiabetic subjects in AASK and in both diabetic and nondiabetic subjects in CRIC. The rates of CKD progression were lowest for European Americans (who essentially lack APOL1 risk variants), intermediate for African Americans with zero or one APOL1 risk variant, and highest for African Americans with two APOL1 risk variants (65). Interactions between APOL1 and several modifiable environmental factors, or between different genes, produce the variable clinical phenotypes, which show different response to conventional therapies targeting reductions in systemic blood pressure and proteinuria.

Protein- or mRNA-based biomarkers often provide a snap-shop at time of analysis over a long-term picture, which underlies individual progression of CKD. Recent studies suggest that these limitations can be overcome by analysis of epigenetic markers, because epigenetics in general offer the advantage of greater stability but do underlie modifications of gene expression during disease progression (82). Unlike genetic polymorphisms, epigenetic modifications can be more easily therapeutically modified. There are three major epigenetic mechanisms, namely DNA methylation, micro-RNAs, and histone modifications, which interact and impact each other. DNA methylation refers to clustering of methylated cytosine bases within a specific promoter region (CpG island promoters) (101). In the CRIC study, which was established to follow a diverse group of patients with chronic renal insufficiency with intensive screening and follow-up for the purpose of identifying high-risk groups, patients characterized as rapid progressors had different DNA methylation profiles of a number of genes that have been implicated in inflammation, oxidative stress, or fibrosis (97). Altered presence of a single micro-RNA causes altered expression of numerous genes, typically requiring additional transcriptional profiling to assess context-dependent relevance (84). Renal biopsy specimens from patients with so-called “hypertensive nephrosclerosis” have enrichment of miR-200a, miR-200b, miR-141, miR-429, miR-205, and miR-192 expression, and the degree of upregulation correlated with disease severity (94). Histone modifications are most complex, since those occur at multiple sites within multiple genes, blurring assessment of biological impact of identified modification (83). Transforming growth factor-β (TGF-β) increases histone H3 lysine methylation (H3K4me1, H3K4me2, and H3K4me3), which increased expression of connective tissue growth factor (CTGF), a downstream effector of TGF-β’s profibrotic effects, collagen-1α1, and plasminogen activator inhibitor-1, which inhibits fibrinolysis and proteolysis in mesangial cells (81). Blocking class I histone deacetylatase through the selective class I histone deacetylase inhibitor MS-275 led to inhibition of TGF-β signaling and blocked renal fibroblast activation (53).

AKI and CKD.

Several studies indicate that AKI has a deleterious long-term effect on the morbidity and mortality of patients (12, 55). As a significant risk factor, AKI induced an 8.8-fold increase in risk for CKD and a 3.3-fold increase in risk for ESRD (16). One study showed acute protective effects by a p53 inhibitor in an ischemia-reperfusion model but worsened fibrosis after 8 wk, indicating different mechanism in AKI vs. AKI-to-CKD transition (18). The degree of increase in serum creatinine during the AKI episode has been linked to increased subsequent development of ESRD (11). The severity, duration, and frequency of episodes of AKI are now recognized as key determinants influencing progression to CKD. Kidney fibrosis probably starts as a beneficial reparative mechanism in response to an initial damage. If one or more of the initial stages of this process are not correctly regulated, a pathological fibrosis is originated and progresses to CKD. The maladaptive repair to AKI represents a necessary but not sufficient ingredient to promote progression (92). The mechanism by which AKI leads to CKD is unclear, but several mechanisms have been proposed, such as nephron loss, inflammation, endothelial injury with vascular rarefaction and hypoxia, as well as epigenetic changes and cell cycle arrest in epithelial cells (3, 12, 100). For instance, vascular rarefaction of peritubular capillaries is correlated with the severity of fibrosis and predicts both interstitial damage and decreased GFR (15). Furthermore, many experimental findings in rodents strongly suggest that vascular rarefaction contributes to the decrease of GFR and the progression of CKD (41).

AKI not only can transform into CKD but also contribute to the progression of CKD from other causes. Brenner and colleagues showed that glomerular hypertension and hyperfiltration are major factors accounting for progression of CKD in animal models and humans (10). However, tubular atrophy and interstitial fibrosis are the common end points of practically all progressive kidney diseases, irrespective of the initial etiology, and cardinal features of CKD (9). Studies indicated that interstitial scarring may not be directly progressive in nature, but it exaggerates responses to secondary injury, reduces renal functional reserve, and contributes to the development of hypertension (39, 91). Broadly, a vicious cycle of “glomerulus-tubulointerstitial-glomerulus” injury can promote CKD progression. Interdicting any feedback in this cycle, for example, by reducing hypoxia or interstitial inflammation, could contribute to slow or stop the progression of CKD. The clinical follow-up of survivors of AKI is low, which may result in missed opportunity to prevent chronic disease (28).

New Treatment Approaches for Progressive CKD

The primary aims when treating CKD are both to slow the progression of CKD and to prevent cardiovascular disease, the principal cause of morbidity and mortality in the CKD population (93). The main approaches to slowing the rate of CKD progression are treatment of the underlying disease, if possible; treatment of reversible causes of renal failure, which, if identified and corrected, may result in the recovery of renal function; and treatment of secondary factors that are predictive of progression, such as elevated blood pressure and proteinuria, when the renal damage has already occurred. Furthermore, strong evidence from murine studies suggest that renal fibrosis in principle is a treatable target and that possible regression of fibrosis would translate into preservation of kidney function, although regression of CKD without intervention is rare in humans. The concept of regenerative nephrology is just now emerging, focusing on two key ideas. Kidney regeneration could be achieved through use of growth factors and morphogens, or multipotent cells could be “taught” to regenerate the chronically injured kidney. Both concepts require either recreation of a growth factor environment within the kidney to facilitate renal regeneration or generation of renal cell type-specific progenitor cells in vitro to repopulate the kidney. There are several common concepts related to standard and regenerative medical therapies of CKD (Table 2).

Table 2.

Approaches for CKD treatment

	Strategy	Drug Name	Ref. No.
Optimize and maximize RAAS blockade	RAAS blocker	Renin inhibitor, ACEI, ARB, Aldosterone synthesis inhibitor	(25, 57, 66, 73, 77)
New targets	ETAR antagonist	Atrasentan	(21, 42)
	TGF-β inhibitor	Pirfenidone	(14, 75)
	Antioxidant	Allopurinol, Febuxostat	(27, 31, 40, 54)
	Anti-inflammation	CCX140, Pentoxifylline	(20, 61)
	SGLT2 inhibitor	Empagliflozin	(95)
Regenerative medicine	Stimulate renal regeneration	BMP-7	(59, 80, 102)
	Stem cell-based regenerative therapy	HSCs, MSCs, EPCs	(2, 23, 37, 64, 69, 76, 79, 85)

RAAS, renin-angiotensin-aldosterone system; ACEI, angiotensin-converting enzyme inhibitor; ARB, ANG II receptor blocker; ET_AR, endothelin receptor type A; TGF-β, transforming growth factor-β; SGLT2, sodium glucose cotransporter 2; BMP-7, bone morphogenetic protein-7; HSCs, hematopoietic stem cells; MSCs, mesenchymal stem cells; EPCs, endothelial progenitor cells.

Optimize and maximize renin-angiotensin-aldosterone system blockade.

Current renoprotection paradigms generally depend on the use of angiotensin-converting enzyme inhibitor (ACEI) and/or ANG II receptor blockers (ARBs), which have been shown to reduce proteinuria and retard the progression of CKD. However, ANG II and aldosterone levels increase after chronic ACEI or ARBs treatment, so-called ANG II-escape and aldosterone escape. A reactive rise in renin levels occurs when mineralcorticoid receptor antagonists or renin inhibitors are used. Chronically increased ANG II and aldosterone worsens diseases such as heart failure and renal disease (73, 77). These compensatory responses at different levels prove that single renin-angiotensin-aldosterone system (RAAS) blocker cannot provide full blockade of the RAAS cascade, suggesting dual therapy may have more benefit. However, kidney outcomes with telmisartan, ramipril, or both, in people at high vascular risk (ONTARGET), and combined angiotensin inhibition for the treatment of diabetic nephropathy (VA-Nephron-D trial), unexpectedly showed increased risk of adverse outcomes and events, such as AKI, hyperkalemia, and/or need for dialysis (25, 57). The combination therapy of a renin inhibitor (aliskerin) along with an ARB or an ACEI in type 2 diabetes (ALTITUDE) showed similar increased risks of cardiovascular events (66). Despite this side effect, dual blockade reduced proteinuria and decreased ESRD events compared with monotherapy. In animal studies, combination of an aldosterone synthesis inhibitor and ARB showed more renal benefit with low risk of hyperkalemia, suggesting this combination could be an additional choice for RAAS. Another consideration is that these dual therapy approaches used recommended doses for monotherapy for both drugs. A different therapeutic strategy based on the combination of lower than recommended doses for monotherapy of an ACEI and an ARB has been suggested to effectively block the renin-angiotensin system without excess blood pressure reduction and side effects. Now, the ongoing VALID trial is testing whether halved doses of an ACEI and an ARB may be more effective than full doses of each agent alone in diabetic nephropathy (ClinicalTrials.gov: NCT00494715). In this case, the dual therapy could be considered for patients with residual proteinuria despite maximal monotherapy of RAAS blockade, with close monitoring of blood pressure, heart and renal function.

New targets for CKD.

Considering the incomplete efficacy of RAAS blockade, it is necessary to find new drugs that could either exert a complementary action to ACEI and ARBs or act on other pathophysiological processes involved in the progression of CKD. The great expectations of novel drug therapies for CKD management over the last decade have not come to fruition. Several recent candidates have failed to show improved outcome for therapy of diabetic nephropathy because of the following three major themes: 1) insufficient studies of preclinical models to support efficacy or explore potential toxicity, such as the BEACON (bardoxolone, a Nrf2 inducer) and ASCEND [avosentan, endothelin (ET) receptor blocker] studies (19, 56), 2) lack of benefit, such as the SUN-micro (sulodexide) study (63), and 3) sponsors' decisions to discontinue therapeutic development because of business and/or regulatory considerations, such as ruboxistaurin (PKC-β inhibitor) and FG-3019 (anti-CTGF antibody) (1, 88). However, some ongoing clinical trials still offer promise of further gains.

Plasma ET-1 is increased in CKD patients and correlates with urinary albumin excretion and renal function. ET-1 affects renal and extrarenal via activation of two receptor subtypes: endothelin receptor type A and B (ET_AR, ET_BR). ET_AR activation promotes podocyte and mesangial dysfunction, renal inflammation, and oxidative stress, leading to proteinuria and glomerulosclerosis (62). Inhibition of ET_BR may induce fluid overload and body weight increase. Although the study for avosentan failed, atrasentan, a more selective ET_AR antagonist (ET_AR-ET_BR blockade 1,800:1 vs. 50-300:1 for avosentan), was studied (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with atrasentan; the RADAR study). A total of 211 subjects with type 2 diabetes mellitus and kidney disease who were on maximum ACEI or ARBs received either 0.75 or 1.25 mg/day of atrasentan or placebo for 12 wk. Albuminuria was maximally reduced by 35 and 38% in the 0.75 and 1.25 mg/day groups, respectively (21). There was no appreciable increase in edema over that of placebo with low-dose atrasentan therapy, suggesting that a renoprotective effect can be obtained in the absence of clinically significant fluid retention. Currently, a large phase 3 trial [Study of Diabetic Nephropathy with Atrsentan (SONAR)] is underway. The study, with a projected enrollment of over 4,000 subjects, will evaluate the effects of atrasentan compared with placebo on cardiovascular morbidity and mortality, urine albumin excretion, changes in eGFR, and impact on quality of life (42).

Pirfenidone is an oral compound with antifibrotic properties. Although its mechanism of action is not fully understood, it inhibits production and activity of TGF-β. The major clinical trial on this topic was performed on 77 patients with diabetic nephropathy (75). After 54 wk, there was a significant improvement in eGFR in patients receiving 1,200 mg of pirfenidone while no statistically significant differences were found in the group receiving a higher dose or in the placebo group. Moreover, no statistical differences were found in the secondary end points: proteinuria and urinary TGF-β level. This failure to decrease albuminuria was also observed in a recent open-label clinical study of pirfenidone in patients with advanced focal segmental glomerulosclerosis, suggesting that the treatment was associated with a reduction in the rate of renal function decline but without attenuating albuminuria (14). These phase II studies could be interpreted as showing a hemodynamic-based effect on eGFR, or, alternatively, the improved eGFR could reflect structural improvement in injury but without change in proteinuria. The latter possibility would be quite different from the current understanding of linkage of benefit of effects on progressive scarring and proteinuria.

Oxidative stress is a contributor to tissue injury in CKD. GKT-137831, a NADPH oxidase 1/4 inhibitor, shows negative data in a phase 2 trial. In contrast, inhibition of xanthine oxidase is more promising. Allopurinol has already shown efficacy in preventing vascular events and slowing kidney function loss in several clinical trials (27, 40). The ongoing clinical trials, PEARL and FEATHER, are currently investigating the specific usefulness of anti-xanthine oxidase (allopurinol and febuxostat) in CKD (31, 54).

Chemokine receptors, such as CCR2, are main drivers of monocyte and macrophage recruitment in diseased kidney. Various resident cells also express CCR2, which drives some of the renal impairment in CKD. Levels of monocyte chemoattractant protein-1, the main ligand for CCR2, are elevated in the kidneys of patients with kidney disease, suggesting reduction of chemokine production is a potential treatment target in CKD. Although a phase II trial of CCR 2/5 antagonists (PF-04634817) failed, another recently completed phase II trial in diabetic nephropathy provided promising results for CCX140, an oral small molecule inhibitor of CCR2. Treatment with CCX140 (5 mg/day) added to standard of care treatment (an ACEI or ARB) resulted in 24% decreasing in albuminuria and the slope of eGFR loss, beyond that achieved with standard of care alone over a 52-wk treatment period. The results of a phase III trial, however, did not confirm any significant impact on GFR but did confirm the anti-proteinuric effect in response to CCX140 (20). Another anti-inflammatory drug, pentoxifylline, showed a slower rate of eGFR loss together with the significant reduction in urine protein excretion when it was added to maximal renin-angiotensin system blockade in CKD patients (61).

The most recent remarkable additional benefits on top of standard RAAS blockade of sodium glucose cotransporter 2 inhibition by empagliflozin in type 2 diabetic patients with high cardiovascular risk to markedly decrease diabetic nephropathy progression are not directly explained by improved glucose control (95). Mechanisms may involve changes in tubuloglomerular feedback, with beneficial intrarenal hemodynamic changes, or other changes in tubular work load, oxidative stress, or other injuries. Thus, one could speculate that benefits may even occur in nondiabetic patients.

Regenerative medicine.

Renal regeneration after acute injury is associated with increased expression of mediators of kidney development, such as Pax-2, Pax-8, Wnt-4, and Wnt-9b, whereas impaired regenerative capacity of the chronically injured kidney is associated with decreased expression of these mediators. A growth factor microenvironment reminiscent of the fetal kidney could be created through administration of selected recombinant growth factors. Bone morphogenetic protein (BMP)-7 is an essential morphogen during kidney development that remains highly expressed in adult kidney (22). Chronic kidney injury is associated with suppression of BMP-7 expression, and supplementation with exogenous recombinant BMP-7 not only inhibits progression of experimental kidney fibrosis but also facilitates reversal of established fibrotic lesions in mice (59, 80, 102). Small-molecule mimetics of BMP-7 are currently undergoing clinical testing.

Cell-based regenerative therapy is being extensively evaluated as an alternative treatment modality. The chief cell types under investigation are hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and endothelial progenitor cells (EPCs). CKD is characterized by reduced renal regenerative capacity with impaired EPC number and function, but there is conflicting evidence regarding MSC functionality and vitality (13, 46, 70, 98). Several studies suggest beneficial regenerative effects of cell-based therapies in animal models of CKD (24, 89, 105). A systematic review and meta-analysis of 71 articles of various animal models found that cell-based therapy reduced development and progression of CKD with decreased urinary protein and plasma urea levels (64). MSCs are being used in several clinical trials in kidney transplant recipients with the aim of increasing immunosuppression and improving regeneration (69, 85). However, the majority of the clinical studies using HSC therapy are focused on lupus nephritis and are all nonrandomized and uncontrolled studies (2, 23, 37, 79). It is noteworthy that several renal diseases, including thrombotic microangiopathy and calcineurin inhibitor nephrotoxicity, can develop after HSC transplantation (76). Drug treatment to indirectly manipulate cell function could also be considered for repopulating progenitor/stem cells. Several randomized trials showed a statin-induced increase in circulating EPC number ranging from 25.8 to 223.5% (30). Several other drugs also affect EPCs, including erythropoietin-stimulating agents, calcium channel blockers, biguanides without or with thiazolidinedione, and dipeptidyl peptidase-4 inhibitors (49). Drugs, such as pravastatin, rosiglitazone, or coenzyme Q10, improve function and reduce senescence or apoptosis in MSCs (5, 90). Last, both EPCs and MSCs release microparticles, which carry genetic and protein cargo. These noncellular elements are not subject to apoptosis and senescence and might have a longer-lasting impact. Different conditions, disease vs. normal, young vs. aging, affect these paracrine factors from EPCs or MSCs (99). Further studies are needed to determine impact of such cellular or noncellular elements and whether cells derived from CKD patients potentially pack harmful cargo.

Perspectives and Significance

CKD progression to ESRD has become a public health problem. New biomarkers and surrogate end points allow potential intervention and treatment in the earlier stages of CKD, which could reduce or even reverse the progression rate. New omic-based technologies reveal new genomic and epigenomic mechanisms related to CKD incidence and/or progression. AKI has been recognized as a major risk for CKD progression. In addition to optimizing RAAS blockade, new drugs targeting ET-1 and TGF-β, and cell-based regenerative therapy, may further ameliorate the progression of CKD. Last, the gap from suitable experimental models to human disease must be narrowed to be able to efficiently translate new mechanistic understanding to evidence-based treatments for human progressive CKD.

GRANTS

This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-56942 (A. B. Fogo).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

J.Z. and H.Y. drafted manuscript; J.Z., H.Y., and A.B.F. edited and revised manuscript; A.B.F. approved final version of manuscript.