Precision medicine in diabetic nephropathy and chronic kidney disease

Progressive chronic kidney disease (CKD) in individuals with type 2 diabetes mellitus is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, CKD leading to uremia can be seen as a systemic disease with a critical impact on virtually all organ systems. Thus it is of particular importance to identify patients with incipient CKD and ongoing CKD progression, but the individual course of CKD is challenging to predict. Patterns of progression in persons with CKD include linear and nonlinear trajectories of glomerular filtration rate (GFR) loss. Kidney function can also remain stable for years, especially in the elderly. In particular, one-fifth of individuals show a substantial GFR decline in the absence of high albuminuria (nonproteinuric CKD), rendering albuminuria less suitable for predicting the progression in such individuals.

THE GLOBAL UNAWARENESS FOR CHRONIC KIDNEY DISEASES

Recently, three major nephrology societies—the International Society of Nephrology (ISN), the American Society of Nephrology (ASN) and the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA)—announced a joint statement about the worldwide impact of kidney diseases: ‘The hidden epidemic: Worldwide, over 850 million people suffer from kidney diseases’ (https://web.era-edta.org/uploads/180627-press-era-asn-isn.pdf). This figure is based on recent estimates of the worldwide prevalence of chronic kidney diseases (CKDs) across different regions of the world [1, 2]. The major causes of progressive CKD are kidney injury due to diabetes and hypertension, but (repetitive) acute kidney injury (AKI) is nowadays recognized as an emerging cause of end-stage kidney disease (ESKD) as well [1–4]. The initiative launched by the three nephrology societies (ERA-EDTA, ISN and ASN) also highlighted the fact that kidney diseases have so far been underestimated in many respects and that most people are not aware of their impaired kidney function. The latter may be due to the fact that, in general, kidney disease is ‘silent’. According to the data published on the website of the Centers for Disease Control and Prevention, awareness of CKD in the US population is low: only 12.4% of individuals with CKD Stages 3 and 4 knew about their impaired kidney function (http://nccd.cdc.gov/CKD). Presumably the situation is not much better elsewhere. This unawareness may have serious consequences for the affected because progressive CKD is associated with substantial comorbidity, reduced life expectancy and the risk of reaching ESKD, necessitating kidney replacement therapy [5–7]. Taken together, progressive CKD leading to severe uremic complications is a ‘systemic’ disease with a critical impact on virtually all organ systems that goes in parallel with high healthcare resource utilization [8]. Thus reliable identification of patients with ongoing CKD progression has broad consequences not only for their well-being, but also for saving of healthcare resources.

CHALLENGES IN THE ACCURATE RECOGNITION OF PROGRESSIVE CKD

CKD progression is commonly defined by a decrease in various aspects of kidney function until kidney failure (ESKD) is diagnosed. Currently, established markers for prediction of CKD progression are glomerular filtration rate (GFR) and albuminuria. In the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, patients with CKD of different etiologies are categorized as having low, moderate, high or very high risk for kidney disease progression according to their estimated GFR (eGFR) and albuminuria [9]. With the support of this so-called kidney test, the individual kidney function trajectory is challenging to predict within a specific risk category, particularly under disease-modifying therapeutic interventions. This circumstance has been highlighted by Hall and Himmelfarb [10] in their comment on the currently used CKD classification system: ‘Although useful for epidemiology, lumping all kidney diseases together irrespective of etiology simply makes little sense for optimizing clinical care, something that every clinician knows intuitively’. Thereby a new challenge has been brought forward with four hypothetical diverse case scenarios: a healthy elderly woman, a young man with refractory hypertension homozygous for apolipoprotein L1 risk alleles, a middle-aged woman with type 2 diabetes mellitus (T2DM) and a young man with biopsy-proven membranous nephropathy. According to their eGFRs, all of them would have been classified as having Stage 3 CKD, but virtually every aspect of clinical decision-making would greatly differ, also taking into account their very individual CKD progression risks.

In order to resolve this situation, kidney failure risk equations (KFREs) have been developed based on eGFR and albuminuria and including clinical and biochemical variables [11]. While refining equations with inclusion of even more putative progression, as biomarkers/indicators have been selected to further improve accuracy at the population level, the individual CKD course remains variable and difficult to predict by too-general equations [10, 12]. Indeed, studies have shown that patterns of individual CKD progression include linear and nonlinear GFR trajectories. Moreover, kidney function can also remain stable for years in some individuals without any progression of their kidney disease. For example, in 1.7 million participants from 35 cohorts with 12 344 kidney failure events, a highly variable individual CKD progression was observed even within subjects classified in the same KDIGO risk category [13]. In patients with a baseline eGFR of 35 mL/min/1.73 m², in whom eGFR remained stable within the first 2 years of the subsequent observation period, the risk of reaching ESKD after 10 years was 18%. In contrast, patients with the same baseline eGFR who experienced a mean eGFR decline of 57% within the first 2 years had a risk of 99% to reach ESKD in the following 10 years. Finally, results of recent studies in the general population and in patients at high risk for progressive CKD revealed that a substantial GFR loss may occur even in the absence of higher-grade albuminuria (termed the nonproteinuric CKD pathway) [14–16]. Thus identifying subjects at risk for faster CKD progression—whatever the cause may be—remains challenging, but is of overriding importance for the management of the individual patient.

PRECISION MEDICINE IN THE MANAGEMENT OF CKD PATIENTS

The term ‘precision medicine’ was coined by the United States National Research Council working group charged with developing a ‘new taxonomy of human disease based on molecular biology’ in order to replace the classical descriptive diagnostic terms. In clinical practice, precision medicine should take into account individual variability when disease prevention and treatment strategies are considered. The goal of precision medicine has also been described as characterizing diseases based on the underlying molecular pathways in order to identify specific biomarkers and therapeutic targets that will ultimately improve clinical outcomes [17, 18].

Until today, a series of studies have reported on specific genetic polymorphisms and on epigenetic and transcriptional variations associated with the risk of incipient CKD as well as CKD progression [19, 20]. Moreover, a battery of biomarkers for the assessment of CKD progression has been tested in numerous experimental studies and epidemiological cohort studies using different technologies, including proteomics and metabolomics. However, so far none of the tested genetic traits or disease biomarkers were able to improve the prediction of CKD progression beyond that of the currently used clinical models, nor to ‘predict individual loss of kidney function’ [21, 22]. Nevertheless, from results of molecular biology studies, it became clear that the tubulointerstitial compartment of the kidney is playing a pivotal role in CKD progression, regardless of the cause of injury. It not only represents the major compartment of the kidney, but is also exceptionally vulnerable to a variety of injuries such as hypoxia. While it has long been postulated that tubular epithelia cells (TECs) represent the main victim of such injury, recent experimental data identified TECs as a key driving force in CKD progression [23, 24]. In response to injury, TECs can undergo unfavorable changes in phenotype and function and subsequently act as proinflammatory and profibrotic cells. They produce various bioactive molecules that perpetuate the damage, eventually leading to irreversible renal scaring. The latter is referred to as tubulointerstitial fibrosis and represents the common pathological hallmark of etiologically different CKD entities that finally results in organ failure [25, 26]. So far, convincing biomarkers for this specific renal pathology are not available. However, this is mandatory for the development of specific therapeutics to halt CKD progression independent of its etiology. In experimental studies, many profibrotic molecules secreted by TECs have been identified, e.g. transforming growth factor β and platelet-derived growth factor [27, 28]. Moreover, modulation of specific pathways such as Notch and the Wingless–Int1 (Wnt)/β-catenin pathway involved in tubulointerstitial fibrosis by TECs has been documented [29, 30].

MONITORING Wnt PATHWAY ACTIVITY AS AN EXAMPLE OF PRECISION MEDICINE IN CKD

In the kidney, the effects of the complex Wnt/β-catenin pathways may considerably differ in acute versus chronic kidney injury models [31–33]. Depending on the level of activity and the duration of activation, either repair processes predominate or kidney damage progresses. It has been postulated that TECs can produce Wnt ligands, which then activate the neighboring fibroblasts in a paracrine manner to promote tubulointerstitial fibrosis and thus progressive CKD [33]. One of these ligands is thought to be Dickkopf 3 (DKK3), a member of the Dickkopf family that has been linked to more rapid cystic growth and disease progression in patients with adult polycystic kidney disease [34]. Experimental data imply that DKK3 represents a profibrotic glycoprotein produced by TECs under stress conditions and subsequently secreted into the urine [35]. Therefore it may also serve as a noninvasive diagnostic biomarker for ongoing TEC injury and thereby progressive CKD.

In order to evaluate this issue in humans, we assessed the relationship between urinary DKK3 concentrations and future annual changes of GFR in the prospective CARE FOR HOME study, with a mean follow-up of 5.1 years, comprising patients of various CKD etiologies [36]. For this purpose, a total of 2035 person-years were available for 1-year block analysis from annual patient visits. Indeed, urinary DKK3 concentrations were significantly and independently associated with a GFR decline in the subsequent 12 months after full adjustment for confounders including baseline GFR and albuminuria. This finding was confirmed in patients from the STOP-IgAN trial [36], where a baseline urinary DKK3 >1000 pg/mg creatinine was independently associated with a mean GFR decline of 12.2% during the next 6 months of the run-in phase. Even more interesting, in the following first 6 months of the treatment phase, an increase in urinary DKK3 concentration was associated with a significant GFR decline, whereas stable or decreasing urinary DKK3 indicated a more favorable course of kidney function, independent from the randomization to the treatment arms [36, 37]. In this respect, the evaluation of short-term loss of GFR is a different approach from predicting long-term CKD prognosis by looking at predefined renal endpoints such as ESKD or a certain percent GFR decrease after several years. The latter gives a risk estimate of how many patients from the tested cohort will reach a renal endpoint, while a ‘single urinary DKK3 measurement indicates forthcoming short-term loss of kidney function in the individual patient’. In this respect, urinary DKK3 was superior to albuminuria, and this was particularly true in patients without significant albuminuria, i.e. nonproteinuric CKD [36].

We have further explored the clinical utility of urinary DKK3 as a biomarker of prevailing TEC ‘stress’ and therefore also as a potential predictor of the AKI–CKD transition in individuals undergoing elective cardiac surgery. Elevated preoperative urinary DKK3 was independently associated with a significantly higher risk of AKI after surgery and the ensuing loss of kidney function during long-term follow-up (Figure 1) [38]. Importantly, urinary DKK3 also predicted AKI in patients with normal GFR before surgery, i.e. in patients with apparently normal kidney function. These findings highlight the measurement of urinary DKK3 as a precision medicine approach for assessment of individual CKD progression, but even more so as a measure of tubulointerstitial damage in the entire kidney injury continuum, including the AKI–CKD transition [39]. This holds true also under therapeutic interventions to prevent or halt CKD progression.

BRINGING ALL TOGETHER

First, the challenge is to diagnose kidney disease; second, to categorize the level of kidney function and damage; and third, to predict progression, response to therapy and outcome. All steps should be evaluated and done within an individual, the approach to precision medicine. As suggested, diagnosis of CKD in individuals with T2DM can be done best through an easily available and cost-saving ‘kidney test’, represented by eGFR determination in serum and urinary albumin:creatinine ratio (UACR) measurement in a spot urine sample. Once established and categorized by general practitioners and/or specialists (nephrology, endocrinology/diabetology, cardiology) more distinct diagnostic tools are available to distinguish progressors from nonprogressors to kidney failure. This sequence of stepwise procedures serves to select the best treatment at the best moment in time in order to avoid progression to kidney failure. Today, several options for precision medicine are available and include renin–angiotensin system inhibition, sodium–glucose cotransporter 2 inhibition and mineral corticoid receptor blockade through finerenone [40–43]. These interventions have been shown to be effective in all individuals with kidney disease, with the latter intervention particularly effective in subjects with T2DM.

FUNDING

This article is part of a supplement supported by a sponsorship from Amicus Therapeutics UK Limited, a research grant from Boehringer Ingelheim RCV GmbH & Co KG, an educational sponsorship agreement from Astellas Pharma, a restircted research grant from Vifor Pharma Osterreich GmbH. This supplement is part of the project DC-rein that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 848011.

CONFLICT OF INTEREST STATEMENT

D.F. was associated with DiaRen. C.W. has received honoraria for advisory board participation from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, MSD and Mundipharma.

REFERENCES