Introduction
Chronic kidney disease (CKD) is characterized by kidney damage or an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2, present for at least 3 months (1). Based on the KDIGO 2012 and 2022 classification, it is divided into six clinical stages based on eGFR (G1, G2, G3a, G3b, G4, G5) and three stages based on albuminuria (A1, A2, A3) (2). Since mild to moderate CKD is often asymptomatic, it is quite difficult to precisely quantify the general prevalence of CKD. However, according to the most complete data available, its prevalence is estimated to lie between 10% and 14% of the general population (3). When looking at the proportion of the global burden of disease that CKD carries, around 1% of disability adjusted life years and 1-3% of life years are lost because of CKD (4).
Because CKD affects patients within a wide age, race, and sex range, treating it as a single clinical entity is not recommended. Several attempts have been made to classify types of CKD using different features and criteria, but one of the most sensible approaches is probably the community versus referred CKD. This split emphasizes the different rates of renal function decline in the two groups. The community CKD group refers to patients from the general population in whom kidney failure is diagnosed and comprises mostly elderly patients who have been suffering from atherosclerosis, arterial hypertension, and diabetes mellitus for a longer time. The rate of renal function decline in this group is estimated between 0.75 and 1 mL/min/1.73 m2 per annum after the age of 50 (5). Since these patients are exposed to different cardiovascular (CV) risk factors for long time periods, they often suffer from major adverse cardiac events (MACE), rather than complete loss of renal function. For example, one study showed that 1% of patients with CKD G3 and 20% of patients with CKD G4 increased to end stage renal disease (ESRD) and demanded renal replacement therapy. However, 24% of G3 patients and 45% of G4 patients died from MACE (6).
In comparison, referred CKD describes patients who have been referred directly to the nephrologist and their disease was diagnosed there, as in cases of hereditary (ADPKD) or acquired nephropathy (diabetic kidney disease, tubulointerstitial disease, or glomerulonephritis). The rate of CKD progression in these patients is highly variable due to widely differing mechanisms of the underlying disease processes affecting them.
Regardless of etiology and type, there are certain interventions that have been proven to reduce the rate of CKD progression. Twelve of those will be examined and discussed in the text below.
Dietary interventions
The question of the utility of dietary interventions in CKD progression prevention is often debated, and the path to finding the answer is often complicated due to the large number of possible dietary interventions, different types of diets, and the inherent bias of studies relying on self-reporting. However, an attempt to systematically review the outcomes of various types of dietary interventions on CKD progression and overall health of patients with CKD has been made in the form of a Cochrane review published in 2017 (7). The review included 17 studies and 1639 patients with CKD. Approximately 10% of patients were kidney transplant recipients, 20% were on hemodialysis, and 70% had active non-dialysis CKD. Due to the design of the included studies, the effect of dietary interventions on progression to ESRD was not clear or certain. According to the authors’ calculations, they estimated that dietary interventions may prevent progression of CKD to ESRD in 1 out of every 3000 patients treated for one year. Additionally, several other beneficial effects were observed following dietary interventions, namely a reduction of systolic (MD -9.26 mmHg) and diastolic pressure (MD -8.95mmHg) and higher eGFR and serum albumin concentrations. Furthermore, the Mediterranean diet provided the benefit of lowering serum LDL concentrations (MD -1 mmol/L). Another systematic review evaluated the effectiveness of combination interventions in diet and dietician engagement on slowing the progression of CKD (8). Among the twelve studies included, one of them showed a significant decrease in eGFR decline over three years in patients with high base-producing vegetable and/or fruit (-10.0; 95% CI: -10.6 to -9.4 mL/min/1.73 m2) or oral bicarbonate (-12.3; 95% CI: -12.9 to -11.7 mL/min/1.73 m2) intake compared with usual care (-18.8; 95% CI: -19.5 to -18.2 mL/min/1.73 m2) (9).
Treatment of anemia
Anemia in CKD is a well-known and researched clinical entity, with novel treatment modalities rapidly emerging and being implemented into daily practice, the newest of which are hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors, which have been shown to increase serum hemoglobin (Hb) concentrations by as much as 9.1 g/L (10). One systematic review from 2020 undertook the task of quantifying the increase in CKD progression risk in various degrees of anemia severity (11). The results showed a hazard ratio (HR) for the progression of CKD of 1.65 (95% CI: 1.36-2.00) for patients with serum Hb concentrations of <100g/L and a 1.41 hazard ratio (95% CI: 1.27-1.56) for patients with serum Hb concentrations of 100-120 g/L. The renoprotective benefits of successful anemia treatment were also demonstrated: the HR for CKD progression was 0.85 for every 10g/L increase in serum Hb concentration.
Finerenone
Mineralocorticoid receptor antagonists (MRA) are a long-standing therapeutic staple of managing patients with hypertension, proteinuria, or CKD. There are several different subclasses of these drugs within the same group: eplerenone (selective), spironolactone and canrenone (non-selective), and finerenone (non-steroidal). A Cochrane review from 2020 evaluated the effects of MRAs on proteinuria, systolic pressure, and decline of renal function (12). The results of 14 studies with 1193 patients showed that MRA therapy concomitant with ACEi or angiotensin receptor blocker (ARB) use decreases proteinuria (SMD -0.51, 95% CI: -0.82 to -0.20). In 14 studies with 911 patients, there was a decline in systolic pressure (MD -4.98 mmHg, 95% CI: -8.22 to -1.75), and eGFR decline was observed in 13 studies with 1165 patients (MD -3.00 mL/min/1.73 m2, 95% CI: -5.51 to -0.49). Non-steroidal MRAs such as finerenone have shown promising results in CKD treatment in the population of patients with type 2 diabetes mellitus (T2D). A review of the currently published trials quantified the available findings on the benefits and limitations of finerenone (13). The most current and complete data on finerenone in patients with CKD and T2D was obtained from FIDELITY (14), a pooled analysis of two phase 3 studies (FIDELIO and FIGARO-DKD). The FIDELITY study evaluated two different primary outcomes, one of which was a composite of CV adverse events (nonfatal stroke, nonfatal myocardial infarction, hospitalization due to HF or CV death), while the other was a renal composite outcome (sustained eGFR decrease of at least 57% from baseline or death from renal causes). The secondary outcome evaluated renal failure, eGFR decrease of at least 40% from baseline, or death due to renal causes. In summary, finerenone decreased the CV outcome by 14% (p=0.002), the “reduction of eGFR 57% from baseline” by 23% (p=0.0002), the “reduction of eGFR 40% from baseline” by 15% (p=0.0004), and progression to dialysis by 20% (p=0.04) when compared with control group. Finerenone seems to have no outcome on HbA1c or body mass and does not increase the propensity for adverse side effects such as gynecomastia but has a modest impact on reduction of blood pressure (BP). In patients with CKD who have heart failure (HF) with reduced ejection fraction, finerenone displayed better renal outcomes in comparison with eplerenone, better mortality outcomes in comparison with spironolactone, and lower rates of high potassium compared with eplerenone or spironolactone (13).
SGLT2 inhibitors
While the first instances of the use of SGLT2 inhibitors (SGLT2i) were in the role of antidiabetic medications, this class of drugs is rapidly becoming a ubiquitous treatment staple in HF and CKD. DAPA-CKD was the most important trial to demonstrate efficiency of SGLT2i, which showed a 44% reduction of decline in eGFR, worsening to CKD stage 5, or death from kidney-related causes (p<0.001) (15). Data derived from primarily CV outcome studies of SGLT2i medications also support their efficiency in prevention of CKD progression: a meta-analysis quantifying renal outcomes in cardiovascular SGLT2i studies (VERTIS CV, EMPA-REG OUTCOME, DECLARE-TIMI 58, CANVAS) demonstrated a 42% depletion in the outcome of a constant ≥40% decline from baseline in eGFR, progression to CKD stage 5, or ESRD and death due to renal causes with SGLT2i therapy in comparison with placebo [HR 0.58 (95% CI: 0.51-0.65)] (16). SGLT2 inhibitors have also been shown to be effective in patients with advanced CKD stage 4. A recently published meta-analysis showed a significant 23% reduction in eGFR decline, death, or progression to ESRD due to renal causes with SGLT2i therapy in patients with advanced CKD (15-30 mL/min/m2) when compared with the control group (p=0.04) (17). The authors also calculated the difference in yearly eGFR decline between SGLT2i and placebo, demonstrating a reduction in decline of 1.24 mL/min/1.73 m2/year with SGLT2i therapy (95% CI: 0.06-2.42, p=0.04).
Treatment of hyperuricemia
While high levels of uric acid have been demonstrated as a new risk factor for de novo CKD occurrence, its role in CKD progression remains somewhat unclear due to conflicting evidence. This may be a consequence of manifest CKD being the product of several different risk factors, such as diabetes, hypertension, etc. However, even in patients with nondiabetic CKD stage III and IV, such as those in the MDRD study, high levels of uric acid were not a separate risk element for progression of CKD (18). Furthermore, an analysis of Swedish Renal Disease Registry (SRR-CKD) found no association of hyperuricemia with eGFR decline or time to initiation of hemodialysis in patients with CKD stages III-V (19). On the other hand, several observational studies have demonstrated an association between hyperuricemia and renal function decline, one of which was an 8-year longitudinal analysis of more than 700 Chinese patients (20). Another interesting finding related to hyperuricemia is that women seem to be more susceptible to renal function decline caused by hyperuricemia, as demonstrated by several Japanese studies (21,22).
Be that as it may, urate lowering therapy seems to provide at least a modest reduction in the rate of renal function decline. A Cochrane review from 2017 on 2 studies with 83 patients reported lower creatinine in serum (MD -73.35 µmol/L, 95% CI: -107.28 to -39.41) and recovery of eGFR (MD 5.50 mL/min/1.73 m2, 95% CI: 0.59 to 10.41) in 1 study with 113 patients with urate lowering therapy compared with placebo after one year (23). However, the benefit seems to disappear after two years. A meta-analysis that included 19 RCTs with 992 participants found a statistically significant rise in eGFR with allopurinol therapy compared with placebo (3.2 mL/min/1.73 m2, 95% CI: 0.16-6.2 mL/min/1.73 m2, p=0.039) (24). Another meta-analysis from 2018, which included 12 RCTs with 832 participants, compared treatment with any urate lowering agent to placebo and found a statistically significant rise in eGFR with any urate lowering agent (3.88 mL/min/1.73 m2, 6.49 mL/min/1.73 m2, p=0.004) (25). Finally, a meta-analysis from 2022 that compared different urate lowering agents found that topiroxostat significantly improved eGFR in patients with CKD with and without hyperuricemia (MD 1.49 mL/min/m2, 2.90 mL/min/m2, p=0.038), that febuxostat significantly improved eGFR only in a patient with hyperuricemia (MD 0.85 mL/min/m2, 1.67 mL/min/m2, p=0.04), and that pegloticase or allopurinol showed no effects on renal function (26).
Appropriate transition of care from pediatric to adult hypertension
One of the most underestimated and understudied topics in hypertension management is the proper transition from pediatric care to adult antihypertensive care. While there are several factors in play that contribute to this problem, including the lack of an organized transition of care algorithm and attending physician allocation for each patient in the transitory period, along with an undefined age for definite transition, there has been an attempt to establish congruency between pediatric and adult hypertension guidelines, thus streamlining and simplifying care for both groups as well as the transition itself (27). As the 2017 American College of Cardiology/American Heart Associations (ACC/AHA) and American Academy of Pediatrics (AAP) Hypertension Guidelines were being composed, the societies decided to appoint authors to both groups to achieve congruency between the two guidelines and identify potential issues. This resulted in the most congruent pediatric/adult hypertension guidelines created so far, and we strongly recommend each provider caring for hypertensive patients in the pediatric-adult transition period to read the whole document (available in the references). Some of the most important highlights from the document are:
Diagnostic assessments designed to identify secondary hypertension and target organ damage.
The hypertension grading stages and thresholds are identical for children aged 13 and older and adults.
The number of BP measurements in the doctor’s office necessary for diagnosis of hypertension are 2 for adults and 3 for pediatric patients.
Both guidelines recommend drug treatment initiation for stage 2 hypertension (BP> 140/90 mmHg in those over 13 years of age), with pediatric guidelines allowing for a weight loss trial in obese children before initiating medical treatment. In children aged 13 and older and adults, the treatment target is 130/80 mmHg, while in children younger than 13, it is <90th percentile of BP for patient age.
The decision to initiate treatment for stage 1 hypertension (130/80 mmHg<BP<140/90 mmHg in those over 13 years of age) is dependent on risk evaluation in both pediatric and adult patients; however, the risk evaluation itself differs based on patient age: in all pediatric patients with hypertension, obtaining an echocardiogram is recommended prior to treatment initiation. Also, several conditions have been listed as an immediate trigger for initiation of treatment regardless of other risk factors in pediatric patients, those being: secondary hypertension, CKD, or diabetes mellitus.
Regarding transition of care itself, the guidelines recommend: “Adolescents with elevated BP or HTN (whether they are receiving antihypertensive treatment) should typically have their care transitioned to an appropriate adult care provider by 22 y of age (recognizing that there may be individual cases in which this upper age limit is exceeded, particularly in the case of youth with special health care needs). There should be a transfer of information regarding HTN etiology and past manifestations and complications of the patient’s HTN.”
Hypertension in progression of renal disease –the role of renal denervation
The impact of heightened sympathetic system activity on the advancement of renal disease and the worsening of hypertension was first studied over 50 years ago, in 1972, when a group of researchers found that among uremic patients, those with hypertension had significantly higher values of peripheral vascular resistance than those without hypertension (28). It has also been demonstrated that muscle sympathetic nerve activity (MSNA) is inversely proportional to eGFR in patients with CKD, further confirming the role of increased sympathetic tone in the progression of renal disease (29). Patients with CKD and hypertension bear the highest risk for mortality, and non-compliance with anti-hypertensive therapy significantly hampers the effectiveness of drug therapies. It is evident that additional interventions beyond medication are necessary for hypertensive patients (30). Renal denervation (RDN) is an alternative and additional rather than a competitive method of treating patients with various form of hypertension (not only for resistant hypertension) (30).
Catheter-based RDN involves utilizing radiofrequency energy to ablate the renal sympathetic nerves through the renal arterial wall, effectively interrupting both sensory and motor nerves. Initial investigations into renal denervation have shown a marked reduction in arterial pressure in most patients. The first question and concern when performing renal denervation on patients with chronic kidney disease was the effect of reduced BP and sympathetic tone on renal perfusion, but studies have shown that renal perfusion did not significantly change 3 months after renal denervation and showed no statistically significant decrease in eGFR from baseline in patients with preserved renal function, meaning that the procedure is safe for patients with CKD (30-32). One of the first studies on renal denervation in patients with CKD showed not only significant decreases in BP at 12 months follow-up, but also a trend towards improvement of several important CKD disease parameters, namely elevated hemoglobin concentration and the gradual reduction of various factors such as plasma brain natriuretic peptide levels, urinary albumin to creatinine ratio, proteinuria, and plasma HbA1c levels (33). Another observational study from 2013 demonstrated a significant reduction in the annual eGFR decline in hypertensive patients who underwent renal denervation (-4.8±3.8 mL/min/1.73 m2 per year before RDN, whereas after RDN eGFR improved by +1.5±10 mL/min/1.73 m2 at 12 months; p=0.009) (34). Newer studies have shown similar results in patients with CKD – both the effective lowering of BP and a mild improvement in eGFR at 3 months, with no significant changes at 12 months (35). More recent studies have also demonstrated both the safety and efficiency of RDN on BP reduction in patients with ESRD (36,37).
Post-COVID and kidney injury
COVID-19 has affected a significant portion of the human population, with the number of confirmed infections surpassing 660 million and causing over 6.5 million cumulative death worldwide (38). Owing to the affinity of the SARS-CoV-2 virus for angiotensin converting enzyme 2 (ACE2), which is expressed in neural, gastrointestinal, vascular, cardiac, and other tissues (39), it has been reported that COVID-19 not only manifests with different clinical symptoms depending on the tissue affected, but also causes lasting clinical sequelae even after the patient’s recovery from the acute infection (40). A retrospective analysis of over 190 000 post-COVID patients found that 14% of the studied population manifested at least one novel clinical entity that required treatment (41). SARS-CoV-2 has been shown to cause renal injury through both direct and indirect pathways (42). A confirmation of the existence of a direct pathway of renal injury is the presence of viral particles proven in both tubular cells and podocytes through electron microscopy (43), as well as SARS-CoV-2 viral load (RNA and protein particles) detected in all renal compartments of infected patients, with a clear preference for glomerular tissue (44). There is evidence of excess eGFR decline (approximately 3.26 mL/min/1.73 m2 per year) in non-hospitalized patients who had COVID-19, compared with non-infected controls (45). A retrospective study from a tertiary care center that analyzed renal outcomes of non-hospitalized post-COVID patients examined in the emergency department, hypertension clinic, and general internal medicine found an incidence of new-onset renal injury following COVID-19 of 6% (40). Another study on mainly non-hospitalized patients post-COVID suggested a system of standardized screening 6 to 9 months following active COVID-19 that consists of evaluating renal, cardiac, pulmonary, and venous structural and functional integrity (46).
Onconephrology
The concept of onconephrology, a discipline or perhaps even a subspecialty of nephrology dedicated to the management of renal pathology in oncology patients, is hardly novel, with the OncoNephrology forum established over 10 years ago under the American Society of Nephrology (47). Although the scope of onconephrology practice was not precisely defined in its initial phase, a paper published in 2016 attempted to describe and outline the ten crucial practice points for future onconephrologists (48). These were, in no specific order:
Acute kidney injury and the development of chronic kidney disease in patients with cancer.
Nephrotoxic effects caused by cancer treatments, which can include traditional chemotherapy drugs as well as newer molecularly targeted therapies.
Renal complications associated with paraneoplastic syndromes.
Management of patients who have undergone nephrectomy as a treatment for kidney cancer.
Renal replacement therapy in conjunction with ongoing cancer treatments.
Kidney transplantation in cancer survivors and the evaluation of cancer risk in patients with ESRD.
Oncological therapies for kidney transplant recipients.
Pain management for patients coping with both cancer and kidney disease.
Development of comprehensive guidelines for onco-nephrology patients.
Clinical trials designed specifically for onco-nephrology.
That same year, reviews of various renal injury patterns and mechanisms associated with specific anti-cancer medication groups were published (49-52).
Air pollution
The move from considering patients as isolated individuals to examining them in the context of their everyday living environment and circumstances has allowed for novel theories and research questions. A recent meta-analysis that included 14 papers investigated the association between the incidence of CKD and living near petrochemical plants (53). The results showed a statistically significant increased risk for CKD (OR = 1.70, 95% CI: 1.44-2.01), lower eGFR (OR = 0.55, 95% CI: 0.48-0.67) and higher serum creatinine (OR = 1.39, 95% CI: 1.06-1.82) in patients who were situated near oil and natural gas sources or petrochemical plants, in contrast to groups with lower or no exposure to air pollution from the agents. An analysis of the data from the China National Survey of Chronic Kidney Disease examined the link between urbanization, air pollution, and CKD and found that a 10-μg/m3 increase in PM2.5 (fine particulate matter <2.5 mm in diameter) at 3-year moving average, a 10-μg/m3 increase in NO2 (nitrogen dioxide) at 5-year moving average, and a 10-U increase in NLI (night light index). The 5-year moving average was strongly linked to higher odds of increased CKD prevalence [OR = 1.24 (95% CI: 1.14, 1.35); OR = 1.12 (95% CI: 1.09, 1.15); OR = 1.05 (95% CI: 1.02, 1.07)] (54). Another meta-analysis covering 13 studies found similar results (55). Finally, a recent study examined the connection between air pollution and the development of CKD progression, defining progression as a decrease in eGFR of more than 25% from the baseline. A population of 5301 patients was followed for a mean of 30 months, and the authors established a clear association between exposure to air pollution and progression of CKD in the following manner: patients with the highest quartile exposure to CO [HR = 1.53 (95% CI: 1.24, 1.88)], NO (nitric monoxide) [HR = 1.38 (95% CI: 1.11, 1.71)], NO2 [HR = 1.63 (95% CI: 1.36, 1.97)], SO2 [HR = 2.27 (95% CI: 1.83, 2.82)], PM2.5 [HR = 7.58 (95% CI: 5.97, 9.62)], and PM10 [HR = 3.68 (95% CI: 2.84, 4.78)] had notably greater risk of renal progression compared with those in the lowest quartile of exposure (56). We recommend a deeper dive into the environmental medicine literature (57,58).
Diffusion kurtosis imaging
Diffusion kurtosis imaging (DKI) is a novel mode of magnetic resonance imaging that emerged in the last decade, primarily as a method of evaluating the microstructure of cerebral tissue in infarctions, ischemia, trauma, and neoplasms (59). DKI provides a non-invasive solution for both the evaluation and prognosis of CKD progression and renal fibrosis and should be used when available.
While the technical aspects of this imaging modality are far too complex to be properly addressed and explained in this segment, the reader is more than welcome to obtain more detail information, so we provide a reference as a starting point (60). The clinical aspects are a different story altogether: in recent years, several studies have been performed to evaluate the viability of DKI as a prognostic tool for patients with chronic kidney disease. One such study followed 42 patients for a median of 43 months to determine the relationship between markers obtained with DKI and eGFR decline. A measurement called apparent diffusion coefficient (ADC) was demonstrated to be a reliable and precise prognostic marker for both ESRD [area under the curve (AUC) 0.936, sensitivity 92.31%, specificity 82.76%] and the composite endpoint of a decline in eGFR >30% or ESRD (AUC 0.881, sensitivity 66.67%, specificity 96.3%) (61). Additionally, the ADC values were statistically significantly associated with the eGFR slopes, both with the first-last time point slope (p<0.001) and with the regression slope (p<0.001). Another study with a population of 70 patients with CKD and 20 healthy volunteers also found a strong correlation between ADC and eGFR and determined that DKI offered better diagnostic performance for renal pathology than diffusion weighted imaging (DWI) (62). Finally, a Japanese study has shown that DKI can also be used to estimate the degree of renal fibrosis in patients with CKD using histograms (63).
LDL-C and CKD
Research on the role of LDL-cholesterol is hardly novel. The first mentions of a connection between dyslipidemia and CKD progression date back more than 30 years, when a group of authors studied the association between the presence of apolipoproteins B and E in renal tissue and the degree of renal injury, finding more advanced stages of renal tissue damage in patients whose renal biopsy tissues were positive for deposits of those apolipoproteins (64). A study on 2702 middle-aged men with dyslipidemia from 1995 found that patients with an HDL-C/LDL-C ratio of more than 4.4 had a 20% higher rate of decline in renal function (estimated by creatinine levels) than those with an HDL-C/LDL-C ratio of less than 3.2 (65). An open label trial comparing atorvastatin in patients with CKD treated with ACE inhibitors or ARBs to no treatment found a statistically notable decrease in proteinuria and a more gradual decline in creatinine clearance in patients on atorvastatin (66). However, there is also evidence pointing to little or no benefit of statin therapy on prevention of CKD progression. A study from the SHARP research group randomized patients with CKD to either 20 mg of simvastatin plus 10 mg of ezetimibe or placebo and followed them for 4.8 years. The findings indicated an average decrease in LDL-C levels of 0.96 in the simvastatin/ezetimibe group, but with no significant effect on the rate of eGFR decline (67). Additionally, the CRIC study showed no statistically significant correlation between LDL-C levels and the rate of CKD progression (68). The reason for this discrepancy in the evidence might lie in the dosing of statin therapy: a meta-analysis from 2015 that included 10 studies found a significant decrease in the rate of eGFR decline per year [3.35 (95% CI: 0.91 to 5.79) mL/min/1.73 m2] in patients using high-intensity statin therapy, but no such decrease in patients on low or moderate-intensity statins (69). Another meta-analysis included 57 studies and 143 888 patients and showed a statistically significant decrease in eGFR decline per year in patients using statins [0.41 (95% CI: 0.11-0.70) mL/min/1.73 m2] and a statistically significant decrease in proteinuria or albuminuria (70). The same meta-analysis also demonstrated a statistically significant decrease in risk for CV events in patients with CKD using statins (OR = 0.69; 95% CI: 0.61-0.79; p<0.001).
Conclusion
While the topics and talking points discussed in this article are far from the only factors influencing the progression of CKD, they are certainly areas in which significant and practice-changing evidence has emerged in the last few years and are therefore of utmost interest for the practicing physician.