Renoprotective Interventions Efficacy in the Late Stages of CKD

Abstract

The efficacy of renoprotective interventions in the late stages of chronic kidney disease (CKD) varies significantly from that in the early stages, with approaches in advanced CKD being insufficiently developed and sometimes conflicting. In a small prospective study, we evaluated the effectiveness of intensive follow-up protocol aimed at reducing CKD progression rates, cardiovascular complications, and improving outcomes among 100 patients with CKD3B-5 stages at a single center. This evaluation was compared with the outcomes of standard nephrology care. Positive changes in modifiable parameters resulting from interventions (such as serum albumin, hemoglobin, and standard bicarbonate) or reductions in negative parameters (like serum phosphate, plasma calcium deviation from target range, uric acid, and systolic blood pressure) were independently associated with a comparable reduction in the decrease of glomerular filtration rate (GFR). For the treatment group, the predicted time to reach the need for renal replacement therapy (RRT) from a conditional GFR of 20 ml/min/1.73 m² was 5 months longer than in the regular follow-up group. The distribution of average GFR at the start of dialysis suggested a late and possibly premature start in the control group, with less than 60% of cases being planned. In contrast, the treatment group always had a planned start.

1. Introduction

In the new millennium, the death rate from chronic kidney disease (CKD) has nearly doubled and its prevalence increased by 30% to more than 700 million worldwide, surpassing those of diabetes mellitus and chronic obstructive pulmonary disease (COPD) [1]. Cardiovascular diseases (CVDs) now account for almost half of deaths in CKD patients [2]. The cardiovascular risk in CKD, especially below an estimated glomerular filtration rate (eGFR) of 45 ml/min/1.73 m² or a urine albumin-to-creatinine ratio (ACR) exceeding 300 mg/g, is significantly higher compared to the non-CKD population.

The impact of traditional and nontraditional risk factors for cardiovascular disease (CVD) differs in CKD. Despite the definite position in Kidney Disease Improving Global Outcomes Chronic Kidney Disease (KDIGO CKD) guidelines (≤120/80 mmHg) [3], the optimal target blood pressure for hypertension remains uncertain, as it is controversial and based on weak evidence [4, 5]. Standardized blood pressure measurements pose challenges in nonresearch settings, and the recommended target is not readily applicable to routine measurements. This situation may expose multimorbid patients to heightened risks of falls and fractures. Furthermore, achieving the suggested blood pressure target might prove challenging for a significant proportion of CKD patients.

Cardiovascular (CV) risks in patients with CKD involve salt and water retention causing sympathetic activation and stimulation of renin-angiotensin-aldosterone system (RAAS). Uremic toxin retention contributes to increased oxidative stress, inflammation, and platelet activation; phosphate accumulation plays a pivotal role in vascular calcification and parathyroid bone disease. In this chapter, we will limit our discussion to novel mechanisms and approaches related to CKD progression because others were reviewed in detail in the update of KDIGO CKD guidelines. We’ll particularly emphasize the advanced stages, aligning with our study’s dedication to exploring nephroprotection possibilities on CKD3B-5 stages.

2. Lifestyle modification forms the foundation of nephroprotection

Understanding the impact of exercise in advanced stages of CKD on disease progression remains unclear. A meta-analysis of 18 randomized controlled trials (RCTs) showed insignificant effects on mortality and eGFR. However, physical exercise did enhance peak/maximum oxygen consumption, physical performance, and walking ability in predialysis CKD patients. These improvements could potentially reduce the risk of falls, fractures, and enhance long-term prognosis. An umbrella review of 31 meta-analyses with 120 different outcomes [6] revealed small effect sizes for most cardiorenal outcomes, with generally low-quality studies.

Obesity is an important risk factor for CKD development and progression, only partially explained by the diabetes mellitus and hypertension in obese patients. The adipose tissue also possesses high endocrine functions that contribute to low-grade inflammation with risk of kidney damage. Moreover, the effect of bariatric surgery on elimination of hyperfiltration highly depends on the downregulation of inflammasome signaling [7].

Several randomized controlled trials (RCTs) on sodium-glucose cotransporter 2 (SGL2) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, and bariatric surgery in diabetic kidney disease showed renoprotective effects. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) provided better renal outcomes, while glucagon-like peptide-1 receptor agonists (GLP1-RA) demonstrated better weight loss effect; there is dearth of RCT data concerning combination of SGLT2i plus GLP1-RA (as well as plus bariatric surgery) but the available data are already very promising [8]. Unfortunately, the advanced stage CKD patients are minority in mentioned trials (besides the last SGLT2i trials).

The concept of slowing down the progression of CKD through a low-protein diet has been around since the last century. However, large-scale studies like Modification of Diet in Renal Disease (MDRD) have yielded negative results, and achieving the target protein intake remains challenging.

Limiting protein intake poses the risks of protein-energy wasting. Conversely, patients often restrict protein intake as azotemia worsens. Modern approaches echo those of the past, with consistent goals: a protein intake of 0.6 and 0.3 g /kg/day (the latter, in combination with ketoanalogues of amino acids, to reach equivalent of 0.6 g/kg/day). Monitoring protein intake through daily urea excretion is essential. However, the real-world effectiveness of low-protein diets remains inconclusive. KDIGO CKD guidelines (2024) suggest maintaining a protein intake of 0.8 g/kg/day in adults with CKD G3-G5 stages. Additionally, it’s advised not to restrict protein intake in adults with sarcopenia, cachexia, or conditions leading to undernutrition.

Despite lacking hard clinical evidence, there’s some indication of the positive impact of plant-based proteins on CKD progression, blood pressure, and acidosis. This insight is highlighted in a review prepared for KDIGO CKD guidelines in 2024 [3], encouraging further research.

Notably, very low-protein diets seem to decrease the number of patients in CKD4–5 stages and the need for renal replacement therapy (RRT). Diets with low-protein content have a modest effect on this indicator, and those with low or very low-protein content do not influence mortality. However, they carry the risk of developing protein-energy wasting.

Reducing sodium intake is crucial in the general population, but in CKD, there is a J-shaped link between adverse outcomes and natremia. Hyponatremia’s association with comorbidities like cardiovascular issues and protein-energy wasting may explain this. Salt restriction leads to a decrease in blood pressure, extracellular fluid volume, and albuminuria, with less convincing evidence for slowing CKD progression; the studies conducted on this topic were of relatively short duration. In the studies involving RAAS blockade, salt restriction was beneficial, enhancing the nephrocardioprotective effect. However, a short-term decrease in GFR can be expected due to the elimination of hyperfiltration. Accumulation of sodium in nonionic form within the intradermal layer can act as an internal source explaining delayed manifestation of positive effects after the introduction of dietary restriction [9].

In the general population, the interaction of sodium and potassium influences hypertension development more than sodium levels alone. In CKD, higher potassium intake slows down progression. A diet rich in vegetables and fruits slows down the CKD progression and adds a hypotensive effect to medications. Questions persist about what is positive in a vegetarian diet: potassium-rich food, dietary fiber content (with an effect on the microbiota, inflammation, and intestinal uremic toxins’ generation), or a limitation of rapidly absorbed phosphates [10]. Potassium intake reduction becomes relevant in CKD stage 3B, set at 2.5 g/day with kalemia monitoring.

Phosphate consumption, especially from processed products, exceeds needs in the general population, but in CKD, hyperphosphatemia poses greater risks. It accelerates the progression of CKD and counteracts the nephroprotective effect of RAAS blockade. The challenge arises from the need to combat hyperphosphatemia without imposing substantial restrictions on protein intake. Additional dietary control measures involve the use of medications such as phosphate binders and absorption blockers, along with addressing hyperparathyroidism.

Vascular calcification risks in predialysis CKD stages limit the use of calcium-free phosphate binders. Invasive techniques [11] may become relevant for predialysis CKD stages due to restrictions in calcimimetics (due to the outpacing growth of phosphate in comparison with the rate of suppression of hyperparathyroidism) and vitamin D use (due to the risk of hypercalcemia).

The use of synbiotics in CKD stages 3B-4 resulted in a significant transformation of the intestinal microbiome, enriching it with bifidobacteria, lactobacilli, and Subdoligranulum. This intervention also led to a reduction in the level of indoxyl sulfate in the blood, an improvement in eGFR, and the decrease in C-reactive protein (CRP) levels. The initial studies on this subject, when combined in a meta-analysis, demonstrated positive effects [12]. Additionally, the inclusion of polyunsaturated fatty acids (PUFAs) as supplements in CKD showcased enhancements in lipid profiles and a reduction in oxidative stress [13].

The consumption of easily digestible carbohydrates in the broader population is linked to the development of metabolic syndrome, hypertension, albuminuria, and the onset of CKD. Although there are no direct studies focused on CKD, it’s crucial to note that an elevated content of glycation end products in food heightens the risk of death in CKD. Reducing the intake of these compounds in the diet has been shown to improve kidney function and lower inflammatory markers [14]. It’s noteworthy that among 120,000 patients with obesity and hypertension, the use of prescribed RAAS blockers increased the risks of developing or progressing CKD [15].

Tobacco smoking is one of the leading causes of preventable deaths, including cardiovascular diseases and cancer. It is associated with proteinuria and a decrease in GFR in the general population and accelerates the progression of established CKD and exacerbates proteinuria. Moreover, smoking reduces the survival rate of kidney transplant recipients and worsens the graft survival. These effects depend on the dose and time and can be attenuated by quitting smoking. Quitting smoking slows down the progression of kidney disease [16].

3. RAAS blockade

As per a meta-analysis network [17], the use of ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) in CKD patients is associated with a decreased risk of kidney failure and cardiovascular events. ACEi, in particular, demonstrated a 28% reduction in the risk for all-cause mortality by 28% and proved to be superior to ARBs across various outcomes. This suggests that ACE inhibitors could be considered the preferred choice for treatment, especially in populations primarily dealing with CKD stages 1-3A. Of note, only quarter of 119 studies included patients with CKD3 or higher. Both ACE inhibitors and ARBs significantly lowered the odds of kidney failure by 39 and 30%, respectively, compared to a placebo. When compared with other active controls, other active controls showed no significant impact on kidney failure. Moreover, both ACE inhibitors and ARBs demonstrated a reduction in major cardiovascular events. While controls did not exhibit a notable effect on the risk of cardiovascular death. In comparisons between ARBs and ACEis, the latter consistently showed higher probabilities of reducing kidney failure, cardiovascular death, or all-cause death. It’s crucial to consider potential risks associated with these drugs. Implementing protocols for the prevention and treatment of hyperkalemia can help balance potassium levels and facilitate the initiation or continuation of RAAS blockade in CKD3–5.

A large (involving more than 5000 patients) study of real-world practice [18] showed that the initiation of therapy of RAAS blockers, in comparison with calcium blockers, reduces the risk of dialysis by 21% in progressive CKD3–5, with comparable cardioprotective efficacy. On the contrary, the termination of the RAAS blockade was associated with higher absolute risks of death and serious cardiovascular events, simultaneously, a lower absolute risk of the need for RRT [19]. The negative impact of RAAS blockade on kidney function may only be a matter of necessary dose adjustment, raising questions about the threshold at which the previously effective nephroprotective approach becomes ineffective.

The extent to which intensive blood pressure control, with target levels below 120/80 mmHg, is beneficial or acceptable remains unclear. Attempts to intensify antihypertensive therapy to achieve this goal led to an accelerated decrease in kidney function (while reducing the risks of cardiovascular events) and an increase in episodes of acute kidney injury (AKI). The nephroprotective effect of antihypertensive therapy is lower with proteinuria of less than 1 g/day. The discussion on this topic was sharpened by the release of KDIGO clinical recommendations on blood pressure in CKD [20], which emphasized the importance of standardized measurement and strict control of blood pressure. However, the target systolic blood pressure level of less than 120 mmHg is controversial. The recommendation is based on weak evidence and may not be applicable to most patients with CKD. Striving for such a target in routine practice may expose multimorbid patients to adverse events, including falls and fractures, and is often unattainable for most CKD patients [4].

In 2019, a meta-analysis of randomized controlled trials (RCTs) failed to conclusively support the use of RAAS blockers as nephroprotective therapy in CKD3–4 and even in populations with CKD1–4. The odds ratio (OR) is 1.05; 95% confidence interval (CI) 0.99–1.11. The same meta-analysis confirmed the effectiveness of lipid-lowering therapy (OR 1.04; 95% CI 1.00–1.08) and glycemic control (OR 1.06; 95% CI 1.02–1.10) [21].

A network meta-analysis systematically evaluates the efficacy of various interventions, even in the absence of direct head-to-head comparisons. In a recent publication addressing such comprehensive comparisons [22], it was observed that ACEi and ARBs demonstrate nephrocardioprotection in the broader category of CKD patients. However, uncertainties persist regarding the effectiveness and safety of these drugs specifically in individuals with CKD3–4.

4. Angiotensin receptor/neprilysin inhibitor

For over two decades, therapy with ACE inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) has been employed in patients with chronic heart failure (HF) and reduced ejection fraction to mitigate the risk of mortality. Neurohormonal activation resulting from ACEi or ARB monotherapy contributes to lingering cardiovascular risk, particularly in patients with concomitant resistant hypertension.

In this context, newer agents, such as ARNI (angiotensin receptor/neprilysin inhibitor), may offer additional benefits by counteracting neurohormonal activation stemming from ACEi or ARB monotherapy. These agents operate by enhancing cyclic guanosine monophosphate (cGMP) levels in cardiomyocytes and inhibiting the renin-angiotensin-aldosterone system (RAAS). ARNI, exemplified by the first-in-class combination of sacubitril and valsartan, has demonstrated superiority over ACEi or ARB in reducing inflammation and cardiorenal fibrosis in animal studies.

Due to the additional benefits of ARNI, it may potentially achieve a more significant reduction in blood pressure compared to ACEi or ARB monotherapy. The first-in-class ARNI represented by a combination of sacubitril and valsartan demonstrated superior efficacy compared to ACEi or an ARB monotherapy in patients with heart failure, as evidenced in the PARADIGM-HF and PARAGON-HF trials. A comprehensive analysis of these studies revealed that sacubitril/valsartan reduced the risk of serious adverse renal outcomes and decline in eGFR, compared to valsartan or enalapril, irrespective of baseline renal function [23].

But renal advantages of ARNI over monotherapy with renin-angiotensin system (RAS) blockers in patients with heart failure remain a subject of debate. Three observational studies and a small-scale randomized controlled trial (RCT) have produced conflicting results. A post hoc analysis of the PARADIGM-HF trial revealed a 21% lesser annual decline in GFR in the sacubitril/valsartan arm compared to the ACEi monotherapy arm, despite a greater increase in albuminuria by 25% in a subset of the study with known albuminuria [24]. A recent retrospective study involving patients with advanced CKD (eGFR<30 ml/min) reported no additional benefit of ARNI over ACEi monotherapy in reducing renal outcomes [25]. In PARAGON-HF trial, ARNI demonstrated a noteworthy 50% reduction in the risk of renal outcomes compared to ARB monotherapy [23]. However, a small RCT involving patients with eGFR 20–60 ml/min/1.73 m² did not reveal benefits of ARNI in patients with eGFR <30 ml/min/1.73 m² both in the presence and absence of heart failure (HF). Intriguingly, ARNI treatment in patients with end-stage kidney disease (ESKD) showed improvement in echocardiographic (echo) parameters after 1 year of treatment [26]. Moreover, there is a lack of studies evaluating the efficacy of ARNI over ACEi or ARB monotherapy in patients with CKD in the absence of HF. Given this information, it seems reasonable to consider ARNIs over ACEi or ARB monotherapy primarily for reducing cardiovascular events in patients with HF and with cautious use in patients with HF and comorbid CKD. This therapeutic approach should be avoided in individuals at risk of hyperkalemia, particularly in patients with eGFR <30 ml/min/1.73 m² and a systolic blood pressure < 110 mmHg. Anticipating a decline in eGFR within 1 month after initiating therapy is prudent, blood pressure should be closely monitored to rule out hypotension, and if necessary, downtitration of other antihypertensive drugs might be required. Currently, there is no indication for utilizing this drug in patients with CKD without HF solely for the purpose of preventing CKD progression [27].

5. Selective mineralocorticoid receptor antagonist

Patients with type 2 diabetic chronic kidney disease are commonly managed with renin-angiotensin-aldosterone system inhibitors (RAASi), SGLT2i, and hypoglycemic agents. Despite the use of ACEi/ARB, these patients often face adverse cardiorenal outcomes. Steroidal mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, can be considered in combination with RAASi and SGLT2i, although there are associated risks of side effects, such as acute kidney injury and hyperkalemia, particularly when used concomitantly with ACEi/ARB. A newer nonsteroidal and selective MRA, finerenone, has been introduced, offering a better tolerability compared to traditional MRAs due to intraclass pharmacological differences. Finerenone demonstrates higher potency for anti-inflammatory and antifibrotic effects compared to other MRAs. The FIGARO-DKD trial involved individuals with type 2 diabetes mellitus (type 2 DM) with eGFR 25–90 ml/min/1.73 m² and ACR 30–300 mg/g, or with eGFR above 60 ml/min/1.73 m² and ACR 300–5000 mg/g. Finerenone exhibited an 18% improvement in the composite cardiovascular outcome. The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial assessed the efficacy of finerenone in patients with type 2 DM with urinary ACR between 30 and 300 mg/g and eGFR 25–60 ml/min/1.73 m², or ACR between 300 and 5000 mg/g and eGFR over 25 ml/min/1.73 m². Finerenone reduced the progression of CKD by 18% and the composite cardiovascular outcome by 13%. In a pooled analysis of both trials, finerenone demonstrated a 14–23% reduction in cardiorenal outcomes in patients with type 2 diabetic CKD at risk of incident heart failure [28].

Subgroup analyses indicate that the beneficial effects of finerenone might be more pronounced in patients with baseline CV disease. It should be noted that the eligibility for those studies was based on the tolerability of maximal doses of ACEi/ARB and the serum potassium below 4.8 mmol/l. Following randomization, 18% developed hyperkalemia, 5% experienced AKI and there was an additional drop in mean systolic blood pressure by 3 mmHg accompanied by an acute decline in eGFR at the initiation of finerenone, which subsequently stabilized during follow-up. It is intriguing that in the FIDELIO-DKD trial, 4% of the participants were already on treatment with SGLT2i; however, it remains unclear whether patients already on SGLT2i could benefit from the addition of finerenone. This question is being investigated in the ongoing CONFIDENCE (Combination effect of finerenone and empagliflozin in participants with chronic kidney disease and type 2 diabetes using a UACR endpoint) study that aims to evaluate how effective and safe is this combination [29].

As MRAs are RAAS blockers, the combined use (dual RAAS blockade) raises concerns about potential higher incidence of renal dysfunction, up to dialysis dependence, identified two decades ago. Consequently, the use of finerenone in addition to ACEi/ARB for patients with type 2 diabetes mellitus (DM) and CKD, with an eGFR 25–60 ml/min/1.73 m² and microalbuminuria or eGFR 25–75 ml/min/1.73 m² and macroalbuminuria, may be justifiable in the absence of hyperkalemia on the previous maximal ACEi/ARB dose. Initiating this treatment requires thorough monitoring for AKI, hypotension, and hyperkalemia, with an expected acute drop in eGFR during the first month of therapy. The potential use of this combination in patients with nephrotic range proteinuria (ACR >5000 mg/g) remains unconfirmed.

It is imperative for nephrologists to adopt a more precise approach, seeking better information solutions that consider inflammatory signals, platelet activation, baseline patient characteristics, metabolic abnormalities, and other advanced CKD disorders. Previous large CV outcome trials recruited participants enriched for CV diseases where CKD was either underrepresented, or excluding those with eGFR <30 ml/min/1.73 m².

6. Sodium-glucose transporter 2 inhibitors

The EMPA-KIDNEY study [30] (Empagliflozin in Patients with Chronic Kidney Disease) distinguished itself from comparable previous investigations by having a lower proportion of patients with diabetes mellitus (46%) than without diabetes. Furthermore, the study included a higher representation of individuals with low kidney function and low levels of albuminuria (Figure 1).

Figure 1.

Patients distribution by kidney function and albuminuria in EMPA-KIDNEY study. Dotted line represent borders of 30 and 300 mg/g in albumin to creatinine ratio in albuminuria distribution, and borders 30 and 45 ml/min/1.73 m² - in eGFR distribution.

The study showed that allocation to empagliflozin resulted in a modest initial 2-month dip in kidney function of 2 ml/min/1.73 m² (or 6%), followed by a subsequent halving of the decrease rate in chronic phase of study. This overall outcome underscored a notable 29% reduction in the categorical composite outcome (ESKD, a 40% reduction of eGFR to below 10 ml/min/1.73 m², or death from kidney failure). Consistent with other trials of SGLT2 inhibitors, the favorable effects of empagliflozin on CKD progression exhibited variations based on diabetes status, eGFR, most significantly, albuminuria. The relative effect might be more pronounced in certain populations. The great variety of patients included in the large EMPA-KIDNEY trial facilitated a thorough evaluation of these differences, especially since EMPA-KIDNEY included participants with an eGFR <25 ml/min/1.73 m² and with ACR <200 mg/g who were excluded from other trials.

The acute dip in eGFR in EMPA-KIDNEY averaged <3 ml/min/1.73 m² or < 10% of baseline eGFR and was more prominent in patients with diabetes, reflecting the higher prevalence and degree of hyperfiltration in DM. The associated rapid reduction in albuminuria supports this hypothesis with the decrease in intraglomerular pressure presumed mechanism of the SGLT2i beneficial effects on kidney function [31]. The secondary analysis of EMPA-KIDNEY suggests that the albuminuria reduction is possibly the most crucial predictor of the benefits, explaining a substantial portion of the effect on significant outcomes [32].

The chronic slope of eGFR is more informative for longer time periods. Although the magnitude of the acute dip correlates with the relative reduction in the chronic slope, measuring the total slope over 2–3 years reduces variation between subgroups. For the objective of delaying kidney failure, it is necessary to consider longer treatment durations. There was no strong evidence that the beneficial effect was significantly modified by the presence or absence of diabetes. Contrary to the KDIGO CKD guidelines (2024) that only suggest (but not definitely recommend) using SGLT2i in patients without diabetes and moderate albuminuria (ACR <200 mg/g), secondary analysis of EMPA-KIDNEY suggests that such patients are likely to gain substantial benefit in terms of preservation of kidney function, in addition to the cardiovascular benefits and reductions in risk of acute kidney injury with longer treatment.

7. Prevention of episodes of acute renal injury

If the effectiveness of pharmacological interventions within the framework of a nephroprotective strategy has not been confirmed for all stages of CKD, the effectiveness of preventing episodes of AKI is beyond doubt under any circumstances. AKI episodes are closely linked with substantial mortality and comorbidity, elevating the risk of compromised renal function. The AKI process, being interconnected, acts as a pathway and catalyst for subsequent AKI episodes and, potentially, the onset of CKD, irrespective of whether renal function is restored following AKI episodes [33]. Biomarkers of AKI play a pivotal role in successfully predicting its development and guiding the selection of interventions for prevention.

8. Nosotropic treatment within the framework of nephroprotection

The etiologies of CKD exert diverse impacts on the progression of kidney disease. Strategies for etiotropic treatment of CKD remain inadequately defined.

Glomerulopathy is a heterogeneous group of diseases and is the cause of a significant number of CKD variants. Despite efforts to find new diagnostic tools, such as “liquid biopsy,” for specific markers, kidney biopsy is still the gold standard for diagnosis. Proteinuria exceeding 1 g/day is a risk factor for a rapid decrease in GFR. Certain genetic factors, such as the apolipoprotein L1 (APOL1) genotype in focal segmental glomerulosclerosis or Fabry disease, contribute to accelerated GFR loss. In 2021, KDIGO issued extensive clinical guidelines on glomerular diseases.

Diabetes mellitus is the most widespread etiology of CKD, globally encompassing CKD5. Diabetic nephropathy manifests more often not only in patients with inadequate glycemic control, but it also develops in 30–40% of patients with intensive glycemic control, highlighting the complex and multifactorial pathogenesis of the disease [34]. Alongside optimal glycemic control, SGLT2i and RAAS blockade are central elements in the treatment of diabetic nephropathy. Pentoxifylline and statins exhibit an antiproteinuric effect and decelerate the progression of CKD in patients already receiving RAAS blockers [35].

Chronic kidney disesase associated with hypertension ranks among the most prevalent causes of diminished kidney function. While the question of the target blood pressure values and the justified intensity of therapy remains open, blood pressure reduction stands as one of the most crucial strategies in managing patients with hypertension and CKD. Pharmacotherapy, in addition to lifestyle changes, remains indispensable in most cases.

Nephrolithiasis significantly increases the risk of developing CKD and manifesting in 2–3% of CKD5 cases. Patients experiencing stone formation have a lower eGFR, since nephrolithiasis shares several common risk factors with CKD, including nephrotoxic analgesic use, reduced water intake, recurrent infections, structural disorders of the urinary tract, and contrast nephropathy. It is noteworthy that both surgery and shockwave lithotripsy cause damage to the renal parenchyma, inflammation, and fibrosis. Different types of stones correlate with different risks of developing CKD, with the highest risk being cystine, urate, and struvite stones [36].

Autosomal dominant polycystic kidney disease (ADPKD) stands out as the predominant genetic cause of advanced CKD. Traditional nephroprotection has a limited effect on the rate of GFR decrease, so transplantation is the best strategy in this case.

Tolvaptan, a vasopressin-2 receptor (V2R) antagonist, demonstrates efficacy in randomized controlled trials (RCTs) and real-world settings by reducing kidney volume growth from 11–3% and decreasing the GFR decline from 3.3 to 2.3 ml/min/1.73 m²/year [37]. Importantly, positive GFR dynamics persist, irrespective of variations in total kidney volume growth rates. The incidence of complications, such as elevated liver enzymes, thirst, and hyperuricemia, remains low (7–8% each).

9. Correction of chronic kidney disease syndromes as part of a nephroprotective strategy

Clinical manifestations of CKD vary depending on the etiology, stage, and comorbidity. The kidneys not only provide solute excretion and water-electrolyte balance, but also support endocrine homeostasis. As CKD progresses, these vital functions diminish, leading to the accumulation of uremic toxins. Managing complications arising from CKD not only alleviates associated symptoms but also holds the potential to decelerate the progression of kidney disease.

The incidence of metabolic acidosis rises proportionally with the decline in GFR, heightening the risks of adverse outcomes, including the CKD progression. The implementation of alkylating therapy, such as sodium bicarbonate preparations or dietary measures, proves effective in retarding CKD development [38]. The multifaceted mechanism behind this process may encompass heightened ammonia production in the remaining nephrons, which can lead to the activation of complement with tubulointerstitial lesions and increased endothelin production. Besides renal implications, metabolic acidosis detrimentally impacts cardiovascular outcomes by intensifying inflammatory reactions, boosting aldosterone secretion, and enhancing endothelin synthesis, thereby disrupting contractile ability. Furthermore, metabolic acidosis is linked to impaired bone mineralization, insulin resistance, and overall elevation in all-cause mortality [35].

The exploration of erythropoiesis-stimulating drugs to correct anemia and potentially confer nephroprotection has been ongoing for years. The theoretical nephroprotective effect of these drugs could stem from mitigating renal hypoxia or activating pleiotropic mechanisms. Studies have identified erythropoietin receptors in the mesangium, proximal tubules, and cells of medullary collecting tubules. However, attempts to fully correct anemia did not lead to any benefit and may have caused harm [39]. A decade after the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) and Correction of Hemoglobin in Outcomes and Renal Insufficiency (CHOIR) studies, efforts were again made to impede the CKD progression with low doses of long-acting erythropoietin drugs in patients without anemia or diabetes mellitus with the previous high target hemoglobin levels of 110–130 g/l, but these efforts were unsuccessful [40, 41]. Nevertheless, there is consensus on the efficacy of correcting anemia from low levels to the target range defined by current clinical recommendations [35]. Phase III registration studies have not confirmed the theoretical possibility of slowing the progression of CKD with the use of hypoxia-induced factor stabilizers. The optimal timing for the use of these drugs during CKD progression may be a crucial factor in achieving the desired effect [42].

The association of hyperuricemia with higher rates of CKD progression has been consistently confirmed over an extended period. However, the ability of hypouricemic drugs to impede the CKD progression by reducing the uric acid levels is less unequivocal. A systematic analysis of randomized controlled trials in 2022 [43] concluded that topiroxostat significantly improved eGFR and reduced ACR. While febuxostat did not exhibit an overall positive effect, it significantly improved renal function (eGFR) in a subgroup of patients with CKD and hyperuricemia. Conversely, allopurinol and pegloticase did not demonstrate a positive effect. Dietary efforts to limit uric acid intake appear reasonable in any case.

10. Evaluation of CKD progression by surrogate criteria

The predictive utility of the GFR reduction curve slope in anticipating robust clinical outcomes was scrutinized in a comprehensive meta-analysis encompassing 47 RCTs with 11 distinct interventions [44]. The meta-regression analysis revealed that each 0.75 ml/min/1.73 m²/increase in treatment effect on the overall GFR slope was associated with an average risk reduction of 27% (95% CI 20–34%) in hard clinical outcomes. Across the 47 studies involving 60,000 patients, the average eGFR stood at 62 ± 26 ml/min/1.73 m² with a median albuminuria of 60 mg/g. The combined average total slope for all studies over 3 years was −3.49 (95% CI–4.04 ÷ −2.93) ml/min/1.73 m²/year in the control group and − 2.94 (95% CI–3.45 ÷ −2.43) ml/min/1.73 m²/year in the treatment group. In another meta-analysis [45] involving 41 RCTs with nearly 30,000 participants, the cumulative clinical endpoint was reached by 13% of patients over a median duration of 3.4 years.

In meta-regression analysis, a notable 30% reduction in the geometric mean value of albuminuria resulting from treatment, when compared with the control group, demonstrated an associated average decrease of 27% in the risk of reaching hard clinical endpoints. This correlation exhibited further enhancement when the analysis was confined to patients with baseline albuminuria exceeding 30 mg/g. Consequently, alterations in albuminuria can serve as a meaningful surrogate endpoint for gauging the progression of CKD, especially in patients with high baseline albuminuria. Another meta-analysis, involving 28 cohorts comprising 700,000 participants in observational studies, underscored the significance of a 30% reduction in albuminuria, linking it to a substantial 22% decrease in the risk of advancing to ESKD (95% CI 34 ÷ 8%) [46].

The existing approach to managing patients with late-stage CKD is deemed suboptimal, lacking the necessary correction for pivotal uremic syndromes and exacerbating the likelihood of subsequent prolonged dialysis treatment. Previous publications by the authors outlined the conventional practice for managing late-stage CKD patients [47, 48]. Comparing its results with the results of the implementation of the intensive follow-up program in a prospective study, we assessed the importance of the program components in the “transition center” model.

11. Single center experience of renoprotection on CKD3B-5 stages

The effectiveness of conventional nephroprotection is reduced in the late stages of CKD; the search for effective algorithms is hampered by accelerating decline in glomerular filtration rate. The absence of universally accepted methods for evaluating the effectiveness of conventional nephroprotection prompted our two-year study, aimed at constructing a predictive model for the glomerular filtration decline rate. This model served as a tool to assess the effectiveness of intensive follow-up strategies.

From the city’s comprehensive database (n = 7696), we carefully selected a representative group undergoing regular follow-up (n = 540) to build the model predicting the annual glomerular filtration decline rate. This model is used to evaluate the effectiveness of intensive monitoring in the target group of patients (n = 100) with CKD3B-5 using the difference between predicted and actual glomerular filtration rate decline. A matched subgroup (n = 200) was utilized for a direct comparison of both hard and surrogate outcomes.

Patients in the advanced stages of CKD are at significant risk of early mortality, comorbidities, and declines in physical and mental functions as the disease progresses. These risks compete with the risk of developing the need for renal replacement therapy (RRT). The classical concepts of nephroprotective therapy aimed at improving intrarenal hemodynamics with the exception of hyperfiltration [3] are currently complemented by a set of measures that can slow down the decline in renal function, which simultaneously reduces the risks of the development and manifestations of renal insufficiency syndromes. To assess the effectiveness of these interventions, often administered concurrently, operational tools are needed that do not involve a long waiting for results. This prompts the pertinent question within the nephrology community: “Is it right to wait for dialysis to evaluate nephroprotective therapy?” [49].

The intensive follow-up program, integral to our study, involved a heightened frequency of visits—every 2–3 months for CKD3B, every 2 months for CKD4, and monthly for CKD5, with increased frequency as deemed necessary, including remote consultations. During the visit, clinical and laboratory assessments were carried out with the measurement of eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, as well as proteinuria assessment. In cases of eGFR uncertainty, GFR was directly measured (average value between renal creatinine/urea clearances). Quarterly assessments included parathyroid hormone, ferritin, magnesium, and urate levels, while vitamin D and lipid spectrum evaluations were conducted semiannually. Echocardiography (echo), ultrasound (US) examination, and densitometry were performed once and, if necessary, repeatedly. The Charlson Comorbidity Index (CCI) assessed comorbidity, and additional interventions, such as bioimpedance, consultations with vascular surgeons and psychologists, and scintigraphy/ultrasound examinations of the parathyroid glands, were conducted based on indications. Joint decision about the time of RRT start and the chosen method was made, with due consideration for the feasibility of living donor transplantation. Vaccinations against hepatitis B and pneumococcus were administered as required. The key interventions are detailed in Table 1.

Intervention	Details
Implementing lifestyle modifications	Incorporating physical activity, achieving weight normalization, and promoting smoking cessation.
Limiting salt intake	For individual patients, monitoring daily sodium excretion and assessing water volumes through bioimpedance.
Limiting protein intake to 0.6–0.8 g/kg/day	In specific patients, monitoring daily urea excretion, supplemented with ketoanalogues of amino acids, aiming for a protein intake of less than 0.6 g/kg/day.
Limiting potassium intake or addressing potassium deficiency	Monitoring is essential when prescribing or adjusting doses of RAAS blockers, diuretics, and mineralocorticoid receptor antagonists, with particular attention to “life-saving therapy” involving potassium sorbents
Prescription of RAAS blockers when proteinuria exceeds 1 g/day (if not prescribed previously)	Assessment of the Renin-Angiotensin-Aldosterone System (RAAS) effectiveness in reducing proteinuria, monitored alongside creatinine levels and potassium dynamics.
Prescribing or adjusting antihypertensive therapy	Aiming for a target blood pressure below 140/90 mmHg or tailored to individual needs
Adjusting phosphatemia to values below 1.45 mmol/l, achieving calcemia within the target range of 2.15–2.5 mmol/l, and managing hyperparathyroidism within the target range based on CKD stages	Implementing a dietary regimen, reducing excessive inorganic phosphate load, utilizing phosphate binders, and managing secondary hyperparathyroidism through vitamin D and alfacalcidol (paricalcitol).
Correction anemia to achieve a hemoglobin target level of 110–120 g/l	Administering intravenous iron when ferritin levels are below 100 mcg/l and C-reactive protein is less than 5 mg/l, subsequently prescribing erythropoietin
Rectifying acidosis to achieve a standard bicarbonate level of 22 mmol/l or higher	Oral administration of sodium bicarbonate, coupled with dietary measures
Prescribing statins for individuals at high risk of cardiovascular events	In accordance with the KDIGO CKD guidelines
Prescribing SGLT2 inhibitors	Collaborative decision-making involving an endocrinologist
Correcting magnesium deficiency	Exclusion of hypermagnesemia
Feasible correction of the inflammatory state	Incorporating dental consultation

Table 1.

The program of intensive follow-up.

The recruitment process for the treatment group was nonselective, encompassing all consecutively admitted patients for follow-up with CKD3B or higher. The control group, intended for assessing advanced CKD progression under standard care, comprised 540 patients with regular follow-up (at least five visits annually). Among these, 200 patients were meticulously matched with the intensive care group based on gender, age, and primary diagnosis. The initiation of follow-up for each pair of patients in control group was attributed to the eGFR level of the matched patient from the intensive care group. For the majority of patients (72%), individual eGFR reduction trajectories were best described by a polynomial function corresponding to the acceleration of eGFR decline:

$$eGFR=-0.0078\times x^2+0.8377+11.98$$E1

where x – time till actual or potential RRT need (10 ml/min/1.73 m²).

The overall rates of eGFR decline were − 2,76 (−3,26÷ − 2,36) for CKD3B, −4,34 (−5,01÷ − 3,46) for CKD4, and − 6,01 (−7,11÷ − 5,23) ml/min/1.73 m²/year for CKD5.

To predict the “instantaneous” rate of GFR decrease, the calculation of the first derivatives of each of the nonlinear functions was employed. The obtained forecasts of the rate of decrease were then compared with the actual rates of the GFR decrease of each patient. The standard deviation for the models was 0.467, 0.472, 1.046, and 1.763 ml/min/1.73 m²/year, respectively, when using polynomial, power, logarithmic, and linear functions. The optimal curve approximating this set is:

$$\Delta \left(eGFR\right)=-0.0007\times {\left(eGFR\right)}^2+0.0155\times \left(eGFR\right)+0.738$$E2

where Δ(eGFR) is the month rate of GFR decrease and eGFR is the current level of GFR. This equation predicts the rate of eGFR decrease by its actual level for the group of regular care (n = 540). The uncertainty, associated with factors other than the level of renal function, decreases with GFR lowering and for eGFR 20–10 ml/min/1.73 m² does not exceed 10%.

According to the model developed (in the standard follow-up group), the predicted rate of GFR decline was calculated for each patient in the intensive follow-up group. The predicted values were then compared with the actual rates of CKD progression. The predicted value was 9.06 ± 0.59 ml/min/1.73 m²/year, while the actual value was 5.98 ± 1.69 ml/min/1.73 m²/year. This indicates that in the intensive follow-up group, the real rate of GFR decrease was less than the forecast by 3.09 ± 1.92 ml/min/1.73 m²/year (i.e., by 34 ± 19%).

In the multiple regression analysis with the dependent variable “annual rate of GFR decrease,” the association of CKD progression rate with various factors in the intensive follow-up group (n = 100) was estimated (Table 2).

Regression parameter	B	SD(B)	p	95%CI for B
Constant	−4.026	2.111	0.06	−8.22÷ + 0.168
Systolic blood pressure (per 5 mmHg)	−0.145	0.04	0.0005	−0.045÷ − 0.013
Phosphates (per 0.2 mmol/l)	−0.13	0.04	0.001	−1.052÷ − 0.269
Hemoglobin (per 1 g/dl)	0.14	0.07	0.055	−0.0003÷ + 0.028
Albumin (per 1.5 g/l)	0.146	0.057	0.012	0.034÷0.257
Urates (per 0.1 mmol/l)	−0.137	0.064	0.034	−2.637÷ − 0.103
Deviation of the calcium level (0.1 mmol/l from the target)	−0.150	0.076	0.052	−3.004÷ + 0.012
Proteinuria (per 0.1 g/l)	−0.146	0.067	0.032	−2.783÷ − 0.126
Standard bicarbonate; (per 2 mmol/l)	0.153	0.067	0.022	0.011÷0.142
The final GFR; (per 1 ml/min/1.73 m^2)	0.132	0.029	>0.0001	0.074÷0.19
Initial GFR; (per 2 ml/min/1.73 m^2)	−0.134	0.042	0.002	−0.11÷ − 0.025
Diagnosis (for one category in sequential list*)	−0.247	0.054	>0.0001	−0.353÷ − 0.14

Table 2.

Model of multivariate regression analysis with a dependent variable “annual rate of glomerular filtration rate decline” (n = 100).

*

The diagnoses are arranged in order of increasing average eGFR decline rate.

As a result of nephroprotective measures, many parameters have been improved that affect the prognosis of patients’ survival, the development of cardiovascular complications, and manifestations of uremic syndrome, as well as the progression of CKD (Table 3).

Parameter	Baseline	During treatment	Difference in paired comparisons, p
Administration of RAAS blockers* for proteinuria of more than 1 g/day or hypertension, without episodes of hyperkalemia (n = 71)
Proteinuria, Me (Q1–Q3), g/l	0.61 (0.38–1.12)	0.51 (0.27–0.89)	−18% (−0.11; 0.03÷ − 0.24)	<0.001
Creatinine, M ± SD, mmol/l	0.198 ± 0.033	0.234 ± 0.087	+18% (0.04 ± 0.02)	<0.001
Episodes of K+ > 6 mmol/l, n	0/71	4/71	+6%	0.042
Correction of arterial hypertension (n = 51)*
Mean systolic blood pressure, M ± SD, mmHg	151 ± 7	140 ± 8	−8 ± 6	<0.001
Proportion of patients with hypertension, n (%)	51/100 (51%)	20/100 (20%)	31 reached normal BP	<0.001
Correction of anemia** (at baseline hemoglobin <100 g/l (n = 21)
Hemoglobin, M ± SD, g/dl	9.6 ± 0.3	11.1 ± 1.1	+1.4 ± 0.7	<0.001
Ferritin#, Me (Q1–Q3), mcg/l	17 (13–44)	104 (88–243)	89 (74–176)	<0.001
Transferrin saturation, M ± SD	18 ± 4%	22 ± 6%	+3 ± 5%	=0.012
Correction of protein and energy wasting**
Albumin (at baseline <3.5 g/dl), M ± SD, g/l (n = 32)	3.2 ± 0.2	3.4 ± 0.3	+0.2 ± 0.2	<0.001
Transferrin (at baseline <2 g/l), M ± SD, g/L (n = 36)	1.69 ± 0.29	1.86 ± 0.38	+0.16 ± 0.36	0.012
Lymphocytes (at baseline <2.0 × 109/L), M ± SD, (n = 31)	1.48 ± 0.31	1.88 ± 0.32	+0.39 ± 0.52	<0.001
Correction of mineral and bone disorders
Phosphates* (at baseline >1.13 mmol/l), M ± SD, n = 77)	1.73 ± 0.42	1.53 ± 0.29	−0.21 ± 0.18	<0.001
Calcium* (at baseline >2.5 mmol/l), M ± SD, (n = 28)	2.66 ± 0.08	2.51 ± 0.10	−0.14 ± 0.11	<0.001
Calcium* (at baseline <2.1 mmol/L), M ± SD, (n = 34)	1.97 ± 0.09	2.12 ± 0.11	+0.16 ± 0.13	<0.001
Parathyroid hormone** (at baseline >70 pg./ml) (n = 56), Me (Q1–Q3), pg./ml	174; 79–380	87; 36–209	−140 (−2... − 278)	<0.001
25(OH)D3***, normal/insufficiency/deficiency	9%/62%/29%	18%/79%/3%	shift towards normal	<0.001
Counteraction to inflammatory state***
Exacerbation of chronic inflammatory diseases*	11/100	6/100		0.205
The necessary sanitation of the oral cavity			35/78
C-reactive protein* (at baseline >5 mg/l) (n = 34), Me (Q1–Q3)	8 (6–14)	6 (4–11)	-2 (−3... + 1)	0.023
Correction of acid-base state*
SB* (at baseline <22 mmol/l), M ± SD, (n = 64)	19 ± 2	23 ± 3	+5 ± 3	<0.001
(proportion of patients achieving the goal)			38/64

Table 3.

Immediate results of nephroprotective measures.

*

Assessment every visit.

**

Assessment every 3 months.

***

Assessment every 6 months.

^#

Without signs of inflammation.

To ascertain the comparative impact of interventions, a multiple regression analysis was conducted, with the dependent variable being “the effect of intensive follow-up on the reduction in the rate of eGFR decrease,” that is, the size of reduction in the actual rate of GFR decline in contrast to the predicted rate. The statistical significance of the model is F = 28.610, p < 0.001 (Figure 2).

Figure 2.

A model of multiple regression analysis with a dependent variable “the effect of intensive follow-up on reducing estimated glomerular filtration rate decline”; * - diagnosis ranged in increasing order by average rate of GFR decline.

Each improvement in modifiable positive parameters resulting from interventions (serum albumin by 0.15 g/dl, hemoglobin by 1 g/l, and standard bicarbonate (SB) by 2 mmol/l) or reduction in negative parameters (serum phosphate by 0.25 mmol/l, plasma calcium deviation from target range by 0.1 mmol/l, uric acid by 0.1 mmol/l, systolic blood pressure by 5 mmHg) was independently associated with approximately similar (2.5%) reduction of the rate of GFR decline.

The predicted time to reach the threshold for RRT starting from a conditional point of 20 ml/min/1.73 m² for the treatment group was 5.2 ± 1.9 months longer than in the regular follow-up group. Although the average GFR values at the initiation of dialysis were comparable in the treatment group (6.6 ± 1.1 ml/min/1.73 m²) and the matched group (6.0 ± 1.7 ml/min/1.73 m²; p = 0.35), its distribution suggested the presence of a delayed and possibly premature start. In the treatment group, the initiation was consistently planned, whereas in the control group, only 58.5% (31/53) of patients commenced dialysis under planned circumstances (χ²-test; p < 0.0001). Notably, in the matched control group, 18.8% (9/53) of patients initiated hemodialysis urgently with a central venous catheter, and in 20.5% (8/39) of cases, initiation with an arteriovenous fistula was necessitated before the lapse of 2 weeks.

12. Discussion

Retrospective studies often concentrate on patients reaching the need for dialysis, with higher progression rates as “progressors” are more likely to necessitate dialysis. In a meta-analysis [50] involving 43 CKD3–4 cohorts and 17 retrospective studies with patients initiating dialysis, annual eGFR decreases were reported as 2.4 (95% CI 2.2–2.6) and 8.5 (95% CI 6.8–10.1) ml/min/1.73 m², respectively. Notably, only 4 out of 60 studies, including our present study, explored the nonlinearity of CKD progression. The predominant assumption of linearity in GFR reduction rates in many studies masks potential nonlinearity. Standard care in advanced CKD does not effectively impede CKD progression, surpassing the rates observed in some studies [50], with considerable variations across populations. Urgent dialysis initiation is prevalent in large registers, a situation deemed unsatisfactory [51].

The proposed model of CKD progression makes it possible to predict the rate of eGFR reduction in the conditions of standard nephrology care for CKD3–5. The currently recommended by the European Renal Best Practice (ERBP) and International Society of Nephrology (ISN) the Kidney Failure Risk Equation [52] model for four or eight variables suggests the risk calculation of developing a need for RRT after 2 or 5 years (as a percentage). The model favorably differs from the presented one by including several additional parameters, but proceeds from a linear rate of progression. Predicting only the risk of RRT needs development over a certain period of time, the model of N. Tangri et al. cannot evaluate the results of nephroprotective interventions.

In a brief review, we presented the current landscape of nephroprotective interventions in advanced CKD. While individual components show varying degrees of confirmation, their combined effects and real-world application conditions are not considered in detail, and currently there is no generally accepted approach. The Remission Clinic concept (combined almost two decades ago), incorporating classical nephroprotective approaches, demonstrates effectiveness and continues to expand [53]. Few pragmatic studies have been published covering a significant number of interventions [54], although in recent years several groups of drugs have been increasingly evaluated and compared (sometimes in post hoc analysis), even in moderate to severe chronic kidney disease [55]. At the same time, the relative contribution of individual components and their real-world impacts require further analysis, considering potential population variations. Our implemented follow-up program achieves significant improvements in clinically relevant surrogate and hard outcomes for advanced CKD patients, as assessed through multiple regression analysis (Figure 2).

In the treatment group, the need for RRT has been postponed, and conditions for a “healthy” dialysis start have been provided: only with permanent dialysis access, most of the patients chose peritoneal dialysis, all patients started with targeted eGFR showcasing better correction of anemia, phosphatemia, and calcemia, as well as arterial hypertension. The predicted time to achieve the need for RRT from 20 ml/min/1.73 m² in the treatment group was 5 months longer. Thus, in real practice, the accuracy of previous simulation modeling has been confirmed: the predicted lengthening of the predialysis stage of treatment was 1.6 ± 1.7 years (p = 0.002) from the baseline GFR level of 20–40 ml/min/1.73 m² [56].

The search for new drugs and methods to slow down the progression of CKD continues intensively.

Interventions aimed at enhancing the elimination of uremic toxins, fluids, and electrolytes from the intestine, as well as the modulation of the intestinal microbiota, may represent new therapeutic strategies for the treatment of uremia in patients with CKD [57].

Although fibrosis can play a protective role, under certain circumstances, it can gradually turn into an uncontrolled irreversible and self-sustaining process. Several systems, molecules, and reactions are involved in the pathogenesis of pathological fibrosis in chronic kidney disease (CKD) such as: inflammation, renin-angiotensin system, parathyroid hormone, fibroblast growth factor 23 (FGF23), Klotho, microRNA (miRNA), and the vitamin D system. These key factors can control/exacerbate fibrosis, having a great effect on the kidneys and heart in CKD [58]. A number of clinical and preclinical studies on the prevention of renal fibrosis are ongoing now [59]. Doubtless, new opportunities will become available in the near future, in particular in relation to patients with advanced CKD stages.

The limitation of this study is the small number (n = 100) of patients in the treatment group, but the developed algorithm continues to be used in real-world practice, and ongoing recruitment of patients with an extended period of active follow-up will reduce the effect of this restriction. Validation of eGFR decrease in rate prediction internally and externally is planned as part of ongoing work in similar programs across different centers.

13. Conclusion

Assessing the rate of GFR decline serves as a valuable method not only for gauging the progression of CKD and predicting the timing of RRT, but also for promptly characterizing intervention outcomes. It is essential to consider the variability and nonlinear nature of the GFR reduction. To reliably evaluate this rate in each patient, utilizing five or more time-spaced eGFR values is recommended. The proposed algorithm of intensive follow-up in the advanced CKD demonstrates the capability to reduce the rate of eGFR decline by a third compared to standard care results. This reduction contributes to mitigating the risks of mortality, delaying the requirement for RRT, and enhancing the correction of uremic syndrome—significant factors in CKD progression.

Acknowledgments

I thank my mother Helena for her support and love, invaluable in my life.

Conflict of interest

The author declares no conflict of interest.