A Changing Perspective For Treatment Of Chronic Kidney Disease

Keywords: chronic kidney disease; CKD–MBD; hyperkalemia; vascular calcification; Cistanche benefits.

Chronic kidney disease (CKD) is now a huge worldwide health problem. the incidence and prevalence of CKD are high and still increasing, mainly due to obesity and diabetes, and are associated with increased morbidity and mortality. the overall mortality rate from CKD has increased by ~ 32% in the last 10 years, making it one of the fastest-growing leading causes of death, along with diabetes and dementia. CKD and end-stage renal disease (ESRD) are characterized by the progressive development of a range of complications such as hypertension, left ventricular hypertrophy [LVH] anemia, hyperkalemia, hypervolemia, hyperphosphatemia with mineral and bone disease (CKD - MBD), metabolic acidosis, hyperuricemia blood, and wasting; all of these complications have been shown to be associated with adverse outcomes and can contribute, either alone or in association, to the cardiovascular morbidity and mortality observed in CKD.

Current treatment of CKD includes blood pressure control, treatment of proteinuria with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, nutritional interventions, avoidance of potential nephrotoxins and obesity, medication dose adjustment, and cardiovascular risk reduction. Recent advances in our understanding of the pathophysiology of CKD, coupled with the development of novel therapeutic agents, have led to a renewed interest in the treatment of CKD and its associated metabolic complications, which are now amenable to intervention. It is this that has led to the creation of this related special issue. I am pleased to know that scientists from around the world have enthusiastically responded to this opportunity by sending papers dealing with genetics, pathophysiology, and epidemiology, as well as new therapeutic approaches to CKD.

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Genome-wide association studies have identified hundreds of genetic variants at loci associated with CKD; however, more than 90% of these variants are located in non-coding regions of the genome and how they contribute to the disease is unknown. Lysosomal β - d - mannosidase (MANBA) is an exo-glycosidase involved in the sequential degradation of n -glycosyl proteoglycans. Recently, the MANBA gene was proposed as a kidney disease severity gene. In this issue, Hye-Rim Kim et al. evaluated the effects of MANBA gene variants on CKD and renal function-related traits by integrating CKD-related variants and renal expression quantitative trait loci (eQTL) data in the Korean Genomic and Epidemiological Study (KoGES) cohort. Their study observed 20 single nucleotide polymorphisms (SNPs) in 229 SNPs of the MANBA gene showing a statistically significant correlation with CKD and renal function-related traits. In addition, rs4496586 had the highest significance for CKD and correlated with MANBA gene expression in tubules and glomeruli. In conclusion, this study strongly suggests that MANBA gene variants are associated with CKD and renal function-related traits.

Even though obesity and diabetes largely contribute to the prevalence of CKD, their interactions with nephrotoxins are not fully understood. Hagedoorn et al. investigated whether lifestyle-related exposures (diet and smoking) contribute to blood concentrations of cadmium and lead and whether they are associated with the prevalence of diabetic nephropathy (DKD). In a cross-sectional analysis of 231 patients with type 2 diabetes in the Diabetes and Lifestyle Cohort20 (DIALECT-1), median blood concentrations of cadmium and lead were below acute toxicity values [2.94 nmol/L for cadmium and 0.07 μ mol/L for lead, respectively]. However, each doubling of lead concentration increased the risk of albuminuria by 1.75-fold (95% confidence interval [CI]: 1.11-2.74). In addition, both cadmium and lead were associated with an increased risk of reduced creatinine clearance. The association between cadmium and lead and the prevalence of DKD suggests that they may contribute to the development of this major diabetic complication.

The prediction of acute and chronic kidney injury after renal surgery remains challenging. This is mainly due to the lack of sensitive and specific biomarkers for early prediction of CKD progression. the development of ESRD may take years and therefore alternative endpoints such as proteinuria and serum creatinine have been increasingly used in hard endpoint tests to predict CKD progression. Acute kidney injury (AKI) is a common complication after nephrectomy for renal cell carcinoma, and radical nephrectomy is associated with a higher risk than partial nephrectomy. Several predictors of CKD after radical nephrectomy (RN) or partial nephrectomy (PN) have been identified. However, the relationship between AKI and long-term renal function after radical nephrectomy has not been fully evaluated. In a retrospective study of 558 radical nephrectomy patients (median follow-up 35 months), Won Ho Kim et al. found that AKI occurred in 43.2% of patients and, more importantly, in 40.5% of patients with CKD3a. The incidence of new-onset CKD in patients with AKI was significantly higher at all postoperative follow-up time points. The incidence of CKD was significantly higher in patients with AKI than in patients without AKI at all postoperative follow-up time points. In conclusion, their analysis suggests a strong correlation between AKI after radical nephrectomy and long-term renal function deterioration.

Preservation of renal function improves prognosis and can be achieved through non-pharmacological strategies and CKD-targeted pharmacological interventions. Gout and asymptomatic hyperuricemia have been associated with several traditional cardiovascular risk factors in adults and pediatric patients with CKD. In vitro studies and animal models support the role of uric acid in mediating hemodynamic and tissue toxicity, leading to glomerular and tubular interstitial damage, respectively. However, the failure of two recent well-designed trials to show any benefit of allopurinol treatment on renal outcomes casts doubt on the expectation of renal protection with urate-lowering therapy. In addition, a trend toward increased mortality was observed in the interventional group. Russo et al. critically reviewed the results of all available randomized controlled trials that compared uric acid-lowering agents with a placebo or no study drug for at least 12 months. According to the authors, the analysis of the literature seems to leave open the possibility of demonstrating the beneficial effects of uric acid-reducing agents in future trials. Considering that uric acid-induced vascular and renal damage does not subside once established, patients and children with better preserved renal function may be better served by early treatment. Adequate, randomized, placebo-controlled trials and appropriate selection criteria are needed to determine whether specific patient populations may benefit from uricosuric agents.

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Early identification of risk factors for CKD and its progression is essential to prevent renal damage and adverse outcomes. Cheng-Sheng Yu et al. applied clustered heat maps and random forest methods in a retrospective cohort study to provide interactive visualization of patients with different CKD stages. They observed that body composition index (waist circumference) and some biochemical parameters (uric acid, blood urea nitrogen, serum glutamate transaminase, and glycated hemoglobin) were significantly associated with CKD. In their analysis, CKD was associated with obesity, hyperglycemia, and liver function. Interestingly, hypertension and glycosylated hemoglobin levels had similar patterns in the same cluster. Despite the limitations of the study (inherent in its retrospective, cross-sectional cohort approach), their data suggest that clustering heat maps may provide a novel predictive model for the high risk of rapid CKD progression.

The continued increase in the incidence of DKD is a major driver of the burden of CKD. DKD is the leading cause of morbidity and mortality in diabetes. Despite advances in diabetic nephroprotective therapy, DKD remains the most common complication driving the need for renal replacement therapy (RRT) globally, and its incidence is increasing. Until recently, prevention of DKD progression was based on strict control of blood pressure (BP), use of renin-angiotensin system blockers to reduce both BP and proteinuria, adequate glycemic control, and control of cardiovascular risk factors. Newer agents that alter intrarenal hemodynamics (e.g., renin-angiotensin-aldosterone pathway modulators and SGLT2 inhibitors) may protect the kidney from damage by lowering intra-glomerular pressure independently of BP and glycemic control, while other newer agents (e.g., mineralocorticoid receptor antagonists) may protect the kidney through their antifibrotic mechanisms in DKD. In this issue, Gorriz et al. review the potential of glucagon-like peptide-1 receptor agonists (GLP- 1RA) to adequately control blood glucose without increasing the risk of hypoglycemia in multiple stages of DKD; in addition, GLP-1RA may prevent the development of massive albuminuria and slow the decline in glomerular filtration rate (GFR) in diabetic patients, and also in weight loss, cardiovascular and other renal prognostic aspects provide additional benefits. Trials to assess the impact of GLP-1RA treatment on the primary renal endpoint of DKD is ongoing, and some of these trials will be available soon.

Cardiovascular [CV] disease is a major cause of morbidity and mortality in patients with CKD and hemodialysis [HD] [11] and is closely associated with atherosclerosis and vascular calcification [VC]. As renal function declines, the incidence of vascular calcification is higher in CKD patients, which leads to increased mortality. Serum calprotectin particles [CPPs] are colloidal nanoparticles that play an important role in the development and progression of VC. In this issue, Silaghi et al reviewed the usefulness of the T50 test, a new test that measures the conversion of primary to secondary CPPs, indicating trends in serum calcification, in the assessment of VC. They also provided a comprehensive review of the regulation of serum CPP levels and explored the impact of CPPs and calcification tendencies on the outcome. In addition, new topics are presented regarding the possible clinical application of T50 in the assessment of VC, especially in patients with CKD, including possible opportunities in the management of VC.

Hyperphosphatemia is a common complication of CKD. Even when severe hyperphosphatemia is clinically asymptomatic, it is associated with morbidity and poor prognosis. Hyperphosphatemia is an emerging cardiovascular risk factor in CKD and can lead to vascular calcification. However, the mechanism by which hyperphosphatemia is associated with CV complications is unclear. Abbasian et al. studied the effect of phosphate [Pi] on the procoagulant activity of endothelial microvesicles [MV] release in male sd rats with experimental CKD; randomized to high phosphorus (1.2%) and low phosphorus groups (0.2%); sham-operated controls received high phosphorus (1.2%). After 14 days, compared to sham controls High phosphorus CKD rats had elevated total plasma MVs, elevated expression of CD144 (a major component of endothelial adhesion junctions, expressed by endothelial cells during development), and enhanced procoagulant activity. The results observed by Abbasian et al. in a rat model suggest that hyperphosphatemia induces an increase in circulating procoagulant MVs, suggesting a link between elevated circulating phosphate and the risk of CKD thrombosis an important link exists.

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In both CKD and HD patients, volume and pressure overload eventually lead to LVH, which is an important predictor of increased CV events. Although many studies have used pre-HD blood pressure (BP) to determine optimal BP levels, the optimal timing and measurement techniques for BP in HD patients are not well established. In a prospective observational study, Hiroaki et al aimed to determine the ideal time and setting for BP measurement; they observed an association between increased CV events and LVMI and gt; 156 g/m2, by multiple regression analysis. In addition, they found that pre-HBP at the beginning of the week, post-HBP at the end of the week, and weekly mean blood pressure (WABP) were independently associated with LVMI in a univariate regression analysis at follow-up. The finding that multiple blood pressure measurements before, during, and after dialysis proved to be the most accurate form of assessment suggests that in this clinical setting, multiple blood pressure measurements should be performed and then averaged.

Hyperkalemia is a very common complication of CKD with a high emergency rate and high mortality rate in the emergency department. Hyperkalemia is common in patients with chronic heart failure (CHF), CKD stages 3-5, and diabetes mellitus. Among patients with CKD, those requiring dialysis are at particularly high risk for hyperkalemia. For a long time, the only therapeutic option to increase fecal potassium excretion was sodium polystyrene sulfonate, a cation exchange resin. In recent years, new agents capable of promoting gastrointestinal potassium elimination, namely Patromax and sodium zirconium cyclosilicate, have been developed and studied in large trials, demonstrating their efficacy and safety in different clinical situations. In this review, Esposito et al. [16] review the pathophysiology of hyperkalemia, highlighting the mechanism of action and clinical profile of Patromer and sodium zirconium cyclosilicate, suggesting that these new treatments may represent an opportunity to improve the management of acute and chronic hyperkalemia.

Assessing the cognitive, nutritional, and functional status of elderly CKD subjects is emerging as a new tool to stratify the risk of developing ESRD and death. In addition, prognostic assessment of elderly CKD patients is essential to determine the most appropriate clinical decision-making process for patients and their families. Multidimensional assessment (MPI) may be an important aspect in predicting short- and long-term all-cause mortality in older patients with CKD. In particular, MPI is more accurate in predicting mortality compared to eGFR alone in patients with CKD. In the present study, Lai et al. longitudinally investigated the correlation between hospitalization and mortality (at least 3 months) in patients with clinically stable CKD (n = 105) treated with MPI, conservative therapy (eGFR ≤ 60 mL/min, KDOQI stage 3 - 5) or renal replacement therapy (HD = 32 patients or PD = 36 patients). A total of 173 patients with a median age of 76 years were studied. The median duration of all hospitalizations was 6 days and the number of deaths was 33. MPI was significantly associated with the number of days and the number of hospitalizations per year. According to the results of the study, MPI correlated with the prognosis of patients with kidney disease, suggesting that a multidimensional assessment should be implemented in this clinical context.

Many important questions about the prevention and treatment of CKD are addressed in this volume. We thank the authors, a large number of investigators, and the MDPI staff for their leadership in producing this special issue. We hope readers will enjoy and benefit from the new insights.

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Cistanche extract is a natural supplement that has been used for centuries in traditional Chinese medicine to improve kidney health, among other benefits. Chronic kidney disease (CKD) is a progressive, irreversible disease that affects millions of people worldwide. Several studies have investigated the potential effectiveness of Cistanche extract in managing the symptoms and progression of chronic kidney disease.

Cistanche extract contains a variety of bioactive compounds, including echinocandins and acetonides, which have been shown to have antioxidant and anti-inflammatory properties. These properties may help protect the kidney from damage caused by oxidative stress and inflammation, which contribute to the development and progression of CKD.

A study conducted in rats with CKD found that treatment with Cistanche extract improved kidney function and reduced oxidative stress and inflammation. Another study in humans with early CKD found that treatment with Cistanche extract improved kidney function and reduced levels of inflammatory markers in the blood.

While these studies suggest that Cistanche extract may have potential benefits for patients with CKD, more studies are needed to confirm these findings and to determine the optimal dose and duration of treatment. In addition, it is important to note that Cistanche extract should not be used as a substitute for medical treatment or advice.

In conclusion, due to its antioxidant and anti-inflammatory properties, Cistanche extract may be potentially beneficial for patients with CKD. However, further studies are needed to confirm these findings and to determine their optimal application in the management of CKD.

References

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Giacomo Garibotto

Department of Internal Medicine, University of Genoa, 16128 Genova, Italy