Therapeutic Insights in Chronic Kidney Disease Progression

Abstract

Chronic kidney disease (CKD) has been recognized as a leading public health problem worldwide. Through its effect on cardiovascular risk and end-stage kidney disease, CKD directly affects the global burden of morbidity and mortality. Classical optimal management of CKD includes blood pressure control, treatment of albuminuria with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, avoidance of potential nephrotoxins and obesity, drug dosing adjustments, and cardiovascular risk reduction. Diabetes might account for more than half of CKD burden, and obesity is the most important prompted factor for this disease. New antihyperglycemic drugs, such as sodium-glucose-cotransporter 2 inhibitors have shown to slow the decline of GFR, bringing additional benefit in weight reduction, cardiovascular, and other kidney outcomes. On the other hand, a new generation of non-steroidal mineralocorticoid receptor antagonist has recently been developed to obtain a selective receptor inhibition reducing side effects like hyperkalemia and thereby making the drugs suitable for administration to CKD patients. Moreover, two new potassium-lowering therapies have shown to improve tolerance, allowing for higher dosage of renin-angiotensin system inhibitors and therefore enhancing their nephroprotective effect. Regardless of its cause, CKD is characterized by reduced renal regeneration capacity, microvascular damage, oxidative stress and inflammation, resulting in fibrosis and progressive, and irreversible nephron loss. Therefore, a holistic approach should be taken targeting the diverse processes and biological contexts that are associated with CKD progression. To date, therapeutic interventions when tubulointerstitial fibrosis is already established have proved to be insufficient, thus research effort should focus on unraveling early disease mechanisms. An array of novel therapeutic approaches targeting epigenetic regulators are now undergoing phase II or phase III trials and might provide a simultaneous regulatory activity that coordinately regulate different aspects of CKD progression.

Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease

“…Although there are tests to detect CKD, as mentioned above, there is a scarcity of biomarkers to diagnose this disease early and precisely and avoid its progression to ESKD and other complications [37,38]. Thus, some potential early biomarkers for CKD have been studied over the years, as reviewed by Shabaka, A., et al [37], such as Dickkopf-3 (DKK-3), a glycoprotein associated to the degree of tubulointerstitial fibrosis, of which high levels in the urine indicate an elevated risk for a reduction in eGFR within a year [39]. Neutrophil gelatinase-associated protein (NGAL) [40] is another example of a potential biomarker for CKD.…”

“…These and other possible biomarkers, however, do not represent increased advantages in CKD diagnosis when compared to the traditional markers analyzed. Therefore, the study of new molecules for diagnostic purposes is still necessary [37].…”

“…Regarding therapeutic approaches, there are non-pharmacological options for the treatment of CKD, such as weight reduction and blood pressure control. Still considering the study of Shabaka, A., et al [37], though, CKD is a complex disease, so the use of some drugs alongside non-pharmacological treatments is also important. Some examples of pharmacological treatment that can be used are sodium-glucose-cotransporter 2 inhibitors, such as empagliflozin-which induce both renal and extrarenal benefits for patients [37]-and renin-angiotensin-aldosterone system (RAAS) inhibitors, such as blockers for angiotensin II receptors and inhibitors for angiotensin-converting enzymes [37].…”

“…Still considering the study of Shabaka, A., et al [37], though, CKD is a complex disease, so the use of some drugs alongside non-pharmacological treatments is also important. Some examples of pharmacological treatment that can be used are sodium-glucose-cotransporter 2 inhibitors, such as empagliflozin-which induce both renal and extrarenal benefits for patients [37]-and renin-angiotensin-aldosterone system (RAAS) inhibitors, such as blockers for angiotensin II receptors and inhibitors for angiotensin-converting enzymes [37]. These are relevant therapeutic options, due to the fact that they are able to reduce the loss of eGFR, through the decline of intraglomerular pressure.…”

“…These are relevant therapeutic options, due to the fact that they are able to reduce the loss of eGFR, through the decline of intraglomerular pressure. Moreover, new drugs are under development, such as a mineralocorticoid receptor antagonist and potassium-lowering therapies [37]. Considering the complexity of CKD, however, the development of new therapeutic strategies is of pivotal importance.…”