Novel therapeutic approaches in chronic kidney disease and uremia management ,

Pharmacologic epigenetic modulators of alkaline phosphatase in chronic kidney disease Purpose of review In chronic kidney disease (CKD), disturbance of several metabolic regulatory mechanisms cause premature ageing, accelerated cardiovascular disease (CVD), and mortality. Single-target interventions have repeatedly failed to improve the prognosis for CKD patients. Epigenetic interventions have the potential to modulate several pathogenetic processes simultaneously. Alkaline phosphatase (ALP) is a robust predictor of CVD and all-cause mortality and implicated in pathogenic processes associated with CVD in CKD. Recent findings In experimental studies, epigenetic modulation of ALP by microRNAs or bromodomain and extraterminal (BET) protein inhibition has shown promising results for the treatment of CVD and other chronic metabolic diseases. The BET inhibitor apabetalone is currently being evaluated for cardiovascular risk reduction in a phase III clinical study in high-risk CVD patients, including patients with CKD (ClinicalTrials.gov Identifier: NCT02586155). Phase II studies demonstrate an ALP-lowering potential of apabetalone, which was associated with improved cardiovascular and renal outcomes. Summary ALP is a predictor of CVD and mortality in CKD. Epigenetic modulation of ALP has the potential to affect several pathogenetic processes in CKD and thereby improve cardiovascular outcome.

Plant-based diets for prevention and management of chronic kidney disease Purpose of review Plant-based diets have been used with growing popularity for the treatment of a wide range of lifestyle-related diseases, including diabetes, hypertension, and obesity. With the reinvigoration of the dietary management of chronic kidney disease (CKD) and the use of low protein diets for secondary prevention of CKD to delay or prevent dialysis therapy, there is an increasing interest in the potential role of plant-based diets for these patients. Recent findings Recently, a body of evidence related to the role of plant-based diets in preventing CKD has reemerged. Several observational studies have shown that red and processed meat have been associated with increased risk of CKD as well as faster progression in those with preexisting CKD. In several substitution analyses, replacement of one serving of red and/or processed meat has been linked with sizable reductions in CKD risk. Although limited, experimental trials for the treatment of metabolic acidosis in CKD with fruits and vegetables show outcomes comparable to oral bicarbonate. The use of plant-based diets in CKD may have other benefits in the areas of hypertension, weight, hyperphosphatemia, reductions in hyperfiltration, and, possibly, mortality. The risk of potassium overload from plant-based diets appears overstated, mostly opinion-based, and not supported by the evidence. Plant-based diets are generally well tolerated and provide adequate protein intake, including essential amino acids as long as the diet is correctly implemented. Summary Plant-based diets should be recommended for both primary and secondary prevention of CKD. Concerns of hyperkalemia and protein inadequacy related to plant-based diets may be outdated and unsupported by the current body of literature. Healthcare providers in general medicine and nephrology can consider plant-based diets as an important tool for prevention and management of CKD.

Fluid overload as a therapeutic target for the preservative management of chronic kidney disease Purpose of review There is growing clinical evidence of adverse effects of fluid overload on kidney outcomes in patients with cardiovascular disease who are not yet receiving kidney replacement therapy. In this review, we discuss the patient populations most at risk for fluid overload, the pathophysiology associated with fluid overload, and finally treatment options. Recent findings The severity of fluid overload is an independent risk factor for both an increased risk of rapidly declining kidney function and increased risk for the need of kidney replacement therapy. High venous pressure within the kidney secondarily causes a decrease in kidney perfusion, which in turn signals salt retention and the resulting increase in plasma volume completes a vicious cycle propagating ongoing kidney injury. Fluid overload has also been identified as a risk factor for the combined outcome of all-cause mortality and cardiovascular morbidity. This increased risk in some studies has been identified as more important than hypertension in predicting both the increased risk of kidney disease progression and morbidity and mortality from cardiovascular disease. Once fluid status is accurately assessed, a combination of salt restriction and effective diuretic therapy is the first-line therapy to manage this complication. In those patients who require additional therapy, use of a V2 receptor antagonists can be considered. Finally, some patients may benefit from peritoneal dialysis to bring about volume removal even if they do not yet require dialysis for uremic complications. Summary Excess fluid or fluid overload appears to enhance chronic kidney disease progression and its treatment and resolution is a potential disease-modifying intervention.

Potassium binding for conservative and preservative management of chronic kidney disease Purpose of review Hyperkalemia is a life-threatening complication of chronic kidney disease (CKD). Risk factors include advanced kidney impairment, diabetes, hypertension, heart failure, and consumption of a K+-enriched diet. High-K+ diets provide health benefits to include reductions in blood pressure, stroke risk, and osteoporosis. Individuals at the highest risk for developing hyperkalemia are those who would benefit most from high K+ diets. Inhibitors of the renin--angiotensin--aldosterone system (RAASi) are effective in reducing cardiovascular events and slowing the progression of CKD, yet hyperkalemia is a risk factor. Discussed are new strategies facilitating use of both high-K+ diets and pharmacology to preserve kidney function and reduce cardiovascular events. Recent findings Sodium zirconium cyclosilicate and patiromer are new K+-binding drugs approved for the treatment of hyperkalemia. Both are efficacious in the short-term and long-term treatment of hyperkalemia. These binders are effective in treating hyperkalemia while facilitating RAASi therapy. Summary Hyperkalemia is a life-threatening condition. New K+-binding drugs allow for optimal use of pharmacological therapy, such as RAASi, enhancing their cardiorenal protection. Health benefits from consumption of high K+ foods may also be enhanced by use of these binders. In conclusion, there are new well tolerated and effective K+-binding agents for acutely and chronically managing hyperkalemia.

Novel dietary and pharmacologic approaches for acid–base modulation to preserve kidney function and manage uremia Purpose of review We review mechanisms for chronic kidney disease (CKD) progression that might be addressed with nonpharmacologic and novel pharmacologic interventions as strategies by which to slow or even prevent CKD progression. Recent findings Evolving data support the contribution of the broad spectrum of disorders of acid (H+) accumulation, which we refer to as ‘H+ stress’, to CKD progression. Recent studies support that amelioration of H+ stress, including spectra of H+ accumulation that are insufficient to cause metabolic acidosis, is kidney-protective. In addition, gut-derived toxins appear to contribute to CKD progression and to the well described increased cardiovascular disease (CVD) risk in patients with CKD. Dietary and novel pharmacologic interventions hold promise as strategies to slow CKD progression through reducing levels of these gut-derived toxins. In addition, oxidative stress appears to mediate CKD progression and contributing factors like diet and cigarette smoking can exacerbate oxidative stress. Dietary changes and smoking cessation hold promise to favorably affect CKD progression by reducing kidney oxidative stress. Summary The urgent need to add to the traditional armamentarium of blood pressure control and antiangiotensin II pharmacologic therapy for kidney protection has led to investigations into additional kidney-protective strategies. Acid stress, a disordered gut microbiome, and oxidative stress each appear to contribute to CKD progression and can be potentially addressed by nonpharmacologic and novel pharmacologic interventions.

Microbiome modulation to correct uremic toxins and to preserve kidney functions Purpose of review The association between dysbiosis and CKD is well established. This review focuses on the current understanding of microbiome, in normal individuals and CKD patients, in order to hypothesize how to correct uremic toxins levels and preserve the renal function and reduce associated comorbidities. Here we discuss our current opinion on microbiome modulation in order to manage the CKD-associated dysbiosis. Recent findings Emerging evidence confirms the role of gut microbiome in the progression of CKD. In this scenario, the need is felt to set up multifaceted approaches for dysbiosis management. Among many strategies able to improve gut wellness, a crucial approach is represented by the functional nutrition. At the same time, drug-based treatments show significant results in microbiome modulation. Furthermore, we examine here the potentialities of fecal microbiome transplantation (FMT) in CKD, an approach currently applied in Clostridium difficile infection. Summary The gut microbiome plays a pivotal role in the pathophysiology of CKD. The vicious cycle triggered by kidney function decline leads to gut dysbiosis. Considering the gut microbiome as a therapeutic target in CKD, multiple approaches aimed at its modulation should be envisioned to preserve kidney function. Dietary interventions and pharmacological strategies are able to improve microbiome dysbiosis, oxidative stress and fibrosis. Additionally, FMT could represent a promising novel therapy in the management of CKD-associated dysbiosis.

Perspiration interventions for conservative management of kidney disease and uremia Purpose of review There has been an increasing interest in developing novel technologies to treat patients with chronic kidney disease as evidenced by KidneyX, the public–private partnership between government and industry. Perhaps a simple technology for treating kidney failure would be to utilize perspiration. It is a physiological process, and when used properly it might not be an unpleasant experience. This review will explore the current state of knowledge regarding perspiration therapy in the setting of far advanced kidney failure. Recent findings A literature review using the PubMed database was conducted between 1 April 2019 and 3 September 2019. Search terms are shown in Table 1. Major themes of the results include diaphoresis therapy for patients with chronic kidney disease, excessive perspiration causing kidney disease, analysis of sweat to diagnose cystic fibrosis, and analysis of sweat to replenish lost electrolytes. This review will focus on intentional perspiration for the treatment of patients with end-stage renal disease (ESRD). Studies have shown that perspiration, or sweat-based therapies, can provide some of the most important currently recognized therapeutic goals in treating ESRD. These goals include decreased interdialytic weight gain, reduced serum potassium levels, and benefits to cardiovascular status. Research has shed light on some of the mechanisms, both molecular and clinical, that may be involved in induced perspiration therapy in ESRD. Summary There is a long history of humans using perspiration for both recreation and therapy. Perspiration therapy for ESRD experienced a surge in the United States in the 1960s but does not have much modern momentum. With the continued growth of the ESRD population worldwide this could be considered an appropriate time to conduct more research into this promising therapy.

Intestinal dialysis for conservative management of Uremia Purpose of review Renal replacement therapies, such as hemodialysis are invasive and impose significant financial burden as well as burden on quality of life. Conservative and ‘gentler’ forms of renal replacement therapy for the frail and palliative care patient is an unmet medical need. Recent findings The treatment of uremia using the gut as a substitute for the kidney has been proposed but is not practiced widely because of proven lack of long-term mortality benefit coupled with complications like edema and hyperchloremia. Mounting evidence showed that endotoxins from gastrointestinal tract are a major source of chronic inflammation in chronic kidney disease (CKD). The high load of nitrogenous waste elimination through the bowel could potentially serve as an alternative modality to remove uremic wastes especially in people who opt for conservative management for end-stage renal disease with some recent studies in Iran and China showing promising benefits in uremia. Summary In this review, we will discuss the history, recent evidence and potential of these therapies and their implications in CKD for conservative and easy management of uremia.