Hyperphosphatemia in Chronic Kidney Disease: The Search for New Treatment Paradigms and the Role of Tenapanor.

Hyperphosphataemia represents a significant challenge in the management of chronic kidney disease, exerting a pronounced influence on the pathogenesis of cardiovascular complications and mineral bone disorders. Traditional approaches to address hyperphosphataemia involve implementing dietary phosphate restrictions, administering phosphate binders, and, in cases of end-stage renal disease, resorting to dialysis. Unfortunately, these interventions frequently prove inadequate in maintaining phosphate levels within recommended ranges. Additionally, commonly employed pharmacological agents are not immune to eliciting adverse events, thereby limiting their prescription and therapeutic adherence. There is a growing focus on exploring novel therapeutic strategies in this context. The current discussion centres on tenapanor, a pharmacological agent predominantly acting as a selective inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3). Its mechanism of action involves modulating tight junctions, resulting in reduced sodium absorption and intestinal paracellular permeability to phosphate. Furthermore, tenapanor downregulates sodium-dependent phosphate 2b transport protein (NaPi2b) expression, thereby impeding active transcellular phosphate transport. Clinical trials have elucidated the efficacy and safety profile of tenapanor. This evidence hints at a potential paradigm shift in the management of hyperphosphataemia. However, the burgeoning optimism surrounding tenapanor warrants tempered enthusiasm, as further research remains indispensable. The imperative lies in meticulously delineating its efficacy and safety contours within the crucible of clinical practice. In this review, we synthesize the intricate interplay between hyperphosphataemia and Chronic Kidney Disease-Mineral Bone Disorder, and we discuss the existing pharmacological interventions for hyperphosphataemia and explore emerging treatment paradigms that offer novel perspectives in managing elevated phosphate levels in CKD patients.

Investigational new drugs for the treatment of chronic renal failure: an overview of the literature.

INTRODUCTION: Chronic kidney disease (CKD) is widespread throughout the world, with a high social and health impact. It is considered a 'silent killer' for its sudden onset without symptoms in the early stages of the disease. The main goal of nephrologists is to slow the progression of kidney disease and treat the associated symptoms with a range of new medications. AREAS COVERED: The aim of this systematic review is to analyze the new investigational drugs for the treatment of chronic renal failure. Data were obtained from the available scientific literature and from the ClinicalTrials.gov website. EXPERT OPINION: Among the drugs currently being researched, SGLT2 inhibitors appear to be the most promising drugs for the treatment of CKD, has they have slower progression of CKD and protection of cardiorenal function. An important role in the future of CKD treatment is played by autologous cell-therapy, which appears to be a new frontier in the treatment of CKD. Other therapeutic strategies are currently being investigated and have been shown to slow the progression of CKD. However, further studies are needed to determine whether these approaches may offer benefits in slowing the progression of CKD in the near future.

Review and Practical Excursus of the Propensity Score: Low Protein Diet Compared to Mediterranean Diet in Patients With Chronic Kidney Disease.

Although Randomized clinical trials (RCT) represent the gold standard to compare two or more treatments, the impact of observational studies cannot be ignored. Obviously, these latter are performed on unbalanced sample, and differences among the compared groups could be detected. These differences could have an impact on the estimated association between our allocation and our outcome. To avoid it, some methods should be applied in the analysis of observational cohort. Propensity score (PS) can be considered as a value which sums up and balances the known variables. It aims to adjust or balance the probability of receiving a specific allocation group, and could be used to match, stratify, weight, and perform a covariate adjustment. PS is calculated with a logistic regression, using allocation groups as the outcome. Thanks to PS, we compute the probability of being allocated to one group and we can match patients obtaining two balanced groups. It avoids computing analysis in unbalanced groups. We compared low protein diet (LPD) and the Mediterranean diet in CKD patients and analysed them using the PS methods. Nutritional therapy is fundamental for the prevention, progression and treatment of Chronic Kidney Disease (CKD) and its complications. An individualized, stepwise approach is essential to guarantee high adherence to nutritional patterns and to reach therapeutic goals. The best dietary regimen is still a matter of discussion. In our example, unbalanced analysis showed a significant renal function preservation in LPD, but this correlation was denied after the PS analysis. In conclusion, although unmatched analysis showed differences between the two diets, after propensity analysis no differences were detected. If RCT cannot be performed, balancing the PS score allows to balance the sample and avoids biased results.

Autoimmunity and Infection in Glomerular Disease.

The ongoing glomerular damage of infections is not limited to the most widely known form of post-streptococcal glomerulonephritis, which is today less common in the Western world; other forms of glomerulonephritis are associated with several bacterial, viral and parasitic pathogens. The mechanisms responsible range from the direct damage of glomerular cells to the formation and deposition of immunocomplexes to molecular mimicry to the secretion of superantigens. Similarly, in the course of glomerular disease, infections are more frequent than in the general population due to the loss of immunoglobulins in urine and the immunosuppressive agents used to treat the autoimmune disease that decrease the activity of the immune system. Recognizing this two-way link, understanding its pathogenetic mechanism, and identifying the most appropriate therapeutic choice are essential for the personalized management of patients. In this continuously developing field, this short review summarizes the current state of the art as support for physicians, who are increasingly involved in managing patients with glomerular disease and infections.

Progress in pharmacotherapy for the treatment of hyperphosphatemia in renal failure.

INTRODUCTION: Among the clinical and metabolic complications of progressive chronic kidney disease (CKD), CKD-mineral bone disorder (CKD-MBD) significantly contributes to morbidity and mortality. While overt and persistent hyperphosphatemia is typical of advanced CKD and requires treatment, other abnormalities of calcium/phosphate metabolism begin to occur since the early stages of the disease. AREAS COVERED: We searched on the PubMed database, without restrictions for language or time range, for randomized clinical trials and meta-analyses investigating phosphate-lowering therapies. The various phosphate binders show different safety profiles and diverse effects on calcium/phosphate metabolism and vascular calcification. The in-depth knowledge of the characteristics of these drugs is crucial to ensure adequate treatment to CKD patients. EXPERT OPINION: A proper control of serum phosphate can be achieved using phosphate binders. These medications may induce side effects. Moreover, data on their impact on clinical outcomes are partly controversial or scarce, especially for the new generation drugs. Hyperphosphatemia favors cardiovascular disease and increases the risk for CKD progression. These effects are partially mediated by fibroblast growth factor 23 (FGF23), a phosphaturic hormone that raises to maintain normal serum phosphate. Since there are no data supporting the use of phosphate-lowering agents when phosphataemia is normal, a key role is played by reducing dietary phosphate intake with the aim to control serum phosphate and the compensatory FGF23 and parathyroid hormone (PTH) increase.

PLAIN LANGUAGE SUMMARY: The progressive reduction in renal function, a condition known as chronic kidney disease (CKD), is characterized by several clinical and metabolic complications. Among them are the alterations of calcium and phosphorous metabolism that are part of the so-called CKD-MBD (chronic kidney disease-mineral bone disorder) and contribute to increase morbidity and mortality, especially due to vascular calcification. Persistent hyperphosphatemia is typical of advanced CKD but other abnormalities occur earlier to maintain normal serum calcium and phosphorus levels. These compensatory mechanisms are also involved in the pathophysiology of CKD-MBD and should be counteracted to improve clinical outcomes of CKD patients. Given the crucial role of hyperphosphatemia, numerous therapeutic strategies have been developed over time to help maintain phosphate serum levels within the normal range and prevent or treat CKD-MBD and its consequences. Phosphate binders act by binding dietary phosphate in the gastrointestinal lumen to prevent its absorption. According to their molecular structure, these drugs can be classified into calcium-based (calcium carbonate, calcium acetate), non-calcium-containing (sevelamer carbonate, sevelamer hydrochloride, lanthanum carbonate), aluminum-containing (aluminum hydroxide), and iron-based (sucroferric oxyhydroxide, ferric citrate) compounds. The various phosphate binders show different safety profiles and diverse effects on calcium/phosphate metabolism and vascular calcification. Despite the ability of hyperphosphatemia to favor CKD-MBD development and cardiovascular risk, there are no data supporting the use of phosphate-lowering agents when serum phosphate is normal also due to the potential adverse effects of long-term therapies. Accordingly, a key role is played by reducing dietary phosphate overload since the first stages of CKD.

Phosphate Control in Peritoneal Dialysis Patients: Issues, Solutions, and Open Questions.

Hyperphosphatemia is a common complication in advanced chronic kidney disease and contributes to cardiovascular morbidity and mortality. The present narrative review focuses on the management of phosphatemia in uremic patients receiving peritoneal dialysis. These patients frequently develop hyperphosphatemia since phosphate anion behaves as a middle-size molecule despite its low molecular weight. Accordingly, patient transporter characteristics and peritoneal dialysis modalities and prescriptions remarkably influence serum phosphate control. Given that phosphate peritoneal removal is often insufficient, especially in lower transporters, patients are often prescribed phosphate binders whose use in peritoneal dialysis is primarily based on clinical trials conducted in hemodialysis because very few studies have been performed solely in peritoneal dialysis populations. A crucial role in phosphate control among peritoneal dialysis patients is played by diet, which must help in reducing phosphorous intake while preventing malnutrition. Moreover, residual renal function, which is preserved in most peritoneal dialysis patients, significantly contributes to maintaining phosphate balance. The inadequate serum phosphate control observed in many patients on peritoneal dialysis highlights the need for large and well-designed clinical trials including exclusively peritoneal dialysis patients to evaluate the effects of a multiple therapeutic approach on serum phosphate control and on hard clinical outcomes in this high-risk population.

Immune Checkpoint Inhibitors and the Kidney: A Focus on Diagnosis and Management for Personalised Medicine.

Immunity plays a crucial role in fighting cancer, but tumours can evade the immune system and proliferate and metastasize. Enhancing immune responses is a new challenge in anticancer therapies. In this context, efficacy data are accumulating on immune checkpoint inhibitors and adjuvant therapies for various types of advanced-stage solid tumours. Unfortunately, immune-related adverse events are common. Although infrequent, renal toxicity may occur via several mechanisms and may require temporary or permanent drug suspension, renal biopsy, and/or immunosuppressive treatment. This short review aims to provide a practical approach to the multidisciplinary management of cancer patients with renal toxicity during treatment with immune checkpoint inhibitors.

Comparison between Creatinine Clearance and eGFRcyst-crea: a real-life experience.

Introduction: The evaluation of renal function is computed using the estimated glomerular filtration rate methods or the measured glomerular filtration rate. Cystatin C has been well studied as marker of renal function compared to serum creatinine, but only few studies compare Glomerular Filtration Rates estimated including both creatinine and cystatin (eGFRcyst-crea) to creatinine clearance (CrCl). This cross-sectional study compares CrCl and eGFRcyst-crea with eGFRcrea and searches for correlation with comorbidities. Methods: This cross-sectional study consists of 78 patients hospitalized for acute and/or chronic renal disease. We performed the concordance correlation coefficient analysis between the eGFRcrea and the CrCl and eGFRcyst-crea in the whole sample and in the various subgroups. Results: Steiger's comparison of correlations from dependent samples showed a correlation coefficient between C-reactive protein and eGFRcyst-crea stronger than between C-reactive protein and CrCl (Z: 2.51, p=0.012). Similar results were showed with the association with procalcitonin (Z: 5.24, p<0.001), serum potassium (Z: -3.13, p=0.002), and severe CKD (Z: -2.54, p=0.011). The concordance correlation coefficient test showed major differences between diagnostic methods compared to eGFR-crea in diabetic subgroup, severe CKD, and in procalcitonin higher than 0.5ng/ml. Discussion: The demonstration of a strong concordance between the eGFRcrea and the eGFRcyst-crea allows us to diagnose and to stage CKD better than creatinine clearance in patients with high inflammatory status. Furthermore, this information opens new research scenarios, and further, larger studies are needed to confirm these hypotheses.

Gender differences in new hypoglycemic drug effects on renal outcomes: a systematic review.

INTRODUCTION: Lifetime diabetes risk is greater in women than in men. Women with diabetes mellitus (DM) have a greater prevalence of diabetic kidney disease (DKD) risk factors. The diagnosis of DM is often delayed in women, with poorer outcomes and with expected therapeutic goals missed. AREA COVERED: A systematic literature review following PRISMA guidelines was conducted in the PubMed gateway of the MEDLINE database and Clinicaltrials.gov. The purpose of our research was to establish the sex differences on renal outcomes in users of the new hypoglycemic drugs: sodium-glucose transport protein 2 inhibitors (SGLT-2i), dipeptidyl peptidase-IV Inhibitors (DPP-IVi) and glucagon-like peptide-1 inhibitors (GLP-1i). EXPERT OPINION: New hypoglycemic drugs represent promising tools in the treatment and prevention of severe complications of diabetes, cardiovascular diseases and chronic kidney disease. Even if renal outcomes are investigated in both randomized controlled trials and cardiovascular outcome trials, gender-based analysis is not always performed. Our systematic review demonstrated that the gap among sexes in DKD can be partially filled using new hypoglycemic drugs. Sexual dimorphism analysis could represent a keystone for the development of adequate gender-specific therapies.

Indole-3-acetic acid correlates with monocyte-to-high-density lipoprotein (HDL) ratio (MHR) in chronic kidney disease patients.

PURPOSE: Indole-3-acetic acid is a protein-bound indolic uremic toxin deriving from tryptophan metabolism. Increased levels are associated with higher thrombotic risk and both cardiovascular and all-cause mortality. An emerging biomarker of cardiovascular disease is the monocyte-to-high-density lipoprotein ratio (MHR). The main purpose of this study was to investigate the association of indole-3-acetic acid with MHR and other markers of cardiovascular risk in patients with chronic kidney disease (CKD). METHODS: We enrolled 61 non-dialysis CKD patients and 6 dialysis patients. Indole-3-acetic acid levels were measured with ELISA technique. RESULTS: In the whole cohort of 67 patients, indole-3-acetic acid was directly related to Ca × P (ρ = 0.256; P = 0.0365) and MHR (ρ = 0.321; P = 0.0082). In the 40 patients with previous cardiovascular events, indole-3-acetic acid correlated with uric acid (r = 0.3952; P = 0.0116) and MHR (ρ = 0.380; P = 0.0157). MHR was related with fibrinogen (ρ = 0.426; P = 0.0010), arterial hypertension (ρ = 0.274; P = 0.0251), C-reactive protein (ρ = 0.332; P = 0.0061), gender (ρ = - 0.375; P = 0.0017; 0 = male, 1 = female), and CKD stage (ρ = 0.260; P = 0.0337). A multiple regression analysis suggested that indole-3-acetic acid might be an independent predictor of MHR. CONCLUSION: This study shows a significant association between indole-3-acetic acid and MHR. Prospective studies are required to evaluate if decreasing indole-3-acetic acid concentrations may reduce MHR levels and cardiovascular events and improve clinical outcomes.

Correlation between Hyperkalemia and the Duration of Several Hospitalizations in Patients with Chronic Kidney Disease.

(1) Background: This observational study aimed to verify the association between serum potassium levels and hospitalization days in patients with chronic kidney disease in a follow up of nine months. (2) Methods: Patients with chronic kidney disease were divided into group A (180 patients, potassium ≤ 5.1 mEq/L) and B (90 patients, potassium > 5.1 mEq/L). Student's t-test, Mann-Whitney test, Pearson's Chi-Square test, Pearson/Spearman's correlation test and linear regression test were performed in the entire sample and in stage-G4/5 subsample. (3) Results: Groups A and B differed for estimated glomerular filtration rate (eGFR) (34.89 (IQR, 16.24-57.98) vs. 19.8 (IQR, 10.50-32.50) mL/min/1.73 m2; p < 0.0001), hemoglobin (11.64 ± 2.20 vs. 10.97 ± 2.19 g/dL, p = 0.048), sum of hospitalization days (8 (IQR, 6-10) vs. 11 (IQR, 7-15) days; p < 0.0001) and use of angiotensin II receptor blockers (40.2% vs. 53.3%; p = 0.010). Considering patients with eGFR 6-30 mL/min/1.73 m2, differences in the sum of hospitalization days were confirmed. Multivariable regression analysis showed that hyperkalemia is an independent risk factor of increased hospital length. In stage G4-G5, regression analysis showed that hyperkalemia is the only independent risk factor (ß = 2.93, 95% confidence interval, 0.077-5.794, p = 0.044). (4) Conclusions: We observed significantly greater odds of increased length of hospital stay among patients with higher potassium, mostly in stages G4-G5 chronic kidney disease.

Monocyte to HDL ratio: a novel marker of resistant hypertension in CKD patients.

BACKGROUND: Inflammation, oxidative stress (OS), atherosclerosis and resistant hypertension (RH) are common features of chronic kidney disease (CKD) leading to a higher risk of death from cardiovascular disease. These effects seem to be modulated by impaired anti-oxidant, anti-inflammatory and reverse cholesterol transport actions of high-density lipoprotein cholesterol (HDL). HDL prevents and reverses monocyte recruitment and activation into the arterial wall and impairs endothelial adhesion molecule expression. Recently, monocyte count to HDL-cholesterol ratio (MHR) has emerged as a potential marker of inflammation and OS, demonstrating to be relevant in CKD. Our research was aimed to assess, for the first time, its reliability in RH. METHODS: We performed a retrospective study on 214 patients with CKD and arterial hypertension who were admitted between January and June 2019 to our Department, 72 of whom were diagnosed with RH. RESULTS: MHR appeared inversely related to eGFR (ρ = - 0.163; P = 0.0172). MHR was significantly higher among RH patients compared to non-RH ones (12.39 [IQR 10.67-16.05] versus 7.30 [5.49-9.06]; P < 0.0001). Moreover, MHR was significantly different according to the number of anti-hypertensive drugs per patient in the whole study cohort (F = 46.723; P < 0.001) as well as in the non-RH group (F = 14.191; P < 0.001). Moreover, MHR positively correlates with diabetes mellitus (ρ = 0.253; P = 0.0002), white blood cells (ρ = 0.664; P < 0.0001) and C-reactive protein (ρ = 0.563; P < 0.0001). CONCLUSIONS: MHR may be a reliable biomarker due to the connection between HDL and monocytes. Our study suggests that MHR is linked with the use of multiple anti-hypertensive therapy and resistant hypertension in CKD patients, and can be a useful ratio to implement appropriate treatment strategies.

Commonly used immunosuppressive drugs for kidney diseases and pregnancy: focus on open questions.

Pregnancy is still a challenge in women with autoimmune diseases or kidney transplantation. In this context, management of the immunosuppressive therapy is critical, but, in spite of more than 60 years of experience, many issues remain open, also because of the difficulty in disentangling, in complex patients, the effect of the disease and of the frequent multiple treatments. For this purpose, we have tried to synthesize the existing knowledge and the unresolved issues, to support counseling and promote patient empowerment.

Kidney Biopsy in Type 2 Diabetic Patients: Critical Reflections on Present Indications and Diagnostic Alternatives.

Roughly 3% of patients worldwide with a new diagnosis of type 2 diabetes mellitus (T2DM) already have an overt nephropathy at diagnosis and about 20-30% of the remaining ones develop a complication of this kind later in life. The early identification of kidney disease in diabetic patients is important as it slows its progression, which is important not only because this reduces the need for renal replacement therapy, but also because it decreases the high rate of mortality and morbidity associated with a reduction in kidney function. The increasing prevalence of type 2 diabetes and the consequent greater probability of finding different types of kidney diseases in diabetic patients frequently gives rise to overlapping diagnoses, a definition encompassing the differential diagnosis between diabetic and non-diabetic kidney disease. The issue is made more complex by the acknowledgement of the increasing frequency of presentations of what is termed "diabetic kidney disease" without relevant proteinuria, in particular in T2DM patients. Distinguishing between diabetes related and non-diabetes related forms of kidney disease in diabetic patients is not only a semantic question, as different diseases require different clinical management. However, while the urologic and macrovascular complications of diabetes, as well as overlapping parenchymal damage, can be diagnosed by means of imaging studies, often only a kidney biopsy will make a differential diagnosis possible. In fact, the coexistence of typical diabetic lesions, such as nodular glomerulopathy or glomerulosclerosis, with different glomerular, vascular and tubulo-interstitial alterations has been extensively described, and an analysis of the dominant histological pattern can contribute to determining what therapeutic approach should be adopted. However, due to the high frequency of kidney diseases, and to the fact that T2DM patients are often affected by multiple comorbidities, a kidney biopsy is not generally performed in T2DM patients. What follows is a review aiming to discuss the diagnostic work-up, on the base of clinical, laboratory and imaging criteria, and evaluate the present indications and alternatives to renal biopsy.

Maternal peripheral blood CD34+ cells for prediction of fetal kidney malformations: results from a case-control analysis.

PURPOSE: To evaluate the relation between CD34+ cells count in maternal blood and potential development of fetal congenital renal abnormalities. MATERIALS AND METHODS: We enrolled 16 women that gave birth to newborns carrying congenital renal malformations over a 3-year period and 48 women with uncomplicated pregnancies (controls) in a 1:3 ratio (three controls per case). RESULTS: CD34+ cells in the maternal peripheral blood were significantly lower in the group of women who gave birth to newborns carrying congenital renal malformations compared to the controls (p < .0001). CONCLUSIONS: CD34+ cells in maternal blood could be validated as a potential marker to predict the development of possible kidney malformations.

Maternal and Fetal Outcomes of Pregnancy in Nephrotic Syndrome Due to Primary Glomerulonephritis.

Chronic kidney disease (CKD) affects 3% of pregnancies, impacting on maternal and fetal outcomes, and at the same time, a recurrent question in nephrology regards gestation impact on kidney function. Observational studies stated that CKD stage, pre-existent hypertension, and proteinuria are the main predictors of possible complications, such as maternal CKD progression, maternal or fetal death, prematurity, small for gestational age (SGA) newborn, or admission to the neonatal intensive care unit. In this regard, given the prominence of proteinuria among other risk factors, we focused on primary nephrotic syndrome in pregnancy, which accounts for 0.028% of cases, and its impact on materno-fetal outcomes and kidney survival. Data extracted from literature are scattered because of the small cohorts investigated in each trial. However, they showed different outcomes for each glomerular disease, with membranous nephropathy (MN) having a better maternal and fetal prognosis than focal and segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), or minimal change disease (MCD). Nephrotic syndrome does not have to discourage women to undertake a pregnancy, but the correct management may include a specific evaluation of risk factors and follow-up for adverse materno-fetal events and/or maternal kidney disease progression.

Clinical Evaluation of the Safety, Efficacy and Tolerability of Lanthanum Carbonate in the Management of Hyperphosphatemia in Patients with End-Stage Renal Disease.

Patients with progressive chronic kidney disease (CKD) commonly develop mineral and bone abnormalities and extraskeletal calcifications with following increased cardiovascular risk. A key pathophysiological role is played by hyperphosphatemia. Since diet and dialysis are often insufficient to control serum phosphorus levels, many patients require treatment with phosphate binders. Among them is lanthanum carbonate, an aluminum-free non-calcium-based compound. The present review summarizes the most recent literature data concerning the safety, efficacy and tolerability of lanthanum carbonate in patients with end-stage renal disease and hyperphosphatemia. The drug is taken orally as chewable tablets or powder with only minimal gastrointestinal absorption and resulting reduced risk of tissue deposition and systemic drug interactions. The dissociation of the drug in the acid environment of the upper gastrointestinal tract induces the release of lanthanum ions, which bind to dietary phosphate forming insoluble complexes then excreted in the feces. Even though there is no clear evidence that lowering serum phosphorus levels can improve patient-centered outcomes, a mortality benefit with all phosphate binders, especially non-calcium containing ones, is not excluded. Lanthanum carbonate has been suggested to decrease all-cause mortality but not cardiovascular event rate compared to other phosphate binders. It induces a lower suppression of bone turnover than calcium carbonate and calcium acetate and may improve systolic function and cardiac dimension compared to calcium carbonate. Moreover, the use of lanthanum carbonate has been associated with better nutritional status compared to other phosphate binders, lower risk for hypercalcemia than calcium-containing binders, and amelioration of mild metabolic acidosis contrary to sevelamer hydrochloride. Main adverse effects include nausea, alkaline gastric reflux, gastric deposition of lanthanum, gastrointestinal obstruction, subileus, ileus, perforation, fecal impaction, and reduction of gastrointestinal absorption of some drugs including statins, angiotensin-converting enzyme inhibitors and some antibiotics such as fluoroquinolones or tetracyclines.

Antiproteinuric effect of DPP-IV inhibitors in diabetic and non-diabetic kidney diseases.

Diabetes Mellitus (DM) is a chronic and severe metabolic disease, characterized by chronic hyperglycemia due to insulin resistance and/or reduced insulin secretion. Concerning the non-insulin glucose-lowering therapy for diabetes, Dipeptidyl-peptidase-4 (DPP-4) inhibitors, members of the incretin family, represent new agents, capable of a glycemic control improvement with an advantageous safety profile, given the absence of weight gain, the low incidence of hypoglycemia and the good renal tolerance in patients suffering from chronic renal failure. In addition to demonstrating efficacy in glycemic control through inhibition of GLP-1 degradation, DPP-4 inhibitors (DPP-4is) seem to demonstrate pleiotropic effects, which also make them interesting in both diabetic and non-diabetic nephropathies, especially for their capacity of reducing proteinuria. Several studies about diabetic nephropathy on patients' cohorts and murine models have demonstrated a solid direct relationship between DPP-4 activity and urinary albumin excretion (UAE), thus confirming the capacity of DPP-4is to reduce proteinuria; the mechanism responsible for that effect was studied to assess if it was the result of a direct action on renal impairment or a secondary consequence of the better glycemic control related to these agents. As a result of these more in-depth studies, DPP-4is have demonstrated an improvement of renal inflammation markers and consequent proteinuria reduction, regardless of glucose concentrations. Considering the nephroprotective effects of DPP-4is might be glycemic independent, several studies were conducted to prove the validity of the same effects in non-diabetic nephropathies. Among these studies, DPP-4is demonstrated an improvement of various renal inflammatory markers on several models of non-diabetes dependent renal impairment, confirming their capacity to reduce proteinuria, independently from the action on glucose metabolism. The objective of this review is to present and discuss the so far demonstrated antiproteinuric effect of DPP-4is and their effects on diabetic and non-diabetic nephropathies.

Complement Inhibition Therapy and Dialytic Strategies in Paroxysmal Nocturnal Hemoglobinuria: The Nephrologist's Opinion.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease that presents an estimated incidence of 1.3 cases per million per year, with a prevalence of 15.9 cases per million. It is characterized by hemolysis, bone marrow dysfunction with peripheral blood cytopenia, hypercoagulability, thrombosis, renal impairment and arterial and pulmonary hypertension. Hemolysis and subsequent hemosiderin accumulation in tubular epithelium cells induce tubular atrophy and interstitial fibrosis. The origin of PNH is the somatic mutation in the X-linked phosphatidylinositol glycan class A (PIG-A) gene located on Xp22: this condition leads to the production of clonal blood cells with a deficiency in those surface proteins that protect against the lytic action of the activated complement system. Despite the increased knowledge of this syndrome, therapies for PNH were still only experimental and symptomatic, until the introduction of the C5 complement blockade agent Eculizumab. A second generation of anti-complement agents is currently under investigation, representing future promising therapeutic strategies for patients affected by PNH. In the case of chronic hemolysis and renal iron deposition, a multidisciplinary approach should be considered to avoid or treat acute tubular injury or acute kidney injury (AKI). New promising perspectives derive from complement inhibitors and iron chelators, as well as more invasive treatments such as immunoadsorption or the use of dedicated hemodialysis filters in the presence of AKI.

RAS inhibition modulates kynurenine levels in a CKD population with and without type 2 diabetes mellitus.

Kynurenine pathway of tryptophan metabolism is involved in the pathophysiology of chronic kidney disease (CKD) and diabetes mellitus, mainly through the inflammation-induced activity of indoleamine 2,3-dioxygenase (IDO), and few studies have investigated its potential link with proteinuria. Renin-angiotensin system inhibitors (RASis) are recommended in these patients to decrease proteinuria, slow CKD progression and reduce cardiovascular risk, but whether these drugs influence kynurenine levels in humans is unknown. We evaluated serum tryptophan and kynurenine in patients suffering from CKD with or without type 2 diabetes mellitus, their correlations with markers of reduced kidney function, and their relationship with RAS-inhibiting therapy. Of 72 adult patients enrolled, 55 were receiving RASis, whereas 17 were not. Tryptophan was assessed by HPLC (high-performance liquid chromatography); kynurenine was measured using an enzyme-linked immunosorbent assay kit; IDO activity (%) was calculated with the formula (kynurenine/tryptophan) × 100. Kynurenine levels were significantly lower in the group under RASis compared to the untreated group (1.56 ± 0.79 vs 2.16 ± 1.51 µmol/l; P = 0.0378). In patients not receiving RASis, kynurenine was inversely related to estimated glomerular filtration rate (eGFR) (r = - 0.4862; P = 0.0478) and directly related to both proteinuria (ρ = 0.493; P = 0.0444) and albuminuria (ρ = 0.542; P = 0.0247). IDO activity was higher in patients with history of cardiovascular disease compared to patients with no such history, and it negatively correlated with eGFR (ρ = - 0.554; P = 0.0210) in the same group. These findings may contribute to explain the well-known beneficial effects of RAS inhibition in CKD population, especially considering that kynurenine is emerging as a potential new biomarker of CKD.