Valeria Cernaro

Relaxin: New Pathophysiological Aspects and Pharmacological Perspectives for an Old Protein

Human relaxin‐2 (hereafter simply defined as “relaxin”) is a 6‐kDa peptidic hormone best known for the physiological role played during pregnancy in the growth and differentiation of the reproductive tract and in the renal and systemic hemodynamic changes. This factor can also be involved in the pathophysiology of arterial hypertension and heart failure, in the molecular pathways of fibrosis and cancer, and in angiogenesis and bone remodeling. It belongs to the relaxin peptide family, whose members comprehensively exert numerous effects through interaction with different types of receptors, classified as relaxin family peptide (RXFP) receptors (RXFP1, RXFP2, RXFP3, RXFP4). Research looks toward the in‐depth examination and complete understanding of relaxin in its various pleiotropic actions. The intent is to evaluate the likelihood of employing this substance for therapeutic purposes, for instance in diseases where a deficit could be part of the underlying pathophysiological mechanisms, also avoiding any adverse effect. Relaxin is already being considered as a promising drug, especially in acute heart failure. A careful study of the different RXFPs and their receptors and the comprehension of all biological activities of these hormones will probably provide new drugs with a potential wide range of therapeutic applications in the near future.

New therapeutic strategies under development to halt the progression of renal failure.

Introduction: Chronic kidney disease (CKD) is a pathological condition associated with high morbidity and mortality. Accordingly, prevention of CKD onset and progression is mandatory. As pharmacological agents already used in clinical practice are not yet able to halt the progression of renal damage, new therapeutic strategies are being explored. Areas covered: The authors carried out a systematic review on completed and ongoing Phase I and II clinical trials with an aim to evaluate the safety and efficacy of novel therapeutic approaches to CKD. The data in this manuscript was retrieved from the currently available scientific literature as well as from the ClinicalTrials.gov website. Expert opinion: Several drugs are currently under investigation due to their supposed antiproteinuric action, such as selective endothelin-A receptor antagonists and vitamin D analogues. Other drugs could be used in CKD because of their antifibrotic, anti-inflammatory and antioxidative properties or due to the hypothetical ability to repair damaged podocytes. A fascinating therapeutic approach involves the use of progenitor/stem cells. There is still some way to go in the use of stem cells in clinical practice but remarkable progress has been made. This is especially true in terms of the understanding of their biology and behaviour, as well as in the procedures required to mobilize and activate endogenous stem cells in damaged kidneys or simply introducing them.

Antioxidant agents for delaying diabetic kidney disease progression: A systematic review and meta-analysis

Background Oxidative stress is a key player in the genesis and worsening of diabetic kidney disease (DKD). We aimed at collecting all available information on possible benefits of chronic antioxidant supplementations on DKD progression. Study design Systematic review and meta-analysis. Population Adults with DKD (either secondary to type 1 or 2 diabetes mellitus) Search strategy and sources Cochrane CENTRAL, Ovid-MEDLINE and PubMed were searched for randomized controlled trials (RCTs) or quasi-RCTs without language or follow-up restriction. Intervention Any antioxidant supplementation (including but not limited to vitamin A, vitamin C, vitamin E, selenium, zinc, methionine or ubiquinone) alone or in combination. Outcomes Primary outcome was progression to end-stage kidney disease (ESKD). Secondary outcomes were change in albuminuria, proteinuria, serum creatinine and renal function. Results From 13519 potentially relevant citations retrieved, 15 articles referring to 14 full studies (4345 participants) met the inclusion criteria. Antioxidant treatment significantly decreased albuminuria as compared to control (8 studies, 327 participants; SMD: -0.47; 95% CI -0.78, -0.16) but had apparently no tangible effects on renal function (GFR) (3 studies, 85 participants; MD -0.12 ml/min/1.73m2; 95% CI -0.06, 0.01). Evidence of benefits on the other outcomes of interest was inconclusive or lacking. Limitations Small sample size and limited number of studies. Scarce information available on hard endpoints (ESKD). High heterogeneity among studies with respect to DKD severity, type and duration of antioxidant therapy. Conclusions In DKD patients, antioxidants may improve early renal damage. Future studies targeting hard endpoints and with longer follow-up and larger sample size are needed to confirm the usefulness of these agents for retarding DKD progression.

Renal biopsy: Still a landmark for the nephrologist

Renal biopsy was performed for the first time more than one century ago, but its clinical use was routinely introduced in the 1950s. It is still an essential tool for diagnosis and choice of treatment of several primary or secondary kidney diseases. Moreover, it may help to know the expected time of end stage renal disease. The indications are represented by nephritic and/or nephrotic syndrome and rapidly progressive acute renal failure of unknown origin. Nowadays, it is performed mainly by nephrologists and radiologists using a 14-18 gauges needle with automated spring-loaded biopsy device, under real-time ultrasound guidance. Bleeding is the major primary complication that in rare cases may lead to retroperitoneal haemorrhage and need for surgical intervention and/or death. For this reason, careful evaluation of risks and benefits must be taken into account, and all procedures to minimize the risk of complications must be observed. After biopsy, an observation time of 12-24 h is necessary, whilst a prolonged observation may be needed rarely. In some cases it could be safer to use different techniques to reduce the risk of complications, such as laparoscopic or transjugular renal biopsy in patients with coagulopathy or alternative approaches in obese patients. Despite progress in medicine over the years with the introduction of more advanced molecular biology techniques, renal biopsy is still an irreplaceable tool for nephrologists.

Phosphate binders for the treatment of chronic kidney disease: role of iron oxyhydroxide

Chronic kidney disease-mineral bone disorder is frequent in patients with renal failure. It is characterized by abnormalities in mineral and bone metabolism with resulting hyperphosphatemia, low serum vitamin D, secondary hyperparathyroidism, altered bone morphology and strength, higher risk of bone fractures, and development of vascular or other soft tissue calcifications. Besides the recommendation to reduce phosphorus dietary intake, many drugs are currently available for the treatment of calcium/phosphate imbalance. Among them, phosphate binders represent a milestone. Calcium-based binders (calcium carbonate, calcium acetate) are effective in lowering serum phosphate, but their use has been associated with an increased risk of hypercalcemia and calcifications. Calcium-free binders (sevelamer hydrochloride, sevelamer carbonate, and lanthanum carbonate) are equally or slightly less effective than calcium-containing compounds. They would not induce an increase in calcium levels but may have relevant side effects, including gastrointestinal symptoms for sevelamer and risk of tissue accumulation for lanthanum. Accordingly, new phosphate binders are under investigation and some of them have already been approved. A promising option is sucroferric oxyhydroxide (Velphoro®, PA21), an iron-based phosphate binder consisting of a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. The present review is focused on pharmacology, mode of action, and pharmacokinetics of sucroferric oxyhydroxide, with a discussion on comparative efficacy, safety, and tolerability studies of this drug in chronic kidney disease and patient perspectives such as quality of life, satisfaction, and acceptability. Sucroferric oxyhydroxide has proven to be as effective as sevelamer in reducing phosphatemia with a similar safety profile and lower pill burden. Experimental and clinical studies have documented a minimal percentage of iron absorption without inducing toxicity. In conclusion, the overall benefit–risk balance of sucroferric oxyhydroxide is deemed to be positive, and this new drug may therefore represent a good alternative to traditional phosphate binders for the treatment of hyperphosphatemia in dialysis patients.

Apelin, Plasmatic Osmolality and Hypotension in Dialyzed Patients

Background/Aims: To evaluate the balance between arginine-vasopressin (AVP) and apelin during hemodialysis and its role in hypotension onset and in the inflammation status. Methods: We enrolled 50 patients chronically treated with hemodialysis. We assessed plasmatic osmolality, AVP, apelin, mean blood pressure (BP), high-sensitivity C-reactive protein (hsCRP) and β2-microglobulin. Results: Apelin rises during dialytic treatment (from 0.68 ± 0.34 to 1.89 ± 0.56 pg/ml, p < 0.0001), while plasmatic osmolality (from 325 ± 4.54 to 311 ± 1.20 mosm/kg H2O, p < 0.0001), AVP (from 4.28 ± 1.12 to 2.48 ± 0.50 pg/ml, p < 0.0001) and mean BP (from 124 ± 6 to 110 ± 7 mm Hg, p < 0.0001) decrease. At multivariate regression with respect to apelin, only mean BP remains (r = –0.95, p < 0.0001). We also correlated the AVP/apelin ratio with BP. Moreover, apelin is inversely related to hsCRP (r = –0.79, p < 0.0001). Conclusions: The AVP/apelin balance changes with plasmatic osmolality variations induced by hemodialytic sessions and could represent a physiopathological marker of arterial hypo- and hypertension. Finally, apelin appears inversely related to inflammation markers.

Down with the erythropoietin. Long live the erythropoietin

In recent years the use of erythropoietin has exploded, and the anaemia of patients with chronic renal failure has been practically resolved with the administration of rHuEpo (recombinant human, Erythropoietin). However, as a result of an intense commercial campaign, strong therapies with this growth hormone, prescribed to achieve surprising sporting performances, got athletes to run the risk of thrombosis and vascular accidents because of red blood cells increase. Erythropoietin represents a significant subject of research. In fact, besides the ability of stimulating erythrocyte production, it has many pleiotropic effects. Several studies allow the assertion that EPO, in different concentrations, has protective effects mainly on central nervous system and cardiovascular system through various mechanisms, among which a key role seems to be held by the ability to stimulate angiogenesis. The consequent problem is that anaemia therapy with rHuEpo in patients with cancer may accelerate the progression of neoplastic disease by promoting tumour angiogenesis and, thus, metastasization. The study of angiogenic process in tumours led to the synthesis of drugs that, blocking VEGF, exert an anti-angiogenic action, contrasting cancer spread. However, benefits are relatively modest. Is erythropoietin perhaps the further angiogenic hormone to block in tumour pathology? Therefore, Epo plays a role in Regenerative Medicine since it intervenes in a persistent natural regenerative activity of humans: angiogenesis. The understanding of the regeneration mechanisms of complex structures in the adult salamander has opened original lines of research. Regenerative Medicine tries to develop therapeutic pathways through the stimulation of natural regenerative processes in humans.

Metformin-related lactic acidosis: is it a myth or an underestimated reality?

Abstract Metformin, belonging to a class of drugs called biguanides, is the recommended first-line treatment for overweight patients with type 2 diabetes mellitus. It has multiple mechanisms of action, such as reduction of gluconeogenesis, increases peripheral uptake of glucose, and decreases fatty acid oxidation. However, a potential serious complication, defined metformin-associated lactic acidosis (MALA), is related to increased plasma lactate levels, linked to an elevated plasma metformin concentrations and/or a coexistent condition altering lactate production or clearance. The mortality rate for MALA approaches 50% and metformin has been contraindicated in moderate and severe renal impairment, to minimize its potential toxic levels. Nevertheless, metformin prescription or administration, despite the presence of contraindications or precipitating factors for MALA, was a common topic highlighted in all reviewed papers. Routine assessment of metformin plasma concentration is not easily available in all laboratories, but plasma metformin concentrations measured in the emergency room could ensure the correct diagnosis, eliminating metformin as the cause of lactic acidosis if low plasma levels occurred. Renal replacement therapies have been successfully employed to achieve the correction of metabolic acidosis and rapidly remove metformin and lactate, but the optimal treatment modality for MALA is still controversial.

Monoclonal antibodies for renal diseases: current concepts and ongoing treatments

Introduction: In recent years, technological innovations in the field of molecular biology have provided new therapeutic options. In particular, human monoclonal antibodies (mAbs), initially used in the treatment of malignancies, have become a therapeutic tool for many other diseases. Most of the application of mAbs revealed encouraging findings to treat patients with immune-mediated glomerular diseases, for whom the standard protocols based on corticosteroids and non-specific immunosuppressants with heavy side effects have for decades been the only therapies. Area covered: Rituximab, an mAb directed against a specific antigen expressed on B lymphocytes, CD20 antigen, inducing a premature cell apoptosis became very important in the treatment of membranous glomerulonephritis, steroid-resistant nephrotic syndromes and membranoproliferative glomerulonephritis (MPGN). Another important mAb, eculizumab, is used successfully for treatment of atypical hemolytic uremic syndrome, C3 nephropathy and MPGN. Many other mAbs are now under premarketing investigation, such as adalimumab, daclizumab, fresolimumab, belimumab, tocilizumab, although some of these mAbs are already approved for different medical applications. Expert opinion: The availability of novel mAb may therefore constitute the basis for a revolution in the treatment of immune-mediated renal diseases. However, the cost for this therapy remains very high and represents a barrier for its widespread use.

From Water to Aquaretics: a Legendary Route

Man is water. When life appeared on earth, the primordial cell had a simple structure and could immediately ascertain from the surrounding aquatic environment the substances for nutrition and oxygen, without any need for structural complexity. As part of evolution, during the transition from aquatic to terrestrial life, vertebrates had to fight against dehydration as well as fish in the sea. In this complex mechanism of osmoregulation, the structure and function of some osmoregulatory hormones have been maintained during the evolution of species, from fish to man. Within the homeostatic mechanism, the renin-angiotensin-aldosterone system (RAAS) is crucial in the regulation of renal reasorption of water and sodium. It is also involved in the regulation of renal plasma flux, blood volume and blood pressure. Vasopressin plays a hormonal function in the mechanisms of water homeostasis acting through Aquaporins (AQP), channel-proteins that allow bi-directional water transport across cell membranes.