Kidney disease in diabetes: From mechanisms to clinical presentation and treatment strategies.

Metabolic and haemodynamic perturbations and their interaction drive the development of diabetic kidney disease (DKD) and its progression towards end stage renal disease (ESRD). Increased mitochondrial oxidative stress has been proposed as the central mechanism in the pathophysiology of DKD, but other mechanisms have been implicated. In parallel to increased oxidative stress, inflammation, cell apoptosis and tissue fibrosis drive the relentless progressive loss of kidney function affecting both the glomerular filtration barrier and the renal tubulointerstitium. Alteration of glomerular capillary autoregulation is at the basis of glomerular hypertension, an important pathogenetic mechanism for DKD. Clinical presentation of DKD can vary. Its classical presentation, often seen in patients with type 1 diabetes (T1DM), features hyperfiltration and albuminuria followed by progressive fall in renal function. Patients can often also present with atypical features characterised by progressive reduction in renal function without albuminuria, others in conjunction with non-diabetes related pathologies making the diagnosis, at times, challenging. Metabolic, lipid and blood pressure control with lifestyle interventions are crucial in reducing the progressive renal function decline seen in DKD. The prevention and management of DKD (and parallel cardiovascular disease) is a huge global challenge and therapies that target haemodynamic perturbations, such as inhibitors of the renin-angiotensin-aldosterone system (RAAS) and SGLT2 inhibitors, have been most successful.

Vascular growth factors as potential new treatment in cardiorenal syndrome in diabetes.

BACKGROUND: Cardiorenal syndrome in diabetes is characterised by alterations of the cardiovascular system paralleled by kidney disease with progressive renal function decline. In diabetes, chronic metabolic and haemodynamic perturbations drive endothelial dysfunction, inflammation, oxidative stress and progressive tissue fibrosis which, in turn, lead to heart and renal anatomo-functional damage. In physiology, vascular growth factors have been implicated in vascular homeostasis; their imbalance, in disease setting such as diabetes, leads to vascular dysfunction and cardiorenal damage. AIMS: To define the role of vascular growth factors and angiopoietins in cardiorenal syndrome. MATERIAL AND METHODS: We will focus on the two most studied vascular growth factors, vascular endothelial growth factor (VEGF) and angiopoietins (Angpt). The balance and crosstalk between these growth factors are important in organ development and in the maintenance of a healthy vasculature, heart and kidney. The observed alterations in expression/function of these vascular growth factors, as seen in diabetes, are a protective response against external perturbations. RESULTS: The chronic insults driving diabetes-mediated cardiorenal damage results in a paradoxical situation, whereby the vascular growth factors imbalance becomes a mechanism of disease. Studies have explored the possibility of modulating the expression/action of vascular growth factors to improve disease outcome. Experimental work has been conducted in animals and has been gradually translated in humans. DISCUSSION: Difficulties have been encountered especially when considering the magnitude, timing and duration of interventions targeting a selective vascular growth factor. Targeting VEGF in cardiovascular disease has been challenging, while modulation of the Angpt system seems more promising. CONCLUSION: Future studies will establish the translatability of therapies targeting vascular growth factors for heart and kidney disease in patients with diabetes.

Calcitonin Gene-Related Peptide Protects Against Cardiovascular Dysfunction Independently of Nitric Oxide In Vivo.

[Figure: see text].

The endoplasmic reticulum stress and the unfolded protein response in kidney disease: Implications for vascular growth factors.

Acute kidney injury (AKI) and chronic kidney disease (CKD) represent an important challenge for healthcare providers. The identification of new biomarkers/pharmacological targets for kidney disease is required for the development of more effective therapies. Several studies have shown the importance of the endoplasmic reticulum (ER) stress in the pathophysiology of AKI and CKD. ER is a cellular organelle devolved to protein biosynthesis and maturation, and cellular detoxification processes which are activated in response to an insult. This review aimed to dissect the cellular response to ER stress which manifests with activation of the unfolded protein response (UPR) with its major branches, namely PERK, IRE1α, ATF6 and the interplay between ER and mitochondria in the pathophysiology of kidney disease. Further, we will discuss the relationship between mediators of renal injury (with specific focus on vascular growth factors) and ER stress and UPR in the pathophysiology of both AKI and CKD with the aim to propose potential new targets for treatment for kidney disease.

Endoplasmic Reticulum stress in chronic kidney disease. New molecular targets from bench to the bedside.

The identification of new biomarkers/pharmacological targets for chronic kidney disease (CKD) is required for the development of more effective therapies. Several studies in vitro and in vivo have shown the importance of the endoplasmic reticulum (ER) (cellular organelle devolved to protein biosynthesis and maturation, and cellular detoxification processes) in the pathophysiology of CKD. Hence, the synthesis and development of novel drugs against the different ER intracellular pathways is crucial in order to slow down the development and progression of renal diseases. This review aims to dissect the role of the different ER branches (PERK, IRE1α, ATF6) and their function in CKD, providing potential insights for the development of new treatments.

Overexpression of Circulating Soluble Nogo-B Improves Diabetic Kidney Disease by Protecting the Vasculature.

Damage to the vasculature is the primary mechanism driving chronic diabetic microvascular complications such as diabetic nephropathy, which manifests as albuminuria. Therefore, treatments that protect the diabetic vasculature have significant therapeutic potential. Soluble neurite outgrowth inhibitor-B (sNogo-B) is a circulating N-terminus isoform of full-length Nogo-B, which plays a key role in vascular remodeling following injury. However, there is currently no information on the role of sNogo-B in the context of diabetic nephropathy. We demonstrate that overexpression of sNogo-B in the circulation ameliorates diabetic kidney disease by reducing albuminuria, hyperfiltration, and abnormal angiogenesis and protecting glomerular capillary structure. Systemic sNogo-B overexpression in diabetic mice also associates with dampening vascular endothelial growth factor-A signaling and reducing endothelial nitric oxide synthase, AKT, and GSK3ß phosphorylation. Furthermore, sNogo-B prevented the impairment of tube formation, which occurred when human endothelial cells were exposed to sera from patients with diabetic kidney disease. Collectively, these studies provide the first evidence that sNogo-B protects the vasculature in diabetes and may represent a novel therapeutic target for diabetic vascular complications.

The Myth of Water and Salt: From Aquaretics to Tenapanor.

The impact of water intake has been studied in several renal diseases. For example, increasing water intake is useful to prevent primary and secondary nephrolithiasis. In autosomal dominant polycystic kidney disease, arginine vasopressin (AVP) is involved in the progression of the disease, and water intake could play a therapeutic role by inhibiting the synthesis of AVP, but its efficacy is still controversial. Conversely, the use of aquaretics, which are antagonists of AVP V2 receptors, results in the reduction of the increase rate of total kidney volume with a slower decline of glomerular filtration rate. In chronic kidney disease, AVP contributes to glomerular hyperfiltration, arterial hypertension, and synthesis of renin, resulting in renal sclerosis. Increased water intake could reduce AVP activation determining a potential protective effect on the kidney, but its efficacy has not yet been clearly demonstrated. On the other side, sodium and potassium play an important role in the control of arterial blood pressure and are involved in the development and progression of chronic kidney disease. Reduction of sodium intake and increase of potassium intake determine a decrease of arterial blood pressure with a beneficial effect on the kidney; however, adherence to sodium restriction is very poor. Regarding this, sodium-hydrogen exchanger isoform 3 inhibitors may reduce sodium absorption in the gut. The most recent sodium-hydrogen exchanger isoform 3 inhibitor, known as tenapanor, reduces extracellular fluid volume, left ventricular hypertrophy, albuminuria, and blood pressure in experimental studies and increases fecal loss of sodium in humans.

Persistent left superior vena cava and partially left inferior vena cava: a case report of a dangerous central venous catheterization.

BACKGROUND: The coexistence of a double superior vena cava (SVC) and a partially left inferior vena cava (PLIVC) with a circumaortic collar, associated with other congenital malformations, was not described previously. CASE DESCRIPTION: We present a 33-year-old woman in hemodialysis with complete exhaustion of the brachial routes for vascular access, admitted to our Nephrology Unit for a long-term central venous catheter (CVC) implant, usually by us performed under EchoScopic Technique (EST), an echographic venipuncture followed by continuous radioscopic control of guidewire and catheter in all the steps of implant. An intraoperative venography showed a complete stop of right internal jugular vein, a right SVC, a persistent left SVC, a left inferior vena cava in the iliac and subrenal tracts, a circumaortic venous collar in the renal tract, and normal right suprarenal and hepatic tracts. CONCLUSIONS: The double SVC was related to the persistence of the caudal part of the anterior cardinal veins. As to the PLIVC, the iliac and subrenal parts of the inferior vena cava can be related to the persistent left supracardinal vein, while the circumaortic venous collar to the persistent intersupracardinal and left subsupracardinal anastomoses. All invasive procedures, and particularly those potentially complicated, must be performed under EST, now considered a mandatory tool for CVC implants, owing to the hypothesis of possible venous congenital anomalies.

Renoprotective effect of erythropoietin in zebrafish after administration of gentamicin: an immunohistochemical study for ß-catenin and c-kit expression.

BACKGROUND: Gentamicin is an aminoglycoside antibiotic widely used in the treatment of infections caused by Gram-negative bacteria. The main limitation to its therapeutic effectiveness is the potential nephrotoxicity. Erythropoietin has a tissue protective effect widely demonstrated in the kidney. The aim of the present study was to evaluate the renoprotective effects of erythropoietin in a model of zebrafish (Danio rerio) after administration of gentamicin. METHODS: Sixty adult zebrafish were subdivided into three groups: group A was treated with gentamicin; group B received gentamicin and, 24 h later, epoetin alpha; group C received drug diluent only. In order to analyze the renoprotective activity of erythropoietin, the expression of c-kit and ß-catenin was evaluated by immunohistochemistry. RESULTS: Generally, the zebrafish renal tubule regenerates 15 days after an injury. Conversely, 7 days after gentamicin administration, animals treated with erythropoietin (group B) showed a better renal injury repair as documented by: increased expression of ß-catenin, less degenerated tubules, greater number of centers of regeneration, positivity for c-kit only in immature-looking tubules and lymphohematopoietic cells. CONCLUSION: The expression of c-kit and ß-catenin suggests that erythropoietin may exert a role in regeneration reducing the extent of tubular damage from the outset after gentamicin administration.

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.

Sclerostin levels in uremic patients: a link between bone and vascular disease.

Sclerostin is a marker of low-turnover bone disease in end stage renal disease patients. The aim of this study was to evaluate serum sclerostin in uremic patients, analyzing its behavior during a single hemodialysis session. Twenty-one adult patients on intermittent hemodialysis treatment were enrolled. Acetate Free Bio-filtration (AFB) was the technique employed. Uremic patients were characterized by higher levels of serum sclerostin when compared with values observed in healthy subjects. Sclerostin assessed in pre-dialysis samples was 1.4 ± 1.02 ng/mL, whereas, in post dialysis samples, a reduction of sclerostin values was observed (0.8 ± 0.6 ng/mL; p: 0.008). Sclerostin correlated with parameters of dialysis adequacy, such as creatinine levels and Kt/V values, and it was significantly associated with atherosclerotic disease. Receiver operating characteristics analysis revealed a good diagnostic profile in identifying atherosclerotic disease. Sclerostin, a full dialyzable substance during AFB dialysis, is closely associated with atherosclerotic disease. Its reduction obtained through AFB could represent a defensive mechanism, improving vascular disease and renal osteodystrophy.

The concept of the urine test and specific reaction of the urine in various diseases according to Enrico Cauchi - member of the medical council of Malta (1933).

The Study of urine from the outset has always aroused the interest of scientists and physicians all over the world, from ancient Greeks and Romans to Hindus , Hulcos in Mexico, Australian native etc. The urine in such case was considered not only as a waste product but also as a therapeutic product. In the late XIX century scientific knowledge had already identified the function of substances that favor the increase of urinary output, and physicians over the centuries have always tried to analyze urine in various ways. In Cauchis work in 1933 all chemistry and pathophysiological knowledge of the time was condensed. Cauchi signed the preface as Member of the medical council of Malta. He was a medical doctor of the early20thcentury, He wrote about the physiopathology of urine ranging from chemical and physical behavior, to the analysis of sediments and the special reactions of the urine in various pathologies. In particular Cauchi emphasizes the main diseases of the time combines the behavior of the reaction of urine as a diagnostic and prognostic instrument, stressing the importance of the urine test and describing the method used for analysis at the time. The analyses of the text in the issue seems to belong to archaic medicine, and it is difficult to think today, that what was presented as very up-to-date- science at that time, took place only 80 years ago. Reading the full original text with today experience we are led to consider the increasing importance that scientific community gave in the past, and still gives to urine test.

Treatment of kidney diseases in the thermal springs of Pithecusa during the XVIII Century.

The island of Pithecusa (Ischia) is a volcanic island in the Tyrrhenian Sea in the north end of the Gulf of Naples at about 30 kilometers from the same city. Pithecusa is very popular for its hot springs which even the ancients used. This report aims to analyze the renal therapeutic benefits of the Pithacusa thermal mineral spring through a review of two different manuscripts: i) "Di Napoli il seno cratero"(The gulf of Naples) of Domenico Antonio Parrino (1642-1708) and ii) "De' rimedi naturali che sono nell'isola di Pithecusa oggi detta Ischia"(On the natural cures of the island of Pithecusa known today as Ischia)of Giulio Iasolino (1583-1622). These two manuscripts published during the 18th century and both manuscripts highlight the thermal virtues of the thermal springs of Pithecusa. In the past natural remedies were important in the treatment of different diseases including that of thermal springs dating back to ancient Rome. Thermal springs were used to treat spasms, skin diseases, hair loss and various renal ailments. Both manuscripts describe the thermal springs in Ischia and their therapeutic benefits in medical diseases.

Arnaldo Da Villanova medieval physician (1235-1311). A first approach.

Arnaldo de Villanova, was a Catalan Physician, born in Villanova de Grau, a suburb of Valencia - Spain about 1235. He died off the coast of Genoa in 1311 during a sea voyage departing from Messina in Sicily, during a diplomatic mission by Pope Clement V in Avignon on orders by the King of Sicily. He was a so famous and clever scientist of the thirteenth century, to give his name to the Universitary Hospital of Montpellier - France. His interests ranged from theology, to politics, medicine, and anymore alchemy. He was an adviser and physician of Kings of Aragon, like Peter III the Great (1276-1285) and James II the Right (1285-1327), of Robert of Angi (1309-1343) of Naples, and of Popes, like Innocenzo V (1276), Bonifacio VIII (1294-1303), Benedetto XI (1303-1304), Clemente V (1305-1314), and of the King of Sicily Federico II of Aragon (1296-1337). For the Pope Bonifacio VIII, suffering from renal colic due to kidney stones, he prescribed Hydrotherapy with Fiuggi Thermal water, that was specially transported for him from its source to Rome and Anagni, in jars wrapped in coarse carpets or wool fabrics, to better maintain the source temperature. In addition in July of 1301, he also produced an astrological seal (Talisman) made of gold loaded of virtues, obtained exposing the seal to the power of the Sun, in those days in the Leo Constellation. This seal was worn by the Pope in an hernial belt of leather to support the kidney,probably to improve hisnephroptosis. Arnaldo produced this seal according to what was described in the book Picatrix - The goal of the wise of the Arabic astronomer and alchemist "Abu l-Qasim Maslama b.- Ahmad al-Majriti, known with the pseudonym Ghayat al hakim died in Cordova about 1008. Ten years later, after his mysterious death at sea on a Sicilian royal ship, his body was not buried at sea, but was reported in Sicily and buried in the Federician Castle of Montalbano of Elicona at the end of Peloritans Mountains near Milazzo, about 90 km from Messina, where he loved to stay and to write.

Kidney disease and psoriasis: novel evidences beyond old concepts.

Psoriasis is an immune-mediated inflammatory disease for a long time considered as a type of pathology characterized by an exclusive skin involvement. Recently it has been shown that patients affected by this disease have a higher risk of developing comorbidities such as cardiovascular diseases, arterial hypertension, diabetes mellitus, and metabolic syndrome. Even the kidneys can be affected by psoriasis through three different mechanisms: immune-mediated renal damage, drug-related renal damage and chronic renal damage. Renal function should be monitored periodically to minimize the risk of renal adverse events.

Salt-water imbalance and fluid overload in hemodialysis patients: a pivotal role of corin.

Natriuretic peptides (NP) play a key role in regulation of salt and water balance. Corin, a serine protease which activates NP, plays a key role in regulation of blood pressure and cardiac function. The aim of the study was to evaluate the involvement of corin in renal physiopathology, analyze its levels in dialyzed patients and evaluate its relation with fluid overload and comorbidities such as heart failure and blood hypertension. We studied serum corin in uremic patients (n = 20) undergoing hemodialysis therapy (HD) and in healthy subjects (HS). Corin levels in uremic patients were higher than in HS (p < 0.0001). Moreover, its concentration did not change after a single HD session. Hypertensive patients and subject suffering from heart failure were characterized by high values of corin. After multivariate analysis, direct correlations were maintained between corin and dialysis vintage (ß = 0.83; p = 0.0002), heart failure (ß = 0.42; p < 0.0001), systolic blood pressure (ß = -0.70; p = 0.0002) and body weight (ß = -0.39; p < 0.0001). Corin might be implicated in the regulation of salt and water balance and the disturbances of volume homeostasis of HD patients. However, further studies are warranted to understand the role of corin in kidney diseases and to define its diagnostic and prognostic role.

[Periorbital purpura: a pathognomonic but late sign of AL amyloidosis]. / Porpora periorbitaria: un segnale patognomonico ma tardivo di amiloidosi AL.

INTRODUCTION: AL amyloidosis is the most common type of systemic amyloidosis and is caused by the deposition of an amyloidogenic protein composed of immunoglobulin light chains produced by a clonal population of plasma cells. CASE REPORT: We report the case of a 77-year-old woman with arterial hypotension, peripheral edema and renal failure. Electrocardiogram reveals low voltage on peripheral leads. Echocardiogram shows normal values for left ventricle size with increased wall thickness and cardiac wall reflectance with ground glass appearance. Serum immunofixation electrophoresis (IFE) is negative while urine IFE detects type monoclonal light chains. Abdominal Fat Pad biopsy is positive for Congo red with typical apple green birefringence after polarization under optical microscopy (OM) while ultrastructural analysis does not show presence of amyloid deposition. Two months later, the patient undergoes further worsening of general clinical condition and development of purpura in the periorbital area, at the base of the neck and in the anterior chest wall. DISCUSSION: This clinical case presents classic signs of AL amyloidosis, such as cardiac and renal involvement with the presence of a urine monoclonal component. Periorbital purpura is a pathognomonic sign of AL amyloidosis but it appears late. Final diagnosis is "AL amyloidosis with prevalent cardiac, renal and soft tissue involvement".

[Metformin and Diabetes: still has a sense of its use in patients CKD stage II or is an additional risk factor?]

Pz woman of 62 years comes to P.S.G. for fatigue, low-grade fever, diuresis present. A history of hypertension refers to therapy for about five years, diabetes mellitus for about two years in therapy with Metformin 1gr x 3 gg / day. Blood tests: BUN 195 mg / dL, creatinine 8.0 mg / dl, Ph 6877, HCO3 5.1 mmol / L BE -29.1 mmol / l. Rapid clinical deterioration with occurrence of arterial hypotension - 85/60 mmHg, stupor. Start therapy Bicarbonates ev, is positioned in Urgency CVC and it undergoes AFB with infusion of bicarbonates 2000 ml / h for 4 hours, blood flow rate 250 ml / min., the hemodynamics has been supported with dopamine infusion 200 mg: 2 vials in 250 cc of physiological vel 30 - 40 ml / h, The pc after undergoing three AFB, interrupted the dialysis for resumption of diuresis spontaneous and progressive improvement of renal function and blood pressure. Monitored, after discharge, the parameters of renal function decreased to within normal limits, clearance compatible with IRC II - III stage. CONCLUSIONS: dehydration, fever, IRC II stadium, undiagnosed caused, in a very short time, an accumulation of metformin, which has been the cause of metabolic acidosis. The pc. saved thanks to the positioning of the CVC and to the AFB in the treatment with the infusion of large quantities of Bicarbonates e.v. The use of metformin in pcs. > 50 years and / or creatinine clearance <60 ml / min., must be subordinated to the preliminary study and periodic renal function.