Kidney Disease in Diabetic Patients: From Pathophysiology to Pharmacological Aspects with a Focus on Therapeutic Inertia.

Diabetes mellitus represents a growing concern, both for public economy and global health. In fact, it can lead to insidious macrovascular and microvascular complications, impacting negatively on patients' quality of life. Diabetic patients often present diabetic kidney disease (DKD), a burdensome complication that can be silent for years. The average time of onset of kidney impairment in diabetic patients is about 7-10 years. The clinical impact of DKD is dangerous not only for the risk of progression to end-stage renal disease and therefore to renal replacement therapies, but also because of the associated increase in cardiovascular events. An early recognition of risk factors for DKD progression can be decisive in decreasing morbidity and mortality. DKD presents patient-related, clinician-related, and system-related issues. All these problems are translated into therapeutic inertia, which is defined as the failure to initiate or intensify therapy on time according to evidence-based clinical guidelines. Therapeutic inertia can be resolved by a multidisciplinary pool of healthcare experts. The timing of intensification of treatment, the transition to the best therapy, and dietetic strategies must be provided by a multidisciplinary team, driving the patients to the glycemic target and delaying or overcoming DKD-related complications. A timely nephrological evaluation can also guarantee adequate information to choose the right renal replacement therapy at the right time in case of renal impairment progression.

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.

Amyloidosis and Glomerular Diseases in Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease with autosomal recessive transmission, characterized by periodic fever attacks with self-limited serositis. Secondary amyloidosis due to amyloid A renal deposition represents the most fearsome complication in up to 8.6% of patients. Amyloidosis A typically reveals a nephrotic syndrome with a rapid progression to end-stage kidney disease still. It may also involve the cardiovascular system, the gastrointestinal tract and the central nervous system. Other glomerulonephritis may equally affect FMF patients, including vasculitis such as IgA vasculitis and polyarteritis nodosa. A differential diagnosis among different primary and secondary causes of nephrotic syndrome is mandatory to determine the right therapeutic choice for the patients. Early detection of microalbuminuria is the first signal of kidney impairment in FMF, but new markers such as Neutrophil Gelatinase-Associated Lipocalin (NGAL) may radically change renal outcomes. Serum amyloid A protein (SAA) is currently considered a reliable indicator of subclinical inflammation and compliance to therapy. According to new evidence, SAA may also have an active pathogenic role in the regulation of NALP3 inflammasome activity as well as being a predictor of the clinical course of AA amyloidosis. Beyond colchicine, new monoclonal antibodies such as IL-1 inhibitors anakinra and canakinumab, and anti-IL-6 tocilizumab may represent a key in optimizing FMF treatment and prevention or control of AA amyloidosis.

Vitamin D and Glomerulonephritis.

Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeostasis. It is an efficient endocrine regulator of the Renin-Angiotensin-Aldosterone System (RAAS) and erythropoiesis, exerts immunomodulatory effects, reduces the cardiovascular events and all-cause mortality. In Chronic Kidney Disease (CKD) patients, Vitamin D function is impaired; the renal hydrolyzation of its inactive form by the action of 1α-hydroxylase declines at the same pace of reduced nephron mass. Moreover, Vitamin D major carrier, the D-binding protein (DBP), is less represented due to Nephrotic Syndrome (NS), proteinuria, and the alteration of the cubilin-megalin-amnionless receptor complex in the renal proximal tubule. In Glomerulonephritis (GN), Vitamin D supplementation demonstrated to significantly reduce proteinuria and to slow kidney disease progression. It also has potent antiproliferative and immunomodulating functions, contributing to the inhibitions of kidney inflammation. Vitamin D preserves the structural integrity of the slit diaphragm guaranteeing protective effects on podocytes. Activated Vitamin D has been demonstrated to potentiate the antiproteinuric effect of RAAS inhibitors in IgA nephropathy and Lupus Nephritis, enforcing its role in the treatment of glomerulonephritis: calcitriol treatment, through Vitamin D receptor (VDR) action, can regulate the heparanase promoter activity and modulate the urokinase receptor (uPAR), guaranteeing podocyte preservation. It also controls the podocyte distribution by modulating mRNA synthesis and protein expression of nephrin and podocin. Maxalcalcitol is another promising alternative: it has about 1/600 affinity to vitamin D binding protein (DBP), compared to Calcitriol, overcoming the risk of hypercalcemia, hyperphosphatemia and calcifications, and it circulates principally in unbound form with easier availability for target tissues. Doxercalciferol, as well as paricalcitol, showed a lower incidence of hypercalcemia and hypercalciuria than Calcitriol. Paricalcitol demonstrated a significant role in suppressing RAAS genes expression: it significantly decreases angiotensinogen, renin, renin receptors, and vascular endothelial growth factor (VEGF) mRNA levels, thus reducing proteinuria and renal damage. The purpose of this article is to establish the Vitamin D role on immunomodulation, inflammatory and autoimmune processes in GN.

Role of Vitamin D Status in Diabetic Patients with Renal Disease.

Diabetes mellitus (DM) poses a major public health problem worldwide, with ever-increasing incidence and prevalence in recent years. The Institute for Alternative Futures (IAF) expects that the total number of people with type 1 and type 2 DM in the United States will increase by 54%, from 19,629,000 to 54,913,000 people, between 2015 and 2030. Diabetic Nephropathy (DN) affects about one-third of patients with DM and currently ranks as the first cause of end-stage kidney disease in the Western world. The complexity of interactions of Vitamin D is directly related with progressive long-term changes implicated in the worsening of renal function. These changes result in a dysregulation of the vitamin D-dependent pathways. Various studies demonstrated a pivotal role of Vitamin D supplementation in regression of albuminuria and glomerulosclerosis, contrasting the increase of glomerular basement membrane thickening and podocyte effacement, with better renal and cardiovascular outcomes. The homeostasis and regulation of the nephron's function are absolutely dependent from the cross-talk between endothelium and podocytes. Even if growing evidence proves that vitamin D may have antiproteinuric, anti-inflammatory and renoprotective effects in patients with DN, it is still worth investigating these aspects with both more in vitro studies and randomized controlled trials in larger patient series and with adequate follow-up to confirm the effects of long-term vitamin D analogue supplementation in DN and to evaluate the effectiveness of this therapy and the appropriate dosage.

Association of Higher Advanced Oxidation Protein Products (AOPPs) Levels in Patients with Diabetic and Hypertensive Nephropathy.

Background and Objectives: Diabetes mellitus (DM) and hypertension (HT) are characterized by cell damage caused by inflammatory and metabolic mechanisms induced by alteration in reduction-oxidative status. Serum advanced oxidation protein products (AOPP) are new markers of protein damage induced by oxidative stress. We evaluated serum levels of AOPP in a cohort of patients with DM and HT, with or without renal complications, compared with a control healthy population. Materials and Methods: The study group comprised of 62 patients with type 2 DM and 56 with HT. The 62 patients affected by DM were further distinguished in 24 subjects without renal impairment, 18 with diabetic nephropathy (DN), 20 with chronic kidney disease (CKD) stage 2-3 secondary to DN. The subgroup of 56 patients with primary HT comprised 26 subjects without renal complications and 30 with CKD (stage 2-3) secondary to HT. Thirty healthy controls, matched for age and sex, were recruited among blood donors. Results: Increased AOPP levels were found in DM patients compared with healthy subjects, although not significantly. This index was higher and more significant in patients with DN and CKD secondary to DN than in DM patients without nephropathy (p < 0.05) or controls (p < 0.0001). Patients with HT and with kidney impairment secondary to HT also had significantly higher AOPP serum levels than controls (p < 0.01 and p < 0.0001, respectively). There were no significant differences in mean AOPP levels among DM and HT patients. Conclusion: Our study showed that oxidative stress was higher in diabetic or hypertensive subjects than in healthy controls and, in particular, it appeared to be more severe in patients with renal complications. We suggest that the assessment of AOPP in diabetic and hypertensive patients may be important to predict the onset of renal failure and to open a new perspective on the adoption of antioxidant molecules to prevent CKD in those settings.

C3 glomerulopathy in cystic fibrosis: a case report.

BACKGROUND: C3 glomerulonephritis is a rare glomerulopathy characterized at renal biopsy by C3 deposition, alone or with scanty immunoglobulins, as well as by an electron-dense material in mesangium, subendothelial and subepithelial space. An abnormal systemic activation of the alternative pathway of the complement cascade is responsible for the development of the disease if triggered by several possible environmental conditions. We report the first case in literature of a patient affected by cystic fibrosis and C3GN. CASE PRESENTATION: Our case involves a young woman with cystic fibrosis, who had persistent microscopic hematuria, proteinuria and hypocomplementemia C3 for over three months. Renal biopsy confirmed the diagnosis of C3 glomerulopathy. Complement system dysregulation was tested and resulted in a strong terminal pathway activation proved by high levels of sC5b-9 complex, amounting to 1588 ng/ml (normal value < 400 ng/ml). Next generation sequencing (NGS) showed polymorphism in CFH (p.V62I in SCR1) and THBD (p.A473V), already known as pathogenic for C3GN, as well as a mutation in C3 (p.R102G) associated only with age-related macular degeneration (AMD) so far. Treatment was based on ACE inhibitors and kidney function is currently stable (GFR 50 ml/min, serum creatinine 1.7). CONCLUSIONS: The co-existence of C3 glomerulopathy in a patient with CF, which is characterized by chronic infection/inflammation, makes this case an interesting model of chronic altered systemic activation of the alternative pathway of the complement cascade.

Venous Doppler flow patterns, venous congestion, heart disease and renal dysfunction: A complex liaison.

The World Journal of Cardiology published an article written by Kuwahara et al that we take the pleasure to comment on. We focused our attention on venous congestion. In intensive care settings, it is now widely accepted that venous congestion is an important clinical feature worthy of investigation. Evaluating venous Doppler profile abnormalities at multiple sites could suggest adequate treatment and monitor its efficacy. Renal dysfunction could trigger or worsen fluid overload in heart disease, and cardio-renal syndrome is a well-characterized spectrum of disorders describing the complex interactions between heart and kidney diseases. Fluid overload and venous congestion, including renal venous hypertension, are major determinants of acute and chronic renal dysfunction arising in heart disease. Organ congestion from venous hypertension could be involved in the development of organ injury in several clinical situations, such as critical diseases, congestive heart failure, and chronic kidney disease. Ultrasonography and abnormal Doppler flow patterns diagnose clinically significant systemic venous congestion. Cardiologists and nephrologists might use this valuable, non-invasive, bedside diagnostic tool to establish fluid status and guide clinical choices.

Food insecurity and kidney disease: a systematic review.

BACKGROUND: The risk of developing and worsening chronic kidney disease (CKD) is associated with unhealthy dietary patterns. Food insecurity is defined by a limited or uncertain availability of nutritionally adequate and safe food; it is also associated with several chronic medical conditions. The aim of this systematic review is to investigate the current knowledge about the relationship between food insecurity and renal disease. METHODS: We selected the pertinent publications by searching on the PubMed, Scopus, and the Web of Science databases, without any temporal limitations being imposed. The searching and selecting processes were carried out through pinpointed inclusion and exclusion criteria and in accordance with the Prisma statement. RESULTS: Out of the 26,548 items that were first identified, only 9 studies were included in the systemic review. Eight out of the nine investigations were conducted in the US, and one was conducted in Iran. The studies evaluated the relationship between food insecurity and (i) kidney disease in children, (ii) kidney stones, (iii) CKD, (iv) cardiorenal syndrome, and (v) end stage renal disease (ESRD). In total, the different research groups enrolled 49,533 subjects, and food insecurity was reported to be a risk factor for hospitalization, kidney stones, CKD, ESRD, and mortality. CONCLUSIONS: The relationship between food insecurity and renal disease has been underestimated. Food insecurity is a serious risk factor for health problems in both wealthy and poor populations; however, the true prevalence of the condition is unknown. Healthcare professionals need to take action to prevent the dramatic effect of food insecurity on CKD and on other chronic clinical conditions.

Residents' satisfaction and suggestions to improve nephrology residency in Italy, and comparison with the organization in other European countries.

BACKGROUND: In Italy, nephrology residency is available in twenty-one nephrology schools, each with its own strengths and weaknesses. The present study is aimed at exploring the residents' satisfaction with their training programs. METHODS: Between April 20th and May 19th, 2021, a questionnaire on residency satisfaction consisting of 49 items was sent to 586 residents and 175 recently certified specialists (qualified to practice as nephrologists in 2019 and 2020), with a response rate of 81% and 51%, respectively. The teaching organization was contextualized with a survey involving 13 European nephrology schools. RESULTS: Most residency fellowship programs received a good rating with regard to "satisfaction", in particular for the following items: number of hospitalizations followed-up, chronic hemodialysis training, follow-up of transplanted patients, diagnosis and treatment of glomerulonephritis. The teachings that were identified as being of lower quality or insufficient intensity included vascular access management, ultrasound diagnostics and renal nutrition. The need for improvement in formal teaching programs was underlined. Young nephrologists were rather satisfied with their salary and with the quality of the work they were doing, but only few were interested in an academic career since it was generally held that it is "too difficult" to obtain a university position. Many young nephrologists who filled in the questionnaire felt that lack of experience in peritoneal dialysis and vascular access management was a barrier to finding an ideal job. Compared to other European training programs, the Italian program differs with regard to longer exposure to nephrology (as compared to internal medicine), and greater flexibility for internships in different settings, including abroad. CONCLUSIONS: This first nationwide survey on the satisfaction of residents in nephrology indicates that, despite rather good overall satisfaction, there is room for improvement to make nephrology a more appealing choice and to fulfill the needs of a growing number of renal disease patients.

Financial Toxicity in Renal Patients (FINTORE) Study: A Cross-Sectional Italian Study on Financial Burden in Kidney Disease-A Project Protocol.

Financial toxicity (FT) refers to the negative impact of health-care costs on clinical conditions. In general, social determinants of health, especially poverty, socioenvironmental stressors, and psychological factors, are increasingly recognized as important determinants of non-communicable diseases, such as chronic kidney disease (CKD), and their consequences. We aim to investigate the prevalence of FT in patients at different stages of CKD treated in our universal health-care system and from pediatric nephrology, hemodialysis, peritoneal dialysis and renal transplantation clinics. FT will be assessed with the Patient-Reported Outcome for Fighting Financial Toxicity (PROFFIT) score, which was first developed by Italian oncologists. Our local ethics committee has approved the study. Our population sample will answer the sixteen questions of the PROFFIT questionnaire, seven of which are related to the outcome and nine the determinants of FT. Data will be analyzed in the pediatric and adult populations and by group stratification. We are confident that this study will raise awareness among health-care professionals of the high risk of adverse health outcomes in patients who have both kidney disease and high levels of FT. Strategies to reduce FT should be implemented to improve the standard of care for people with kidney disease and lead to truly patient-centered care.

Personalized Medicine in Kidney Disease.

The Special Issue "Personalized Medicine in Kidney Disease" is focused on the importance of customized medicine in nephrology as it represents one of the main characteristics of successful therapeutic results [...].

[Tic douloureux sustained by an eye tumor].

Cancer is a major cause of morbidity and mortality in solid organ transplantation. Nonmelanoma skin cancer (NMSC) such as basocellular (BCC) and spinocellular (SCC) carcinoma, are common in renal transplant recipients. We report a case of an SCC affecting a lacrimal gland in a subject with kidney transplantation. A man aged 75 years who had suffered from glomerulopathy since 1967 and subsequently started haemodialysis, in 1989 was transplanted from a living donor. In 2019, he suffered paresthesia and pain in his right eyebrow arch and he was diagnosed to have neuralgia of the fifth cranial nerve. The failure of medical treatment and the development of a mass in his eyelid plus exophthalmos induced healthcare professionals to perform a magnetic resonance. The latter showed a retrobulbar mass measuring 39×22×16 mm3. Biopsy revealed an SCC and the patient underwent eye exenteration. Although NMSC of the eye is an extremely rare condition, risk factors such as male sex, history of glomerulopathy, and duration of immunosuppression should be taken into consideration at the time of the onset of eye symptoms.

The Hypertensive Disorders of Pregnancy: A Focus on Definitions for Clinical Nephrologists.

About 5-10% of pregnancies are complicated by one of the hypertensive disorders of pregnancy. The women who experience these disorders have a greater risk of having or developing kidney diseases than women with normotensive pregnancies. While international guidelines do not provide clear indications for a nephrology work-up after pregnancy, this is increasingly being advised by nephrology societies. The definitions of the hypertensive disorders of pregnancy have changed greatly in recent years. The objective of this short review is to gather and comment upon the main definitions of the hypertensive disorders of pregnancy as a support for nephrologists, who are increasingly involved in the short- and long-term management of women with these disorders.

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.

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.

Role of Zinc in Diabetic Kidney Disease.

Diabetic Kidney Disease (DKD) represents the most common cause of Chronic Kidney Disease (CKD) in developed countries. Approximately 30% to 40% of diabetes mellitus (DM) subjects develop DKD, and its presence significantly increases the risk for morbidity and mortality. In this context, Zinc seems to have a potential role in kidney and body homeostasis in diabetic individuals as well as in patients at a high risk of developing this condition. This essential element has functions that may counteract diabetes-related risk factors and complications, which include stabilization of insulin hexamers and pancreatic insulin storage and improved glycemic control. In our review, we analyzed the current knowledge on the role of zinc in the management of renal impairment in course of DM. Several studies underline the critical role of zinc in reducing oxidative stress levels, which is considered the common denominator of the mechanisms responsible for the progression of kidney disease. Reaching and maintaining a proper serum zinc level could represent a valuable target to reduce symptoms related to DM complications and contrast the progression of kidney impairment in patients with the high risk of developing end-stage renal disease. In conclusion, analyzing the beneficial role of zinc in this review would advance our knowledge on the possible strategies of DM and DKD treatment.

Cardiorenal Syndrome: New Pathways and Novel Biomarkers.

Cardiorenal syndrome (CRS) is a multi-organ disease characterized by the complex interaction between heart and kidney during acute or chronic injury. The pathogenesis of CRS involves metabolic, hemodynamic, neurohormonal, and inflammatory mechanisms, and atherosclerotic degeneration. In the process of better understanding the bi-directional pathophysiological aspects of CRS, the need to find precise and easy-to-use markers has also evolved. Based on the new pathophysiological standpoints and an overall vision of the CRS, the literature on renal, cardiac, metabolic, oxidative, and vascular circulating biomarkers was evaluated. Though the effectiveness of different extensively applied biomarkers remains controversial, evidence for several indicators, particularly when combined, has increased in recent years. From new aspects of classic biomarkers to microRNAs, this review aimed at a 360-degree analysis of the pathways that balance the kidney and the heart physiologies. In this delicate system, different markers and their combination can shed light on the diagnosis, risk, and prognosis of CRS.

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.