Cyclosporin-induced hypertension is associated with the up-regulation of Na+-K+-2Cl- cotransporter (NKCC2).

BACKGROUND: The use of cyclosporin A (CsA) is hampered by the development of nephrotoxicity including hypertension, which is partially dependent on renal sodium retention. To address this issue, we have investigated in vivo sodium reabsorption in different nephron segments of CsA-treated rats through micropuncture study coupled to expression analyses of sodium transporters. To translate the findings in rats to human, kidney-transplanted patients having CsA treatment were enrolled in the study. METHODS: Adult male Sprague-Dawley rats were treated with CsA (15 mg/kg/day) for 21 days, followed by micropuncture study and expression analyses of sodium transporters. CsA-treated kidney-transplanted patients with resistant hypertension were challenged with 50 mg furosemide. RESULTS: CsA-treated rats developed hypertension associated with reduced glomerular filtration rate. In vivo microperfusion study demonstrated a significant decrease in rate of absolute fluid reabsorption in the proximal tubule but enhanced sodium reabsorption in the thick ascending limb of Henle's loop (TAL). Expression analyses of sodium transporters at the same nephron segments further revealed a reduction in Na+-H+ exchanger isoform 3 (NHE3) in the renal cortex, while TAL-specific, furosemide-sensitive Na+-K+-2Cl- cotransporter (NKCC2) and NHE3 were significantly upregulated in the inner stripe of outer medulla. CsA-treated patients had a larger excretion of urinary NKCC2 protein at basal condition, and higher diuretic response to furosemide, showing increased FeNa+, FeCl- and FeCa2+ compared with both healthy controls and FK506-treated transplanted patients. CONCLUSION: Altogether, these findings suggest that up-regulation of NKCC2 along the TAL facilitates sodium retention and contributes to the development of CsA-induced hypertension.

Efficacy of erythropoietin as a neuroprotective agent in CKD-associated cognitive dysfunction: A literature systematic review.

Patients with chronic kidney disease (CKD) often experience mild cognitive impairment and other neurocognitive disorders. Studies have shown that erythropoietin (EPO) and its receptor have neuroprotective effects in cell and animal models of nervous system disorders. Recombinant human EPO (rHuEPO), commonly used to treat anemia in CKD patients, could be a neuroprotective agent. In this systematic review, we aimed to assess the published studies investigating the cognitive benefits of rHuEPO treatment in individuals with reduced kidney function. We comprehensively searched Pubmed, Cochrane Library, Scopus, and Web of Science databases from 1990 to 2023. After selection, 24 studies were analyzed, considering study design, sample size, participant characteristics, intervention, and main findings. The collective results of these studies in CKD patients indicated that rHuEPO enhances brain function, improves performance on neuropsychological tests, and positively affects electroencephalography measurements. These findings suggest that rHuEPO could be a promising neuroprotective agent for managing CKD-related cognitive impairment.

Measurement of Glomerular Filtration Rate in Patients Undergoing Renal Surgery for Cancer: Estimated Glomerular Filtration Rate versus Measured Glomerular Filtration Rate in the Era of Precision Medicine.

BACKGROUND: In the era of precision medicine, determining reliable renal function assessment remains a critical and debatable issue, especially in nephrology and oncology. SUMMARY: This paper delves into the significance of accurately measured glomerular filtration rate (mGFR) in clinical practice, highlighting its essential role in guiding medical decisions and managing kidney health, particularly in the context of renal cancer (RC) patients undergoing nephrotoxic anti-cancer drugs. The limitations and advantages of traditional glomerular filtration rate (GFR) estimation methods, primarily using serum biomarkers like creatinine and cystatin C, are discussed, emphasizing their possible inadequacy in cancer patients. Specifically, newer formulae designed for GFR estimation in cancer patients may not perform at best in RC patients. The paper explores various methods for direct GFR measurement, including the gold standard inulin clearance and alternatives like iohexol plasma clearance. KEY MESSAGE: Despite the logistical challenges of these methods, their implementation is crucial for accurate renal function assessment. The paper concludes by emphasizing the need for continued research and innovation in GFR measurement methodologies to improve patient outcomes, particularly in populations with complex medical needs.

Zebrafish as a Model of Cardiac Pathology and Toxicity: Spotlight on Uremic Toxins.

Chronic kidney disease (CKD) is an increasing health care problem. About 10% of the general population is affected by CKD, representing the sixth cause of death in the world. Cardiovascular events are the main mortality cause in CKD, with a cardiovascular risk 10 times higher in these patients than the rate observed in healthy subjects. The gradual decline of the kidney leads to the accumulation of uremic solutes with a negative effect on every organ, especially on the cardiovascular system. Mammalian models, sharing structural and functional similarities with humans, have been widely used to study cardiovascular disease mechanisms and test new therapies, but many of them are rather expensive and difficult to manipulate. Over the last few decades, zebrafish has become a powerful non-mammalian model to study alterations associated with human disease. The high conservation of gene function, low cost, small size, rapid growth, and easiness of genetic manipulation are just some of the features of this experimental model. More specifically, embryonic cardiac development and physiological responses to exposure to numerous toxin substances are similar to those observed in mammals, making zebrafish an ideal model to study cardiac development, toxicity, and cardiovascular disease.

Stem Cells in Kidney Ischemia: From Inflammation and Fibrosis to Renal Tissue Regeneration.

Ischemic nephropathy consists of progressive renal function loss due to renal hypoxia, inflammation, microvascular rarefaction, and fibrosis. We provide a literature review focused on kidney hypoperfusion-dependent inflammation and its influence on renal tissue's ability to self-regenerate. Moreover, an overview of the advances in regenerative therapy with mesenchymal stem cell (MSC) infusion is provided. Based on our search, we can point out the following conclusions: 1. endovascular reperfusion is the gold-standard therapy for RAS, but its success mostly depends on treatment timeliness and a preserved downstream vascular bed; 2. anti-RAAS drugs, SGLT2 inhibitors, and/or anti-endothelin agents are especially recommended for patients with renal ischemia who are not eligible for endovascular reperfusion for slowing renal damage progression; 3. TGF-ß, MCP-1, VEGF, and NGAL assays, along with BOLD MRI, should be extended in clinical practice and applied to a pre- and post-revascularization protocols; 4. MSC infusion appears effective in renal regeneration and could represent a revolutionary treatment for patients with fibrotic evolution of renal ischemia.

Therapeutic Plasmapheresis: a revision of literature.

BACKGROUND: Therapeutic Plasmapheresis (TP) is an extracorporeal therapy that allows the removal of pathogens from plasma. The role of TP in immuno-mediated diseases and toxic conditions has been of interest for decades. SUMMARY: We reviewed the recent literature on the application and the optimal choice of TP technique ranging from Plasma Exchange, Double Filtration Plasmapheresis, Rheopheresis, Immunoadsorptions and Lipidoapheresis. In addition, we report our experience in the application of TP for various diseases ranging in different medical specialties, following the American Society for Apheresis (ASFA) recommendations. KEY MESSAGES: Overall patients receiving TP showed an improvement in clinical and laboratory parameters. Our review and single center experience suggest a benefit of the application of TP in multiple clinical disciplines.

Ischemic Nephropaty: The Role of the Renal Artery Stenosis Revascularization on Renal Stem Cells.

We report the case of a 65-year-old man with acute GFR decline to 37 mL/min and uncontrolled high blood pressure. He was suspected for renovascular hypertension and underwent a renal color Doppler ultrasound scan that detected a bilateral atherosclerotic renal artery stenosis. A digital selective angiography by percutaneous transluminal angioplasty and stenting (PTRAs) was successfully performed. Blood pressure rapidly normalized, GFR increased within a few days, and proteinuria disappeared thereafter. These clinical goals were accompanied by a significant increase of circulating renal stem cells (RSC) and a slight increase of resistive index (RI) in both kidneys. This single observation suggests the need for extensive studies aimed at evaluating the predictive power of RI and RSC in detecting post-ischemic renal repair mechanisms.

Kidney Transplant Modifies the Architecture and Microenvironment of Basal Cell Carcinomas.

BACKGROUND/AIMS: Basal cell carcinoma (BCC) is a frequent type of nonmelanoma skin cancer, which shows a greater prevalence in kidney-transplanted (KT) patients than in the general population. The study of this tumor in KT patients may allow us to understand the influence of the tumor inflammatory microenvironment on cancer behavior, and to design new image analysis methods to determine prognosis and apply personalized medicine. The major hypothesis of the present work is that antirejection drugs, by modifying the B-cell/T-cell balance, induce measurable differences in tumoral cell microarchitecture and in the inflammatory microenvironment in KT patients compared to nontransplanted controls. METHODS: In this retrospective study in an Italian cohort including 15 KT patients and 15 control subjects from the general population who developed BCC, we analyzed tissue microarchitecture and inflammatory infiltrates of BCC using state-of-the-art nonlinear image analysis techniques such as fractal dimension and sample entropy of internuclear distances. RESULTS: KT patients showed a nonsignificant trend to a greater number of nuclei in the basal cell layer compared to non-KT controls and subtle changes in the intact skin compared to controls. Similarly, the number of mitoses per unit length was almost doubled in the patients with KT compared to controls. However, when the number of mitotic cells was normalized by the total number of cells in the basal layer (mitotic index), these differences were not significant, although a clear trend was still present. Finally, KT patients showed a nonsignificant trend to an increased -density of inflammatory cells close to the tumoral cell layer. When considering the intact skin, this difference was significant, with a 70% increase in the density of inflammatory cells. CONCLUSION: Data comparing the microarchitecture of BCC in normal subjects and KT patients are scanty, and the present study is the first to use nonlinear image analysis techniques to this aim. The observed differences underscore the relevance of T-cell suppression in cancer behavior. These data suggest that BCC develops in treated patients with specific biological characteristics which should be further analyzed in terms of therapeutic response.

An open-label, randomized, placebo-controlled study on the effectiveness of a novel probiotics administration protocol (ProbiotiCKD) in patients with mild renal insufficiency (stage 3a of CKD).

PURPOSE: Gut dysbiosis has been described in advanced, but not in initial stages of CKD. Considering the relevant impact of gut dysbiosis on renal and cardiovascular risk, its diagnosis and treatment are clinically relevant. METHODS: We designed, open-label, placebo-controlled intervention study (ProbiotiCKD) to evaluate gut microbiota metabolism in a cohort of KDIGO CKD patients (n = 28) at baseline and after a randomly assigned treatment with probiotics or placebo. Gut microbiota status was evaluated on:. RESULTS: Basal mean fecal Lactobacillales and Bifidobacteria concentrations were abnormally low in both groups, while urinary indican and 3-MI levels were, indicating a mixed (fermentative and putrefactive) dysbiosis. After treatment, mean fecal Lactobacillales and Bifidobacteria concentrations were increased, only in the probiotics group (p < 0.001). Conversely, mean urinary indican and 3-MI levels only in the group treated with probiotics (p < 0.001). Compared to placebo group, significant improvements of C-reactive protein (p < 0.001), iron (p < 0.001), ferritin (p < 0.001), transferrin saturation (p < 0.001), ß2-microglobulin (p < 0.001), serum iPTH and serum calcium were observed only in the probiotics group. CONCLUSIONS: ProbiotiCKD is the first intervention study demonstrating that an intestinal mixed dysbiosis is present even in early CKD stage and can be effectively corrected by the novel mode of administration of high-quality probiotics with improvement of inflammatory indices, iron status and iPTH stabilization.

Correction to: An open-label, randomized, placebo-controlled study on the effectiveness of a novel probiotics administration protocol (ProbiotiCKD) in patients with mild renal insufficiency (stage 3a of CKD).

In the original publication of the article, few of the authors were missed in the author group.

Diuretic Resistance in Cardio-Nephrology: Role of Pharmacokinetics, Hypochloremia, and Kidney Remodeling.

BACKGROUND: Diuretic resistance is among the most challenging problems that the cardio-nephrologist must address in daily clinical practice, with a considerable burden on hospital admissions and health care costs. Indeed, loop diuretics are the first-line therapy to overcome fluid overload in heart failure patients. The pathophysiological mechanisms of fluid and sodium retention are complex and depend on several neuro-hormonal signals mainly acting on sodium reabsorption along the renal tubule. Consequently, doses and administration modalities of diuretics must be carefully tailored to patients in order to overcome under- or overtreatment. The frequent and tricky development of diuretic resistance depends in part on post-diuretic sodium retention, reduced tubular secretion of the drug, and reduced sodium/chloride sensing. Sodium and chloride depletions have been recently shown to be major factors mediating these processes. Aquaretics and high-saline infusions have been recently suggested in cases of hyponatremic conditions. This review discusses the limitations and strengths of these approaches. SUMMARY: Long-term diuretic use may lead to diuretic resistance in cardio-renal syndromes. To overcome this complication intravenous administration of loop diuretics and a combination of different diuretic classes have been proposed. In the presence of hyponatremia, high-saline solutions in addition to loop diuretics might be beneficial, whereas aquaretics require caution to avoid overcorrection. Key Messages: Diuretic resistance is a central theme for cardio-renal syndromes. Hyponatremia and hypochloremia may be part of the mechanisms for diuretic resistance. Aquaretics and high-saline solutions have been proposed as possible new therapeutic solutions.

ERK1,2 Signalling Pathway along the Nephron and Its Role in Acid-base and Electrolytes Balance.

Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.

Current evidence on the use of anti-RAAS agents in congenital or acquired solitary kidney.

RATIONAL: The inhibition of renin-angiotensin-aldosterone system (RAAS) is a major strategy for slowing the progression of chronic kidney disease (CKD). The utility of anti-RAAS agents in patients with congenital or acquired solitary kidney is still controversial. OBJECTIVE: A systematic literature review was conducted. MAIN FINDINGS: The conclusions of the few available studies on the topic are homogeneously in agreement with a long-term reno-protective activity of anti-RAAS drugs in patients with solitary kidney, especially if patients are hypertensive or proteinuric. However, angiotensin 2 (ANG2) levels permit a functional adaptation to a reduced renal mass in adults and is crucial for sustaining complete kidney development and maturation in children. A hormonal interference on ANG2 levels has been supposed in women. Consequently, at least in children and women, the use of ARBs appears more appropriate. Principle conclusions: Available data on this topic are limited; however, by their overall assessment, it would appear that anti-RAAS drugs might also be reno-protective in patients with solitary kidney. The use of ARBs, especially in children and in women, seems to be more appropriate. However, more experimental data would be strictly necessary to confirm this hypothesis.

Quality of life, clinical outcome, personality and coping in chronic hemodialysis patients.

RATIONAL: Our aim was to investigate the quality of life (QoL) in 103 patients undergoing chronic hemodialysis (HD) in an integrated assessment of clinical, personological, and adaptation parameters, also in a non-urban context. OBJECTIVES: We collected data from all chronic HD patients attending four HD units. Clinical status was assessed by Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines and by Age-adjusted Charlson Comorbidity Index (ACCI). Patients completed the following questionnaires: Kidney Disease Quality of Life Short Form (KDQOL-SF), Pittsburgh Sleep Quality Index (PSQI). Personality profile and coping style were assessed by Temperament and Character Inventory (TCI) revised and Coping Inventory for Stressful Situation (CISS). Data were analyzed by conventional descriptive statistics. Multiple forward stepwise linear regression analyses were performed. MAIN FINDINGS: Variables significantly associated with physical and mental components of KDQOL-SF were: intact parathyroid hormone (iPTH) (p = .004; p = .0015), typology of cohabitant (family member or not) (p = .022; p = .007), years of dialysis (p = .022; p = .048). Variables associated with mental component of KDQOL-SF were: PSQI (p = .000), task-coping (p = .000), avoidance-coping (p = .003), work status (p = .021). Principle conclusions: Our results suggest the importance of an integrated and multidirectional management of patients chronically undergoing HD and living in a non-urban context.

The correct renal function evaluation in patients with thyroid dysfunction.

Thyroid dysfunction induces several renal derangements involving all nephron portions. Furthermore, dysthyroidism is a recognized risk factor associated with the development of chronic kidney disease. Current data, in fact, demonstrate that either subclinical or overt thyroid disease is associated with significant changes in creatinine, estimated glomerular filtration rate, measured glomerular filtration rate and Cystatin C. Herein, we systematically reviewed several relevant studies aiming at the identification of the most sensitive and specific parameter for the correct renal function evaluation in patients with thyroid dysfunction, that are usually treated as outpatients. Our systematic review indicates that estimated glomerular filtration rate, preferably with CKD-EPI equation, appears to be the most reliable and wieldy renal function parameter. Instead, Cystatin C should be better used in the grading of thyroid dysfunction severity.

Renal Cystinuria and Immune Cells (T Lymphocytes) Dysfunction: What We Know about?

INTRODUCTION: Cystinuria (CYS) is the most common monogenic kidney stone disease. METHODS: Starting from an unusual case of CYS associated to primary sclerosing cholangitis, inflammatory bowel disease (IBD), and autoimmune hepatitis in a young male, we carefully review the literature and propose here a working hypothesis regarding the potential risk of cystinuric patients to develop conditions due to immune system dysregulation. To corroborate this hypothesis, we retrospectively evaluate the frequency of dysimmunity in a monocentric cohort including 36 cystinuric patients compared to healthy and disease controls. RESULTS: CYS patients have an increased prevalence of atopic disease compared to disease controls (p = 0.03) and 16.7% of CYS subjects were diagnosed with allergic disease to a variety of antigens. CONCLUSION: Further studies are needed to define the relationship between proximal tubular transport defect of CYS and dysregulated immunity.

[Hyponatremia and Electrolyte Disorders in Cancer Patients].

Onconephrology is a rising and rapidly expanding field of medicine in which nephrology and oncology meet each other. Besides multidisciplinary meetings, oncologists and nephrologists often discuss on timing of the treatment, dosage, and side effects management. Cancer patients often encounter different electrolyte disorders. They are mostly secondary to the tumor itself or consequences of its treatment. In the last years, the great efforts to find new therapies like targeted, immune, and cell-based led us to many new side effects. Hyponatremia, hypokalemia, hyperkalemia, hypercalcemia, and hypomagnesemia are among the most common electrolyte disorders. Data have shown a worse prognosis in patients with electrolytic imbalances. Additionally, they cause a delay in chemotherapy or even an interruption. It is important to diagnose promptly these complications and treat them. In this review, we provide a special focus on hyponatremia and its treatment as the most common electrolytes disorder in cancer patients, but also on newly described cases of hypo- and hyperkalemia and metabolic acidosis.

Impact of Thyroid Cancer Treatment on Renal Function: A Relevant Issue to Be Addressed.

Thyroid cancers require complex and heterogeneous therapies with different impacts on renal function. In our systematic literature review, we analyzed several aspects: renal function assessment, the impact of radiotherapy and thyroid surgery on kidney functioning, and mechanisms of nephrotoxicity of different chemotherapy, targeted and immunologic drugs. Our study revealed that the renal impact of thyroid cancer therapy can be a limiting factor in all radiotherapy, surgery, and pharmacological approaches. It is advisable to conduct a careful nephrological follow-up imposing the application of body surface based estimated Glomerular Filtration Rate (eGFR) formulas for the purpose of an early diagnosis and treatment of renal failure, guaranteeing the therapy continuation to thyroid cancer patients.

Fabry Disease in Women: Genetic Basis, Available Biomarkers, and Clinical Manifestations.

Fabry Disease (FD) is a rare lysosomal storage disorder caused by mutations in the GLA gene on the X chromosome, leading to a deficiency in α-galactosidase A (AGAL) enzyme activity. This leads to the accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3), in vital organs such as the kidneys, heart, and nervous system. While FD was initially considered predominantly affecting males, recent studies have uncovered that heterozygous Fabry women, carrying a single mutated GLA gene, can manifest a wide array of clinical symptoms, challenging the notion of asymptomatic carriers. The mechanisms underlying the diverse clinical manifestations in females remain not fully understood due to X-chromosome inactivation (XCI). XCI also known as "lyonization", involves the random inactivation of one of the two X chromosomes. This process is considered a potential factor influencing phenotypic variation. This review delves into the complex landscape of FD in women, discussing its genetic basis, the available biomarkers, clinical manifestations, and the potential impact of XCI on disease severity. Additionally, it highlights the challenges faced by heterozygous Fabry women, both in terms of their disease burden and interactions with healthcare professionals. Current treatment options, including enzyme replacement therapy, are discussed, along with the need for healthcare providers to be well-informed about FD in women, ultimately contributing to improved patient care and quality of life.