The interplay between sodium/glucose cotransporter type 2 and mitochondrial ionic environment.

Mitochondrial volume is maintained through the permeability of the inner mitochondrial membrane by a specific aquaporin and the osmotic balance between the mitochondrial matrix and cellular cytoplasm. Various electrolytes, such as calcium and hydrogen ions, potassium, and sodium, as well as other osmotic substances, affect the swelling of mitochondria. Intracellular glucose levels may also affect mitochondrial swelling, although the relationship between mitochondrial ion homeostasis and intracellular glucose is poorly understood. This article reviews what is currently known about how the Sodium-Glucose transporter (SGLT) may impact mitochondrial sodium (Na+) homeostasis. SGLTs regulate intracellular glucose and sodium levels and, therefore, interfere with mitochondrial ion homeostasis because mitochondrial Na+ is closely linked to cytoplasmic calcium and sodium dynamics. Recently, a large amount of data has been available on the effects of SGLT2 inhibitors on mitochondria in different cell types, including renal proximal tubule cells, endothelial cells, mesangial cells, podocytes, neuronal cells, and cardiac cells. The current evidence suggests that SGLT inhibitors (SGLTi) may affect mitochondrial dynamics regarding intracellular Sodium and hydrogen ions. Although the regulation of mitochondrial ion channels by SGLTs is still in its infancy, the evidence accumulated thus far of the effect of SGLTi on mitochondrial functions certainly will foster further research in this direction.

[Examination of Urinary Sediment in a Patient with Lupus-Like HIV-Associated Immune Complex Kidney Disease (HIVICK) - Case Report and Review of the Literature].

Renal involvement is very common in patients with HIV infection. The phenotype varies from the most frequently "collapsing" variant of focal and segmental glomerulosclerosis (FSGS) to "lupus-like HIV-immune complex kidney disease" (HIVICK). The latter is characterized by a histological picture that recalls lupus nephropathy. Through a clinical case, we underline the importance of urinary sediment analysis in patients with suspected glomerulopathy. Findings such as the characteristic cells that show the typical appearance of Herpes virus (HSV) infection or LE cells have significantly supported the diagnosis of HIVICK. In light of the present observations, we suggest systematically carrying out a cytological examination of the urinary sediment to confirm diagnostic hypotheses of rare pathologies.

[Apheresis Techniques for the Treatment of Hyperbilirubinemia in the Nephrology Unit].

Therapeutic apheresis is an important hematological and nephrological method for conditions with altered plasma composition. It is also indicated for the removal of protein-bound molecules, such as bilirubin. Several techniques can remove these compounds, such as the extracorporeal circulation molecular adsorption system (MARS), plasma exchange (PEX), and plasma adsorption and perfusion (PAP). Here we report our experience in the comparison between MARS, PEX and PAP, since current guidelines do not specify which method is the most appropriate and under which circumstances it should be used. The choice of technique cannot be based on the desired plasma bilirubin concentration, since these three techniques show similar results with a similar final outcome (exitus). In fact, PAP, PEX and MARS significantly reduce bilirubin levels, but the degree of reduction is not different among the three. Furthermore, the three techniques do not differ in the rate of cholinesterase change, while less reduction of liver transaminases was found by using PAP. MARS should be preferred in the case of renal involvement (hepatorenal syndrome with hyperbilirubinemia). PAP has the advantage of being simple and inexpensive. PEX remains an option when emergency PAP is not available, but the risk of using blood products (plasma and albumin) must be considered.

Mechanisms of Diabetic Nephropathy Not Mediated by Hyperglycemia.

Diabetes mellitus (DM) is characterized by the appearance of progressive kidney damage, which may progress to end-stage kidney disease. The control of hyperglycemia is usually not sufficient to halt this progression. The kidney damage is quantitatively and qualitatively different in the two forms of diabetes; the typical nodular fibrosis (Kimmelstiel Wilson nodules) appears mostly in type 1 DM, whereas glomerulomegaly is primarily present in type 2 obese DM. An analysis of the different metabolites and hormones in type 1 and type 2 DM and their differential pharmacological treatments might be helpful to advance the hypotheses on the different histopathological patterns of the kidneys and their responses to sodium/glucose transporter type 2 inhibitors (SGLT2i).

miR-218 Promotes Dopaminergic Differentiation and Controls Neuron Excitability and Neurotransmitter Release through the Regulation of a Synaptic-Related Genes Network.

In the brain, microRNAs (miRNAs) are believed to play a role in orchestrating synaptic plasticity at a higher level by acting as an additional mechanism of translational regulation, alongside the mRNA/polysome system. Despite extensive research, our understanding of the specific contribution of individual miRNA to the function of dopaminergic neurons (DAn) remains limited. By performing a dopaminergic-specific miRNA screening, we have identified miR-218 as a critical regulator of DAn activity in male and female mice. We have found that miR-218 is specifically expressed in mesencephalic DAn and is able to promote dopaminergic differentiation of embryonic stem cells and functional maturation of transdifferentiated induced DA neurons. Midbrain-specific deletion of both genes encoding for miR-218 (referred to as miR-218-1 and mir218-2) affects the expression of a cluster of synaptic-related mRNAs and alters the intrinsic excitability of DAn, as it increases instantaneous frequencies of evoked action potentials, reduces rheobase current, affects the ionic current underlying the action potential after hyperpolarization phase, and reduces dopamine efflux in response to a single electrical stimulus. Our findings provide a comprehensive understanding of the involvement of miR-218 in the dopaminergic system and highlight its role as a modulator of dopaminergic transmission.SIGNIFICANCE STATEMENT In the past decade, several miRNAs have emerged as potential regulators of synapse activity through the modulation of specific gene expression. Among these, we have identified a dopaminergic-specific miRNA, miR-218, which is able to promote dopaminergic differentiation and regulates the translation of an entire cluster of synapse related mRNAs. Deletion of miR-218 has notable effects on dopamine release and alters the intrinsic excitability of dopaminergic neurons, indicating a direct control of dopaminergic activity by miR-218.

A Reanalysis of Historical Figures With Depression and Dropsy.

OBJECTIVES: Recent studies suggest a link between chronic kidney disease and brain dysfunctions such as depression and cognitive problems. A review of medieval and early-modern historical figures with aspects of both kidney disease (gout and edema [dropsy]) and depression (melancholia) shows that these conditions were observed together in the past. MATERIALS AND METHODS: References to the diseases of gout, dropsy, and melancholia were compared in literature on historical subjects. Case studies are reported to detail a previously unremarked com-bination of current kidney disease and depression comorbidity in historical writings. RESULTS: The poet Boccaccio had gout and melancholia, and some descendants of the Portuguese Avis and Spanish Trastàmara dynasties, known for melancholia and madness, also had gout and dropsy. Historical case series of causes of death for sultans of the Ottoman Empire suggest an association among dropsy, gout, and melancholia. CONCLUSIONS: In this article, we reviewed the medical research on the comorbidity of kidney disease and depression and shared case studies of historical figures with these conditions and posit not previously noted data supporting comorbidity observations in historical writings.

Wall Tension and Tubular Resistance in Kidney Cystic Conditions.

The progressive formation of single or multiple cysts accompanies several renal diseases. Specifically, (i) genetic forms, such as adult dominant polycystic kidney disease (ADPKD), and (ii) acquired cystic kidney disease (ACKD) are probably the most frequent forms of cystic diseases. Adult dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by multiple kidney cysts and systemic alterations. The genes responsible for the condition are known, and a large amount of literature focuses on the molecular description of the mechanism. The present manuscript shows that a multiscale approach that considers supramolecular physical phenomena captures the characteristics of both ADPKD and acquired cystic kidney disease (ACKD) from the pathogenetic and therapeutical point of view, potentially suggesting future treatments. We first review the hypothesis of cystogenesis in ADPKD and then focus on ACKD, showing that they share essential pathogenetic features, which can be explained by a localized obstruction of a tubule and/or an alteration of the tubular wall tension. The consequent tubular aneurysms (cysts) follow Laplace's law. Reviewing the public databases, we show that ADPKD genes are widely expressed in various organs, and these proteins interact with the extracellular matrix, thus potentially modifying wall tension. At the kidney and liver level, the authors suggest that altered cell polarity/secretion/proliferation produce tubular regions of high resistance to the urine/bile flow. The increased intratubular pressure upstream increases the difference between the inside (Pi) and the outside (Pe) of the tubules (∆P) and is counterbalanced by lower wall tension by a factor depending on the radius. The latter is a function of tubule length. In adult dominant polycystic kidney disease (ADPKD), a minimal reduction in the wall tension may lead to a dilatation in the tubular segments along the nephron over the years. The initial increase in the tubule radius would then facilitate the progressive expansion of the cysts. In this regard, tubular cell proliferation may be, at least partially, a consequence of the progressive cysts' expansion. This theory is discussed in view of other diseases with reduced wall tension and with cysts and the therapeutic effects of vaptans, somatostatin, SGLT2 inhibitors, and potentially other therapeutic targets.

[Anti-MBG crescentic glomerulonephritis with negative immunofluorescence: case report and literature review].

Anti-glomerular basement membrane (anti-GBM) antibody disease is a rapidly progressive glomerulonephritis characterized by (i) positivity to anti-GBM in serum reacting with a specific antigen present in type IV collagen at both the glomerular and alveolar levels (ii) presence of crescent on light microscopy and positivity to linear deposits of IgG and C3 on immunofluorescence. In the classic variant, the clinic is that of a nephro-pneumological syndrome but there are variants. Rarely, the glomerular damage is pauci-immune. We describe a case of a variant in which there is anti-MBG positivity in serum but negative immunofluorescence and offer a review of the literature and potential treatments.

Metabolomic fingerprinting of renal disease progression in Bardet-Biedl syndrome reveals mitochondrial dysfunction in kidney tubular cells.

Chronic kidney disease (CKD) is a major clinical sign of patients with Bardet-Biedl syndrome (BBS), especially in those carrying BBS10 mutations. Twenty-nine patients with BBS and 30 controls underwent a serum-targeted metabolomic analysis. In vitro studies were conducted in two kidney-derived epithelial cell lines, where Bbs10 was stably deleted (IMCD3-Bbs10-/-cells) and over-expressed. The CKD status affected plasmatic metabolite fingerprinting in both patients with BBS and controls. Specific phosphatidylcholine and acylcarnitines discriminated eGFR decline only in patients with BBS. IMCD3-Bbs10-/ cells displayed intracellular lipidaccumulation, reduced mitochondrial potential membrane and citrate synthase staining. Mass-Spectrometry-based analysis revealed that human BBS10 interacted with six mitochondrial proteins, in vitro. In conclusion, renal dysfunction correlated with abnormal phosphatidylcholine and acylcarnitines plasma levels in patients with BBS; in vitro, Bbs10 depletion caused mitochondrial defects while human BBS10 interacted with several mitochondria-related proteins, suggesting an unexplored role of this protein.

Phosphate in the Context of Cognitive Impairment and Other Neurological Disorders Occurrence in Chronic Kidney Disease.

The nervous system and the kidneys are linked under physiological states to maintain normal body homeostasis. In chronic kidney disease (CKD), damaged kidneys can impair the central nervous system, including cerebrovascular disease and cognitive impairment (CI). Recently, kidney disease has been proposed as a new modifiable risk factor for dementia. It is reported that uremic toxins may have direct neurotoxic (astrocyte activation and neuronal death) and/or indirect action through vascular effects (cerebral endothelial dysfunction, calcification, and inflammation). This review summarizes the evidence from research investigating the pathophysiological effects of phosphate toxicity in the nervous system, raising the question of whether the control of hyperphosphatemia in CKD would lower patients' risk of developing cognitive impairment and dementia.

A Shared Nephroprotective Mechanism for Renin-Angiotensin-System Inhibitors, Sodium-Glucose Co-Transporter 2 Inhibitors, and Vasopressin Receptor Antagonists: Immunology Meets Hemodynamics.

A major paradigm in nephrology states that the loss of filtration function over a long time is driven by a persistent hyperfiltration state of surviving nephrons. This hyperfiltration may derive from circulating immunological factors. However, some clue about the hemodynamic effects of these factors derives from the effects of so-called nephroprotective drugs. Thirty years after the introduction of Renin-Angiotensin-system inhibitors (RASi) into clinical practice, two new families of nephroprotective drugs have been identified: the sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the vasopressin receptor antagonists (VRA). Even though the molecular targets of the three-drug classes are very different, they share the reduction in the glomerular filtration rate (GFR) at the beginning of the therapy, which is usually considered an adverse effect. Therefore, we hypothesize that acute GFR decline is a prerequisite to obtaining nephroprotection with all these drugs. In this study, we reanalyze evidence that RASi, SGLT2i, and VRA reduce the eGFR at the onset of therapy. Afterward, we evaluate whether the extent of eGFR reduction correlates with their long-term efficacy. The results suggest that the extent of initial eGFR decline predicts the nephroprotective efficacy in the long run. Therefore, we propose that RASi, SGLT2i, and VRA delay kidney disease progression by controlling maladaptive glomerular hyperfiltration resulting from circulating immunological factors. Further studies are needed to verify their combined effects.

[Methods for calculating the number of nephrons from ultrasound scans and kidney biopsies for nephrologists' use].

The interest in determining the number of nephrons in the kidney dates back to the 1960s, when an influential laboratory method for determining ex vivo the number of nephrons in the kidneys was described by Bricker. Over the years, various methods have been developed to estimate the number of nephrons in living beings as accurately as possible. These modern methods combine data such as the glomerular density, the percentage of glomeruli in sclerosis calculated from biopsy samples, and the kidney volume, which can be precisely estimated from magnetic resonance, CT scan, or specific ultrasound methods. As the reduction in the number of functioning nephrons is closely connected with an increased risk of progression of renal disease (especially in patients with nephrotic syndrome) and hypertension, its introduction into clinical practice could allow a precise stratification of progression risk in patients with kidney disease and a better understanding of the mechanisms that contribute to the loss of functioning nephrons.

Neuropeptide Y as a risk factor for cardiorenal disease and cognitive dysfunction in chronic kidney disease: translational opportunities and challenges.

Neuropeptide Y (NPY) is a 36-amino-acid peptide member of a family also including peptide YY and pancreatic polypeptide, which are all ligands to Gi/Go coupled receptors. NPY regulates several fundamental biologic functions including appetite/satiety, sex and reproduction, learning and memory, cardiovascular and renal function and immune functions. The mesenteric circulation is a major source of NPY in the blood in man and this peptide is considered a key regulator of gut-brain cross talk. A progressive increase in circulating NPY accompanies the progression of chronic kidney disease (CKD) toward kidney failure and NPY robustly predicts cardiovascular events in this population. Furthermore, NPY is suspected as a possible player in accelerated cognitive function decline and dementia in patients with CKD and in dialysis patients. In theory, interfering with the NPY system has relevant potential for the treatment of diverse diseases from cardiovascular and renal diseases to diseases of the central nervous system. Pharmaceutical formulations for effective drug delivery and cost, as well as the complexity of diseases potentially addressable by NPY/NPY antagonists, have been a problem until now. This in part explains the slow progress of knowledge about the NPY system in the clinical arena. There is now renewed research interest in the NPY system in psychopharmacology and in pharmacology in general and new studies and a new breed of clinical trials may eventually bring the expected benefits in human health with drugs interfering with this system.

Brain dysfunction in tubular and tubulointerstitial kidney diseases.

Kidney function has two important elements: glomerular filtration and tubular function (secretion and reabsorption). A persistent decrease in glomerular filtration rate (GFR), with or without proteinuria, is diagnostic of chronic kidney disease (CKD). While glomerular injury or disease is a major cause of CKD and usually associated with proteinuria, predominant tubular injury, with or without tubulointerstitial disease, is typically non-proteinuric. CKD has been linked with cognitive impairment, but it is unclear how much this depends on a decreased GFR, altered tubular function or the presence of proteinuria. Since CKD is often accompanied by tubular and interstitial dysfunction, we explore here for the first time the potential role of the tubular and tubulointerstitial compartments in cognitive dysfunction. To help address this issue we selected a group of primary tubular diseases with preserved GFR in which to review the evidence for any association with brain dysfunction. Cognition, mood, neurosensory and motor disturbances are not well characterized in tubular diseases, possibly because they are subclinical and less prominent than other clinical manifestations. The available literature suggests that brain dysfunction in tubular and tubulointerstitial diseases is usually mild and is more often seen in disorders of water handling. Brain dysfunction may occur when severe electrolyte and water disorders in young children persist over a long period of time before the diagnosis is made. We have chosen Bartter and Gitelman syndromes and nephrogenic diabetes insipidus as examples to highlight this topic. We discuss current published findings, some unanswered questions and propose topics for future research.

Chronic kidney disease and neurological disorders: are uraemic toxins the missing piece of the puzzle?

Chronic kidney disease (CKD) perturbs the crosstalk with others organs, with the interaction between the kidneys and the heart having been studied most intensively. However, a growing body of data indicates that there is an association between kidney dysfunction and disorders of the central nervous system. In epidemiological studies, CKD is associated with a high prevalence of neurological complications, such as cerebrovascular disorders, movement disorders, cognitive impairment and depression. Along with traditional cardiovascular risk factors (such as diabetes, inflammation, hypertension and dyslipidaemia), non-traditional risk factors related to kidney damage (such as uraemic toxins) may predispose patients with CKD to neurological disorders. There is increasing evidence to show that uraemic toxins, for example indoxyl sulphate, have a neurotoxic effect. A better understanding of factors responsible for the elevated prevalence of neurological disorders among patients with CKD might facilitate the development of novel treatments. Here, we review (i) the potential clinical impact of CKD on cerebrovascular and neurological complications, (ii) the mechanisms underlying the uraemic toxins' putative action (based on pre-clinical and clinical research) and (iii) the potential impact of these findings on patient care.

Cognitive disorders in patients with chronic kidney disease: specificities of clinical assessment.

Neurocognitive disorders are frequent among chronic kidney disease (CKD) patients. Identifying and characterizing cognitive impairment (CI) can help to assess the ability of adherence to CKD risk reduction strategy, identify potentially reversible causes of cognitive decline, modify pharmacotherapy, educate the patient and caregiver and provide appropriate patient and caregiver support. Numerous factors are associated with the development and progression of CI in CKD patients and various conditions can influence the results of cognitive assessment in these patients. Here we review clinical warning signs that should lead to cognitive screening; conditions frequent in CKD at risk to interfere with cognitive testing or performance, including specificities of cognitive assessment in dialysis patients or after kidney transplantation; and available tests for screening and observed cognitive patterns in CKD patients.

Urine concentrating defect as presenting sign of progressive renal failure in Bardet-Biedl syndrome patients.

BACKGROUND: Urine concentrating defect is a common dysfunction in ciliopathies, even though its underlying mechanism and its prognostic meaning are largely unknown. This study assesses renal function in a cohort of 54 Bardet-Biedl syndrome (BBS) individuals and analyses whether renal hyposthenuria is the result of specific tubule dysfunction and predicts renal disease progression. METHODS: The estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (ACR) and maximum urine osmolality (max-Uosm) were measured in all patients. Genetic analysis was conducted in 43 patients. Annual eGFR decline (ΔeGFR) was measured in patients with a median follow-up period of 6.5 years. Urine aquaporin-2 (uAQP2) excretion was measured and the furosemide test was performed in patients and controls. RESULTS: At baseline, 33 (61.1%), 12 (22.2%) and 9 (16.7%) patients showed an eGFR >90, 60-90 and <60 mL/min/1.73 m2, respectively; 27.3% showed an ACR >30 mg/g and 55.8% of patients showed urine concentrating defect in the absence of renal insufficiency. Baseline eGFR, but not max-Uosm, correlated negatively with age. Conversely, truncating mutations affected max-Uosm and showed a trend towards a reduction in eGFR. Max-Uosm correlated with ΔeGFR (P < 0.005), suggesting that urine concentrating defect may predict disease progression. uAQP2 excretion and Na+ and Cl- fractional excretion after furosemide did not differ between hyposthenuric patients and controls, suggesting that specific collecting duct and thick ascending limb dysfunctions are unlikely to play a central role in the pathogenesis of hyposthenuria. CONCLUSIONS: Hyposthenuria is a warning sign predicting poor renal outcome in BBS. The pathophysiology of this defect is most likely beyond defective tubular function.

Nephroplex: a kidney-focused NGS panel highlights the challenges of PKD1 sequencing and identifies a founder BBS4 mutation.

BACKGROUND: Genetic testing of patients with inherited kidney diseases has emerged as a tool of clinical utility by improving the patients' diagnosis, prognosis, surveillance and therapy. METHODS: The present study applied a Next Generation Sequencing (NGS)-based panel, named NephroPlex, testing 115 genes causing renal diseases, to 119 individuals, including 107 probands and 12 relatives. Thirty-five (poly)cystic and 72 non (poly)cystic individuals were enrolled. The latter subgroup of patients included Bardet-Biedl syndrome (BBS) patients, as major components. RESULTS: Disease-causing mutations were identified in 51.5 and 40% of polycystic and non-polycystic individuals, respectively. Autosomal dominant polycystic kidney disease (ADPKD) patients with truncating PKD1 variants showed a trend towards a greater slope of the age-estimated glomerular filtration rate (eGFR) regression line than patients with (i) missense variants, (ii) any PKD2 mutations and (iii) no detected mutations, according to previous findings. The analysis of BBS individuals showed a similar frequency of BBS4,9,10 and 12 mutations. Of note, all BBS4-mutated patients harbored the novel c.332+1G>GTT variant, which was absent in public databases, however, in our internal database, an additional heterozygote carrier was found. All BBS4-mutated individuals originated from the same geographical area encompassing the coastal provinces of Naples. DISCUSSION: In conclusion, these findings indicate the potential for a genetic panel to provide useful information at both clinical and epidemiological levels.