Evolution of the glomerulus in a marine environment and its implications for renal function in terrestrial vertebrates.

Nearly a century ago, Homer Smith proposed that the glomerulus evolved to meet the challenge of excretion of water in freshwater vertebrates. This hypothesis has been repeatedly restated in the nephrology and renal physiology literature, even though we now know that vertebrates evolved and diversified in marine (saltwater) environments. A more likely explanation is that the vertebrate glomerulus evolved from the meta-nephridium of marine invertebrates, with the driving force for ultrafiltration being facilitated by the apposition of the filtration barrier to the vasculature (in vertebrates) rather than the coelom (in invertebrates) and the development of a true heart and the more complex vertebrate vascular system. In turn, glomerular filtration aided individual regulation of divalent ions like magnesium, calcium, and sulfate compatible with the function of cardiac and skeletal muscle required for mobile predators. The metabolic cost, imposed by reabsorption of the small amounts of sodium required to drive secretion of these over-abundant divalent ions, was small. This innovation, developed in a salt-water environment, provided a preadaptation for life in freshwater, in which the glomerulus was co-opted to facilitate water excretion, albeit with the additional metabolic demand imposed by the need to reabsorb the majority of filtered sodium. The evolution of the glomerulus in saltwater also provided preadaptation for terrestrial life, where the imperative is conservation of both water and electrolytes. The historical contingencies of this scenario may explain why the mammalian kidney is so metabolically inefficient, with ∼80% of oxygen consumption being used to drive reabsorption of filtered sodium.

Sex differences in circadian regulation of kidney function of the mouse.

Kidney function is regulated by the circadian clock. Not only do glomerular filtration rate and urinary excretion oscillate during the day, but the expressions of several renal transporter proteins also exhibit circadian rhythms. Interestingly, the circadian regulation of these transporters appears to be sexually dimorphic. Thus, the goal of the present study was to investigate the mechanisms by which the kidney function of the mouse is modulated by sex and time of day. To accomplish this, we developed the first computational models of epithelial water and solute transport along the mouse nephrons that represent the effects of sex and the circadian clock on renal hemodynamics and transporter activity. We conducted simulations to study how the circadian control of renal transport genes affects overall kidney function and how that process differs between male and female mice. Simulation results predicted that tubular transport differs substantially among segments, with relative variations in water and Na+ reabsorption along the proximal tubules and thick ascending limb tracking that of glomerular filtration rate. In contrast, relative variations in distal segment transport were much larger, with Na+ reabsorption almost doubling during the active phase. Oscillations in Na+ transport drive K+ transport variations in the opposite direction. Model simulations of basic helix-loop-helix ARNT like 1 (BMAL1) knockout mice predicted a significant reduction in net Na+ reabsorption along the distal segments in both sexes, but more so in males than in females. This can be attributed to the reduction of mean epithelial Na+ channel activity in males only, a sex-specific effect that may lead to a reduction in blood pressure in BMAL1-null males.NEW & NOTEWORTHY How does the circadian control of renal transport genes affect overall kidney function, and how does that process differ between male and female mice? How does the differential circadian regulation of the expression levels of key transporter genes impact the transport processes along different nephron segments during the day? And how do those effects differ between males and females? We built computational models of mouse kidney function to answer these questions.

Urinary Diversion: Core Curriculum 2021.

Urinary diversion after cystectomy has been a historical standard for the treatment of numerous benign and malignant diseases of the bladder. Since the first published description in the early 1900s, improvements in surgical technique and a better understanding of the metabolic sequelae postoperatively have greatly enhanced patient outcomes. Both continent and incontinent diversions are available to patients after cystectomy. In appropriately selected patients, orthotopic neobladder reconstruction can offer preservation of body image and continence, and continent cutaneous diversions represent a reasonable alternative. Conduit diversion, which remains the most commonly performed diversion technique, is ideal for patients who would benefit from a less morbid surgical procedure that negates the need for self-catheterization. This installment of the Core Curriculum in Nephrology outlines numerous aspects of urinary diversion, in which a multidisciplinary approach to postoperative management at the intersection of nephrology and urology is required to effectively optimize patient outcomes. This article includes a discussion of the various reconstructive options after cystectomy as well as a comprehensive review of frequently encountered short-term and long-term metabolic abnormalities associated with altered electrolyte and acid-base homeostasis.

A novel regulator of thirst behavior: phoenixin.

There are examples of physiological conditions under which thirst is inappropriately exaggerated, and the mechanisms for these paradoxical ingestive behaviors remain unknown. We are interested in thirst mechanisms across the female life cycle and have identified a novel mechanism through which ingestive behavior may be activated. We discovered a previously unrecognized endogenous hypothalamic peptide, phoenixin (PNX), identified physiologically relevant actions of the peptide in brain and pituitary gland to control reproductive hormone secretion in female rodents, and in the process identified the previously orphaned G protein-coupled receptor Gpr173 to be a potential receptor for the peptide. Labeled PNX binding distribution in brain parallels areas known to be important in ingestive behaviors as well in areas where gonadal steroids feedback to control estrous cyclicity (Stein LM, Tullock CW, Mathews SK, Garcia-Galiano D, Elias CF, Samson WK, Yosten GLC, Am J Physiol Regul Integr Comp Physiol 311: R489-R496, 2016). We have demonstrated upregulation of Gpr173 during puberty, fluctuations across the estrous cycle, and, importantly, upregulation during the last third of gestation. It is during this hypervolemic, hyponatremic state that both vasopressin secretion and thirst are inappropriately elevated in humans. Here, we show that central administration of PNX stimulated water drinking in both males and females under ad libitum conditions, increased water drinking after overnight fluid deprivation, and increased both water and 1.5% NaCl ingestion under fed and hydrated conditions. Importantly, losartan pretreatment blocked the effect of PNX on water drinking, and knockdown of Gpr173 by use of short interfering RNA constructs significantly attenuated water drinking in response to overnight fluid deprivation. These actions, together with the stimulatory action of PNX on vasopressin secretion, suggest that this recently discovered neuropeptide may impact the recruitment of critically important neural circuits through which ingestive behaviors and endocrine mechanisms that maintain fluid and electrolyte homeostasis are regulated.

Nitric Oxide Modulates HCN Channels in Magnocellular Neurons of the Supraoptic Nucleus of Rats by an S-Nitrosylation-Dependent Mechanism.

The control of the excitability in magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus has been attributed mainly to synaptic inputs from circunventricular organs. However, nitric oxide (NO), a gaseous messenger produced in this nucleus during isotonic and short-term hypertonic conditions, is an example of a modulator that can act directly on MNCs to modulate their firing rate. NO inhibits the electrical excitability of MNCs, leading to a decrease in the release of vasopressin and oxytocin. Although the effects of NO on MNCs are well established, the mechanism by which this gas produces its effect is, so far, unknown. Because NO acts independently of synaptic inputs, we hypothesized that ion channels present in MNCs are the targets of NO. To investigate this hypothesis, we used the patch-clamp technique in vitro and in situ to measure currents carried by hyperpolarization-activated and nucleotide-gated cation (HCN) channels and establish their role in determining the electrical excitability of MNCs in rats. Our results show that blockade of HCN channels by ZD7288 decreases MNC firing rate with significant consequences on the release of OT and VP, measured by radioimmunoassay. NO induced a significant reduction in HCN currents by binding to cysteine residues and forming S-nitrosothiol complexes. These findings shed new light on the mechanisms that control the electrical excitability of MNCs via the nitrergic system and strengthen the importance of HCN channels in the control of hydroelectrolyte homeostasis. SIGNIFICANCE STATEMENT: Cells in our organism live in a liquid environment whose composition and osmolality are maintained within tight limits. Magnocellular neurons (MNCs) of the supra optic nucleus can sense osmolality and control the synthesis and secretion of vasopressin (VP) and oxytocin (OT) by the neurohypophysis. OT and VP act on the kidneys controlling the excretion of water and sodium to maintain homeostasis. Here we combined electrophysiology, molecular biology, and radioimmunoassay to show that the electrical activity of MNCs can be controlled by nitric oxide (NO), a gaseous messenger. NO reacts with cysteine residues (S-nitrosylation) on hyperpolarization-activated and nucleotide-gated cation channels decreasing the firing rate of MNCs and the consequent secretion of VP and OT.

Role of the kidney in the pathogenesis of hypertension: time for a neo-Guytonian paradigm or a paradigm shift?

The "Guytonian paradigm" places the direct effect of arterial pressure, on renal excretion of salt and water, at the center of long-term control of blood pressure, and thus the pathogenesis of hypertension. It originated in the sixties and remains influential within the field of hypertension research. However, the concept of one central long-term feedback loop, through which arterial pressure is maintained by its influence on renal function, has been questioned. Furthermore, some concepts in the paradigm are undermined by experimental observations. For example, volume retention and increased cardiac output induced by high salt intake do not necessarily lead to increased arterial pressure. Indeed, in multiple models of salt-sensitive hypertension the major abnormality appears to be failure of the vasodilator response to increased cardiac output, seen in salt-resistant animals, rather than an increase in cardiac output itself. There is also evidence that renal control of extracellular fluid volume is driven chiefly by volume-dependent neurohumoral control mechanisms rather than through direct or indirect effects of changes in arterial pressure, compatible with the concept that renal sodium excretion is controlled by parallel actions of different feedback systems, including hormones, reflexes, and renal arterial pressure. Moreover, we still do not fully understand the sequence of events underlying the phenomenon of "whole body autoregulation." Thus the events by which volume retention may develop to hypertension characterized by increased peripheral resistance remain enigmatic. Finally, by definition, animal models of hypertension are not "essential hypertension;" progress in our understanding of essential hypertension depends on new results on system functions in patients.

Association between bipolar episodes and fluid and electrolyte homeostasis: a retrospective longitudinal study.

OBJECTIVES: Imbalance of fluid and electrolyte homeostasis has been suggested to be associated with the neuropathological processes underlying bipolar disorder. However, longitudinal data regarding the association of bipolar episodes with fluid balance are still lacking. We hypothesized that mania may be associated with a relative fluid retention and hemodilution, and depression with a relative hemoconcentration. METHODS: Patients with bipolar disorder (n = 43) admitted to a mental health center, both with depressive and manic episodes, were retrospectively followed between 2005 and 2013. Fluid balance and electrolyte serum indices were compared between their manic and depressive episodes. We adjusted for physical and psychiatric comorbidities and for psychotropic treatment, using two-way analysis of variance with repeated measures. RESULTS: There was a significant reduction in serum fluid balance indices during mania compared to depression: mean hemoglobin concentration 13.9 ± 1.4 g/dL versus 14.5 ± 1.4 g/dL, paired t = -4.2, p < 0.0005; mean hematocrit 41.1 ± 4.1% versus 42.3 ± 3.7%, paired t = -3.0, p < 0.005; mean albumin concentration 4.2 ± 0.3 g/dL versus 4.5 ± 0.3 g/dL, paired t = -4.5, p < 0.0001; and mean sodium concentration 140.3 ± 2.0 mEq/L versus 141.0 ± 2.0 mEq/L, paired t = -2.1, p = 0.04, respectively. Controlling for physical and psychiatric comorbidities and psychotropic treatment did not alter these associations. CONCLUSIONS: Our results support the notion of an imbalance of fluid and electrolyte homeostasis among bipolar episodes, which is suggestive for relative hemoconcentration during depressive episodes and relative hemodilution during manic episodes. These findings may eventually lead to novel therapeutic targets.

Hyperkalemia in patients undergoing hemodialysis: Its pathophysiology and management.

Potassium is a major intracellular cation in the body, regulating membrane potential of excitable cells, such as cardiomyocytes and skeletal muscle cells. Because the kidney plays a critical role in controlling potassium balance, the elevation in serum potassium levels is one of the most common complications in patients with maintenance hemodialysis (MHD). In addition to reduced renal potassium excretion, the alteration in body potassium distribution owing to comorbid conditions may also contribute to dyskalemia. Besides potassium elimination through hemodialysis in MHD patients, accumulating data indicate the potential importance of extra-renal elimination involving the gastrointestinal system, which can be affected by the inhibitors of the renin-angiotensin-aldosterone system. In this article, the literature on potassium physiology in MHD patients is reviewed with an emphasis on the changes from individuals with normal kidney function. This article also summarizes the findings of recent studies on dietary control, dialysate prescription, and pharmacological therapy.

Intra-operative diabetes insipidus associated with cervical spine traction during staged scoliosis surgery.

A 15-year-old boy with cerebral palsy and epilepsy presented for a posterior spinal fusion as part of staged repair of thoracolumbar scoliosis. Total intravenous anaesthesia was induced and maintained with propofol, remifentanil and ketamine. Following prone positioning, cervical traction was applied. Polyuria developed intra-operatively, from 4 to 18 ml.kg-1.h-1. There was a corresponding rise in plasma sodium concentration from 132 to 145 mmol.l-1. Haemodynamic stability was maintained with boluses of Hartmann's solution and a noradrenaline infusion. Given the possibility of diabetes insipidus due to reduced cerebral perfusion pressure, the cervical traction was removed. This initially showed a good response with a transient reduction in polyuria to 3 ml.kg-1.h-1 before rising to 8 ml.kg-1.h-1. Subsequently, a vasopressin infusion was started with normalisation of diuresis and plasma sodium concentration by the end of surgery. Diabetes insipidus is an endocrine disorder related to lack of production or insensitivity to vasopressin. In the peri-operative period, it is mainly associated with pituitary surgery and rarely with spinal surgery. To the authors' knowledge, this is only the second report of diabetes insipidus associated with staged scoliosis surgery. Cervical traction should be considered as a potential cause of intra-operative diabetes insipidus.

A Technology Roadmap for Innovative Approaches to Kidney Replacement Therapies: A Catalyst for Change.

The number of patients dialyzed for ESKD exceeds 500,000 in the United States and more than 2.6 million people worldwide, with the expectation that the worldwide number will double by 2030. The human cost of health and societal financial cost of ESKD is substantial. Dialytic therapy is associated with an unacceptably high morbidity and mortality rate and poor quality of life. Although innovation in many areas of science has been transformative, there has been little innovation in dialysis or alternatives for kidney replacement therapy (KRT) since its introduction approximately 70 years ago. Advances in kidney biology, stem cells and kidney cell differentiation protocols, biomaterials, sensors, nano/microtechnology, sorbents and engineering, and interdisciplinary approaches and collaborations can lead to disruptive innovation. The Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and the US Food and Drug Administration, has convened a multidisciplinary group to create a technology roadmap for innovative approaches to KRT to address patients' needs. The Roadmap is a living document. It identifies the design criteria that must be considered to replace the myriad functions of the kidney, as well as scientific, technical, regulatory, and payor milestones required to commercialize and provide patient access to KRT alternatives. Various embodiments of potential solutions are discussed, but the Roadmap is agnostic to any particular solution set. System enablers are identified, including vascular access, biomaterial development, biologic and immunologic modulation, function, and safety monitoring. Important Roadmap supporting activities include regulatory alignment and innovative financial incentives and payment pathways. The Roadmap provides estimated timelines for replacement of specific kidney functions so that approaches can be conceptualized in ways that are actionable and attract talented innovators from multiple disciplines. The Roadmap has been used to guide the selection of KidneyX prizes for innovation in KRT.

A novel model for studies of blood-mediated long-term responses to cellular transplants.

AIMS: Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h. METHODS: Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability. RESULTS: Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen. CONCLUSION: A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions.

Uptake of different crystal structures of TiO2 nanoparticles by Caco-2 intestinal cells.

The gastrointestinal uptake of different crystal structures of TiO2 was investigated using Caco-2 intestinal cells. Caco-2 monolayers exhibited time-dependent, saturable uptake of Ti from TiO2 exposures of 1 mgl(-1) over 24h, which was influenced by crystal type. Initial uptake rates were 5.3, 3.73, 3.58 and 4.48 nmol mg(-1)protein h(-1) for bulk, P25, anatase and rutile forms respectively. All exposures caused elevations of Ti in the cells relative to the control (ANOVA P<0.05). Electron micrographs of the Caco-2 monolayer showed the presence of particles inside the cells, and energy dispersive spectroscopy (EDS) confirmed the composition as TiO2. Incubating the cells with 120 IU nystatin (putative endocytosis inhibitor) or 100 µmol l(-1) vanadate (ATPase inhibitor) caused large increases in Ti accumulation for all crystal types relative to controls (ANOVA P<0.05), except for the rutile form with vanadate. Incubating the cells with 90 µmol l(-1) genistein (tyrosine kinase inhibitor) or 27 µmol l(-1) chloropromazine (clathrin-mediated endocytosis inhibitor) caused a large decrease in Ti accumulation relative to the controls (ANOVA P<0.05). Cell viability measures were generally good (low LDH leak, normal cell morphology), but there were some changes in the electrolyte composition (K(+), Na(+), Ca(2+), Mg(2+)) of exposed cells relative to controls. A rise in total Ca(2+) concentration in the cells was observed for all TiO2 crystal type exposures. Overall, the data shows that Ti accumulation for TiO2 NP exposure in Caco-2 cells is crystal structure-dependent, and that the mechanism(s) involves endocytosis of intact particles.