Jonathan Thompson, Hon.

• Professor of Anaesthesia and Critical Care, University of Leicester, Leicester

https://www2.le.ac.uk/departments/cardiovascular-sciences/people/thompson-jp

The persistent illness with standard care probably derives at least in part from the failure of dialysis to replace normal kidney functions medications before surgery cheap 60 mg diltiazem with mastercard. Dialysis is particularly deficient in removing certain classes of molecules that are well cleared by the normal kidneys treatment sinus infection cheap diltiazem 60 mg line. These include small proteins medicine review generic diltiazem 60 mg otc, protein-bound solutes symptoms kidney generic diltiazem 180 mg on-line, intracellular sequestered compounds medicine to prevent cold buy generic diltiazem 180 mg on line, and those which undergo high rates of active secretion by the normal tubule medications a to z purchase diltiazem now. The sources of these retained solutes are varied but include diet, enhanced production from human metabolism, and retention of metabolites originating from gut microbes. Recent approaches have begun to identify toxic compounds by epidemiologic studies and animal and cellular experiments, but clinical trials to more specifically remove or reduce production of candidate toxins are still wanting. The classic symptoms of uremia not attributable to electrolyte disorders are listed in Table 14. Those marked by an asterisk are substantially mitigated by current therapy including dialysis itself. Only a few, marked by two asterisks, are essentially completely abrogated by present approaches. The complications of untreated diabetes or hyperthyroidism are similarly extensive. But uremia is different in that we cannot trace all its complications to dysregulation of a single key compound. In addition, except for renal transplantation, current therapy for uremia cannot return affected patients as close to normal as those who require thyroid hormone or insulin replacement. Thus, uremic characteristics may be hard to dissect from complications of the dialysis procedure. Other morbidities that are considered separate from the uremia also commonly interact with it. Similarly, the peripheral neuropathy and gastroparesis of diabetes are difficult to disentangle from uremic neuropathy and uremic anorexia, nausea, and vomiting. Well-Being and Physical Function Given the spectrum of signs and symptoms in Table 14. But it is difficult to distinguish the extent to which depression is caused by uremic solutes, compared with the effects of comorbid disease and the knowledge of ill health and limited life expectancy. Patients identify insomnia, fatigue, cramping, and dysphoria as chief among their burdens10 Not surprisingly, transplantation has rather consistently been found to improve perception of quality of life. The exercise capacity of patients treated with dialysis has been found to be about 50% of normal, with a range of 40e80%. The degree to which they are attributable to the uremic environment itself, deconditioning, and/or comorbid conditions such as diabetes mellitus is difficult to establish. For example, balance, walking speed, and sensory function in these patients were clearly below those of matched controls. When awake, patients may feel a need to continuously move their legs, referred to as the restless legs syndrome. Parathyroid hormone, multiple retention solutes, and more recently potassium have been associated with peripheral neuropathy but without definitive proof of causality. Classic descriptions emphasized that uremic patients could appear alert despite defects in memory, planning, and attention. These include marinobufagenin and telocinobufagin, which have structures related to digitalis. In one report, the plasma concentrations of each of these substances was four- to fivefold higher in patients treated with dialysis compared with normal controls. Many other investigations in the field have relied on antibodybased assays whose specificity may be less reliable. The two compounds noted above, however, may be made by various animals and some others, but apparently not these two, are synthesized by plants (as, of course, is digitalis). Increased concentrations in renal failure could thus reflect impaired clearance of ingested materials rather than overproduction of endogenous products. Investigations in the field have not settled and indeed largely failed to address this question. A major deficiency in the case for endogenous digitalis-like factors has been the failure to define a biosynthetic pathway in mammals for these compounds, although they can be synthesized by plants and toads. Similar measurements of the excretion or production of other digitalis-like compounds in humans or even in animals are not available. Several considerations militate against digitalis-like substances as mediators of uremic toxicity. Cardiac fibrosis, a common complication of uremia, has been induced in rats with infusion of exogenous marinobufagenin. Most studies have used sera from patients or animals with complete renal failure although some, such as the study of marinobufagenin in rats, have used models of renal insufficiency. We assume that at least some of these residual morbidities are due to retained organic solutes that are poorly removed by dialysis. Conventional hemodialysis treatment aims at removing about two-thirds of the accumulated total body urea content during each of three weekly sessions. Removal of other compounds may be limited due to large molecular size, protein binding, or sequestration within body compartments. Consequently, conventional dialysis has widely different effects on uremic solute levels owing to their different chemical characteristics. A rational approach is to first consider those general classes of compounds that are poorly removed by dialysis compared with urea. However, uremic solutes that are relatively large compared with urea, including b-2 microglobulin, are poorly cleared by even high flux dialyzers compared with the normal kidney. Summed over a week, the normal kidneys thus provide about 1000 L of b-2 microglobulin clearance, whereas high flux dialysis provides about 20 L. Even with high flux membranes, levels of b-2 microglobulin in dialysis patients are therefore more than 20-fold higher than normal and would indeed rise even higher if there were not some nonrenal clearance of this solute. Examples of potentially toxic large molecule compounds in addition to b-2 microglobulin include complement factor D, various advanced glycosylation end products, and fragments of parathyroid hormone. Uremic solutes that are relatively large compared with urea are poorly cleared by even high flux dialyzers. The increase in the level of p-cresol sulfate would be of even greater magnitude if free rather than total plasma solute levels were compared. Even in a trial that demonstrated lower levels with hemodiafiltration, the levels of b-2 microglobulin remained more than 10fold normal. Protein-Bound Solutes the protein-bound uremic solutes have a low clearance because only the unbound fraction is available for diffusion across the dialysis membrane. This process transpires with such efficiency that for many such solutes a large fraction of the incoming bound portion is removed in a single pass. Dialysis does not replicate secretion, however, and the weekly dialytic clearance of many of these compounds is less than one-tenth that provided by normal kidneys. As a result, their levels in people treated with maintenance dialysis are typically more than ten times their concentrations in normal serum. Although experimental and clinical studies have suggested that the two most studied proteinbound solutes, indoxyl sulfate and p-cresol sulfate, have toxic effects both in experimental and clinical studies, some controversy still exists. Yet plasma levels of p-cresol sulfate and indoxyl sulfate do not rise higher in peritoneal dialysis patients than in hemodialysis patients. The reasons for this are not completely understood, but appear to include reduced production of the solutes as residual renal function is lost in peritoneal dialysis patients. Urea has selective membrane transporters that facilitate its diffusion in and out of red cells. For this reason changes in hematocrit have little effect on urea clearance by hemodialysis. Therefore, their dialytic clearances are lower than the dialytic urea clearance, and, unlike urea, their clearance may be dependent on hematocrit. Methylamine and methylguanidine are molecules with higher intrared blood cell concentration compared with plasma. For these reasons, their fractional removal by dialysis is less than that of urea and they display considerably more post dialysis rebound, as cellular compartments release them into the extracellular fluid after cessation of treatment. Other Solutes with Very High Clearance by Native Kidneys Urea and similar solutes are cleared at the highest rate by hemodialysis. With normal renal function, urea clearance is only one-half of creatinine clearance. Of course, these high clearances result from active tubular secretion, whereas dialytic clearance depends largely on diffusion. As a result of the much greater relative clearance by the native kidneys, patients treated with maintenance hemodialysis have hippurate levels twenty to forty times those in normal subjects. After raising this Sequestered Solutes A third category of toxic solutes that are difficult to remove through conventional dialysis are those sequestered in compartments where their concentration does not equilibrate rapidly with that of the plasma. Dialysis rapidly reduces the plasma concentration of such solutes, but clears only a limited proportion of the total body solute content if they do not readily transfer out of intracellular water or other reservoirs. The chemical identities of many of these are still unresolved, as they represent peaks in the chromatograms of highresolution mass spectrometry. However, a subset that was chemically identified has extraordinarily high clearances of their free fraction, even exceeding renal plasma flow. For 11 of 13 such solutes, their levels in hemodialysis patients exceeded that in normal subjects by more than 20-fold. Water-soluble vitamins are filtered through the dialysis membrane and require supplementation if intake is low. Another water-soluble vitamin, folic acid, was shown to be significantly cleared or lost during high-efficiency hemodialysis. Loss of amino acids during dialysis has been documented and likely contributes to malnutrition in hemodialysis patients. They derive from protein metabolism and nonenzymatic breakdown of creatine, respectively. The retention of the inorganic components of the uremic extracellular fluidd potassium, phosphate, and hydrogendis also well understood. The elevations in levels of small proteins such as b-2 microglobulin and complement Factor D seem largely to derive from their usual synthetic pathways in the face of impaired clearance. Many of these could be classed as secreted by the normal kidney and many were without previously known structure. However, additional complementary approaches are needed to determine which solutes are toxic and in what ways. Better endpoints than simply mortality or cardiovascular events are needed, and many of the disabilities presented in Table 14. Epidemiologic associations of some solutes with standard endpoints have been determined, suggesting toxicities for indoxyl sulfate, p-cresol sulfate, and asymmetric dimethylarginine, for example. Relatively straightforward adjustments to dialysis techniques enhance removal of protein-bound solutes, for example, but have not been tested for their effects on clinical endpoints. However, morbidities still persist, and attempts to understand their chemical etiologies have lagged behind other major advances in the field, such as more accurate ultrafiltration, bone and mineral therapy, and mitigation of anemia. Over the last decades, a few solutes have begun to receive serious attention as potential toxins, but progress has been slow. The reasons for this slow pace certainly include the chemical complexity of the uremic milieu and the multiplicity of clinical disturbances within the standardly dialyzed population. However, improving techniques for chemical analysis and the prospect of clinically meaningful quantifiable endpoints should propel more investigation. That one solute or even one class will account for all aspects of the residual syndrome seems unlikely. Undoubtedly, other components of chronic hemodialysis therapy beyond retained solutes, for example, episodic volume removal, also contribute to morbidities. The effective therapy of most chronic conditions, however, requires targeting multiple mechanisms. Adequate treatment of diabetes encompasses not just glycemic control but also blood pressure and lipid therapies. Unraveling the complexity of the residual syndrome is daunting, but that does not mean that it is insoluble. Efforts to resolve the residual syndrome by employing yet more intensive dialysis based on urea removal may have some benefits. But such efforts will likely have only a modest impact on some important solutes, while significantly increasing the burden on patients and providers. Quality of life in patients with chronic kidney disease: focus on end-stage renal disease treated with hemodialysis. Cross-sectional study of quality of life and symptoms in chronic renal disease patients: the Modification of Diet in Renal Disease Study. Health-related quality of life, depressive symptoms, anemia, and malnutrition at hemodialysis initiation. Changes in quality of life during hemodialysis and peritoneal dialysis treatment: generic and disease specific measures. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Symptom prioritization among adults receiving in-center hemodialysis: a mixed methods study. Neural and metabolic mechanisms of excessive muscle fatigue in maintenance hemodialysis patients. Subjective and objective physical limitations in high-functioning renal dialysis patients. Acute variation in cognitive function in hemodialysis patients: a cohort study with repeated measures. Chronic kidney disease and cognitive impairment in the elderly: the Health, Aging, and Body Composition study. High prevalence of leukoaraiosis in cerebral magnetic resonance images of patients on peritoneal dialysis.

Patients with chronic visceral pain show sex-related alterations in intrinsic oscillations of the resting brain symptoms precede an illness purchase diltiazem 60 mg overnight delivery. Diminished neurokinin-1 receptor availability in patients with two forms of chronic visceral pain section 8 medications discount 180mg diltiazem. Sex-related differences of cortical thickness in patients with chronic abdominal pain administering medications 8th edition generic 180mg diltiazem amex. Sex differences in emotion-related cognitive processes in irritable bowel syndrome and healthy control subjects medicine 257 buy diltiazem 180 mg low cost. Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndrome treatment varicose veins order diltiazem with american express. Contributions of the cerebellum to disturbed central processing of visceral stimuli in irritable bowel syndrome 72210 treatment order diltiazem 180mg online. Patients with irritable bowel syndrome have altered emotional modulation of neural responses to visceral stimuli. Does acupuncture therapy alter activation of neural pathway for pain perception in irritable bowel syndrome Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome. Tillisch K, Labus J, Nam B, Bueller J, Smith S, Suyenobu B, Siffert J, McKelvy J, Naliboff B, Mayer E. Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study. White matter abnormalities in irritable bowel syndrome and relation to individual factors. Corticotropin-releasing factor receptor 1 antagonist alters regional activation and effective connectivity in an emotional-arousal circuit during expectation of abdominal pain. Acute tryptophan depletion alters the effective connectivity of emotional arousal circuitry during visceral stimuli in healthy women. Altered brain structure in irritable bowel syndrome: potential contributions of pre-existing and disease-driven factors. Regional gray matter density changes in brains of patients with irritable bowel syndrome. Brain networks underlying perceptual habituation to repeated aversive visceral stimuli in patients with irritable bowel syndrome. Reduced brainstem inhibition during anticipated pelvic visceral pain correlates with enhanced brain response to the visceral stimulus in women with irritable bowel syndrome. Sex differences in brain activity during aversive visceral stimulation and its expectation in patients with chronic abdominal pain: a network analysis. Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients. Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia. Novel evidence for hypersensitivity of visceral sensory neural circuitry in irritable bowel syndrome patients. Longitudinal change in perceptual and brain activation response to visceral stimuli in irritable bowel syndrome patients. Brain activation responses to subliminal or supraliminal rectal stimuli and to auditory stimuli in irritable bowel syndrome. Abnormal forebrain activity in functional bowel disorder patients with chronic pain. Sex differences of brain serotonin synthesis in patients with irritable bowel syndrome using alpha-[11C]methyl-L-tryptophan, positron emission tomography and statistical parametric mapping. Regional brain activation in response to rectal distension in patients with irritable bowel syndrome and the effect of a history of abuse. Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome. Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Regional cerebral activity in normal and pathological perception of visceral pain. Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. Excessive coupling of the salience network with intrinsic neurocognitive brain networks during rectal distension in adolescents with irritable bowel syndrome: a preliminary report. Reduced functional connectivity between the hypothalamus and high-order cortical regions in adolescent patients with irritable bowel syndrome. Anatomical connections between brain areas activated during rectal distension in healthy volunteers: a visceral pain network. Visceral sensitivity as a mediator of outcome in the treatment of irritable bowel syndrome. Topological reorganization of the default mode network in irritable bowel syndrome. Interactions between gut permeability and brain structure and function in health and irritable bowel syndrome. Resting-state functional connectivity reflects structural connectivity in the default mode network. Altered gray matter volume in sensorimotor and thalamic regions associated with pain in localized provoked vulvodynia: a voxel-based morphometry study. Physiological and behavioral-responses to corticotropin-releasing factor administration-is Crf a mediator of anxiety or stress responses. Interactions of early adversity with stress-related gene polymorphisms impact regional brain structure in females. Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling. Social regulation of human gene expression: mechanisms and implications for public health. Reduced hippocampal glutamate-glutamine levels in irritable bowel syndrome: preliminary findings using magnetic resonance spectroscopy. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Evidence for alterations in central noradrenergic signaling in irritable bowel syndrome. Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention. Serotonin transporter gene polymorphism modulates activity and connectivity within an emotional arousal network of healthy men during an aversive visceral stimulus. Brain structure and response to emotional stimuli as related to gut microbial profiles in healthy women. Altered brain structure and functional connectivity and its relation to pain perception in female adolescents with irritable bowel syndrome. Pilot study of functional magnetic resonance imaging responses to somatic pain stimuli in youth with functional and inflammatory gastrointestinal disease. The gastrointestinal tract is protected by a specialized immune system which prevents pathogenic infection while preventing unnecessary immune responses to commensal bacteria. The gut microbiome plays important roles in the development and maintenance of the immune system and gastrointestinal motility. Alterations in the composition of the gut microbiome (dysbiosis) can initiate or potentiate autoimmune or inflammatory diseases, such as inflammatory bowel disease and type I diabetes as well as irritable bowel syndrome. Dysbiosis of the gut microbiome may contribute to the development of colorectal cancer and can affect the efficacy of cancer treatments. The gut microbiome A microbiome is the community of microorganisms that inhabit a particular environment, including bacteria, viruses and fungi. The human body contains more bacterial cells than human, with the largest site for colonization being the gastrointestinal tract, containing around 1014 microorganisms belonging to over 2000 species [1, 2]. With each niche in the body harboring a unique environment the microbiome differs vastly, with different species colonizing the gut compared to the skin [3]. The symbiotic relationship between humans and the microbiome is now thought to shape much of our biology, including the immune system and gut motility. However, due to the isolation of bacterial strains from amniotic fluid, umbilical cord blood, and placenta, it is now thought that microbiome development begins in utero [4]. Animal studies have also shown transfer of genetically labeled gut bacteria from a pregnant mother to the developing fetus [5]. This is further supported by data showing antibiotic treatment during late pregnancy can have a great effect on the composition of the infant microbiome [6]. Exposure to vaginal fluid from the mother at birth can alter the gut microbiome of infants born via cesarean section to be more similar to that of vaginal delivery [8]. Human breast milk contains around 109 bacterial cells per liter, including: Bifidobacterium, Propionibacterium, Enterococcus, Lactobacillus, Streptococcus, and Staphylococcus species [9]. It also contains oligosaccharides that encourage the growth of beneficial bacterial species: Bifidobacterium and Lactobacillus [10]. Comparatively, infants fed with formula have larger numbers of Firmicutes, including potential pathogens such as Clostridium difficile, in fecal microbiota [11]. Weaning onto solid foods vastly increases the microbial diversity within the infant gut. The bacterial composition depends on the diet of the child, with a higher ratio of species from the phyla Bacteroidetes to Firmicutes found in children Clinical and Basic Neurogastroenterology and Motility. The stages of gut microbiome development and the dominating phyla or genus of bacteria in each stage. The main factors affecting population composition at each stage are shown in blue. The presence of the gut microbiome benefits the host; contributing to digestion and energy harvest from food, gut and immune development, and the epithelial barrier [1]. However, fungi make up a small proportion of the microbiota, with yeast species Saccharomyces, Malassezia and Candida dominating [14]. Less is known about the composition of the gut virome, but viruses, in particular phage, are anticipated to have important roles in the microbiome [15, 16]. Gastrointestinal immunity the epithelial barrier the gastrointestinal tract has a complex immune system, capable of preventing infection by food borne pathogens, while maintaining colonization by commensal bacteria. These cells prevent the penetration of microbes, while allowing the absorption of nutrients and liquids. This is done through the establishment of tight junctions between cells, by molecules such as occludins and claudins, and the secretion of mucins and antimicrobial peptides [17]. Mucins are complex glycoproteins predominantly secreted by a specialized cell type within the epithelium, the goblet cell. This provides a layer of thick, viscous mucus which acts as a barrier, helping to prevent microbes from adhering to the epithelial surface [18]. These cells are the main producers of antimicrobial peptides, secreting -defensins, -defensins, lysozyme, and cathelicidins [19]. These peptides have bactericidal activity, helping to remove pathogens from the gut. Their importance can be seen in mouse models: Citrobacter rodentium is able to penetrate further into the mucosa in cathelicidin knock out mice [21], and mice with decreased numbers of Paneth cells were much more susceptible to Escherichia coli infection [22]. Innate immunity If any bacteria penetrate the epithelial layer, they reach a layer of connective tissue: the lamina propria. This area is populated by tissue resident phagocytes, including intestinal macrophages and dendritic cells. These cells phagocytose any bacteria that cross the epithelium, preventing systemic infection. The epithelial layer contains goblet cells, releasing mucins, and Paneth cells, releasing antimicrobial peptides, is covered by a thick mucus layer. The follicle associated epithelium differs from surrounding epithelium, with much less mucin production, allowing closer contact with gut microbes [25]. Adaptive immunity Mucosal B cells are predominantly plasma cells, secreting immunoglobulin A (IgA) as dimers or large polymers. The IgA is transported across the epithelium where it binds microorganisms, preventing their adherence to the epithelium. Their importance can be seen in mice unable to transport IgA into the mucosa, which greatly increases susceptibility to infection with the gastrointestinal pathogen Salmonella typhimurium [28]. IgA can also neutralize bacterial toxins, such as cholera toxin protecting against Vibrio cholerae induced diarrhea [29]. This induces maturation and proliferation of T and B cells within the germinal center. Tolerance to commensal microorganisms In order to maintain homeostasis within the gut, it is important that unnecessary inflammatory responses are avoided. Inflammation impairs the integrity of the epithelial barrier, allowing opportunistic pathogens to infect. Inflammatory signals can also turn commensal bacteria into pathogens through the induction of virulence genes. As the gut is continually exposed to food antigens and beneficial bacteria, it is of import that the immune system can differentiate these antigens from harmful antigens. One mechanism by which inflammatory reactions are avoided is by differentiation of tissue specific immune cells. For example, intestinal macrophages are characteristically different from circulating macrophages.

Transplant recipients have lower rate of depression compared with dialysis patients (Answer B) medicine hat jobs discount diltiazem 180mg. Relatively "healthy" dialysis patients with good nutrition and no significant comorbidities still have decline in physical functioning compared with normal individuals (Answer E) treatment quinsy buy discount diltiazem 60 mg online. Loss of appetite is a common uremic symptom and presumably contributes to malnutrition in patients with advanced renal failure B medicine 6 year in us order 60mg diltiazem. Anorexia is eliminated by proper dialysis Answer: E Anorexia is only alleviated symptoms kidney failure dogs generic 180 mg diltiazem fast delivery, but not completely eliminated by proper dialysis treatment (Answer E) symptoms kidney cancer buy diltiazem mastercard. The prevalence of depression is similar in patients receiving dialysis and those with a kidney transplant C medications on airplanes buy diltiazem 180 mg free shipping. Heerspinka, Ton Rabelinkb, Dick de Zeeuwa Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; bDepartment of Nephrology, Leiden University Medical Center, Leiden, Netherlands monitored and optimized as with high blood pressure or high cholesterol levels. This article reviews the pathophysiology of albuminuria and clinical studies that support the use of albuminuria as an independent target for renoprotective therapy. In systemic diseases, such as hypertension or diabetes mellitus, albuminuria is not only a marker of glomerular injury but may also contribute to renal function loss. The development of albuminuria and its adverse consequences is probably a multistep process where, initially, loss of endothelial barrier function may play a role. Endothelial activation within the glomeruli and subsequent shedding of the glycocalyx surface allows albumin to penetrate the subpodocyte space. Podocytes may then take up albumin through scavenger receptors and display actin skeleton rearrangements and injury. In addition, compensatory reabsorption in proximal tubules and the accompanying inflammatory responses may further contribute to the structural interstitial damage that has been associated with albuminuria and may ultimately lead to decreased nephron function. Further evidence regarding the role of albuminuria in the setting of progressive renal functional loss comes from observational studies demonstrating that the presence of albuminuria is associated with a high risk of renal functional loss over time. This association is found in various diseases such as diabetes mellitus, hypertensive kidney disease, primary renal disease of diverse origins, and even in the general, otherwise healthy, population. Certain drugs are available that decrease albuminuria, such as renineangiotensinealdosterone system inhibitors. More recently, other drugs such as sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and endothelin receptor antagonists have been shown to decrease albuminuria as well. It appears that the reduction in albuminuria, observed during the first months of therapy, correlates with the degree of long-term renal protection: the larger the reduction in albuminuria, the slower the rate of renal function decline. Collectively, these data suggest that albuminuria should not only be used to diagnose chronic kidney disease and estimate the risk for increased progressive renal functional loss, but albuminuria can also be used as a target for renoprotective therapy. The presence of albuminuria has emerged as an important risk marker of progressive renal functional loss in various populations. In a seminal article, he described that albumin could be present in otherwise healthy individuals, and he provided perspectives on the pathophysiology as well as suggestions for treatment. From 1960 to 1980, the standard techniques to measure proteinuria could detect only large quantities of proteins, typically in the range of urinary excretion of grams per day. The introduction of these techniques triggered the attention of diabetologists regarding measurement of urinary albumin in their patients. Clinical studies in the 1980s showed that small increases in urinary albumin excretion (termed microalbuminuria) predicted the development of overt nephropathy and the risk of mortality. Even in otherwise healthy persons, microalbuminuria was present in about 5%e10% of the population and predicted the rate of progression of kidney disease. The use of albuminuria as a cardiovascular risk marker and target for treatment has been reviewed elsewhere and will not be discussed. Consequently, tubular fluid contains only proteins of low molecular weight (<60 kD) such as vitamin D-binding protein or free retinol-binding protein, while larger proteins are excluded. Consequently, normal total urinary protein excretion in the normal adult should be less than 150 mg/day. The increased protein leak can be caused by an increase in the circulating levels of several different proteins. For example, one may observe tubular proteinuria consisting of low molecular weight proteins (less than 25 kD). Such proteinuria usually reflects a systemic disease with overproduction of small peptide fragments that are filtered and may cause tubular damage (such as beta 2-microglobulin, immunoglobulin light chains, and polypeptides derived from the breakdown of albumin). In addition, interference with proximal tubular reabsorption, due to tubulointerstitial diseases or genetic mutations, or overproduction of immunoglobulins, such as occurs in myeloma, can lead to increased excretion of these smaller proteins. Urinary albumin excretion more than 30 mg/day and less than 300 mg/day is called microalbuminuria. The composition and biological activity of this surface layer differs in an organ-specific manner. This finding confirmed those of previous studies: no albumin can pass through the glomerular endothelium unless the glycocalyx is disrupted. This direct link between endothelial function and glycocalyx properties may also explain, at least in part, the relationship between cardiovascular risk factors and albuminuria. On the capillary lumen side, mesangial cells are in direct contact with the glomerular endothelium without an intervening basement membrane, as one typically can observe with pericytes. Mesangial cells are considered to function as specialized pericytes and are consequently essential to stabilize glomerular endothelial function. The importance of the mesangium for function of the glomerular filtration barrier is shown by experiments where the mesangium is injured by toxins or antibodies. In the case of primary endothelial injury, widening of the subendothelial space and deposition of proteinaceous material precedes mesangiolytic changes. The middle panel shows on endothelial cell activation, through redox-sensitive signaling mechanisms, the endothelial glycocalyx is shed and albumin can pass the endothelial layer. Podocytes are subsequently exposed to modified albumin and the normal podocyte-endothelial signaling is disturbed. The lower panel shows podocytes take up albumin and undergo transformational changes that may result in podocyte effacement and podocyte drop-off. On endothelial activation, this signaling is disturbed and subendothelial protein deposits may develop. This may result in mesangiolysis and subsequent development of nodular lesions (lower panel). These phenomena typically can be observed in disease that primarily affects the endothelium, such as diabetes mellitus (KimmelstieleWilson lesion) and thrombotic microangiopathy. Genetic mutations of proteins that are required for podocyte function or direct antibody-mediated injury of podocytes may lead to podocyte effacement and dysfunction of the normal signaling between podocytes and endothelium. Consequently, the endothelium loses its highly specialized phenotype with fenestrations and the covering endothelial surface layer, the glycocalyx. This will result in albumin leakage through endothelium and disturbed slit diaphragm function. It provides a scaffold that supports the physiological function of the glomerular endothelium and podocytes. There are at least two different mechanisms by which podocytes can become involved in, and contribute to , the development and extent of albuminuria. Haraldsson and Deen showed elegantly that the most selective part of a multilayered passive filter cannot be in the last layer (that is, the slit diaphragm), because retention and accumulation of albumin would occur within the filter immediately in front of the slit diaphragm and lead to clogging. Interestingly, podocytes are equipped with a megalincubilin system,32 as well as scavenger receptors such as the receptor for advanced glycation end products,33 suggesting that podocytes may endocytose albumin. In the case of diabetes mellitus, podocytes may also be exposed to chemically modified and glycated albumin. Experimental data suggest that endocytosed albumin induces a mesenchymal transformation in podocytes, with loss of slit diaphragm proteins and induction of desmin. Secondly, elegant murine studies have unambiguously demonstrated that normal podocyte function is required for the integrity of the glomerular filtration barrier. Podocyte-specific deletions of genes that control its phenotype lead to loss of the glomerular endothelial phenotype and the development of proteinuria. Such gene deletion not only results in podocyte effacement but also in the disappearance of glomerular endothelial fenestration. Genetics With the increased clinical accessibility to whole exome sequencing, more genetic variants are being discovered that may render the glomerular filtration barrier susceptible to injury. While evolutionary advantageous to resist trypanosomiasis, the presence of variants is also associated with podocytes more susceptible to injury, such as high blood pressure, perhaps explaining the strong association between blood pressure and proteinuria in this population. The higher the concentration of albumin in the urine, the larger the chance of progressive renal functional loss. Albumin reabsorption takes place in the proximal tubule via receptor-mediated endocytosis. Two receptors, cubilin and megalin, have been identified as involved in albumin uptake. Under normal circumstances, the tubular concentration of albumin therefore is below the level that saturates this retrieval system. This means that even if some albumin passes through the glomerular filter, only very little albumin is excreted in the urine. The overall exposure to a certain albumin load over time is an important determinant of progressive renal functional loss, as well as the concentration itself. This has been illustrated in various studies of patients with glomerular diseases. A large Chinese observational study showed patients with immunoglobulin A (IgA) nephropathy with time-averaged urinary protein excretion of more than 1 g/day had a 46-fold increased risk compared with patients with a timeaveraged urinary protein excretion of 0. Similar findings were reported in patients with IgA nephropathies and diabetic kidney disease. If this persists for a short period of time, it does not directly induce visible damage. These data imply that albuminuria should be regularly measured to monitor individual renal risk prediction. To determine whether albuminuria fulfills this criterion, one can analyze within a trial whether a drug-induced change in albuminuria correlates with change in the risk for a renal outcome. The larger the reduction in albuminuria during the first weeks, the slower the rate of subsequent renal functional decline. To answer this one can evaluate studies that used different strategies (drugs or dietary interventions) to lower albuminuria and also monitored renal function. A low protein diet, for example, results in decreased albuminuria, and the magnitude of the reduction in albuminuria correlates with the degree of renoprotection. Post hoc analyses from these trials demonstrated that the degree of albuminuria reduction is associated with the degree of renal and cardiovascular risk reduction. The bias arises from the possibility that patients who show a clear albuminuria response may be a specific population with a lower renal risk. To address this type of bias, one should analyze multiple randomized controlled trials and correlate the effect of the intervention on albuminuria with its effect on hard renal endpoints across all trials. A meta-analysis involving 41 studies, including nearly 30,000 individuals and 7 different types of interventions, demonstrated that each 30% reduction in albuminuria during the first 6 months of treatment with these interventions was associated with a 27% lower hazard for the clinical renal endpoint during a median follow-up of 3. This study also reported that in patients with microalbuminuria or macroalbuminuria, an approximately 25% reduction in albuminuria is required to have high confidence that the drug will reduce the risk of a clinical renal endpoint. These data strengthen the notion that albuminuria is an independent target of renoprotective therapy. Most studies to date are not designed to establish that targeting of albuminuria results in additional renoprotection. To prove that targeting of albuminuria confers renal protection, one would need to randomize for the albuminuria response or design a trial to target albuminuria itself. The albuminuria-lowering properties of these drugs are unintended or off-target effects and are not the only off-target effects. The balance of these positive (those leading to protection) and negative (those inducing harm) surrogate effects determine the ultimate efficacy of a drug on renal outcome. Thus, a drug effect on a single target such as albuminuria should not be evaluated in isolation but considered in the context of all other offtarget surrogate effects as well. These drugs are mainly directed toward reducing the renal/vascular "leak" of albumin and or reducing the inflammatory sequelae of the albumin leak. The high number of congestive heart failure events may be due to the high doses of avosentan used, which resulted in significant sodium and fluid retention. This trial used a unique enrichment design to enhance the selection of patients most likely to benefit. Atrasentan significantly reduced the risk of renal events with no differences seen in hospital admission for heart failure or death. Novel antiinflammatory drugs decrease albuminuria in various relatively short-term studies. In a small phase 2 study involving patients with type 2 diabetes and macroalbuminuria, baricitinib, indicated for the treatment of rheumatoid arthritis, decreased albuminuria by 41%. Emerging experimental data illustrate the importance of the glycocalyx in preventing albumin leakage by glomeruli. When increased amounts of albumin penetrate the subglomerular space, compensatory tubular reabsorption and the accompanying inflammatory responses may further contribute to the structural interstitial damage that has been associated with albuminuria. Numerous large clinical studies showed that the level of albuminuria is associated with ultimate renal outcomes. Clinical trial analyses consistently show that drug-induced changes in albuminuria correlate with the long-term drug effects on renal outcomes. Collectively, these studies provide evidence that albuminuria can be viewed as a separate target for therapy. Reports of medical cases selected with a view to illustrating the symptoms and cure of diseases by a reference to morbid anatomy. Renal pathology and proteinuria determine progression in untreated mild/moderate chronic renal failure. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus.

Physical examination is normal including cardiac lungs and absent peripheral edema treatment 4 syphilis cheap 60 mg diltiazem. Avoidance of sodium phosphate bowel preparations for routine colonoscopy surveillance Answer: D the correct answer is D medicine 8 - love shadow order diltiazem with mastercard. Question 5 All of the following adult patients with laboratory data and characteristics below should be referred for nephrology consultation medications kidney infection cheap 180 mg diltiazem otc, except Answer: E All of the above are associated with early as compared with late nephrology referral symptoms ringworm buy diltiazem 180mg with visa. This requires infrastructure treatment integrity order diltiazem us, expense medicine 029 cheap diltiazem on line, and patient burden that are not feasible in most clinical settings. Endogenous circulating markers cleared primarily by glomerular filtration, particularly creatinine, are more practical and useful to detect level and loss of kidney function. Kidneys have two main roles: eliminating catabolic-induced wastes and regulating the watersodium equilibrium. In addition, the kidney has several endocrine roles, including erythropoiesis and maintenance of phosphorusecalcium balance. Other functions of the kidney include tubular reabsorption of nutrients and proteins, tubular secretion of metabolic wastes, and prevention of crystallization and stone formation in supersaturated urine. Nephron number can be determined from the volume of cortex in the kidney (determined from highresolution kidney imaging with computed tomography) multiplied by the three-dimensional density of glomeruli in the kidney cortex (determined from stereological calculations applied to a kidney biopsy). These discrepancies likely reflect differences in how healthy adults are selected for study, particularly in the older age groups where comorbidities are common and difficult to exclude. There was wide variation in this trend, and one-third actually had an increasing creatinine clearance. However, this analysis did not account for the substantial measurement error that occurs with urinary creatinine clearance or account for increasing creatinine clearance from diseases that cause hyperfiltration. Inulin is a 5200 Da polymer of fructose, which is found in some plants (such as chicory and leek), which use it as energy source. Nevertheless, inulin is not readily available and is expensive, and assays are not easily standardized. Iothalamate can be measured either by isotopic methods or by different analytical methods that do not require radiation. Many, but not all, studies have suggested iothalamate is secreted by renal tubules or has extrarenal clearance. Urinary clearance uses timed urine and plasma samples, and plasma clearance uses only plasma samples. Ideally, for both methods the marker would be infused at a constant rate until a steady state plasma concentration has been achieved. This is also often not practical with the time and expense constraints of clinical testing. For urinary clearance, some centers use a single subcutaneous injection of the marker, while others use constant intravenous infusions, but do not wait until steady state is achieved. Averaging the clearance over multiple urine collections is used to decrease test error. Sonographic scanning to assess bladder emptying with bladder catheters as needed can also be helpful. Like urinary clearances, a constant infusion is too time consuming to be practical, and a bolus infusion of the marker is given instead. Plasma clearances are not accurate in patients with extracellular volume expansion, such as edema or ascites. The two-compartment model is mathematically described as the sum of two exponential functions. The elimination rate constants of the two compartments are b1 and b2 and the corresponding intercepts on the ordinate are I1 and I2 (mg I/mL). This appears to be less problematic with enzymatic methods that show improved precision over Jaffe methods. There are no higher order reference methods or materials available and significant differences between the two assay types have been demonstrated. Rather than focusing on a specific endogenous filtration marker, a nontargeted metabolomic approach can be used to identify endogenous filtration markers. Reliability and standardization of endogenous filtration markers is particularly critical as their concentrations are lower in children than in adults. The African American coefficient may not be accurate in other black populations in Africa, Europe, Caribbean, or indigenous Australians. Thus, methodological differences between studies may explain these race coefficients. Relationship between urine volume and the rate of urea excretion by normal adults. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. The association between age and nephrosclerosis on renal biopsy among healthy adults. Age dependence of renal function: clearance of iohexol and p-amino hippurate in healthy males. The implications of anatomical and functional changes of the aging kidney: with an emphasis on the glomeruli. Renal function in the elderly (>70 years old) measured by means of iohexol clearance, serum creatinine, serum urea and estimated clearance. Comparison of acid and enzymatic methods for inulin dosage: analytical performances and impact on glomerular filtration rate evaluation. Demographic and clinical characteristics associated with glomerular filtration rates in living kidney donors. Glomerular filtration rate in healthy living potential kidney donors: a meta-analysis supporting the construction of the full age spectrum equation. Age-dependent reference intervals for estimated and measured glomerular filtration rate. The reference change value: a proposal to interpret laboratory reports in serial testing based on biological variation. The effect of exercise on the renal plasma flow and filtration rate of normal and cardiac subjects. Selection of routine method for determination of glomerular filtration rate in adult patients. Contrast media as markers for glomerular filtration: a pharmacokinetic comparison of four agents. The clinician and estimation of glomerular filtration rate by creatininebased formulas: current limitations and quo vadis. A simple technique for estimating glomerular filtration rate with subcutaneous injection of (125I)lothalamate. Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate. Iohexol plasma clearance in determining glomerular filtration rate in diabetic patients. Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research: a review. Luis-Lima S, Gaspari F, Negrin-Mena N, Carrara F, Diaz-Martin L, Jimenez-Sosa A, Gonzalez-Rinne F, Torres A, Porrini E. Glomerular filtration rate estimated by cystatin C among different clinical presentations. Evaluation of sample bias for measuring plasma iohexol clearance in kidney transplantation. Definition of chronic kidney disease after uninephrectomy in living donors: what are the implications Specificity characteristics of 7 commercial creatinine measurement procedures by enzymatic and Jaffe method principles. Measurement of muscle mass in humans: validity of the 24-hour urinary creatinine method. For estimating creatinine clearance measuring muscle mass gives better results than those based on demographics. A proposed mechanism for reduced creatinine excretion in severe chronic renal failure. The influence of a cooked meat meal on creatinine plasma concentration and creatinine clearance. Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate. Isolation, physiological importance, inhibitory mechanism, gene structure and relation to hereditary cerebral hemorrhage. Relationships among serum cystatin C, serum creatinine, lean tissue mass and glomerular filtration rate in healthy adults. Potential contribution of adipose tissue to elevated serum cystatin C in human obesity. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Effect of clinical variables and immunosuppression on serum cystatin C and beta-trace protein in kidney transplant recipients. The impact of interlaboratory differences in cystatin C assay measurement on glomerular filtration rate estimation. Filtration markers may have prognostic value independent of glomerular filtration rate. Molecular characterization of beta-trace protein in human serum and urine: a potential diagnostic marker for renal diseases. Beta-trace protein is an alternative marker for glomerular filtration rate in renal transplantation patients. Method of glomerular filtration rate estimation affects prediction of mortality risk. Beta-trace protein in serum: a new marker of glomerular filtration rate in the creatinine-blind range. Factors other than the glomerular filtration rate that determine the serum beta-2-microglobulin level. Inter-laboratory discordance of beta-2 microglobulin results: impact on the validity of the international staging system for multiple myeloma. Beta2-microglobulin for risk stratification of total mortality in the elderly population: comparison with cystatin C and C-reactive protein. A metabolome-wide association study of kidney function and disease in the general population. Metabolomic profiling to improve glomerular filtration rate estimation: a proof-of-concept study. Optimally predicting mortality with kidney function markers is not the same as optimally determining how kidney function predicts mortality. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Predictive performance of the modification of diet in renal disease and Cockcroft-Gault equations for estimating renal function. A systematic comparison of cockcroft-gault and modification of diet in renal disease equations for classification of kidney dysfunction and dosage adjustment. Serum cystatin C predicts vancomycin trough levels better than serum creatinine in hospitalized patients: a cohort study. Cystatin C-guided vancomycin dosing in critically ill patients: a quality improvement project. Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C. Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator. Cathepsins (S and B) and their inhibitor Cystatin C in immune cells: modulation by interferon-beta and role played in cell migration. Estimating the glomerular filtration rate from serum creatinine is better than from cystatin C for evaluating risk factors associated with chronic kidney disease. Performance of glomerular filtration rate estimation equations in Congolese healthy adults: the inopportunity of the ethnic correction. Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating the glomerular filtration rate in multiple ethnicities. Estimation of renal function in subjects with normal serum creatinine levels: influence of age and body mass index. Cystatin C or creatinine for detection of stage 3 chronic kidney disease in anorexia nervosa. Assessment of changes in kidney allograft function using creatinine-based estimates of glomerular filtration rate. Comparison of methods for determining renal function decline in early autosomal dominant polycystic kidney disease: the consortium of radiologic imaging studies of polycystic kidney disease cohort. A comparison of change in measured and estimated glomerular filtration rate in patients with nondiabetic kidney disease. Assessment of glomerular filtration rate in the neonate: is creatinine the best tool

Time-updated systolic blood pressure and the progression of chronic kidney disease: a cohort study treatment 5 shaving lotion purchase on line diltiazem. Blood pressure indexes and end-stage renal disease risk in adults with chronic kidney disease medications covered by medicare diltiazem 180 mg otc. Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: results from the atherosclerosis risk in communities study symptoms 89 nissan pickup pcv valve bad buy 60mg diltiazem. Limitations of the usual blood-pressure hypothesis and importance of variability medicine used to induce labor discount diltiazem 180 mg on-line, instability 911 treatment for hair generic 180mg diltiazem, and episodic hypertension symptoms 16 weeks pregnant purchase diltiazem on line amex. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Association of systolic blood pressure variability with mortality, coronary heart disease, stroke, and renal disease. Chronic dialysis and death among survivors of acute kidney injury requiring dialysis. Other tests such as cystatin C have shown promise as alternative filtration markers to creatinine, but their use has been hampered by cost and limited availability of assays. These mutations are thought to be more common in African populations because they are protective against the parasite causing African sleeping sickness. In numerous experimental models of renal disease, progression is accelerated in male animals. Gender dimorphism in the course of renal disease is replicated by hormonal manipulation, suggesting that the actions of sex hormones, rather than structural differences between the sexes, are responsible for genderrelated differences in renal disease progression. Sex hormones influence many of the processes known to mediate progressive renal injury including cell proliferation, mesangial matrix synthesis and degradation, generation of reactive oxygen species, and the expression of profibrotic proinflammatory cytokines, hormones, and vasoactive agents. Translation of these observations into therapeutic interventions has not yet been realized, although selective estrogen receptor modulators, which lack the detrimental effects of estrogen on reproductive tissue, have shown renoprotective effects. Unlike experimental models, studies describing the relationship between gender and renal disease progression in humans have yielded conflicting results. There have been no large well-designed prospective studies specifically evaluating the rate of decline of renal function in men compared with women. In this context, we performed a meta-analysis involving 11,345 subjects from 68 studies to determine the effect of gender on the progression of nondiabetic renal disease. However, our meta-analysis was limited by the heterogeneity of study endpoints, failure to adequately account for confounding factors and lack of knowledge of menopausal status. As compared with men, the rate of deterioration of glomerular filtration rate the Institute of Medicine has defined "sex" as those traits that are affected by sex chromosomal complement and the presence or absence of sex steroids. Similarly, Cattran and coworkers6 reported a reduced rate of decline in kidney function and/or increased kidney survival in younger women with membranous nephropathy or focal and segmental glomerulosclerosis compared with men. In contrast, these investigators failed to find any effect of gender on the progression of IgA nephropathy. Numerous longitudinal studies have shown that the rate of decline in kidney function was more rapid in men than in woman. However, most of the female participants in these studies were postmenopausal, which may explain why these findings differ from those reported by our earlier meta-analysis. However, the slope of the risk relationship was steeper in women than in men in both the general population and the high cardiovascular risk cohorts. Results did not change when subjects less than 50 years of age were compared with those greater than 65 years of age. Despite the size of this meta-analysis and its robust methodology, the conclusion that gender has no impact on renal disease progression is subject to limitations imposed by competing mortality. However, a significant limitation of this study was the fact that nearly 435,000 subjects were derived from a Veterans Administration cohort severely deficient in women. This result is explained by the fact that men generally have a larger muscle mass and excrete more creatinine than do women. This reanalysis yielded identical albumin excretion rates, expressed as mcg/minute, in men and women. Moreover, interpretation of the data is limited by the small size of many of these studies. They speculate that women, especially those that are elderly and in poor health, are less likely to initiate dialysis than are men of similar circumstance. They confirmed that women were less likely to start dialysis than men, and that this disparity was most pronounced among the elderly where men were more than twice as likely to initiate dialysis. In another large study, women, particularly older women, were 50% more likely to choose conservative care. Interpretation of the data is limited by the small number of subjects in many of these studies. This in turn might contribute to the predominance of men in the incident dialysis population. The impact of gender on the course of type 1 diabetic nephropathy in humans is controversial. Arguably, the preponderance of data support the conclusion that men with type I diabetes have a worse renal prognosis than do women despite the existence of contrary data. Numerous cross-sectional and longitudinal studies in individuals with type I diabetes show a greater prevalence of albuminuria, a greater risk of developing microalbuminuria, and a greater risk of progressing from micro- to macroalbuminuria in men compared with women. Studies evaluating the effect of gender on the rate of decline of renal function in type 1 diabetics have also yielded conflicting results. Adding to this complexity, sexual hormone synthesis and metabolism is dysregulated in both type 1 and type 2 diabetes mellitus. The Collaborative Study Group performed a multicenter, randomized, double-blind, placebo-controlled trial of the effects of Irbesartan on the progression of nephropathy in 1715 hypertensive type 2 diabetics. There is mounting evidence that sex hormone synthesis and metabolism is disturbed in diabetes mellitus. There are also data to suggest that aberrant sex hormone metabolism may influence the development and progression of diabetic nephropathy. Uncomplicated type 1 diabetes was associated with a low serum testosterone level even after correction for multiple metabolic factors. Although sex hormone levels were not correlated with the development of microalbuminuria in a Cox regression model, reduced baseline testosterone levels predicted progression from micro- to macroalbuminuria. Men are more likely to smoke, suffer from poorly controlled hypertension and hyperlipidemia, exhibit poor dietary habits, comply less with dietary restrictions, and ingest increased quantities of sodium, protein, calories, phosphorus, and potassium. Cell Proliferation and Mesangial Matrix Accumulation Serum-stimulated mesangial cell proliferation is inhibited by physiologic concentrations of estrogen by a receptor-mediated mechanism. In transfected human embryonic kidney cells exposed to estrogen, estrogen receptor alpha forms a ternary complex with Smad2/Smad3 and the ubiquitin ligase Smurf. Formation of this complex enhances ubiquination and degradation of these Smad proteins. These actions shift the balance of matrix metabolism away from matrix accumulation and glomerulosclerosis. In addition, several studies in humans found that men have 10e15% more glomeruli than do women. Munger and Baylis96 suggested that an increased renal vascular resistance in female rats may protect their glomeruli from hyperfiltration-induced injury by blunting elevations in glomerular capillary pressure associated with renal insults. In this regard, female rats subjected to unilateral nephrectomy and fed a high-protein diet have lower glomerular capillary pressures and excrete less protein than similarly treated male rats. Moreover, this gender dimorphism may contribute to renoprotection in females by blunting elevations in glomerular capillary pressure which in turn would reduce glomerular hemodynamic stress. Studies performed in normotensive, nonproteinuric type I diabetic adolescents found gender-related differences in the renal hemodynamic response to clamped euglycemia and clamped hyperglycemia. It was suggested that these gender-related differences in the response of the renal microvasculature to hyperglycemia may explain the lack of a consistent protective effect of female gender on the course of nephropathy in type I diabetes. In the rat, regional renal blood flow autoregulation is more efficient and papillary blood flow is lower in males. Evidence that renal disease and hypertension are interconnected is shown by the many studies showing that the use of antihypertensive medications slows the progression of renal injury. Similarly, the roles played by sex steroids in mediating gender differences in hypertension and renal injury have not been completely elucidated. The role of oxidative stress in mediating hypertension in humans is not clear, however. In addition, none of the studies to date have separated depressor response to antioxidants by gender. Thus, hypertensive men may benefit from antioxidant therapy and women may not, as in the animal studies. Thus, additional studies are needed to determine if there are gender differences in the depressor response to chronic antioxidant therapy. There is evidence that hypertension is not as well controlled in aging women as in aging men, despite the fact that women see their care providers more regularly than men and are typically more compliant in taking their medications. The results are contradictory and cannot be entirely explained by differences in estrogen dose, route of administration, or the nature of concomitantly administered progestins. Moreover, healthy user bias complicates interpretation of observations studies because women who take hormone therapy differ in relevant characteristics from those who do not take hormone therapy. Jackson and coworkers have suggested that many of the beneficial effects of estradiol on cellular processes that influence real disease progression are mediated by nonestrogenic metabolites that lack feminizing properties, particularly catecholestradiols. Whether these agents might exert a similar effect on progressive renal injury in humans without adverse effects on reproductive tissues has not been explored. In the case of diabetic nephropathy, inconsistent data may also reflect differences in the age of onset of diabetes and in the intensity of glycemic control. However, in humans, a larger number of variables make the issue of gender and real disease progression more challenging. There have been no dedicated well-designed prospective studies evaluating the rate of decline in renal function in men vs. Individual studies that have taken gender into account when analyzing factors contributing to renal disease progression have often included small numbers of subjects with a short duration of follow-up. A similar case can be made for sexual dimorphism in the course of diabetic nephropathy; however, the evidence for this conclusion is even less robust. Inconsistent data may also reflect differences in the populations studied with respect to duration of follow-up, hormonal status, demographic features, disease-modifying therapy, lipid levels, and References 1. In: Committee on understanding the biology of sex and gender differences, Board on Health Sciences Policy, Institute of Medicine. Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age. The natural history of chronic renal failure: results from an unselected, population-based, inception cohort in Sweden. Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland. The rate of progression of renal disease may not be slower in women compared with men: a patientlevel meta-analysis. Chronic kidney disease prognosis C: associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis. Multinational assessment of accuracy of equations for predicting risk of kidney failure: a meta-analysis. A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010. Prevalence of chronic kidney disease in population-based studies: systematic review. Prevention chronic kidney disease surveillance T: trends in prevalence of chronic kidney disease in the United States. Use of the albumin/ creatinine ratio to detect microalbuminuria: implications of sex and race. Effect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/creatinine ratio. Women and renal replacement therapy in Europe: lower incidence, equal access to transplantation, longer survival than men. Patient Registration Committee of the Japanese Society for Dialysis T: increasing gender difference in the incidence of chronic dialysis therapy in Japan. Gender differences in age-related decline in glomerular filtration rates in healthy people and chronic kidney disease patients. Late initiation of dialysis among women and ethnic minorities in the United States. Explaining trends and variation in timing of dialysis initiation in the United States. Sparke C, Moon L, Green F, Mathew T, Cass A, Chadban S, Chapman J, Hoy W, McDonald S. Estimating the total incidence of kidney failure in Australia including individuals who are not treated by dialysis or transplantation. Longitudinal study of racial and ethnic differences in developing end-stage renal disease among aged medicare beneficiaries. Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease. Alberta Kidney Disease N: factors associated with initiation of chronic renal replacement therapy for patients with kidney failure. Sex and gender differences in chronic kidney disease: progression to end-stage renal disease and haemodialysis. Predicting mortality and uptake of renal replacement therapy in patients with stage 4 chronic kidney disease. Predictors of hospitalization and death among pre-dialysis patients: a retrospective cohort study. Prevalence and cardiovascular risk profile of chronic kidney disease in Italy: results of the 2008-12 National Health Examination Survey. Diabetic nephropathy in 27,805 children, adolescents, and adults with type 1 diabetes: effect of diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset, and sex.

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