Jason K. Wilbur, MD

• Assistant Professor (Clinical)
• Department of Family Medicine
• Roy J. and Lucille A. Carver College of Medicine
• University of Iowa
• Iowa City, Iowa

Finally anti fungal liquid soap buy generic grifulvin v 250mg on line, anabolic steroids may have effects on platelet aggregation and cardiac conduction fungus gnats house buy generic grifulvin v on line. The legal substances tobacco and alcohol exacerbate two of the major killers in cardiovascular medicine fungus gnats ground cinnamon order grifulvin v pills in toronto, coronary artery disease and hypertension antifungal review order grifulvin v 250 mg on line. Public policy aimed at discouraging these behaviors anti fungal infection tablets buy discount grifulvin v 250mg, particularly tobacco use fungus gnats malathion buy grifulvin v 250 mg with visa, has had a significant effect, both through discouraging individual use and by limiting secondhand exposure, but all practitioners must continue to emphasize the significance of alcohol and tobacco as contributors to cardiovascular mortality and morbidity. Specific opportunistic infections that have been implicated include viral (cytomegalovirus, herpes simplex), protozoal (Toxoplasma gondii), bacterial (Mycobacterium tuberculosis, Mycobacterium avium-intracellulare), and fungal (Cryptococcus neoformans, Aspergillus fumigatus, Histoplasma capsulatum, Coccidioides immitis, and Candida spp. Recent studies suggest that asymptomatic pulmonary hypertension may be as high as 5. Cardiac findings are usually subclinical; however, fatal cardiac tamponade and pericardial constriction may occur. In such suspected cases, a pericardial window is the procedure of choice for providing decompression in addition to establishing the diagnosis. Cardiotoxicity from chemotherapy for either malignancy is also possible depending on the agents used. In all cases, treatment is directed toward the underlying etiology and any modifiable risk factors. Clinical manifestations include asymptomatic effusions detected on echocardiography, pericarditis with or without constriction, and tamponade. However, in the presence of antiretroviral therapy, these manifestations are relatively rare. The friable sterile vegetations that form on the cardiac valves are associated with disseminated intravascular coagulation and systemic embolization. This may be due partly to the higher prevalence of traditional risk factors, especially smoking. Staphylococcus aureus and Streptococcus viridans are the major responsible organisms. Thus far, there is no clear evidence that any one of these factors supersedes the others. Additionally, certain regimens may be favorable for one lipid parameter and detrimental for another. These studies and others have evaluated changes in inflammatory markers associated with abacavir use. With refractory hypertriglyceridemia and hypercholesterolemia, both a fibrate and a statin may be necessary, although the risk of toxicity may be compounded. Therefore, interactions between these dually essential classes of drugs are likely. Pravastatin may be less effective when administered with ritonavir, nevirapine, or efavirenz. In addition to lipid management, special focus should also be placed on smoking cessation. Discusses the supporting evidence by which protease inhibitors are involved in endothelial dysfunction, insulin resistance, and accelerated atherosclerosis. This executive summary outlines the conclusions and specific topics of this conference. As with the general population, lifestyle modifications (diet and exercise) should be attempted first. If treatment goals are not reached by 4 to 8 weeks, pharmacologic therapy should then be initiated. Therapy should follow the National Cholesterol Education Program Treatment Guidelines. For patients with significant isolated hypertriglyceridemia (defined as >500 mg/dL), therapy should begin with a fibrate. Starting doses should be relatively low and gradually increased to reach treatment goals. The complex relationship between cellular and viral factors is specifically outlined. Vaughn 67 leep is a reversible physiologic state that is essential for and a benchmark of good health. Even though we do not understand the underlying purpose, sleep stabilizes regulation of the autonomic and endocrine systems, enhances attention and concentration, and promotes a sense of well-being. Disruption of sleep may lead to an array of central nervous system and systemic consequences. Approximately one in three individuals will present with a sleep-related complaint to their physician. These disorders result in complaints of excessive daytime sleepiness and/or difficulty initiating or maintaining sleep or events associated with sleep. The impact of sleep disruption on cardiovascular functioning is complex and widespread. Some disorders such as sleep apnea are a risk factor for cardiovascular disease, whereas other disorders such as heart failure influence sleep maintenance. There is a bidirectional influence and a dynamic relationship between sleep and the cardiovascular system. S the individual becomes drowsy, the heart rate may decrease with a subtle drop in blood pressure. This fluctuation in sympathetic output leads to accelerations and pauses of heart rate and breathing and increased afterload. NormalSleepphySiology the state of sleep is determined by an array of coordinated neuronal processes. Stage N2 (light sleep) is characterized by the presence of K complexes or sleep spindles. They enter sleep through stage N1, progress to stage N2, and after 15 to 25 minutes progress to stage N3, followed by reemergence of stage N2 sleep. As we progress normally through the stages of sleep there are variations in heart rate, blood pressure, peripheral vascular tone, oxygen delivery, coronary blood flow, and respiration. In a healthy individual, transitional periods between quiet wakefulness and light sleep are characterized by mild instability in breathing, making these periods particularly subject to the occurrence of central apnea events and periodic breathing. At the beginning of the twentieth century, it is estimated that individuals spent approximately 9 to 10 hours per night in bed. Sleep deprivation in the short term is associated with greater sympathetic nerve activation, higher blood pressure, increased appetite, lower leptin levels, higher cortisol levels, and increased inflammatory markers. Epidemiologic studies suggest that chronic sleep deprivation is associated with weight gain and obesity. Additionally, individuals who sleep fewer than 5 hours per night are at greater risk for coronary artery disease and development of diabetes, and have a higher mortality risk at 10 years, even after adjustment for other risk factors. Similarly, individuals who sleep longer than 9 hours are also at greater risk for diabetes and cardiovascular events. The underlying mechanism for the link of sleep deprivation and disease is unclear. Yet some believe that dysregulation of the endocrine and autonomic nervous systems and increases in inflammation contribute to the development of hypertension, vascular disease, and weight gain. Patients presenting to a sleep disorders center are typically those with sleep-related breathing disorders. These disorders offer an opportunity to identify predisposing and exacerbating factors of cardiovascular disease and improve long-term risks. These events are commonly accompanied by a decrease in the blood oxygen saturation and a constellation of clinical symptoms (Box 67-2). Significant pathophysiology is also seen with hypopnea events, defined as airflow diminished by more than 30% and oxygen desaturation of at least 4%. Population studies estimate that 1 in 5 individuals has at least mild disease, being more prevalent in males. The mechanisms for both obstructive apnea and hypopnea are linked to airway compromise at one of three levels: the nose, the retroglossal and retropalatal regions, and the pharynx (Box 67-3;. This is followed by a sudden opening of the airway, and the cardiac output increases against high peripheral vasoconstriction and results in a dramatic increase in blood pressure. Beyond repetitive apnea events, other influences may increase systemic blood pressure. Possible mechanisms of causation include intermittent, repeated hypoxia episodes causing chemoreceptor stimulation, increased sympathetic activation, decreased baroreceptor responsiveness, cardiovascular remodeling, and activation of the renin-angiotensin system. This relationship of sleep apnea to hypertension provides therapeutic opportunities. Treatment of hypertension is not known to significantly decrease severity of sleep apnea or disturb normal sleep architecture. The greater negative intrathoracic pressure also results in atrial stretch causing the release of atrial natriuretic peptide, which can result in nocturia. Compounding the effect is an inflammatory cascade characterized by the release of interleukins, cytokines, and tumor necrosis factor-. This increase in inflammation plays a role in advancing coronary artery disease and elevating C-reactive protein levels. Additionally, release of vasoactive substances such as endothelin and nitric oxide synthetase lead to endothelial dysfunction and increase platelet activation and aggregation. Additionally, snoring may cause chronic vibration of carotid arteries and is associated with intimal thickening. Many individuals with normal lung function will not exhibit repetitive oxygen desaturations on overnight pulse oximetry and yet still have mild to moderate disease. Unattended respiratory monitoring has recently been approved by the Center for Medicare Service for use in patients without cardiovascular or respiratory comorbidities, under the supervision of an experienced sleep specialist. Adding to the dilemma is that individuals may vary from night to night in the degree of upper airway obstruction. Although most patients do not jump from normal to severe categories, factors influencing upper airway patency such as alcohol, nasal congestion, and position may contribute significantly to severity. Key points to successful compliance relate to education of the patient, comfortable mask or interface, quick response to therapeutic hurdles, and frequent patient follow-up. Oral appliances advancing the mandible are best targeted for patients with mild to moderate sleep apnea with appropriate dentition. This may require several surgeries, possibly including septoplasty, radiofrequency ablation of turbinates, genioglossus advancement, tongue reduction, bimaxillary advancement, uvulopalatopharyngoplasty, tonsillectomy, and adenoidectomy. All patients with sleep-disordered breathing should avoid excessive alcohol intake and medications that suppress respiratory drive. Treatment errors can arise if the titration does not demonstrate resolution of events in all sleep states or positions. Another pitfall may occur if the titration is not performed with the same physiologic challenges the patient incurs at home. Setup errors may occur from the assumption that the ordered therapy is the one delivered, or that the patient is using the device correctly. This can be avoided by physicians requiring patients to bring the device to the clinic and demonstrate its usage. Patients who have difficulty putting on the mask or are unaware of the power button are unlikely to be using the device. Due to the complexity of etiology in central apneas, treatment errors may arise by not recognizing the underlying drivers of the respiratory disturbance. Patients who use narcotics or respiratory suppressants should have medication minimized. Additionally, some individuals will need further pulmonary or neurologic evaluation to assess primary organ issues. This breathing pattern is typically related to heart failure or central nervous system deficits. Patients may present with symptoms of snoring at night, witnessed apneas, paroxysmal nocturnal dyspnea, frequent awakenings, and unrefreshing sleep. All patients with heart failure should be queried regarding the presence of symptoms of sleep-disordered breathing. Patients with heart failure should have the positive airway pressure titration performed once cardiac output is maximized. Patients with strokes should be re-titrated after brain function has stabilized, typically after 3 months. In both cases, a common error occurs by increasing the positive airway pressure settings, which often increases the central apnea component. Brief respiratory pauses are commonly seen even in healthy individuals during transitions from wakefulness to light sleep. However, when these events become lengthy, frequent (more than five per hour), persist into deeper stages of sleep, and/or are accompanied by oxygen desaturations or arousals, daytime consequences may ensue. Central apneas typically indicate a dysfunction of the regulatory process controlling breathing. Central apneas also occur with narcotic use, excessive alcohol, increasing age (over 65), and acute brain injury or stroke. Clinicians should evaluate for underlying heart failure, alveolar hypoventilation, thyroid or neurologic disease, or drug use that suppresses respiratory drive. Maximal medical therapy for the underlying condition and removal of respiratory depressants are the primary treatments. Other treatment options include respiratory stimulants, supplemental oxygen, and bilevel positive airway pressure with a backup respiratory rate. These individuals may present with daytime sleepiness, fatigue, unrefreshing sleep, insomnia, or morning headache, but may lack a history of snoring. Because of their large thoracic and abdominal girth, these patients have lower pulmonary functional reserve capacity and breathe at lower overall lung volumes in wakefulness. During sleep, the loss of muscle tone translates into further reduction of lung volume, resulting in events of prolonged oxygen desaturation.

Additionally antifungal nappy cream discount grifulvin v 250mg with visa, the presence of nephrotic-range proteinuria can also exacerbate dyslipidemia fungus gnats nicotine buy discount grifulvin v 250mg on-line. This analysis revealed a statistically significant 42% reduction in major cardiovascular events associated with use of atorvastatin; however antifungal shampoo walgreens buy discount grifulvin v 250 mg line, there was no significant impact of atorvastatin on all-cause mortality antifungal and antibacterial shampoo order cheapest grifulvin v. In dialysis patients skin fungus definition discount grifulvin v online amex, the presence of diabetes is an independent risk factor for ischemic heart disease anti fungal yeast infection pill buy cheap grifulvin v 250mg, heart failure, and all-cause mortality. Two large, observational studies have examined the association between glycosylated hemoglobin level and outcomes in hemodialysis patients. In an analysis of Fresenius data, there was no relationship between glycosylated hemoglobin level and mortality at 1 year;89 similarly, in an analysis of DaVita data, there was no significant increased risk of mortality until glycosylated hemoglobin levels rose above 8%, at which time increased mortality risk was only appreciated after extensive multivariable adjustment for case-mix, nutritional, and inflammatory factors. In the general population, diabetes is a powerful risk factor for cardiovascular outcomes. As this process progresses, capillary density decreases and subendocardial perfusion is reduced. Myocardial fibrosis may ensue and, with sustained maladaptive forces, myocyte death occurs. As workload rises over time, increased oxygen demands by the hypertrophied left ventricle may ultimately exceed its perfusion, resulting in ischemia and eventual myocyte death. Pressure overload results from increased cardiac afterload, often due to hypertension, aortic stenosis, and reduced arterial compliance from arteriosclerosis. The concentric thickening of the wall of the left ventricle allows for generation of greater intraventricular pressure, effectively overcoming increased afterload. Volume overload may result in eccentric hypertrophy secondary to the addition of new sarcomeres in series. Chapter 10 Cardiovascular Disease in Patients with Chronic Kidney Disease 137 Other Traditional Risk Factors Other traditional risk factors include advanced age, male sex, and smoking. Importantly, dialysis patients who were former smokers were more similar to nonsmokers than current smokers in risk, demonstrating the potential benefit of smoking cessation efforts in dialysis patients. This system is balanced by a series of antioxidant defenses, some of which work by enzymatically catalyzing reduction of oxidant species. Nitric Oxide, Asymmetrical Dimethylarginine, and Endothelial Function Adequate nitric oxide production is critical for local vascular regulation and endothelial function. Providing a physiological basis for the hypotheses that abnormal calcium and phosphorus handling impacts vascular calcification, in vitro studies have linked increased vascular calcification to both hyperphosphatemia164,165 and hyperparathyroidism,166 and they have shown that less vascular calcification accompanies low to moderate doses of vitamin D receptor activators. Further, as elevated levels of homocysteine can often be reduced using pharmacological doses of B vitamins, it is an attractive potential nontraditional risk factor. These mortality rates were strikingly similar to those seen with dialysis patients in the same study and contrast with patients in the same study with serum creatinine levels below 2. However, the major shortcoming in all of these studies to date is an inability to determine causality. In one study, up to 50% of nondiabetic dialysis patients with symptoms of myocardial ischemia did not have significant large caliber coronary artery disease. These include increased intima-media thickness of the carotid wall that is detectable by ultrasound and that may correlate with disease in other arterial beds. For example, 20% of asymptomatic hemodialysis patients have cardiac troponin T levels that would be consistent with acute myocardial infarction in the general population (>0. Specifically, with loss of arterial elasticity, increased systolic blood pressure with or without a decrease in diastolic blood pressure is common. This results in an increased pulse pressure, which is an independent risk factor for mortality in dialysis patients. Available diagnostic tools are similar to those used in the general population and include resting echocardiography for evaluation of cardiac structure and function, exercise and pharmacological stress testing for detection of perfusion defects, laboratory tests for assessment of both acute ischemia and chronic cardiac risk, and cardiac catheterization for anatomical description and possible repair of coronary anatomy. As a single test, stress echocardiography, either exercise or pharmacological if exercise is not feasible, may be particularly useful as echocardiography also provides information on valvular and other structural disease. Even risk factor management remains uncertain, reflecting the lack of medical evidence, difficulties of balancing blood pressure control with the risk of hypotension, tempering a healthy diet with the risk of malnutrition in the catabolic dialysis milieu, and the challenge of even adequately assessing risk. Heart failure may occur as a result of either left ventricular systolic dysfunction or diastolic dysfunction in which the left ventricle has a normal ejection fraction but impaired filling. Small, asymptomatic pericardial effusions are fairly common in dialysis patients and require no acute intervention, whereas larger effusions present a risk for tamponade. Intensification of hemodialysis is the mainstay of therapy but is only effective approximately 50% of the time. Adjuvant medical therapies, including oral and intravenous glucocorticoids and nonsteroidal antiinflammatory medications, have generally not been effective. For patients with hemodynamic instability, treatment consists of emergent drainage of the pericardial effusion. This is generally accomplished by pericardiocentesis or pericardiotomy with or without pericardiostomy for the instillation of long-acting, nonabsorbable glucocorticoids. It most commonly manifests as acute uremic or dialysis-associated pericarditis although chronic constrictive pericarditis may also be seen (Table 10-7). Uremic pericarditis describes patients who develop clinical manifestations of pericarditis prior to or within 8 weeks of initiation of kidney replacement therapy. With the advent of modern dialysis, uremic pericarditis is exceedingly rare but remains an indication for and responds extremely well to initiation of dialysis. The precise etiology is unknown but may be related to inadequate dialysis and volume overload. Pericarditis may be accompanied by nonspecific symptoms including chest pain, fever, chills, malaise, dyspnea, and cough. When hemodynamically significant, pericardial disease accompanied by an effusion may be characterized by hypotension, particularly during the hemodialysis procedure. Transthoracic and transesophageal echocardiography are important in establishing the diagnosis. Chapter 10 Cardiovascular Disease in Patients with Chronic Kidney Disease 143 Treatment of endocarditis begins with appropriate antibiotic therapy, but even with appropriate therapy, survival is often poor, with case series showing 30% mortality during the initial hospitalization and 1-year mortality over 50%. Factors associated with mortality include hypoalbuminemia, involvement of multiple valves, and severe valvular insufficiency. In one study, 30-day survival among patients who had surgery was 80%, whereas it was only 47% among those managed medically. Valve replacement is the therapy of choice for critical aortic stenosis, and the timing of surgery is dependant on individual patient characteristics with the caveat that surgery should be performed before left ventricular contractility becomes diminished. There currently is no consensus for a benefit of either prosthetic versus bioprosthetic valves in dialysis patients. The pathogenesis of mitral calcification may be linked to altered mineral metabolism. Hemodialysis patients are also exposed to rapid shifts in ions, including potassium, calcium, hydrogen, and magnesium. Atrial Fibrillation Both atrial and ventricular arrhythmias are common in dialysis patients. Mirroring the general population, atrial fibrillation is the most common of these arrhythmias, with an annual incidence of over 10%. Very little data exist as to how common thromboembolism is in dialysis patients with atrial fibrillation. Optimal management involves rate control with or without restoration of sinus rhythm, although patients with symptoms may benefit from a return to sinus rhythm. Aortic Calcification and Stenosis Aortic valve calcification is common in dialysis patients, occurring in 28% to 55% of patients. Although the overall prevalence is similar to that seen in the general population, dialysis patients experience aortic valve calcification 10 to 20 years earlier than the general population. Aortic stenosis occurs when the valve leaflets thicken to the extent that commissural fusion can no longer occur and a pressure gradient develops across the aortic valve. In one study of dialysis patients, the estimated incidence of symptomatic aortic stenosis was 3. Angina, heart failure, and syncope are the cardinal symptoms of critical aortic stenosis. Clinical evidence of aortic stenosis may be more readily evident in dialysis patients as they may have more frequent episodes of intradialytic hypotension, particularly as ultrafiltration can rapidly reduce preload. Treatment of aortic stenosis is multifaceted, encompassing prevention of progression, prevention of endocarditis, and eventual repair of the valve. There are currently no data indicating that cardiac management of patients prone to arrhythmia should be any different than in the general population. Hemodialysis units may benefit from the presence of and training in the use of automated external defibrillators. Other potential interventions may include routine use of beta blockers, although this has not been investigated. Finally, studies of the appropriate use of implantable defibrillators in dialysis patients are needed. Identified arrhythmias and cardiac arrest of unknown cause account for 60% of cardiac deaths in dialysis patients. These complications are customarily divided into micro- and macrovascular categories. Although this categorization is conceptually expedient, there is a great deal of overlap, especially as related to amplification of diabetes risks. Importantly, a positive test for diabetes should be repeated on a separate occasion to confirm the diagnosis. Department of Health and Human Services, Centers for Disease Control and Prevention, 2008. Third, kidney replacement therapies (hemodialysis, peritoneal dialysis, transplant) are discussed in a series of chapters (20 through 44). Diabetes is defined by the condition of hyperglycemia, a fasting blood glucose level greater than or equal to 126 mg/dl, or a casual (random) or 2-hour, post-75 gm glucose load level of blood glucose greater than or equal to 200 mg/dl. If a diagnostic test is positive, it should be repeated on a separate occasion to confirm the diagnosis of diabetes. The goal of reducing blood glucose is to avoid complications of severe hyperglycemia (ketoacidosis and hyperosmolar state) in the short-term and to prevent development and progression of complications in the longterm. The effect of intensive glycemic control to decrease risk of microvascular disease is well-established in types 1 and 2 diabetes. The most common precaution for drugs used to treat hyperglycemia is increased risk of hypoglycemia due to decreased clearance, drug interactions, and impaired kidney gluconeogenesis. Risk of hypoglycemia can usually be managed by reducing dosages or using agents within a particular class that are preferred because dosage adjustment is not required for decreased kidney function (Tables 11-2 and 11-3). In patients with reduced kidney function, the risk of lactic acidosis is increased. In type 1 diabetes, insulin replacement remains the primary approach, although adjunctive agents. If clinically necessary, reduce the dose of repaglinide and monitor blood glucose carefully to avoid hypoglycemia Initiate doses of 2C9 substrates. Although acarbose can be used as monotherapy, it is typically added to insulin or other oral agents to achieve glycemic control in type 2 diabetes. Incretin Therapies and Amylin Analog the incretin therapies and an amylin analog are recently available agents to enter the clinical realm for treatment of hyperglycemia. Pramlintide (amylin analog) and the incretin therapies slow gastric emptying, reduce glucagon secretion, and suppress appetite. An important advantage of the incretin therapies and the amylin analog is that these agents are not associated with weight gain, in contrast to most other types of treatment for hyperglycemia. On the other hand, exenatide is approved for use with oral hypoglycemic agents, but not as monotherapy or in combination with insulin. The most frequent side effects of pramlintide and exenatide are nausea and delayed gastric emptying. Therefore, benefits of even moderate weight loss and a generally healthy lifestyle should be encouraged. According to the National Academy of Sciences, Institute of Medicine, nonprotein calories should be distributed as up to 60% obtained from complex carbohydrates and 30% or less from dietary fats. Additionally, low glycemic index foods (determined by carbohydrate type) can be recommended because they provide an incremental benefit beyond carbohydrate counting alone. This landmark clinical trial clearly demonstrated that diabetes can be effectively prevented by a lifestyle intervention characterized by modest weight loss (5% to 10% of body weight) and 150 minutes per week of moderate exercise. Results of the Diabetes Prevention Program have now been confirmed by subsequent studies across the globe from Europe to Asia. Most importantly, prevention of diabetes, which inherently means preventing hyperglycemia, is paramount to reducing the incidence of diabetic complications. With reduced kidney mass, the amount of gluconeogenesis carried out by the kidney is decreased. About onethird of insulin degradation is carried out by the kidney and impaired kidney function is associated with a prolonged half-life of insulin. Type I diabetic patients receiving insulin who had elevated serum creatinine levels (mean 2. Reduced red blood cell lifespan, hemolysis, and anemia tend to falsely decrease the HbA1c value. Conversely, misleadingly high HbA1c values may be produced by acidosis and carbamylation of hemoglobin. Morgan and colleagues found that the relationship was not different between patients with normal kidney function and those with nondialyzed kidney failure (mean serum creatinine of 6. In addition, relatively small studies indicate that survival improves with better glycemic control in patients on peritoneal dialysis or hemodialysis. Williams and colleagues reported that 1-year survival was not influenced by HbA1c in 24,785 patients with type 1 or 1 diabetes. Increased mortality risk at the low end of HbA1c probably reflects severity of illness. However, high HbA1c levels also appear to impart mortality risk in diabetic hemodialysis patients.

Mycophenolate mofetil and sirolimus as calcineurin inhibitor-free immunosuppression for late cardiac-transplant recipients with chronic renal failure antifungal and hydrocortisone cream buy 250mg grifulvin v visa, Transplantation 77 (4) (2004) 568-574 fungus gnats bug zapper purchase grifulvin v 250mg mastercard. The decision pertaining to whether a potential heart fungus yeast infection generic 250 mg grifulvin v mastercard, lung antifungal oils purchase grifulvin v 250 mg with amex, or liver transplant candidate with advanced kidney disease should undergo multiorgan transplantation that includes a kidney is a difficult one antifungal for candida generic grifulvin v 250 mg fast delivery. This decision should be predicated on the duration and severity of kidney function anti yeast ultraceuticals cheap 250 mg grifulvin v with visa, along with a kidney biopsy to assess chronicity and irreversibility of the underlying kidney disease. Many centers where renal transplantation is performed along with a nonkidney solid organ transplantation use dialysis dependence for 6 or more weeks as a criterion to offer simultaneous kidney transplantation. If a percutaneous kidney biopsy is not feasible, a transjugular approach may be considered. The decision to recommend a heart or liver transplant candidate for simultaneous kidney transplantation should not be based on the severity of kidney dysfunction alone. Despite lack of rigorous evidence of long-term impact on outcome, the number of liver transplant candidates receiving simultaneous liver-kidney transplantation has quadrupled since 2002 and continues to increase at a phenomenally high rate. The excitement stems from the possibility that an organ transplant might quickly restore health. The frustration stems in part from the fact that transplantation can be offered to only a fraction of those with renal failure, owing to the shortage of organs available for transplantation1 and in part from the need to administer for life toxic immunosuppressive drugs to those who are fortunate enough to receive transplants. Here we discuss new developments in medicine and biotechnology that may add substantially to the excitement and to the frustration. Advances in medicine will certainly decrease certain indications for kidney transplantation and related therapies. For example, one can imagine that type I diabetes and some types of glomerulonephritis will be prevented or reversed by new immunological therapies. Similarly, the incidence of renal failure caused by hypertension and hyperlipidemia, and hence the demand for transplantation may decrease with better therapies and better delivery of existing therapies. However, we suspect that despite these and other advances, the overall demand for renal transplantation will increase. This increase will follow the increasing use of kidney transplantation and related therapies to preempt disease, from the impact of renal 628 failure as a disease of aging, and from the temptation to preserve productivity of an aging population. The term preemptive transplantation is generally applied to the performance of transplantation earlier in the course of renal failure. Besides changing the demand for organ replacement, preemptive transplantation potentially changes the standard for acceptable replacement. An injured kidney with marginal function might be offered to a patient with kidney failure suffering complications of dialysis, but this kidney might not be acceptable as preemptive replacement in a patient found to be at high-risk for development of renal cancer at some uncertain date in the future. Rather, the preemption Chapter 44 of cancer might provide a compelling indication for application of new technologies for engineering kidney replacements that are fully histocompatible with the recipient so that immunosuppression could be avoided. Changes in the prevalence of diseases associated with renal failure will also heighten the demand for transplantation and related therapies. This risk may be vitiated if new research into the metabolic syndrome and etiology of diabetes allows the development of specific therapies to counter these problems. However, many will suffer renal failure before those problems can be understood and solved. The number of these subjects will certainly influence demand for renal transplantation into the foreseeable future. Advances in medicine, while offering hope for treatment and prevention of one or another disease, inevitably increase the number of aging persons in society. Since the function of the kidneys and heart are disproportionately affected by aging, one can expect that the prevalence of renal failure will increase as the average age increases. Advancing age of retirement will likely further increase the demand for transplantation over more conservative therapies for chronic renal disease. The demand for kidney replacement might also increase with new insight into the impact of renal function on cardiovascular health. For example, the kidney may clear insulin or phosphate, metabolize vitamin D, or remove a toxin from the blood. If the kidney does contribute to cardiovascular health, then the ideal transplants might consist of two kidneys. This concept suggests the possibility that Emerging Strategies in Kidney Transplantation 629 transplantation of the kidneys or of a type of renal cell might someday be undertaken to prevent vascular disease in those with minimal decreases in renal function, and that scenario could clearly increase the demand for renal transplantation by yet another order of magnitude. Changes in the concept of what is renal failure and what level of function is needed for longevity would further heighten demand for transplantation. Clearly the number of kidneys available for transplantation today is by any measure too small, and even the use of living donors is unlikely to lessen for long what will likely turn to even a more urgent need. Hence, one can anticipate a growing interest in seeking alternatives to the use of human organs for renal replacement. We next will discuss technologies that might be used to augment or replace renal function and some strategies through which those technologies may someday be applied. Detailed consideration of the barriers to xenotransplantation can be found in a collection of recent reviews. Clinical xenotransplantation has been tried in the past; the experience is summarized in Table 44-1. Kidneys from nonhuman primates have been used in some trials of xenotransplantation,21,24,25 and the results in one were quite good. The Barrier to Xenotransplantation of Cells and Tissues Although all foreign transplants, xenografts and allografts, elicit immune responses, the impact of these responses depends to the greatest extent on whether the graft consists of isolated cells or tissues on the one hand or a vascularized organ on the other. Examples of cell and tissue transplants include isolated islets of Langerhans used to treat diabetes, isolated hepatocytes used to correct hepatic failure or deliver a therapeutic protein, and xenogeneic fetal kidney, which after implantation becomes vascularized by in-growth of blood vessels of the recipient. Cell-mediated immune responses to xenotransplantation are thought to be especially severe28,31,32 and may, in our view, be further amplified by the humoral immune reactions and by failure of immune regulation between species. The Barriers to Xenotransplantation of Vascularized Organs Unfortunately, the barriers to transplantation of whole organs, such as the kidney, are much higher than the We shall focus here on the use of lower animals as a source of kidneys, because among other problems, nonhuman primates such as baboons are too small and not sufficiently numerous to address the need. Larger mammals, particularly the pig, are suitable in size, available in large numbers, and these animals can be genetically engineered and bred. Barriers to Xenotransplantation Three major factors pose barriers to clinical xenotransplantation. These include the immune response of the recipient against the graft, the physiological limitations of the transplant in the foreign host, and the possibility of transferring infectious agents from the graft to the recipient and potentially to others in society. Because xenotransplantation has been attempted on a number of occasions over the past 100 years, much more is known about these barriers than the barriers to other technologies, such as stem cells and tissue engineering, that have been touted in recent years. Here we emphasize the immune response to xenotransplantation because this response poses the most difficult barrier to application. The immune responses to xenotransplantation are much more severe than the immune responses to allotransplantation. One reason why immune responses to xenografts are severe is that all normal individuals have innate immunity, including xenoreactive natural antibodies, complement, and natural killer cells against xenogeneic cells. Not only can innate immunity destroy a xenograft, it amplifies adaptive immune responses. Cell and tissue xenotransplants are subject to failure caused by primary nonfunction that may reflect failure of engraftment or a very rapid immune response. If primary nonfunction is bypassed and the tissue or cells engraft, they are then subject to cellular rejection. Humoral rejection usually is not observed because the blood vessels of recipient origin are not damaged by xenoreactive antibodies and complement and instead serve as a partial barrier to these elements, protecting adjacent grafts from injury. Hyperacute rejection can be averted by depleting xenoreactive natural antibodies or inhibiting the complement system in the recipient or by engineering the foreign organ to suppress expression of the target antigen (Gala1-3Gal) or to express complement regulatory proteins such as decay accelerating factor. If hyperacute rejection is averted, the xenotransplanted organ is subject to acute vascular rejection. Preventing antibody mediated injury may allow the organ to achieve "accommodation," a condition in which the organ resists injury from antibody and complement and thus does not undergo acute vascular rejection. If hyperacute and acute vascular rejection are prevented, the graft will still be subject to cellular rejection or chronic rejection. The types of vascular disease observed in xenografted organs are the same as those observed in allografted organs; however, the incidence, severity and resistance to therapy are greater in xenografts. Renal xenografts are quite susceptible to hyperacute rejection, which can destroy the graft within minutes to a few hours. One way to prevent acute vascular rejection may be to suppress the production of xenoreactive antibodies by drug therapy or through induction of tolerance. Various approaches to tolerance have been tried;54 however, most approaches effective in rodents have not proven applicable in humans. One approach that might be effective in humans Emerging Strategies in Kidney Transplantation 631 is the engraftment of hematopoietic cells of the donor. Another way to prevent acute vascular rejection might be to eliminate the antigens targeted by xenoreactive antibodies. Although porcine cells express many antigens potentially recognized by the human immune system, the main antigen target is Gala1-3Gal. Organs lacking Gala1-3Gal do not undergo hyperacute rejection but do suffer from what appears to be acute vascular rejection,65 possibly caused by antibodies directed against other antigens. Accommodation might reflect a change in xenoreactive antibodies or a change in the antigens in the graft;60 however, experimental work in xenograft models suggest accommodation results at least in part from an acquired resistance of the graft to humoral injury. To the extent that chronic rejection is caused by an immune response to the graft, as some experimental evidence suggests,68 then it should be common and severe in xenotransplants. If chronic rejection is caused by qualities of the graft, such as preservation time, ischemia, and donor age, then it should not be much of a problem. In any case, 632 Section V Transplantation foresee using xenografts as the ideal replacement for organs removed to preempt disease. Because cell and tissue xenografts are not susceptible to injury from antibodies of the recipient40 and loss from cellular rejection is not life threatening (unlike loss of heart, liver or lung xenograft), these grafts might be tested soon. Further, if the xenotransplantation of a renal cell or another cell suitably engineered could overcome the vascular disease putatively caused by small decrements in renal function or microalbuminuria, such grafts might gain widespread application. Physiological Hurdles to Xenotransplantation Studies in which porcine kidneys have been transplanted into nonhuman primates suggest that they function sufficiently in a human to sustain life. Rather, the main functional impairment of these xenogeneic organ grafts is from rejection, and aberrant coagulation is rarely seen in the absence of immunity. That is not to say the coagulation system is controlled normally in xenograft but that thrombosis and clotting are controlled by compensatory changes. Porcine erythropoietin does appear to work poorly on human cells, so supplementation with the human hormone would probably be needed if xenotransplantation were to be applied. While other defects might still be discovered, these defects are probably no worse than abnormalities imposed by dialysis. Infectious Agents Another barrier to xenotransplantation is the risk of transferring an infectious agent from the graft to the recipient. However, breeding or special handling cannot eliminate endogenous retroviruses of the pig, and that in turn raises the question of whether one or another of these viruses might be infectious for humans. Once xenotransplantation becomes immunologically and biologically feasible, interest will be driven by what we think will be the very low cost of using intact organs harvested from pigs compared to the cost of using engineered tissues or devices. The main question then should not be whether xenotransplantation is feasible, but rather whether the physiological cost of immunosuppression and immune modulation needed to allow the prolonged survival and function of a xenograft justify this approach to renal replacement. For the patient with renal failure, this biological cost may well be justified, and xenotransplantation might be welcomed. Stem Cells Stem cells are cells capable of self-renewal by proliferation and of generating at least one, and often more than one, differentiated line of cells. The uses include administration of stem cells into injured tissues and the use of stem cells to generate new, mature cells and tissues ex vivo. Here we discuss the potential sources of stem cells and some limitations to application of these cells for augmentation and replacement of renal function. Stem cells obtained from the inner cell mass of blastocysts are called embryonic stem cells. Because embryonic stem cells can be grown in large numbers and selected in cell cultures, they are commonly used to add or target genes in mice. First, the use of embryonic stem cells engenders ethical concerns, because isolation of these cells is usually associated with destruction of the early embryos from which they originate. Second, embryonic stem cells and indeed all pluripotent stem cells can and usually do form teratomas and teratocarcinomas after implantation into mature individuals. These problems raise interest in technologies that might be used to generate pluripotent stem cells from the cells of mature individuals. Chapter 44 Pluripotential stem cells, like embryonic stem cells, can be generated by transferring nuclei from mature cells to immature cell bodies, that is, by cloning. Cloning by nuclear transfer can generate an entire individual, a process called reproductive cloning, or a tissue or organ, a process called therapeutic cloning. One advantage of therapeutic cloning is that it generates cells with the same histocompatibility antigens as the individual from whom the nucleus is obtained (except for mitochondrial antigens, which derive from the oocyte). Another advantage is that the cloned cells, like embryonic stem cells, can develop into any tissue. Using human embryonic cells for cloning mature cells would face the same ethical barriers as using human embryonic stem cells, since the immature cells might be obtained by destroying human embryos; however, cloning has been accomplished using embryonic cells from different species. Hence immunosuppression might be needed or the graft might fail over a period of time. The most promising approach to generating pluripotent stem cells involves reprogramming of the cells by expressing primitive genes. Generating pluripotent stem cells in this way would overcome most ethical hurdles and would assure that the pluripotent cells, and their progeny would be fully histocompatible with the individual from which the reprogrammed cells were obtained. However, reprogramming cells by transfection would raise concerns about the potential development of tumors. This concern might be addressed in part if reprogramming factors could be delivered as proteins rather than as genes encoding them. Adult stem cells can migrate through the blood and take up residence in injured tissues. However, effective application of stem cells for regeneration may require overcoming barriers still unknown that prevent the natural stem cells of the patient from regenerating the diseased kidney in the first place.

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Weight in glucose patients increased without increase in body water antifungal bath mat purchase 250 mg grifulvin v overnight delivery, suggesting fat gain antifungal horse grifulvin v 250mg low cost. Icodextrin achieves better ultrafiltration than hypertonic glucose in the long exchange and prevents any fluid reabsorption in high/high average transport patients conk fungus definition grifulvin v 250mg overnight delivery. Icodextrin was associated with better metabolic control (assessed by glycosylated hemoglobin) antifungal yeast treatment buy cheapest grifulvin v, triglycerides fungus gnats walls cheap grifulvin v 250mg with visa, fluid status antifungal upholstery spray buy grifulvin v 250 mg with mastercard, blood pressure, echocardiography, and fewer diabetic complications. Gokal, 1995175 Posthuma, 1997176 Postuma, 1997 & 199860,177 Plum, 200270 I: 20 G: 19 I: 90 G: 85 I: 175 G: 112 I: 58 G: 35 12 weeks 2. This weight gain was not fully explained by increases in fluid status, implying that there was also an additional increase in body fat. Prevention of obesity and efficacy in diabetic subjects emphasizes the metabolic advantages in using icodextrin when compared to the more hypertonic glucose solutions. In nondiabetic subjects, the hyperinsulinemia associated with the continuous use of glucose containing solutions is significantly improved by the use of icodextrin, and this is associated with an improvement in insulin sensitivity. Skin rashes are well-described and appear to be the result of an allergic reaction to starch. In most cases they are transient and the patients can put up with them until they resolve over a few weeks. Occasionally (1%-3% of patients), the patient develops an exfoliating dermatitis that is often generalized and can be quite severe, causing erythroderma. Sterile peritonitis in patients using icodextrin and miniepidemics of this problem have been described. Typically patients with this problem have a sterile peritonitis that does not respond to antibiotics, which on differential white cell count is associated either with raised eosinophils or mononuclear cells but not neutrophils. Although this problem has been identified and largely put right by tightening the quality controls of fluid production, isolated cases of icodextrin-associated sterile peritonitis are occasionally reported. Importantly, however, none of the controlled trials (see Table 28-2) have reported a higher incidence of peritonitis using icodextrin. Concern has been expressed that too rapid ultrafiltration induced by icodextrin might precipitate a significant fall in residual renal function. There is certainly increasing evidence that episodes of volume depletion, intentional or otherwise, are associated with a fall in urine volume. In the short-term (13 weeks) patients randomized to icodextrin reported better physical and mental health status than those using standard glucose. First, there is the issue of local tissue damage to the peritoneum, which will be discussed later under bioincompatibility. Second, there are the unwanted systemic metabolic effects, which have largely been dealt with. Third, there is a more general problem associated with the use of any osmotic agent that relies substantially upon its effects across the aquaporins to achieve ultrafiltration. Precisely because this mechanism of ultrafiltration is water exclusive, solutes such as sodium that are dependent on convection for their loss may not in fact be removed so efficiently because of their sieving by these pores. First, these polymers and their metabolites reach a steady state in plasma between one and two weeks on treatment. The slight hyperosmolality that they cause, combined with its associated hyponatremia, does not appear to have any clinical adverse effects. It does result in some reduction in the efficacy of icodextrin as an ultrafiltration agent, however, and patients who initially report very high ultrafiltration volumes may see a modest reduction with time. The presence of icodextrin and its metabolites in plasma can also interfere with some analytical methods. It is also known, especially for peritoneal dialysis patients, that malnutrition is an Chapter 28 independent predictor of poor survival. Reduction in renal function is associated with a spontaneous fall in appetite,96 which does to some extent improve following the commencement of dialysis treatment,97 although this is certainly reduced once residual renal function is lost. There is, however, another perhaps equally important clinical need for an amino-acid solution-an alternative low molecular weight osmolyte to glucose, for reasons both discussed previously and later in further detail, when considering biocompatibility. Peritoneal Dialysis Solutions 425 lycine, arginine, and methionine, which when replaced by anionic amino acids was largely prevented. The typical amount of amino acids adsorbed per day is 18 g, which, if compared to oral protein, would represent about one quarter, typically 0. Furthermore, improvement but not normalization of the plasma amino acid profile has been reported. However, in order to provide convincing evidence of clinical benefit, three further things are required. First, demonstration that nitrogen from amino acid absorbed from the peritoneal cavity can be incorporated into somatic protein. Second, that patients with impaired nutritional can show an improvement, and third, if possible, that this translates into improved clinical outcomes (see Table 28-3). Detailed studies using 15N-glycine, 2H3 leucine, and 13C leucine have shown that of the total amino acid dose, 55% is absorbed by 1 hour and 80% by 5 hours; about half (48%) is used for protein synthesis, whereas a significant proportion (16%) is oxidized as an energy source during the dwell period. Summarized in Table 28-3, along with open studies describing clinical experience, these have given mixed, although generally encouraging results. Smaller, earlier studies evaluating precursors to the current commercially available solution failed to demonstrate clear benefit and noted variable beneficial or no effects on plasma lipid profiles. The only long-term (3 years) randomized study of Solution Description the only commercially available dialysate fluid containing amino acid is a 1. It contains 87 mmol/L of amino acids, the majority (61%) being essential amino acids. This is not the only amino acid solution that has been formulated over the last 20 years and several different formulations have been evaluated. In the early stages of solution development a number different amino acid concentrations were investigated, ranging from 1%-2. Despite a good total protein/ nitrogen intake, bicarbonate was higher with modified solution. Long-term administration of amino acid dialysate is well-tolerated, tends to improve nutritional status in high-risk patients, especially women, but does not alter patient survival. Patients using amino acids had an improvement in triglyceride levels, and more stable biochemical markers of nutrition. Anthropometrics improved, especially in women in the amino acid treated group, but composite nutritional scores were no different. In summary, the true benefits of amino acid solutions used in malnourished patients remain equivocal. It is perhaps more logical to use amino acid solution as part of a dialysis regimen that prevents the use and complications associated with heavy use of glucose solutions, for example, in improving glycemic control in diabetics,78 improving gastric emptying,81 and preventing fat gain and associated hypertriglyceridemia and even membrane Chapter 28 preservation (see later) with a hope that protein-calorie malnutrition maybe prevented to some extent. Peritoneal Dialysis Solutions 427 Potential Problems the most common side effect seen in patients using amino acid solutions is increased nausea and anorexia. The former may be reported in association with the very slight odor that some patients detect or reflect the modest increase on plasma urea levels that might be observed. In these circumstances there may be symptomatic benefit from increasing the dialysis dose. Some patients will develop mild evidence of metabolic acidosis, manifested by a fall in the plasma bicarbonate. It has been formally defined as "the ability of a material, device, or system to perform without a clinically significant host response in a specific application. The need to develop biocompatible solutions derives from several strands of evidence that, although largely circumstantial, taken together make a very powerful case. These lines of evidence include the intrinsically bioincompatible nature of standard fluids, including their established in vitro and ex vivo toxicity, and the demonstration of both functional and morphological changes to the peritoneal membrane that culminate in ultrafiltration failure and, in the worst cases, sclerosing encapsulating peritonitis. Bioincompatibility of Standard Fluids: this can be conveniently divided into short-term toxicity, associated with low pH, high osmolality, and the use of lactate as buffer, and long-term toxicity because of the damaging effects of glucose, either because of direct cellular toxicity, the formation of glucose degradation products as a consequence of the sterilization procedure or the formation of advanced glycosylation endproducts within the membrane or systemic circulation. The short-term effects of bioincompatibility result in infusion pain, experienced by many patients but considerably variable in severity, combined with cellular toxicity shown in both in vitro and ex vivo studies. As a result, for the first 45 minutes or so of a dialysis exchange, the intra abdominal fluid is at an unphysiologically low pH that causes a fall in the intracellular pH of local cell populations (macrophages, mesothelial cells), which is potentiated in its toxicity by the presence of lactate. The exception might be acetaldehyde, which also results from catabolism of lactate. Extended shelf life will also increase their concentration in dialysate, especially if the storage has been at room temperature or even higher (Anders Wieslander, personal communication, data awaiting publication). The list of culprits is growing steadily (Table 28-4), and some, in particular, are thought to be especially toxic. There are only two studies so far linking morphology and function, but both show that worse membrane damage is associated with worse function, in one case a link between high solute transport and fibrosis,131 the other with increased area of microvessels. Functional and Morphological Changes to the Membrane: There is now convincing evidence from longitudinal studies that peritoneal membrane function changes with time on treatment. There is considerable variability between patients, but the overall pattern is one of increasing rates of small solute transport and reductions in the ultrafiltration capacity of the peritoneal membrane. This rise in the solute transport rate is thought to reflect an increase in the effective peritoneal surface area, such as would occur with increasing vascularity of the membrane. There is now, however, increasing evidence that a second process is contributing to loss in ultrafiltration capacity with time on treatment. Although it is difficult to perform longitudinal studies of membrane morphology, data from the Peritoneal Biopsy Registry have built a convincing picture of what appears to happen. No such single solution can exist, however, as without the presence of an osmotic gradient, short-term ultrafiltration, which will always be needed, cannot be achieved. In each case the principle underlying this approach in the same, although different manufacturers have come up with differing designs. By using more than one compartment during the manufacturing process, it is possible to do two things. First, by confining the glucose to a compartment with a very low pH, (optimally $3. Second, when the two components of the dialysis fluid are brought together, just before instillation by the patient-performed by manually breaking a small septum-the final solution can be made to have a normal pH. Second, this general model can be also be used to enable the predominant buffer to be bicarbonate by separating this from magnesium during storage, preventing its precipitation. In addition, by using a third compartment, the potential number of recombinations can be increased, enabling all three glucose concentrations to be obtained from the same bag, for example, Gambrosol Trio. Studies that involve serial biopsies of the membrane are difficult to justify on ethical and practical grounds, and both functional and morphological changes take many years to develop, which, when combined with high drop-out rates, mean that they are not financially viable. Furthermore, the equipoise of many clinicians is such that the justification for the use of biocompatible fluids can be made on a priori grounds, and if cost implications were not an issue, that it would be unacceptable to randomize patients to bioincompatible solutions. Nevertheless, this difficulty has led to another approach, namely the use of biomarkers within peritoneal dialysis effluent that act as surrogate measures of peritoneal damage or integrity. The one clear advantage is a reduction in infusion pain associated with bicarbonate-lactate neutral pH solution when compared to either lactate or bicarbonate-only solutions. One possible explanation is that supraphysiological concentrations, as are required in a bicarbonate only solution, result in hyperemia of the peritoneal vessels. Evidence of a clinical benefit on membrane function or preservation of residual renal function is less clear and in some cases contradictory. Furthermore, some of these studies were not primarily designed or powered with these clinical endpoints in mind. For example, a cross over design is not ideal for investigation of loss of residual renal function. In those studies with no membrane changes, no change in residual function was found. As discussed previously, sodium removal is dependent mainly of convective losses, although diffusion plays a significant part. This approach has already been shown to work, Potential Problems As would be hoped, there are few if any problems associated with the use of more biocompatible solutions (with the exception of specialized solution specific issues discussed previously). Strong evidence for the safety of biocompatible solutions comes from a large, nonrandomized registry study undertaken in Korea. Patients treated with Balance had a significantly better survival, even when corrected for their more favorable baseline characteristics, although disappointingly time to first peritonitis episode or technique failure was not different. In addition, there Chapter 28 by combining icodextrin with glucose, to significantly enhance both ultrafiltration and sodium removal. A recent exploratory study, investigating two low sodium solutions, found that provided a solution with a 115 mmol sodium concentration was sufficiently compensated with extra glucose (2%) to maintain ultrafiltration that used once a day sodium removal was increased significantly for a given glucose load and associated with improvements in blood pressure, thirst, and fluid status. This invites alternative strategies, and several have been proposed that are either undergoing animal testing or clinical evaluation. These include the use of pyruvate as an alternative buffer,168,169 glycerol as an alternative low molecular weight osmolyte,170 or different combinations of existing dialysate fluids during the 24-hour period to achieve a period of glucose free treatment-often referred to a "portfolio" approach. As already mentioned, the delivery of cytotoxic therapy directly to the peritoneal cavity is already being evaluated and used clinically. However, more potentially exciting possibilities might be considered in an attempt to preserve or enhance peritoneal membrane function. For example, the intraperitoneal injection of hyaluronan, in an attempt to replace the dialysate losses and thus the integrity of the interstitium, has been performed in experimental animals. Optimizing Biocompatibility As indicated previously, the evidence that improved biocompatibility of dialysate solutions results in preservation in either preservation of membrane function or the prevention of membrane morphology is keenly awaited. Further understanding of the mechanisms of how they act and which are important can only enhance this approach. These showed a clear association between small solute clearances received and subsequent clinical outcomes, including survival.