Mike Larvin BSc MBBS FRCS MD

• Professor of surgery, Consultant upper GI
• and pancreatic surgeon and Head of division
• Academic Division of Surgery, School of
• Graduate Entry Medicine and Health, Derby
• City General Hospital, Derby, UK

In addition skin care 90036 discount dapsone american express, the absolute risk reduction of intensive blood pressure lowering was only 0 acne in pregnancy dapsone 100 mg free shipping. Theoretically acne 1800s cheap dapsone 100mg with mastercard, decreasing elevated intraglomerular pressure by any means may have a benefit skin care jobs dapsone 100mg sale. Dietary protein restriction is a proposed method skin care kit cheap dapsone 100mg on-line, and in the animal model of 5/6 nephrectomy skin care 35 year old purchase dapsone discount, dietary protein restriction demonstrated reduced kidney injury by decreasing afferent arteriolar vasodilation, glomerular hypertension, and oncotic pressure. The method of glucose control may also be important for progressive diabetic nephropathy. These findings fit well into the model of hyperfiltration and glomerular hypertension with subsequent albuminuria and provide evidence that intervention can be renoprotective. Animal models reveal that rats fed high-cholesterol diets exhibit a greater degree of glomerulosclerosis and interstitial disease compared with those fed a low-cholesterol diet. Therefore reducing proteinuria to the lowest possible amount would seem beneficial. In another study of overt diabetic nephropathy, the renin inhibitor aliskiren was found to lower albuminuria to a greater degree when used in combination with losartan compared with losartan alone; however, a follow-up study of dual therapy with aliskiren and valsartan was halted early because of increased risk for stroke, kidney complications, hyperkalemia, and hypotension in the dual therapy group. Notably, the severity of albuminuria may be helpful in defining optimal blood pressure goals. These include hemodynamicmediated hyperfiltration and eventual nephron loss and inflammatory and cellular-mediated fibrosis. Exciting novel therapies are eagerly anticipated, but these must be tested through rigorous clinical study for safety, tolerability, and efficacy. Animal models have demonstrated a benefit of endothelin antagonists with a reduction in proteinuria and improvement in creatinine clearance. At present, positive safety and efficacy data from clinical trials evaluating these agents is lacking. Pyridoxamine has been evaluated in a multicenter randomized controlled trial of patients with overt diabetic nephropathy. Sulodexide, a glycosaminoglycan, was rigorously tested in clinical trials of patients with diabetic nephropathy and failed to show a benefit. These therapies may hold promise for the future, but validated long-term controlled trials are currently lacking. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensinconverting enzyme inhibition: a patient-level meta-analysis. Observational modeling of strict versus conventional blood pressure control in patients with chronic kidney disease. The effect of blood pressure intervention on renal function in insulin-dependent diabetes. Using proteinuria and estimated glomerular filtration rate to classify risk in patients with chronic kidney disease: a cohort study. Efficacy of folic acid therapy on the progression of chronic kidney disease: the renal substudy on the China stroke primary prevention trial. We also provide an overview of detection, evaluation, predicting prognosis, and management, with comments on the role of nephrologists in the care of these patients. The mechanisms underlying increased susceptibility have not been completely described or proven. For example, minority race or ethnicity may imply an underlying genetic tendency, or it may be a marker for lack of access to health care. Susceptibility factors may explain why a family history of kidney disease, regardless of the cause, places an individual at increased risk for development of kidney disease. Early stages of kidney disease may be reversible, and individuals with kidney failure can revert to earlier stages through kidney transplantation, shown as dashed arrowheads pointing from right to left. The earlier stages and the risk factors for progression to later stages can be identified, permitting improvements in outcome by prevention, earlier detection, and initiation of therapies that can slow progression and prevent the development of kidney failure. Similarly, nephrotic syndrome occurs in patients with marked albuminuria, but hyperlipidemia and hypercoagulability may be observed with lesser increases in albuminuria. Other complications include threats to patient safety from systemic toxicity from drugs and procedures, as well as an increased risk of infections and impaired cognitive and physical function. Complications may also arise from adverse effects of interventions to prevent or treat the disease. Dashed arrowheads pointing from right to left signify that remission is less frequent than progression. Kidney damage can be within the parenchyma, large blood vessels, or collecting systems, and it is usually inferred from markers rather than direct examination of kidney tissue. The markers of kidney damage often provide a clue to the likely site of damage within the kidney and, in association with other clinical findings, the cause of kidney disease. Because most kidney diseases in North America are caused by diabetes or hypertension, persistent albuminuria is the principal marker. A number of terms refer to severe decrease in kidney function, which is not synonymous with kidney failure. Uremia is defined as elevated concentrations within the blood of urea, creatinine, and other nitrogenous end products of amino acid and protein metabolism that are normally excreted in the urine. The uremic syndrome, the terminal clinical manifestation of kidney failure, is the constellation of symptoms, physical signs, and abnormal findings on diagnostic studies that result from the failure of the kidneys to maintain adequate function. The availability of dialysis and transplantation for the treatment of kidney failure varies around the world, and not all patients with kidney failure choose to receive kidney replacement therapy. The cause of disease is generally classified according to the presence or absence of systemic diseases (secondary or primary) and the presumed location of the pathologic-anatomic lesions (glomerular, tubulointerstitial, vascular, cystic, or disease in the kidney transplant; Table 52. The green, yellow, orange, and red shaded categories represent patients at low, moderate, high, and very high risk of kidney outcomes and mortality, respectively. The proportion of participants in the groups at moderate, high, and very high risk is about 73%, 18%, and 9%, respectively, representing a prevalence in the general population of about 8. Colors reflect the ranking of relative risk for kidney disease progression and cardiovascular risk. Albuminuriaisdeterminedbyone measurement of albumin-to-creatinine ratio, and persistence is estimated. Evaluation of clinical diagnosis for implementation of specific therapy Diabetic kidney disease (type 1 or type 2) Nondiabetic kidney disease (glomerular diseases other than diabetic kidney disease, vascular diseases, tubulointerstitial diseases, cystic diseases) Kidney disease in kidney transplant recipients 5. The need for other measures (urinalysis or imaging) to ascertain other markers of kidney damage depends on the nature of the risk factors. Until evidence is available, it seems reasonable to suggest that others at increased risk be tested at least every 3 years. Evaluation includes a thorough history, including a review of past laboratory data, and physical examination to detect previous evidence of kidney disease, signs, and symptoms that may provide clues to the cause of kidney disease and, in particular, any reversible or treatable causes. The physical examination should include particular attention to details such as blood pressure, fundoscopy, and vascular examination. Laboratory tests should be performed to detect other markers of damage or functional disturbances. Ultrasonography can be performed to detect anatomic abnormalities and to exclude obstruction of the urinary tract. The distinction between acute and chronic is arbitrary but is useful in clinical practice. The duration of kidney disease may be documented or inferred based on the clinical context. In both cases, repeat ascertainment of kidney function and kidney damage is recommended for accurate diagnosis. In addition, the cause of kidney disease has implications for the rate of progression and the risk of complications. The cause of the disease is generally established by recognition of the clinical setting and the presence or absence of markers of kidney damage. A simplified system classifies kidney disease by anatomic location: glomerular, vascular, tubulointerstitial, and cystic kidney disorders (see Table 52. Clinical judgment is required to determine whether additional methods are necessary to characterize kidney disease, including imaging studies, other urine or serum markers, or biopsy of the kidney. Confirmatory tests include a timed urine collection for measurement of albumin excretion rate. Risk prediction instruments can be used to provide a numeric risk for specific outcomes. Relationships between excretion rates and concentration ratios with urine creatinine are inexact. Excretion of urinary creatinine indicates muscle mass and varies with age, gender, race, diet, and nutritional status and generally exceeds 1. Rates of 30 to 300 mg/day and greater than 300 mg/day correspond to microalbuminuria and macroalbuminuria, respectively. Normal urine contains small amounts of albumin, low-molecular-weight serum proteins, and proteins that are from renal tubules and the lower urinary tract. In most kidney diseases, albumin is the main urine protein, comprising about 60% to 90% of total urinary protein when total protein is very high. Values corresponding to normal, high-normal, high, very high, and nephrotic-range total protein are approximately less than 50, 50 to 150, 150 to 500, greater than 500, and greater than 3500 mg/g, respectively. Threshold values for standard international (mg/mol) and conventional units (mg/g) are not exact. Complete management requires behavioral change by the patient, which may include lifestyle alterations, self-monitoring of blood pressure, and adherence to medication regimens and medical follow-up. Patient education is also important with respect to avoiding medications that are toxic to the kidneys. Patients must be aware that any drug or herbal remedy may be directly nephrotoxic or may require a dosage adjustment for the level of kidney function. Recommendations for referral to a kidney disease specialist are not universal because specific practice patterns are dependent on health care systems and available resources in a geographic region. Preparation involves estimating the risk of progression to kidney failure, holding discussions regarding kidney replacement therapy (dialysis and transplantation), and instituting conservative therapy for those who choose not to undergo kidney replacement therapy. Albuminuria changes are associated with subsequent risk of end-stage renal disease and mortality. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Multinational assessment of accuracy of equations for predicting risk of kidney failure: a meta-analysis. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Age and association of kidney measures with mortality and end-stage renal disease. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts. Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis. Developing guidelines for chronic kidney disease: we should include all of the outcomes. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. Relative risks of chronic kidney disease for mortality and end-stage renal disease across races are similar. Changes in nutritional needs and utilization ultimately place kidney disease patients at high risk for nutritional abnormalities. Understanding the applicable nutritional principles and the available methods for improving nutritional status of these patients is essential. National Kidney Foundation Clinical Practice Guidelines for Chronic Kidney Disease and Nutrition in Chronic Kidney Disease provide in-depth information regarding these principles. Commonly, essential amino acid concentrations are low and nonessential amino acid concentrations high. The progressive loss of kidney tissue, where metabolism of several amino acids takes place, is an important factor. Specifically, glycine and phenylalanine concentrations are elevated, and serine, tyrosine, and histidine concentrations are decreased. In contrast, plasma citrulline, cystine, aspartate, methionine, and both 1- and 3-methylhistidine levels are increased. Although inadequate dietary intake is a possible factor in abnormal essential amino acid profiles, certain abnormalities occur even in the presence of adequate dietary nutrient intake indicating that the uremic milieu has an additional effect. Indeed, it has been suggested that the metabolic acidosis commonly seen in uremic patients plays an important role in increased oxidation of branched-chain amino acids. Accumulation of uremic toxins may not be the sole cause of decreased dietary nutrient intake.

Regardless of the above discussion acne quizzes discount dapsone online, it is clear that more attention needs to be paid to dialysis duration if patient outcomes are to continue to improve acne rash cheap dapsone generic. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial acne 404 nuke book download cheap dapsone express. Association between prior peripherally inserted central catheters and lack of functioning arteriovenous fistulas: a case-control study in hemodialysis patients skin care adha buy dapsone on line amex. Perceived knowledge among patients cared for by a nephrologist about chronic kidney disease and end-stage renal disease therapies skin care vitamin e buy 100 mg dapsone with mastercard. Effect of online hemodiafiltration on all cause mortality and cardiovascular outcomes acne makeup generic 100mg dapsone with visa. Effects of a nationwide predialysis educational program on modality choice, vascular access, and patient outcomes. Outcomes associated with intradialytic oral nutritional supplements in patients undergoing maintenance hemodialysis: a quality improvement report. The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. Use and safety of unfractionated heparin for anticoagulation during maintenance hemodialysis. Reflecting dialysis facility capacity issues, nephrologists who wanted to prescribe dialysis times of 6 to 8 hours implemented nocturnal dialysis. Patients begin their dialysis treatment in the evening, spending 6 to 8 hours receiving dialysis (generally while sleeping). Such prolonged dialysis allows for an increase in the total dose of dialysis with much slower rates of ultrafiltration and diffusive clearance. This trial, however, did demonstrate improvement in secondary outcomes of interdialytic weight gain, blood pressure, and predialysis phosphorous levels. Although the concept of nocturnal dialysis is theoretically attractive, patient acceptance, nurse recruitment, and the need for physician visits at night are some of the barriers for this therapy. Nocturnal dialysis can be performed at home, but the fear of catastrophic events, such as severe hypotension and needle dislodgement while the patient is asleep, has limited this strategy. Of note, remote hemodynamic monitoring and devices that are activated by red blood cells and awaken the patient if there is a blood leak are now available; these may improve the safety of nocturnal dialysis procedure, both in-center and at home. These modalities are not mutually exclusive, and, during a lifetime of therapy, patients may transfer from one to the other. Home-based therapies have advantages for many patients and are particularly popular in Canada, the Netherlands, Iceland, Finland, Denmark, Australia, New Zealand, Mexico, and Hong Kong, where more than 20% of the dialysis population receive home therapies. The visceral peritoneal membrane tightly covers the intestine and mesentery, whereas the parietal peritoneum lines the insides of the abdominal cavity. The membrane consists of a single layer of mesothelial cells overlying an interstitium in which the blood and lymphatic vessels lie. The mesothelial cells are covered by microvilli that markedly increase the nominal surface area of the peritoneum, which is approximately 2 m2. The effective peritoneal surface area available for dialysis, however, is estimated to be about onethird of this. There is also some net fluid and solute resorption via the intraperitoneal lymphatics. Solute movement occurs as a result of "diffusion" and "convective transport," whereas fluid shifts relate largely to "osmosis" created by the addition of osmotic agents to the dialysis solutions. Solute movement is mainly by diffusion and is therefore based on the concentration gradient between dialysate and blood. Solutes also move across the peritoneal membrane by convection, which is described as the movement of solutes as a result of fluid flux. When instilled in the peritoneal cavity this hyperosmolar solution causes net fluid removal (ultrafiltration) to occur. Dialysis fluid in the peritoneum is separated from capillary blood by three layers of tissue. These include the mesothelial cell layer, which offers little resistance 539 540 Section11-DialySiSanDtranSplantation to fluid and solute transport, the interstitium, which offers resistance mainly to large molecules, and the endothelium of the peritoneal capillaries, which is most active in restricting and regulating solute and fluid movement. The endothelial lining of the peritoneal capillaries has pores of three different sizes often referred to as the "three pore model. These account for most of the pore area available for solute transport and contribute significantly toward peritoneal ultrafiltration. With increasing dwell time, transperitoneal glucose absorption diminishes the dialysate glucose concentration and the osmotic gradient. Also important are dialysate volume, dwell time, and number of exchanges per day, and these three variables can be manipulated to maximize solute and fluid removal. Various techniques and regimens have emerged as a consequence of increased understanding of peritoneal membrane transport characteristics or permeability in relation to the amount of solute and fluid to be removed. D/D0 represents the ratio of dialysate glucose concentration (D) at a given time point to the dialysate glucose concentration at time 0 (D0). The rate of transport of these molecules depends on the permeability of the membrane: the higher the permeability (high transporter), the more rapid the transport of glucose, with dissipation of the osmotic gradient and therefore less drain volume. With increasing dwell time, solutes move across the peritoneal membrane toward concentration equilibrium, and the ratio of dialysate to serum urea levels approaches 1. Because the peritoneal membrane has a net negative charge, negatively charged solutes, such as phosphate, move across it more slowly than positively charged solutes of similar size, such as potassium. Macromolecules such as albumin cross the peritoneum by mechanisms that are not completely understood, but probably via lymphatics and through large pores in the capillary membranes. During a dwell period, the osmotic gradient created by standard dialysate within the abdominal cavity declines as the glucose is absorbed. In time this can result in net fluid reabsorption back into the systemic circulation because of the added effects of intraperitoneal hydrostatic pressure and intravascular oncotic pressure. The rate of movement of small solutes between dialysate and blood differs from one patient to another. In addition, because the volume of fluid removed also contributes to the solute clearance of equilibrated dialysate via convection, fast transporters also have mL cHapter58-peritonealDialySiS 541 D/P creatinine 1. The intraabdominal portion of the catheter has multiple perforations in addition to the hole at the end through which dialysate flows. The deep cuff placed at the rectus muscle in the mid-line or just laterally and the extraperitoneal portion of the catheter are tunneled through the subcutaneous tissue to exit the skin, pointing laterally and caudally. The superficial cuff is located inside the subcutaneous tunnel at least 2 to 3 cm from the exit site. Ideally, dialysis should be deferred for a few weeks after insertion to allow the surgical wound and exit site to heal properly. Typically this results in three to four shorter dwells during the day and a long dwell overnight. In adults the total volume of fluid exchanged in a day typically ranges from 8 to 10 L. Thus dialysis occurs continuously throughout the entire 24-hour period, and patients are free to go about their business in between exchanges. The prescription specifies the type of dialysis fluid, volume to be used, dwell time, and number of exchanges, and this prescription often varies according to patient size, peritoneal permeability, and residual kidney function. Because the connection between the bag and the transfer set is interrupted three to five times a day to facilitate fluid exchange (approximately 1500 exchanges per year), the procedure must be carried out using a strict, aseptic, nontouch technique, which the patient or helper performs at home. Once the connection has been made, this device allows drainage of the effluent from the abdomen through the connection into the empty bag, before fresh dialysate is instilled. For long-dwell continuous ambulatory peritoneal dialysis, high transporters show both low fluid removal and low CrCl, compared with low transporters. General anesthesia often is reserved for patients with previous abdominal surgery and complicated insertions, particularly those patients in whom laparoscopic insertion is planned. The catheter can be inserted under direct vision through a mini-laparotomy, percutaneously using the Seldinger technique with a guide-wire, or with peritoneoscopic or laparoscopic guidance. Although there are numerous catheter designs, such as the Swan-neck catheter (said to undergo less catheter tip migration and fewer exit-site infections) and curled catheters, none offers a significant proven advantage 542 Section11-DialySiSanDtranSplantation Table 58. The Y-set consists of tubing with a full bag of dialysate at one end and an empty drainage bag at the other, placed on the floor. Fluid flow is by gravity, and the direction of flow is controlled by clamps on the tubing. The exchange procedure comprises five steps: (1) To begin the exchange, the patient connects the Y tubing to the short extension tubing at X. All regimens except continuous ambulatory peritoneal dialysis use a cycler machine and are therefore variants of automated peritoneal dialysis. The proportion of fluid removed can be set on the cycler and is usually between 50% and 85%. The lesser the proportion of fluid removed the more rapid is the cycling required and greater the total volume of dialysate used. When used for this purpose, 90% or more of the expected dialysate volume is typically removed. The cycler delivers a set number of exchanges over 8 to 10 hours, with the last fill constituting the long day dwell, which may be necessary to provide additional dialysis to achieve solute and fluid removal targets. The technique is quite uncommon now, with most cycler-assisted exchanges carried out overnight by patients at home while asleep, thereby allowing freedom of movement during the day. However, lifestyle issues and freedom from daytime exchanges are now major factors in patient modality choice. Assistance may be provided by trained members of the family, paid nurses, or health care professionals, depending on the set-up of the health care system. This level of assistance greatly simplifies the patient role to connecting himself or herself to the machine before going to bed at night and then disconnecting in the morning. Amino acid solutions are used infrequently in practice because evidence for definite nutritional benefit is equivocal, but they do serve to reduce the glucose exposure of the peritoneal membrane. Lactate was initially used as the buffer in preference to the more physiologic bicarbonate for technical reasons, specifically that the low pH of lactate prevents caramelization of the glucose while autoclaving for sterilization during the manufacturing process. Alternative osmotic agents such as "icodextrin" and a mixture of amino acids have also been developed and are in routine use worldwide. While there is no conclusive clinical trial evidence to demonstrate that the newer more physiologic solutions preserve the peritoneal membrane and result in longer technique and patient survival, there is little doubt about their more physiologic constitution; hence increased utilization of these novel solutions appears limited only by higher costs. They may also be used in patients in whom standard solutions cause abdominal pain, as this is less of a problem with the newer solutions possibly because of the more physiologic pH and osmolarity. The long-term adverse effects of this are not known but are not thought to be harmful. Critically, the maltose in the circulation interferes with blood glucose estimation in patients with diabetes using home blood glucose monitoring equipment. Blood glucose measurement therefore must be done with a glucose-specific method to prevent maltose interference. In case of any doubts, the manufacturer(s) of the monitor and test strips should be contacted to seek clarification. Falsely high readings can result in insulin overdose with ensuing hypoglycemia or cause an apparently normal glucose reading when the patient is actually hypoglycemic. Multiple deaths have been reported because of the failure to appreciate maltose cross-reactivity with glucose measures. Most antibiotics are compatible with icodextrin and can be administered dissolved in this solution during the long dwell in the event of peritonitis. While antibiotic combinations are well studied and reported in glucose-based solutions, there is less evidence of their safety and efficacy in icodextrin-based dialysate. The commercially available solution is a mixture of 15 amino acids in a concentration of 1. The solution also contains standard concentrations of sodium, calcium, magnesium, chloride, and lactate. The amino acids act as the osmotic agent and are variably absorbed across the peritoneal membrane during the dwell. The evidence to support improvement in nutrition as well as overall outcome is not compelling, but this dialysate can be considered in malnourished patients both for nutritional supplementation and for reduction of glucose exposure. A 2-L bag contains approximately 25% of the daily protein requirement of a 70-kg adult. Successful utilization of the amino acids is dependent on an adequate calorie load, and amino acid dialysate (Nutrineal) should be instilled after the patient has had a meal. Icodextrin is a starchderived glucose polymer that produces ultrafiltration by exerting colloid oncotic pressure when administered intraperitoneally. It serves to achieve sustained ultrafiltration irrespective of transporter status and even in situations where there is peritoneal inflammation (during an episode of peritonitis). The current license limits the amount of icodextrin used to one exchange per day, with the volume used ranging from 1 L to 2. Small amounts of complex carbohydrate do get absorbed into the circulation via the lymphatic system and, with regular daily use, reach a steady-state plasma level in 7 to 10 days. This carbohydrate polymer is hydrolyzed in part to maltose by circulating amylase, and maltose levels of around 1. For high transporters, short-dwell automated peritoneal dialysis is appropriate; for high-average and low-average transporters, continuous ambulatory peritoneal dialysis would suffice. A prescription entails modifications of the variable components to arrive at a regimen that provides for adequate solute and fluid removal to meet clinical needs and maintain reasonable quality of life. Dialysis adequacy regarding solute removal, fluid status, nutritional status, and clinical well-being are monitored regularly as discussed below, and the prescription is modified accordingly.

This relationship starts at relatively low levels of proteinuria and progressively strengthens with higher degrees of protein excretion - order dapsone master card. Many hypertensive patients may have renovascular atherosclerotic lesions without a role in the pathogenesis of hypertension skin care with vitamin c buy dapsone with american express. Renovascular atherosclerosis is associated with increased cardiovascular risk but should be differentiated from renovascular hypertension acne quizzes buy generic dapsone 100mg on line. Because the other kidney is normal acne bomber jacket purchase dapsone 100 mg, there is pressure-induced natriuresis and the animals do not become volume overloaded skin care industry generic dapsone 100 mg without a prescription. However acne 6 year old buy genuine dapsone line, in humans, perhaps reflecting the chronicity of this process, there is wide variability in plasma renin levels in bilateral disease, although it is generally accepted that kidney tissue renin levels are high. Recent animal models have provided new insights, especially on atherosclerotic disease, demonstrating that renal artery flow restriction induces a proinflammatory and profibrotic environment that results in endothelial dysfunction, microvascular rarefaction, and interstitial fibrosis. The degree of flow restriction to trigger these responses in humans is a matter of debate. The degree of luminal stenosis necessary to produce this pressure gradient typically exceeds 70%, although it may occur with lesions in the 50% to 70% range. All other tests, including renal scintigraphy and several previously used biochemical tests, should no longer be used for screening because of poor sensitivity and specificity. The pressure gradient was induced by progressive inflation of an angioplasty balloon. Renin data are presented for the aorta (squares), renal vein of the stenotic kidney (closed circles), and renal vein of the nonstenotic kidney (open circles). Magnetic resonance angiography has the caveats of requiring breath holding; accordingly, motion artifacts are common. The diagnosis is not made through visualization of the stenosis but by the detection of increased flow velocity at the site of stenosis compared with the adjacent aorta. Panel A shows bilateral renal artery stenosis due to atherosclerotic renovascular disease (blue arrows). Panel B is the three-dimensional reconstruction of the images from panel A, providing greater detail of the vasculature. Panel C shows bilateral multifocal fibromuscular dysplastic changes with undulating, saccular morphology of both renal arteries (blue arrows). The red arrow points to a left renal artery aneurysm, a relatively frequent complication of fibromuscular dysplasia. Acceleration times reflect the time needed for the incident pulse wave to reach its peak. In conditions of restricted flow, the acceleration time is increased (>100 ms), which results in a pulse wave of decreased amplitude and late peak. The resistive index [(peak systolic velocity - diastolic velocity)/peak systolic velocity] is a marker of increased parenchymal resistance to blood flow due to increased renovascular resistance but is also influenced by systemic factors, such as heart rate, peripheral vascular resistance, and arterial stiffness. The resistive index is low in a kidney with a hemodynamically significant inflow restriction, and a low resistive index (<0. However, it is time consuming and dependent on both operator skill and patient body habitus, resulting in unreliable results in up to 25% of patients. This modality is being perfected to identify kidneys that remain viable despite underlying ischemia, allowing clinicians to identify good candidates for revascularization. Unfortunately, difficulties with protocol validation and lack of studies demonstrating its value are still restricted to small case series, and thus its use in clinical practice cannot yet be recommended. Even though there are no data demonstrating a benefit from smoking cessation and antiplatelet therapy, there is general agreement based on the management of vascular disease in other arterial beds that smoking cessation, antiplatelet therapy (aspirin or clopidogrel), and statins should be offered to all patients. There is little evidence from clinical trials to support an advantage of revascularization over medical therapy in patients with disease of mild severity (<70% stenosis), in those incidentally discovered without accompanying hypertension or kidney dysfunction, or in those with well-controlled hypertension and stable kidney function during follow-up. It is important to recognize that the available clinical trials excluded a large number of patients. This is due to the proximal nature of the lesions and shared plaque with the aorta. In addition, stent use results in significantly lower rates of restenosis compared with angioplasty alone. Surgical intervention is rarely needed and is left for patients with extensive aortic disease that would require simultaneous open correction. Approximately one-third of patients undergoing intervention experience worsening kidney function. This may be the result of contrast nephropathy or atheroembolic kidney disease, which often goes unsuspected and undiagnosed. The renal arteries are the vessels most commonly affected (80% to 100% of patients, up to 60% bilateral), although many other sites can be involved, including the carotid and vertebral arteries (up to ~70% in some series, 20% to 30% in most). Most cases are sporadic, although ~10% are familial, and rare cases can be associated with specific genetic diseases, such as neurofibromatosis, tuberous sclerosis, Ehlers-Danlos 636 Section12-HypertenSion syndrome, Alagille syndrome, Williams syndrome, and Turner syndrome. The radiographic appearance does not seem to affect the clinical presentation, which is one of hypertension, usually with preserved kidney function. Stenting is rarely necessary, and surgical correction is reserved for patients with complex anatomic lesions. Antiplatelet therapy (beyond a few weeks postangioplasty) and statins are not necessary, but smoking cessation should be strongly encouraged. While hypokalemia is the most common clue to the diagnosis, the prevalence of primary hyperaldosteronism is quite variable and usually restricted to a minority of patients (only 9% to 37% have serum potassium <3. It is more common in patients with adenomas (~50%) than bilateral hyperplasia, likely reflecting the generally higher aldosterone levels in adenomas. Therefore clinicians must be attuned to the possibility of primary aldosteronism in many other situations. To maximize the accuracy of the test, it is best to obtain it in the morning, after the patient has been out of bed for at least 2 hours, after 5 to 15 minutes in the seated position, and preferably under liberal salt intake and appropriate potassium repletion. Long-acting drugs, such as spironolactone must be stopped for at least 4 weeks before testing. However, one must keep in mind that using higher aldosterone cutoff levels decreases the sensitivity of the approach, while improving specificity. Lowering the cutoff has the opposite effect, but may be worth considering, especially in high-risk patients. Most cases are due to adrenal hyperplasia (~60%), which is typically bilateral, or aldosteroneproducing adrenal adenomas (~40%). Uncommon causes include adrenal carcinoma, unilateral adrenal hyperplasia, and glucocorticoid-remediable aldosteronism. Recent advances have significantly improved the understanding of the pathobiology of adrenal proliferation and aldosterone excess in primary aldosteronism. These mutant channels expressed in the adrenal glomerulosa lose their specificity for potassium and allow inward flow. The same mutation has been identified as a germline mutation in patients with a rare form of adrenal hyperplasia (familial aldosteronism type 3) and results in massive adrenal hyperplasia, aldosterone production, and severe hypertension with cardiovascular complications. Levels between 5 and 10 ng/dL are considered indeterminate and require either repeat testing or an alternative confirmatory test. Because both tests involve the administration of substantial amounts of sodium, they are contraindicated in patients with congestive heart failure, severe hypertension, or severe hypokalemia. The two most common subtypes are bilateral hyperplasia (~60% of cases) and adrenal adenomas (~40% of cases). Rare causes include adrenal carcinoma, unilateral adrenal hyperplasia, and glucocorticoid-remediable aldosteronism. Visualization of a small (<3 cm), hypodense (<10 Hounsfield units) adrenal nodule is virtually diagnostic of an adenoma. This is justified by the very low rate of incidental adrenal masses in this age range. The test starts with the administration of cosyntropin, which is used to produce maximal cortisol secretion from both adrenal glands to provide a good means for "adjustment" of the aldosterone results. Blood is sampled from each of the adrenal glands and a peripheral site (can be the inferior vena cava or an upper extremity vein) and is sent for both aldosterone and cortisol. Confirmatory tests are designed to document persistent autonomous production of aldosterone despite the use of a physiologic factor that strongly suppresses aldosterone secretion. Potassium should be effectively replaced during the collection to avoid hypokalemia. We measure urine creatinine (to assess the completeness of the collection), sodium (to confirm >200 mEq/day intake), and aldosterone. A postinfusion aldosterone greater than 10 ng/dL First, each aldosterone and cortisol level should be analyzed as ratios of aldosterone-to-cortisol from each of the three 638 Section12-HypertenSion sampling sites. Second, the aldosterone/cortisol ratio for the right adrenal vein is compared with the left adrenal vein, and both are compared with the peripheral ratio. If the aldosterone/cortisol ratio on one of the adrenal veins is greater than or equal to 4 times higher than the contralateral side, the diagnosis of lateralization is made, indicating the presence of an aldosterone-producing adenoma or, rarely, unilateral adrenal hyperplasia. In addition, patients with adenomas typically have suppressed secretion from the contralateral side (defined as aldosterone/cortisol ratio from the contralateral side lower than that from the periphery). OtherTesting In the past, several biochemical tests and nuclear medicine imaging (iodocholesterol) were used to help in subtype differentiation. In patients suspected of having glucocorticoid-remediable aldosteronism (early hypertension, personal or family history of hemorrhagic strokes or brain aneurysms), the diagnosis should be made through formal genetic testing to identify the chimeric gene mutation (between the aldosterone synthase and 11-hydroxylase genes). Indirect physiologic tests, such as the dexamethasone suppression test or the measurement of urinary hybrid steroids, are no longer recommended, although they may still be used in resource-poor areas where genetic testing is not available. Patients with an aldosterone-producing adenoma or unilateral adrenal hyperplasia should be offered laparoscopic unilateral adrenalectomy. A recent clinical trial showed that spironolactone was slightly better than eplerenone, although the doses may not have been precisely exchangeable. For those patients who develop intolerable side effects to spironolactone, especially those related to its antiandrogenic effects, I substitute eplerenone using a 2: 1 dosing ratio and twice-daily dosing. The risk of hyperkalemia obviously exists but can be mitigated with the use of smaller doses. Aldosterone synthase inhibitors are under development and have been tested in patients with primary aldosteronism. Thiazide diuretics are often helpful, although potassium levels must be monitored closely as they may drop precipitously with the thiazide. Paraganglioma is a tumor derived from extraadrenal chromaffin cells of the sympathetic paravertebral and neck ganglia. Pheochromocytomas are almost always biochemically active, producing epinephrine, norepinephrine, or dopamine, alone or in combination. Paragangliomas may be biochemically silent, especially when originating in the neck and base of the skull. Overall, pheochromocytomas represent approximately 80% to 85% of these tumors, whereas paragangliomas account for approximately 15% to 20%. However, knowledge about their clinical presentation and the appropriate approach to diagnosis and management are important because of the cardiovascular risk they pose through severe hypertension. These paroxysms are associated with catecholamine release and are clinically characterized by the classic triad of headaches, palpitations, and diaphoresis. Other common symptoms are anxiety, tremulousness, pallor, pale flushing, and orthostatic hypotension. These developments not only have diagnostic and genetic counseling relevance but also may have treatment implications in the future. The exceptions are very young patients or those who have the sudden development of hypertension that is not explained by other more common secondary causes. The measurement of free metanephrines in serum or urine is the preferred diagnostic test. Plasma or urine free metanephrines are acceptable screening measurements, both having an accuracy in the 96% to 99% range. Sensitivity is very high, although there are shortcomings in specificity due to substances that may cause falsely elevated levels. In the case of plasma metanephrines, false-positive normetanephrine can be observed with acetaminophen (only certain assays), tricyclic antidepressants, methyldopa, phenoxybenzamine, and sulfasalazine, whereas buspirone may elevate plasma metanephrines. In addition, labetalol and sotalol can increase both urinary levels (but have no effect on plasma measurements). When levels are obtained in the seated position, there is almost a threefold increase in false positives compared with supine measurements. The Endocrine Society recommends supine measurements; however, it recognizes the practical limitations of this recommendation, as most laboratories are unable to accommodate this request. Accordingly, it is acceptable to obtain samples in the seated position and, in case results are high, have them repeated in the supine position or corroborated by a 24-hour urine collection. The guidelines suggest individual screening for mutations based on the familial distribution, the presence of a defined syndrome, and the guided choice of genes to be tested based on location and biochemical profile of the tumor. Pheochromocytomas can be managed laparoscopically, whereas paragangliomas are usually resected with an open approach. All patients should be treated medically for at least 1 to 2 weeks in anticipation of surgery. The cornerstone of therapy is an alpha-blocker (either the nonselective phenoxybenzamine or a selective alpha1-blocker, such as doxazosin or terazosin). The evaluation and management of metastatic disease are nuanced and beyond the scope of this chapter. In most cases, biochemical screening is repeated 6 months following resection and then yearly. In high-risk patients, such as those with large pheochromocytomas, multifocal paragangliomas, or biochemically silent disease, yearly imaging is indicated. This may be due to an improvement in extracellular volume and a decrease in rostral fluid accumulation during recumbence/sleep. However, they typically come to medical attention due to other features of the syndrome (weight gain, fatigue, muscle weakness, skin changes, anxiety, glucose intolerance, hyperlipidemia, osteopenia) rather than hypertension. Hypertension is seen in ~40% of patients with hypothyroidism and has a predominantly diastolic phenotype associated with increased systemic vascular resistance and decreased arterial compliance.

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Diseases

• Xeroderma pigmentosum
• Neuroendocrine cancer
• Sondheimer syndrome
• Aberrant subclavian artery
• Trimethylaminuria
• Diabetes insipidus, nephrogenic type 2
• Carney syndrome
• Thalassemia minor
• Bellini Chiumello Rinoldi syndrome
• Spherocytosis