E. Magnus Ohman, MD, FRCPI

• Professor of Medicine
• Associate Director, Duke Heart Center?ardiology Clinics
• Director, Program for Advanced Coronary Disease
• Duke Clinical Research Institute
• Duke University Medical Center
• Durham, North Carolina

Long-term effects of small doses of calcitriol in hemodialy Nephrol Dial Transplant 4:105-109 pulmonary hypertension 70 mmhg purchase altace 5 mg fast delivery, 1989 sis patients with moderate secondary hyperparathyroidism arrhythmia heart condition purchase altace 5 mg online. Morita A hypertension in pregnancy buy genuine altace, Tabata T low pressure pulse jet bag filter generic 10 mg altace visa, Inoue T hypertension young cheap 10mg altace with amex, Nishizawa Y blood pressure xanax purchase 2.5 mg altace with mastercard, Morii H: Mechanism and prevention of cardiac arrhythmias in chronic the effect of oral 1 alpha-hydroxycalciferol treatment on hemodialysis patients. Kidney Int 57:2117-2122, Onoyama K, Fujimi S, Omae T: 1-year controlled trial of 1 2000 alpha-hydroxycholecalciferol in patients on maintenance 325. Nephrol Pedret J, Revert L: Systemic involvement of dialysis Dial Transplant 3:768-772, 1988 amyloidosis. Gal R, Korzets A, Schwartz A, Rath-Wolfson L, Hendel D, Korzets A: Sonographic features of dialysis Gafter U: Systemic distribution of beta 2-microglobulin related amyloidosis of the shoulder. J Ultrasound Med 19: derived amyloidosis in patients who undergo long-term 765-770, 2000 hemodialysis. Arch Pathol Lab Med 118:718-721, 1994 de Strihou C: Ultrasonographic detection of thickened joint 330. Nephrol Dial ous ambulatory peritoneal dialysis and hemodialysis popula Transplant 8:1104-1109, 1993 tions. Am J Nephrol 16:484-488, 1996 spondyloarthropathy with beta 2-microglobulin amyloid de 347. Eur J Clin Invest 10:293-300, 2-microglobulin kinetics during chronic hemodialysis Tielemans C, Dratwa M, Bergmann P, Goldman M, Nihei H, Mimura N: Cervical discs are most susceptible to Flamion B, Collart F, Wens R: Continuous ambulatory beta 2-microglobulin amyloid deposition in the vertebral peritoneal dialysis vs haemodialysis:Alesser risk of amyloid column. Blumberg A, Burgi W: Behavior of beta 2-micro ultrasound in dialysis related amyloidosis. Clin Nephrol globulin in patients with chronic renal failure undergoing 35:227-232, 1991 hemodialysis, hemodia ltration and continuous ambulatory 339. Scalamogna A, Imbasciati E, De Vecchi A, Castel gallium-67 and thallium-201 whole-body and single-photon novo C, Pagliari B, De Cristofaro V, Ponticelli C: Beta-2 emission tomography images in dialysis-related beta 2-mi microglobulin in patients on peritoneal dialysis and hemodi croglobulin amyloid. The Co-operative Group on Dialysis-associated Ar Beta 2-microglobulin amyloidosis in hemodialysis patients. Br J Rheumatol 31:157-162, 1992 An autopsy study of intervertebral disks and posterior longi 357. Acta Pathol Jpn 40:820-826, 1990 M, Descamps-Latscha B, Drueke T: In uence of haemodialy 372. Nephrol Dial Transplant 3:284-290, 1988 thy: A survey of 95 patients receiving chronic haemodialy 358. Mayer G, Thum J, Woloszczuk W, Graf H: Beta-2 sis with special reference to beta 2 microglobulin related microglobulin in hemodialysis patients. Contrib Nephrol 62:67-74, kinetics in maintenance hemodialysis: A comparison of 1988 conventional and high ux dialyzers and the effects of 374. Am J Kidney Dis 13:390-395, 1989 der pain syndrome and soft-tissue abnormalities in patients 360. Nephrol Dial Transplant 12:965-972, 1997 K: Chronic arthropathy in long-term hemodialysis. Gejyo F, Homma N, Maruyama H, Arakawa M: ity of a new high-permeability modi ed cellulose membrane Beta 2-microglobulin-related amyloidosis in patients receiv for haemodialysis. Laurent G, Calemard E, Charra B: Dialysis related microglobulin and low ux synthetic dialyzers. Kidney Int 39:990-995, 1991 Sakurabayashi T, Suzuki M, Sakai S, Yuasa Y, Hirasawa Y, 380. Rev Rhem Engl Ed 61:S97-S100, 1994 Drueke T: Beta 2-microglobulin amyloidosis: A sternocla 385. Chylkova V, Fixa P, Rozprimova L, Palicka V, vicular joint biopsy study in hemodialysis patients. Clin Hartmann M, Erben J, Prochazkova J: Beta-2-microglobulin Nephrol 33:94-97, 1990 in patients with renal disease. Shiota E, Matsumoto Y, Nakamoto M: Open surgi Beta-2-microglobulin-derived amyloidosis: Onset, distribu cal treatment for dialysis-related arthropathy in the shoulder. Int J Artif amounts of aluminum in biological tissue by ameless Organs 16:823-829, 1993 atomic absorption analysis of a chelate. Akizawa T, Kinugasa E, Kitaoka T, Koshikawa S, 56, 1976 Nakabayashi N, Watanabe H, Yamawaki N, Kuroda Y: 407. N Engl J Med 296:1389-1390, 1977 lopathy, bone disease and anaemia: the aluminum intoxica 418. J Clin Pathol osteodystrophy: A survey from 1983 to 1995 in a total of 34:1285-1294, 1981 2248 patients. Syndrome associated with aluminum intoxica happens in the other nephrologists dialysis centre. Nephrol Dial Effect of parathyroidectomy on bone aluminum accumula Transplant 10:1874-1884, 1995 tion in chronic renal failure. Recker R, Schoenfeld P, Letteri J, Slatopolsky E, aluminium after very low doses of desferrioxamine. Nephrol Goldsmith R, Brickman A: the ef cacy of calcifediol in Dial Transplant 13:1538-1542, 1998 renal osteodystrophy. Clin Nephrol 52:335-336, 1999 in relation to aluminum bone disease among asymptomatic 439. J Pediatr 105:717-720, 1984 of the deferoxamine infusion test in the diagnosis of alumi 440. Kidney Int 26:201-204, 1984 Debroe M: the desferrioxamine test predicts bone alumi 444. Proc Eur Dial Transplant serum aluminium monitoring in dialysis patients:Amulticen Assoc Eur Ren Assoc 21:371-376, 1985 tre study. J Clin Endocrinol Metab aluminium-free dialysate: Role of aluminium hydroxide 65:11-16, 1987 consumption. Pengloan J, Dantal J, Rossazza C, Abazza M, Nivet desferrioxamine for the estimation of aluminium overload in H: Ocular toxicity after a single intravenous dose of desferri haemodialysis patients. Kidney Int therapy and mucormycosis in dialysis patients: Report of an Suppl 18:S108-S113, 1986 international registry. Galli A, Kleinknecht D: Removal of aluminium from pa Kidney Int 36:852-858, 1989 tients with dialysis encephalopathy. Kidney Int lar and intraperitoneal deferoxamine for aluminum chela Suppl 18:S104-S107, 1986 tion. Ef rol Dial Transplant 11:125-132, 1996 fects on serum aluminum and iron overload. Arch Intern Med amine, feroxamine and iron on experimental mucormycosis 139:1099-1102, 1979 (zygomycosis. Kidney Int 45:667-671, 1994 ence: Diagnosis and treatment of aluminum overload in 482. Acta thyroid gland localization with technetium-99m sestamibi in Chir Austriaca 28:32-34, 1996 (suppl 124) secondary hyperparathyroidism. Arch Surg 130:643-648, 1995 Sonography for early diagnosis of enlarged parathyroid 487. Fabretti F, Calabrese V, Fornasari V, Poletti I: Subto ing compared with subtotal parathyroidectomy in hemodialy tal parathyroidectomy for secondary hyperparathyroidism in sis patients. Tomic Brzac H, Pavlovic D, Halbauer M, Pasini J: M, Kano T, Morimoto T: Subtotal versus total parathyroidec Parathyroid sonography in secondary hyperparathyroidism: tomy with forearm autograft for secondary hyperparathyroid Correlation with clinical ndings. Takagi H, Tominaga Y, Uchida K, Yamada N, Ishii gery in the treatment of renal osteodystrophy and tertiary T, Morimoto T, Yasue M: Preoperative diagnosis of second hyperparathyroidism. Surg Clin North Am 51:1211-1217, ary hyperparathyroidism using computed tomography. Hooghe L, Kinnaert P: Presurgical localization of abnormal Am J Kidney Dis 8:98-104, 1986 parathyroid glands using a single injection of technetium 506. Acta Chir Austriaca 28:14-16, 1996 participation of bone mineral in the defense against chronic (suppl 124) metabolic acidosis. J Clin Invest 45:495-506, 1965 technetium-99m-labelled sestamibi and iodine-123 subtrac 509. Lancet treatment of acidosis on calcium balance in patients with 353:2200-2204, 1999 chronic azotemic renal disease. Ishibashi M, Nishida H, Okuda S, Suekane S, Haya 1967 buchi N: Localization of parathyroid glands in hemodialysis 510. Nephron 78:48 Setti R: Effects of in vivo metabolic acidosis on midcortical 53, 1998 bone ion composition. Am J Physiol 277:F750-F755, 1999 roidism: Detection with I-123-Tc-99m-Sestamibi subtrac 512. Green J, Maor G: Effect of metabolic acidosis on the dent of calcium and parathyroid hormone. W, Sirikulchayanonta V, Ongphiphadhanakul B, Radinaha Proc Eur Dial Transplant Assoc 16:624-629, 1979 med P, Karnsombut P, Kunkitti N, Ruang-raksa C, Rajatan 536. Garabedian M, Silve C, Levy D, Bourdeau A, Ul avin R: Bone mineral density and histology in distal renal mann A, Broyer M, Balsan S: Chronic hypophosphatemia in tubular acidosis. J Clin Invest genesis of hypophosphatemia in kidney necrograft recipi 61:509-527, 1978 ents: A controlled trial. Coen G, Manni M,Addari O, Ballanti P, Pasquali M, lyte Metab 11:167-172, 1985 Chicca S, Mazzaferro S, Napoletano I, Sardella D, Bonucci 539. Miner Electrolyte Metab 21:375-382, 1995 hyperparathyroidism in chronic renal failure. Clinical practice guidelines for nutrition in chronic lyte Metab 12:356-362, 1986 renal failure. Uchida K, Tominaga Y, Tanaka Y, Takagi H: Renal Med Biol 178:207-216, 1984 transplantation and secondary hyperparathyroidism. Loss of regional bone mineral density in the rst 12 months Kidney Int 57:9-18, 2000 following renal transplantation. Proc Eur Dial Transplant Assoc kidney transplantation: A longitudinal study in 115 graft 16:618-623, 1979 recipients. Semin function, serum calcium and serum parathyroid hormone in Nephrol 10:536-545, 1990 normocalcemic long-term survivors. Adv Exp Med Biol 81:603-610, Regnard J: No trend toward a spontaneous improvement of 1977 hyperparathyroidism and high bone turnover in normocalce 553. Nephrol Dial Transplant 5:62-68, 1990 following renal transplantation: Relation with hyperparathy 554. Br Med J 1:712-714, 1979 Losada M, Hernandez D, Lorenzo V: Parathyroid function in 555. Nephrol Dial Transplant transplantation: 1-alpha vitamin D therapy in patients with 13:94-97, 1998 (suppl 3) normal parathyroid gland activity. N Engl J Med 325:544 hyperparathyroidism and acute tubular necrosis following 550, 1991 renal transplantation. Schmid T, Muller P, Spelsberg F: Parathyroidec ism and its sequelae in renal transplant recipients. Long term tomy after renal transplantation: a retrospective analysis of ndings in a series of conservatively managed patients. Nephrol Dial Transplant 12:2393-2396, Scand J Urol Nephrol Suppl 144-148, 1977 1997 591. Vlcek J, Binswanger U, Keusch G, Zaruba J: Hyper 1997 parathyroidism after kidney transplantation: A retrospective 578. Transplantation 40:266-269, 1985 Hypophosphatemia in long-term renal transplant recipients: 597. Tertiary hyperparathyroidism after renal transplantation: Op Nephrol Dial Transplant 13:103-104, 1998 (suppl 3) erative indications. Transplantation 59:1393-1400, 1995 Reversal of lesions following subtotal parathyroidectomy. J Heart Lung Transplant 13:116 position, lipid pro le, and bone mass after renal transplanta 120, discussion 121, 1994 tion. Caglar M, Adeera L: Factors affecting bone mineral chem Biophys 154:566-574, 1973 density in renal transplant patients. Rickers H, Deding A, Christiansen C, Rodbro P: Gokal R: Bone loss in long-term renal transplantation: Mineral loss in cortical and trabecular bone during high Histopathology and densitometry analysis. Calcif Tissue Int 55:387-394, sive regimens on vertebral bone density in renal transplant 1994 recipients: A prospective study. Sambrook P, Birmingham J, Kelly P, Kempler S, 1997 Nguyen T, Pocock N, Eisman J: Prevention of corticosteroid 627. A comparison of calcium, calcitriol, and calci immunosuppressive activity and inhibition of bone resorp tonin. Incidence, morbidity, and potential A and cortisone acetate minimizes the adverse bone effects economic impact in a community. Ponticelli C, Civati G, TarantinoA, Quarto di Palo F, thickness and formation periods of trabecular bone packets Corbetta G, Minetti L, Vegeto A, Belli L: Randomized study in corticosteroid-induced osteoporosis. Calcif Tissue Int with cyclosporine in kidney transplantation: 10-year follow 35:410-417, 1983 up. Resch H, Pietschmann P, Willvonseder R: Estimated Necrosis of the femoral head after kidney transplantation. Kurose H, Seino Y, Shima M, Tanaka H, Ishida M, 1271, 1990 Yamaoka K, Yabuuchi H: Intranasal absorption of salmon 645. Calcif Tissue Int 41:249-251, 1987 Van De Werf F, VanHaecke J: Prevention of bone loss in 659.

How for signi cant vascular calci cation assessed by ever blood pressure high diastolic order altace 2.5mg on-line, the Work Group recognizes the overwhelm ultrasound blood pressure standards order 5 mg altace amex, found by multivariate analysis that ing importance of controlling serum phosphorus the calcium load from phosphate binders was levels blood pressure of normal person buy generic altace from india, which can rarely be done with calcium greater in those with calci cation compared to containing phosphate binders while adhering to those without calci cation blood pressure medication dizzy spells buy altace 10mg low price. This recommendation is not patients with a calci cation score of 4 (P evidence-based and thus the clinician must indi 0 blood pressure monitor discount altace 2.5 mg visa. The latter does re ect the measured levels Maintenance of normal calcium balance and of free calcium if plasma levels of protein are serum calcium levels depend on integrated regu normal heart attack enrique iglesias discount 10 mg altace visa. If plasma levels of albumin are low, a lation of calcium absorption and secretion by the correction of the measured serum levels of cal intestinal tract, the excretion of calcium by the cium should be made. Several formulas have kidney, and calcium release from and calcium been developed to correct total calcium for abnor deposition into bone. The examples of adequate intake and cium balance (intake minus the sum of all losses) upper intake levels of calcium in various age in the healthy population is generally positive groups of healthy subjects are presented in Table ( 200 mg to 300 mg/day) during adolescence, 23. Table 24 provides the calcium content of negative calcium balance in the healthy aged various commercially available calcium-based population is the optimal status is a question for binders. This complication occurs especially in those Strength of Evidence with low-turnover bone disease. The clinical It is accepted that total calcium levels need to presentation of hypercalcemia varies from a mild, be adjusted for the level of albumin to better asymptomatic, biochemical abnormality de re ect the free calcium. With initiation of regular Report with regard to this Guideline indicate that hemodialysis, the levels of serum total calcium hypocalcemia is a risk for bone disease and for usually normalize. After adjusting for comorbid condi with clinical symptoms must be treated appropri tions, plasma albumin and blood hemoglobin, ately. This association renal failure as a consequence of both decreased was similar among patients treated with hemodi calcium intake and decreased fraction of calcium alysis or peritoneal dialysis. The fraction of intesti showed that hypocalcemia in these patients was nal absorption of calcium is decreased early in associated with de novo and recurrent cardiac the course of kidney disease. Initiation of dialysis does A positive relationship has been found be 195-197 not improve calcium absorption. It is com tween serum calcium level and mineralization 105 mon to observe signi cant variability in intestinal surface and osteoid surface, and a statistically calcium absorption within a group of patients with signi cant relationship between the serum cal 103,194-197 the same degree of kidney dysfunction, cium level and the percentage of metacarpal and, therefore, population studies may not be cortical/total bone area assessed by X-ray. The While this recommendation of the Work Group other 3 studies compared the use of calcium is not based on evidence provided in the Evi carbonate to placebo or no calcium supplement. The Work Groups recommendation of provide information that could be utilized to total daily calcium intake of 2. Furthermore, in dialysis patients, calcium Further, the data are not helpful in deciding supplementation of 3. None examined risk for future cal at least 1 year with hemodialysis between 1990 ci cation. Only 2 stud in Ca-P product, there was an 11% increase in ies208,211 provided enough information to calcu relative risk of death. There is no random Dis<30 ng/mL, supplementation with ized, controlled trial suggesting that adequate vitamin D2, (ergocalciferol) should be calcium intake or calcium supplementation will initiated (Table 26. Calcitriol or another 1 -hydroxy the plasma levels of 1,25-dihydroxyvitamin D lated vitamin D sterol should not be used to treat (calcitriol) or lower the elevated serum levels of vitamin D de ciency. With the use of low dosages, these months for 6 months, and every 3 effects occur with no evidence of worsening of months thereafter. Following treatment for 8, 12, or 24 There has been concern about the safety of the months, an improvement of bone biopsy features use of these vitamin D metabolites with regard to was noted in the vitamin D-treated pa a possible adverse effect on kidney function. Studies should evaluate velop during vitamin D treatment, particularly the effect on bone, in particular to ascertain with higher doses, transient or even long-lasting whether improvement in bone mineral content or deterioration of kidney function has been ob in histological features of hyperparathyroid bone served. However, comparisons of newer adynamic bone disease following treatment with vitamin D sterols with calcitriol, alfacalcidol, or alfacalcidol. Trials with cidol, paricalcitol, or doxercalciferol; the newer vitamin D sterols which may be less see Table 28) to reduce the serum calcemic will be of great interest. The result is roid bone disease, and improves musculoskeletal secondary hyperparathyroidism that often symptoms, when these are present. However, there are certain quali the major side effects of active vitamin D cations about the trials combined for this sterols, including calcitriol and alfacalcidol, are meta-analysis: Two trials compared daily oral increases in the serum levels of calcium and treatment with thrice weekly intravenous treat phosphorus leading to hypercalcemia and wors ment287,289; in the trial that studied patients with ening of hyperphosphatemia. The degree of hyperparathyroidism was very mild in such analogs are now in clinical use. Moreover, the earlier placebo-con have shown that doxercalciferol is associated trolled trials with daily oral calcitriol found that 304,305 with less calciuria than alfacalcidol. Also, it is almost certain buffering for the added extracellular calcium;174 that such patients would be considered inappro this likely accounts for the increased risk of priate for a long-term, placebo-controlled trial. There are many of these sterols available to a small number312; however, there is little and others are being developed. Since one of the reason to believe that the bone of adults would side-effects of the therapy with these sterols is not show the effects observed in pediatric-age hypercalcemia, one would want to use a sterol patients. If Trials that compare different vitamin D sterols the levels show a progressive rise, treatment in patients with end-stage kidney disease are should be initiated. Thus, ionized calcium levels were hemodialysis or peritoneal dialysis initially chosen at around 1. Early studies of parathyroid hormone in the late 1960s showed that these Background higher dialysate calcium levels of 3. With detectable by the technology of that era) and this level of calcium in dialysate, little or no seemed preferable to magnesium and calcium for calcium transfer occurs into the patient. With its direct effect on gut absorp calcium transfer into the patient may be achieved tion of calcium, the problems of hypocalcemia safely with dialysate levels up to 3. However, the Rationale traditional high calcium dialysate continued in the constituents of the dialysate have evolved most practices, with the goal being to maintain a over time in a generally logical fashion. The problem has been to only was aluminum absorbed from the gastroin balance the dialysate calcium with the needs for testinal tract, but that it was also quite toxic. However, to designate an optimal dialysate calcium concen it quickly became apparent that deferoxamine tration and it will not be possible until other caused infections with siderophilic organisms, aspects of the abnormal calcium metabolism in particularly mucormycosis, which had an extraor these patients are de ned and stabilized. Such studies were initi riol, lower calcium dialysates began to be intro ated with the best of intentions and often with duced. Changes in other aspects of the use of intravenous, bolus dosing with calcit our knowledge of calcium metabolism generally riol (which had much less effect on gut absorp made these studies obsolete or even unethical tion than oral treatment) and lower calcium dialy before they were completed. In the early days they do not contain calcium, magnesium, or of dialysis, these ndings resulted in recommen aluminum and are, therefore, likely not to impact dations for higher dialysate calcium levels (usu dialysis calcium concentrations directly. Probably, at least as much attention has been increasingly apparent and this is now should be paid to the potential adverse effects of the predominant form of osteodystrophy. In conjunction with this, the problem of have attempted to assess the effects of various metastatic calci cation, especially vascular calci dialysate calcium levels on morbidity, mortal cation, has assumed increasing importance and ity, infections (in peritoneal dialysis patients), is clearly associated with both positive calcium 87,92 various bone markers, and bone mineral den and phosphate balance. Since the studies were done at different Thus, the choice of dialysate calcium concen periods in the history of dialysis and at times tration has been determined largely by other when different measures to control calcium aspects of calcium metabolism over the rst 40 and phosphate were practiced, it is essentially years of dialysis therapy. Since these other as impossible to document or ascertain any clear pects of calcium metabolism remain problem atic, the actual dialysate calcium concentration conclusions from these studies. What is clear will continue to evolve and, of necessity, needs is that studies to assess dialysate calcium in the to remain exible as this dynamic area of re future may be conducted when other aspects of search continues to challenge us. If vidualized to meet speci c patient needs, but this and when that occurs, it may be possible to is not readily feasible economically at this time. Because of the rapid evolution of manage appear clear from the historical record, there is ment of calcium disorders in these patients, no little, if any, evidence to support this particular data exist to document that any particular cal choice. Clinical experience, rather than outcome cium dialysate is safer, more effective, or associ data, have really determined how we have come ated with fewer complications. The dif culties, up to now, of have shown an increase in cardiac arrhythmias obtaining outcome data on various dialysis cal with lower calcium dialysates, but no increase in cium levels have been frustrated by all the other mortality or morbidity has been shown to result. A lower calcium we have settled on a consistent approach to these dialysate concentration (eg, 1. We may also nd Because such treatment will lead to marked bone that, even at a 2. It is calcium loading occurs and contributes to vascu the primary cause of hypercalcemia that should lar disease and calciphylaxis. On the other hand, it has been recognized that Similarly, higher calcium levels in dialysates cardiac arrhythmia is more common in patients may be useful to sustain calcium balance when it being treated with lower-calcium dialysates. Thus, there dialysis, high calcium concentration dialysates remain serious unresolved questions which are (typically 3. Clinical Applications Recommendations for Research At this point in time, the most logical dialysate There is a basic con ict in calcium pathophysi calcium concentration appears to be one of 2. Once that is deter cause of joint pain and immobility in patients on mined, the best ways to achieve the desired result long-term dialysis. Studies to de ne this balance will be both metabolism of -microglobulin is the kidney. In normal individuals, the serum concentration of 2-microglobulin is less than 2 mg/L. In one series, 90% of patients had 2-microglobulin amyloidosis or pathological evidence of A M at 5 years. In addition, the clinical symptoms are considered to stop disease pro often nonspeci c, and easily mistaken for other gression or provide symp articular disorders. All of these factors make tomatic relief in patients with A M particularly dif cult to diagnose clini 2 2-microglobulin amyloidosis. To answer question 2, studies evaluat are good alternative diagnostic tests to biopsy, an ing potential therapies for A 2M have aimed to ideal design would be a direct comparison of reduce the serum level of 2-microglobulin, re these diagnostic techniques to pathological evi move or debulk the amyloid deposit, or reduce dence of the disease by biopsy. However, of the in ammation that may contribute to the develop 10 studies evaluating alternative diagnostic tests ment of the disease. Multiple clinical end points that met the inclusion criteria for evalua were evaluated in the search for therapies, includ tion,335-344 only 3 utilized joint biopsy. Although cal symptoms, or presence of pathological evi dialysis is not an exclusive cause of A 2M as dence of the disease elsewhere (eg, carpal tunnel previously thought, it is plausible that differ syndrome. All of these studies reported creased in ammation and generation of 2 that these alternatives worked well. However, microglobulin, and thus contribute to or exacer most studies suffer from small sample size, lack bate the disease process. The latter is usually in the potential contribution of dialysis membranes to form of predominantly enrolling patients with A 2M, multiple end-points were evaluated, in more severe forms of the disease, prohibiting the cluding serum levels of 2-microglobulin and calculation of true sensitivity/speci city for these clinical end-points. Thus, the applicability of these studies to whether screening for the disease was practical, the general dialysis population is unknown. Fur the answers to the preceding questions and the thermore, the ability to diagnose and differenti natural history of the disease were considered. It should also be noted that eral years, A 2M is particularly dif cult to diag scintigraphy results may be affected by which nose or study. Ideally, appropriate clinical trials carrier protein is labeled, and these are not readily would require large numbers of patients fol available in the United States. Unfortunately, there are apparent usefulness of these various diagnostic limited prospective trials. In addition, depending on how the cohort was de ned (ie, pathological evi Role of Dialysis Membrane dence, long-term dialysis patients, or those with To determine the effect of dialysis membranes clinical symptoms), there could be considerable on the incidence and severity of 2-microglobu bias. Thus, the overall strength of the evidence is lin, 21 studies evaluating the effect of one or weak. Due tive trials, only 3 were randomized,346,347,350 and to the low number of trials for each membrane, only 1 of these looked at clinical signs and and the heterogeneous nature of the results, sum symptoms and had adequate follow-up. Three out of rectly compared exclusive or near-exclusive use four trials, including a high-quality, randomized, of cellulosic membranes such as cuprophane to controlled trial, found that dialysis with polysul noncellulosic, semi-synthetic, high-ef ciency, or fone membranes removes more 2-microglobu high ux dialyzers. Several, but not all, studies lin from the serum than dialysis with cuprophane have demonstrated a bene t of the noncellulosic membranes. Only prevalence of the disease can be Screening determined from a cross-sectional trial. An optimal approach to ascertaining when for long periods of time at the same center were screening for A 2M should begin would be to included in the trial (ie, patients who died, re conduct a prospective cohort study in which a ceived kidney transplants, or relocated were not group of typical kidney failure patients were included in the trial. Thus, the evidence is not followed from the time that they commenced maintenance dialysis and were screened fre optimal. Only 1 study has these study limitations not withstanding, a 2 approached this ideal trial design. After 2 years on hemodialysis, the that they selected groups of patients who had summary odds ratio is 16. For this After 10 years on hemodialysis, the summary reason, the Work Group recommended that rou odds ratio is 51. The natural logarithm (ln) of the summary odds Limitations ratio is graphed versus time on dialysis in 13. These results, in combination with consider the lack of quality studies in this eld may be ations about the effectiveness of treatment for re ective of the slow progressive nature of the A 2M, can be used to determine when screening disease as well as the discordant relationship for A 2M should begin. However, for screening between clinical symptoms and pathological evi for A 2M to be rational, there would need to be dence of the disease. In addition, there was considerable bias in pa Therapies tient selection and very few studies had adequate Unfortunately, there are limited studies evalu and rigorous controls. Thus, the strength of the ating therapy, none of which are controlled and evidence supporting this Guideline is weak.

Induction may be considered earlier if fetal pulmonary maturity is documented by amniocentesis can blood pressure medication kill you altace 2.5 mg overnight delivery. With severely sensitized pregnancies requiring multiple inva sive procedures arrhythmia recognition purchase generic altace pills, the risks of continued umbilical cord blood sampling and transfusions must be considered and compared with those neonatal risks asso ciated with early delivery arteria hypogastrica cheap 5mg altace with visa. Obstetric and Medical Complications 239 Multifetal Pregnancy the incidence of twin and high-order multiple gestations has increased signifi cantly over the past 20 years primarily because of the availability and increased use of ovulation induction agents and assisted reproductive technology prehypertension treatments and drugs buy altace 10 mg with amex. There is increased fetal blood pressure medication vitamins cheap 2.5mg altace with mastercard, neonatal heart attack or stroke buy generic altace 10 mg line, and maternal morbidity and mortality associated with multifetal gestations. Antepartum Management Antepartum management of multifetal pregnancies requires special consider ations in the areas of nutrition, prenatal diagnosis, antepartum surveillance, ultrasonography, and in the diagnosis and treatment of commonly associated pregnancy complications. It is recommended that maternal dietary intake in a multiple gestation be increased by approximately 300 kcal more per day than that for a singleton pregnancy. The optimal weight gain for women with multiple gestations has not been determined. The presence of multiple fetuses increases the mathematical probability that one or more fetuses will be affected and, thus, results in a higher risk for the pregnancy than that attributed to maternal age alone. Amniocentesis or chorionic villous sampling may be technically difficult to accomplish in patients with multiple gestations, and only experienced physicians should perform these procedures in high-order multiple gestations. Technical problems unique to high-order multiple gestation include the need to traverse another fetus sac to reach a different fetus for sampling, incorrect 240 Guidelines for Perinatal Care fetal karyotype caused by cross contamination with other sacs, difficulty in accurately mapping the fetuses and determining which fetus is being sampled, difficulty in accurately determining whether any of the fetuses are monochori onic twins, and difficulty in locating and reducing only the affected fetus in the event an aneuploidy is diagnosed and termination chosen. The nonstress test and the fetal biophysical profile have been shown to be effective in identifying the compromised twin or triplet gestation; however, the most effective fetal surveillance system for such pregnancies is not known. It is also not known at what gestational age testing should be initiated, whether testing should be performed once or twice per week, or whether there is a need to test normally growing dichorionic twins. Ultrasonography can be useful in both prenatal diagnosis and surveillance of multiple gestations. Early ultrasonography should be used for evaluation of chorionicity, given its importance regarding prognosis and risk of certain complications. The risks associated with tocolytic agents are amplified in multiple gestations and thus they should be used judiciously. The effect of ante natal steroid administration and the effects of steroid dose in multiple gestations have not been examined. Nonetheless, the National Institutes of Health recommends that all women in preterm labor likely to give birth between 24 weeks and 34 weeks of gestation who have no contra Obstetric and Medical Complications 241 indications to steroid use be given one course of steroids, regardless of the number of fetuses. There currently is no evidence that prophylactic use of cerclage, hospitalization, bed rest, or home uterine monitoring improves outcome in these pregnancies. One obvious etiology is pla cental pathology; multiple gestations are at increased risk of having at least one fetus with a suboptimal placental implantation site or abnormal umbilical cord morphology. The threshold at which discordant growth is most strongly associated with adverse outcomes is unclear, even in twin gestations. If both fetuses are of normal weight and are progressing appropriately on their own growth curve, then discordance may not indicate a pathologic process. The workup should include a review of all prenatal exposures, a specialized ultrasound examination and, depending on the gestational age, tests of fetal well-being. The ultrasound examination should be performed by someone with skill and experience in evaluating multiple gestations. No fetal monitoring protocol has been shown to predict the most losses of one fetus in a multifetal pregnancy. In addition, authori ties disagree about antepartum management once a demise has occurred. However, if the death is the result of an abnormality of the fetus 242 Guidelines for Perinatal Care itself rather than maternal or uteroplacental pathology and the preg nancy is remote from term, expectant management may be appropriate. The most difficult cases are those in which fetal demise occurs in one fetus of a monochorionic twin pair. In such cases, there may be little or no benefit in immediate delivery, especially if the surviving fetuses are very preterm; allowing the pregnancy to continue may provide the most benefit. Monochorionicity can complicate the reduction procedure; if one fetus of a monochorionic twin pair is inadvertently reduced, sudden hypoten sion and thrombotic phenomena could result in death or damage of the remaining twin fetus. Whether to reduce high-order multiple gestations to twin or triplet gestations and whether to reduce triplet gestations at all are both areas of controversy. Most studies have concluded that the risks associated with a quadruplet or higher-order pregnancy clearly outweigh the risks associated with fetal reduction. Selective fetal termination is the application of the fetal reduction technique to the termination of an anomalous or aneuploid fetus that is part of a multiple gestation. The risks of this procedure are higher than those associated with multifetal reduction, in part because the pregnancy is often more advanced at the time of diagnosis of the anomaly. If the reduced fetus overlies the cervix or if the pregnancy is beyond 20 weeks, the risk of pregnancy loss, preterm delivery, or low birth weight of the remaining fetus may be increased. A variety of therapies have been attempted, including serial therapeutic amniocente ses of the recipient twins amniotic sac. More aggressive therapies usually are considered only for very early, severe cases and include abolishing the placental anastomoses by endoscopic laser coagulation or selective feticide by umbilical cord occlusion. However, no prospective randomized trials have tested the hypothesis that elective delivery at these gestational ages improves outcomes in these pregnancies. If the fetuses are appropriate in size for gestational age with evidence of sustained growth and there is normal amniotic fluid volume and reassuring antepartum fetal testing in the absence of maternal complications, such as preeclampsia or gestational diabetes, the pregnancy may be continued. Alternatively, if the woman is experiencing morbidities that would improve with delivery but do not neces sarily mandate delivery, delivery may be considered at these gestational ages. Determination of fetal pulmonary maturity may be necessary under certain circumstances. The route of delivery of twins should be determined by the position of the fetuses, the ease of fetal heart rate monitoring, and maternal and fetal status. Data are insufficient to determine the best route of delivery for high-order multiples. Other Medical Complications During Pregnancy Antepartum Hospitalization Pregnant patients with complications who require hospitalization before the onset of labor should be admitted to a designated antepartum area, either inside or near the labor and delivery area. Obstetric patients with serious and acute complications should be assigned to an area where more intensive care and sur veillance are available, such as the labor and delivery area or an intensive care unit. When sufficiently recovered, the pregnant patient should be returned to the obstetric service, provided that her return does not jeopardize her care. Written policies and procedures for the management of pregnant patients seen in the emergency department or admitted to nonobstetric services should be established and approved by the medical staff and must comply with the requirements of federal and state transfer laws. When warranted by patient vol ume, a high-risk antepartum care unit should be developed to provide special ized nursing care and facilities for the mother and the fetus at risk. When this is not feasible, written policies are recommended that specify how the care and transfer of pregnant patients with obstetric, medical, or surgical complications will be handled and where these patients will be assigned. Whether an obstetric patient is admitted to the antepartum unit or to a nonobstetric unit, her condition should be evaluated soon thereafter by the primary physician or appropriate consultants. The evaluation should encom pass a complete review of current illnesses as well as a medical, family, and social history. The condition of the patient and the reason for admission should deter mine the extent of the physical examination performed and the laboratory stud ies obtained. A copy of the patients current prenatal record should become part of the hospital medical record as soon as possible after admission. These policies also must comply with the requirements of federal and state transfer laws. The plan should be clear to the medical team and to the patients family, and to the patient herself if she is able to understand. Obstetric and Medical Complications 245 Intrapartum Care If a laboring patient requires critical care services, it is important to determine the optimal setting for her care. If the fetus is previable or the maternal condition unstable, it may be appropriate to undergo vaginal delivery in the intensive care unit. Changes in fetal monitoring should prompt reassessment of maternal mean arterial pressure, acidemia, hypoxemia, or inferior vena cava compression, and every attempt should be made at intrauterine fetal resuscitation. Drugs that cross the placenta may have fetal effects; however, necessary medications should not be withheld from critically ill pregnant women because of fetal concerns. In addition, imaging studies should not be withheld out of potential concern for fetal status, although attempts should be made to limit fetal radiation exposure during diagnostic testing. Nonobstetric Surgery in Pregnancy Nonobstetric surgery is sometimes necessary during pregnancy, and there are no data to support specific recommendations. However, obstetric consultation 246 Guidelines for Perinatal Care to confirm gestational age, discuss pertinent aspects of maternal physiology or anatomy, and make recommendations about fetal monitoring is highly recommended. Pregnant patients who undergo nonobstetric surgery are best managed with communication between involved services, including obstetrics, anesthesia, surgery, and nursing. The decision to use fetal monitoring should be individualized, and its use should be based on gestational age, type of surgery, and facilities available. Psychiatric Disease in Pregnancy ^ Approximately 500,000 pregnancies in the United States each year involve women who have psychiatric illnesses that either predate pregnancy or emerge during pregnancy and the postpartum period. The use of psychotropic medica tion during pregnancy requires attention to the risk of teratogenicity, perinatal syndromes, and neonatal withdrawal. Advising a pregnant or lactating woman to discontinue medication exchanges the fetal or neonatal risks of medica tion exposure for the risks of untreated maternal illness. Multidisciplinary care involving the obstetrician, mental health provider, and pediatrician is recommended. All psychotropic medications studied to date cross the placenta, are present in amniotic fluid, and enter human breast milk. The major risk of teratogenesis is during the third week through the eighth week of gestation. In general, a single medication used at a higher dose is favored over using multiple medica tions to obtain control of symptoms. Providing women with well-referenced patient resources for online information is a reasonable option. Trauma During Pregnancy Trauma is the leading cause of nonobstetric maternal death. In industrialized nations, most cases of trauma during pregnancy result from motor vehicle crashes. Other frequent causes of trauma during pregnancy are falls and direct assaults to the abdomen. The appropriate use of safety restraint systems in auto Obstetric and Medical Complications 247 mobiles, compliance with traffic laws, and early identification and intervention in suspected cases of domestic violence are all preventive measures that may reduce the likelihood of both maternal and fetal morbidity and mortality. Necessary evaluation and management of the trauma patient should not be changed because she is pregnant. Optimum management of the seriously injured pregnant woman requires an integrated effort of multiple specialties, starting with emergency medical technicians, emergency medicine physi cians, trauma surgeons, and other specialists, depending on the type of injury. Their knowledge and expertise are vital to management decisions regarding both the woman and the fetus. The obstetrician may be consulted regarding the condition of a pregnant trauma patient and her fetus or, more commonly, may be the primary physician caring for the patient following trauma.

Emboldened by success and the tenor of the times blood pressure medication voltaren generic altace 2.5 mg free shipping, the largest banks and their reg ulators continued to oppose limits on banks activities or growth arteria bologna 23 novembre purchase altace 1.25mg. Because restrictions on banks had been slowly removed during the previous decade blood pressure glucose chart cheap 5mg altace otc, banks already had beachheads in securities and insurance hypertension 9 code purchase altace 10mg otc. So frst the securities industry prehypertension pregnant purchase genuine altace, then the insurance companies pulse pressure 41 buy 5 mg altace fast delivery, and fnally the agents came over and said lets negotiate a deal and work together. The Fed approved it, citing a technical exemption to the Bank Holding Company Act, but Citigroup would have to divest itself of many Travelers assets within fve years unless the laws were changed. Supporters of the legislation argued that the new holding companies would be more proftable (due to economies of scale and scope), safer (through a broader diversifcation of risks), more useful to consumers (thanks to the convenience of one-stop shopping for fnan cial services), and more competitive with large foreign banks, which already offered loans, securities, and insurance products. Some securities frms immediately expanded their industrial loan company and thrift subsidiaries. The expressed intent of Fed-Lite was to elimi nate excessive or duplicative regulation. The strategies of the largest commercial banks and their holding companies came to more closely re semble the strategies of investment banks. In the af termath, investors dumped higher-risk securities, including those having nothing to do with Russia, and fed to the safety of U. This was a classic setup for a run: losses were likely, but nobody knew who would get burned. Nevertheless, the Feds orchestration raised a question: how far would it go to forestall what it saw as a systemic crisis Each time, the Fed cut short-term interest rates and encouraged fnan cial frms in the parallel banking and traditional banking sectors to help ailing mar kets. This shows the need for insuring that decisions about the appropriate level of capital for risky positions become an issue that is explicitly considered. This slump accelerated after the terrorist attacks on September as the nation slipped into recession. Investors were further shaken by revelations of ac counting frauds and other scandals at prominent frms such as Enron and World com. Enron and its bankers had created entities to do complex transactions generating fctitious earnings, disguised debt as sales and derivative transactions, and understated the frms leverage. Some frms that lent to companies that failed during the stock market bust were successfully hedged, having earlier purchased credit default swaps on these frms. The Wall Street banks pivotal role in the Enron debacle did not seem to trouble senior Fed of fcials. Earlier in the decade, he remembered, senior economists at the Fed had called Enron an example of a derivatives market participant successfully regulated by mar ket discipline without government oversight. By mid, the Fed had cut that rate to just, the lowest in half a century, where it stayed for another year. It also suspended restrictions on bank holding companies so the banks could make large loans to their securities afliates. Talented traders and managers once tethered to their frms were now free agents who could play companies against each other for more money. Though base salaries differed relatively little across sectors, banking and fnance paid much higher bonuses and awarded more stock. And brokers and dealers did by far the best, averaging more than million in compensation. John Gutfreund, reported to be the highest-paid executive on Wall Street in the late s, received. Encouraging the awarding of stock options was legislation making compensation in excess of million taxable to the corporation unless performance-based. The same applied to plans that tied pay to return on equity: they meant that executives could win more than they could lose. These pay structures had the unintended consequence of creating incentives to in crease both risk and leverage, which could lead to larger jumps in a companys stock price. As these options motivated fnancial frms to take more risk and use more lever age, the evolution of the system provided the means. And risk management, thought to be keeping ahead of these develop ments, would fail to rein in the increasing risks. The dangers of the new pay structures were clear, but senior executives believed they were powerless to change it. This is like a continual process of, you know, high-skilled people versus high-skilled people, and the poachers are better paid than the game keepers. Fannie and Freddie executives worked hard to persuade investors that mortgage-related assets were a riskless invest ment, while at the same time covering up the volatility and risks of their own mort gage portfolios and balance sheets. So Fannie counted only half the million on its books, enabling Raines and other executives to meet the earnings target and receive of their bonuses. For mula-driven compensation allows high short-term profts to be translated into generous bonus payments, without regard to any longer-term risks. The in vestment banks also grew signifcantly from to , often much faster than commercial banks. That meant potentially higher returns for shareholders, and more money for compensation. Citigroups increased from : to :, then shot up to : by the end of, when Citi brought off-balance sheet assets onto the balance sheet. In, even after bringing billion worth of assets on balance sheet, substantial assets remained off. Morgan Stanley and Lehman increased about and, respectively, and both reached : by the end of. An increasing amount of the investment banks revenues and earnings was generated by trading and invest ments, including securitization and derivatives activities. At Lehman, similar activities generated up to of pretax earnings in, up from in. Financial frms had grown mainly by simply lending to each other, he said, not by creating opportunities for in vestment. Banks might have been unwilling to lend to these borrow ers, but a subprime lender would if the borrower paid a higher interest rate to offset the extra risk. As Tom Putnam, a Sacramento-based mort gage banker, told the Commission, they traditionally lent based on the four Cs: credit (quantity, quality, and duration of the borrowers credit obligations), capacity (amount and stability of income), capital (sufcient liquid funds to cover down pay ments, closing costs, and reserves), and collateral (value and condition of the prop erty. The banks would securitize and sell the loans to investors or keep them on their balance sheets. Meanwhile, the S&Ls that originated subprime loans generally fnanced their own mortgage operations and kept the loans on their bal ance sheets. Some were what might be called subprime today, but others had outright documen tation errors or servicing problems, not unlike the low-documentation loans that later became popular. Most of the earliest private-label deals, in the late s and early s, used a rudimentary form of tranching. The, mortgages carried the rights to the borrowers monthly payments, which the Citigroup entity divided into tranches of mortgage-backed securities; each tranche gave investors a different priority claim on the fow of payments from the borrowers, and a different interest rate and repayment schedule. Tranches were assigned letter ratings by the rating agencies based on their riskiness. These were riskier than the senior tranches and, because they paid off more slowly, carried a higher risk that an increase in interest rates would make the locked-in inter est payments less valuable. In the structure of this Citigroup deal, which was typical, million, or, was rated triple-A. In, Freddie Mac rolled out Loan Prospector, an automated system for mortgage underwriting for use by lenders, and Fannie Mae released its own system, Desktop Underwriter, two months later. This new process was based on quantitative expectations: Given the borrower, the home, and the mortgage characteristics, what was the probability payments would be on time What was the probability that borrowers would prepay their loans, either because they sold their homes or refnanced at lower interest rates And the bankers conversely say, This is proven to be a business where we can make some money; not a lot, but when you factor that in plus the good will that we get from it, it kind of works. Meanwhile, subprime originators saw the interest rate at which they could borrow in credit markets skyrocket. Several other nonbank subprime lenders that were also dependent on short-term fnancing from the capital markets also fled for bank ruptcy in and. First Union eventually shut down or sold off most of the Money Stores operations. Like Keystone, it too failed after having kept and overvalued the frst-loss tranches on its balance sheet. Many of the lenders that survived or were bought in the s reemerged in other forms. Long Beach was the ancestor of Ameriquest and Long Beach Mortgage (which was in turn purchased by Washington Mutual), two of the more aggressive lenders during the frst decade of the new century. With the subprime market disrupted, subprime originations totaled billion in, down from billion two years earlier. One sticking point was the supervision of nonbank subsidiaries such as subprime lenders. The Fed had the legal mandate to supervise bank holding companies, in cluding the authority to supervise their nonbank subsidiaries. Even so, the shakeup in the subprime industry in the late s had drawn regulators attention to at least some of the risks associated with this lending. They further noted concerns about various accounting issues, notably the valuation of any residual tranches held by the securitizing frm. Higher fees and interest rates combined with compensation incentives can foster predatory pricing. An adequate compliance management program must identify, monitor and control the consumer protection hazards associated with subprime lending. However, the report also recognized the downside of restricting the lending practices that offered many borrowers with less-than-prime credit a chance at homeownership. I think nipping this in the bud in and with some strong consumer rules applying across the board that just simply said youve got to document a customers income to make sure they can re pay the loan, youve got to make sure the income is sufcient to pay the loans when the interest rate resets, just simple rules like that. She reached out to Edward Gramlich, a governor at the Fed who shared her con cerns, to enlist his help in getting companies to abide by these rules. But the Wall Street frms that securitized the loans resisted, saying that they were concerned about possible liability if they did not adhere to the proposed best practices, she recalled. Federal Reserve Chairman Alan Greenspan argued the fnancial system had achieved unprecedented resilience. Increased access to credit meant a more stable, secure life for those who managed their fnances prudently.

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