Written informed consent for living kidney donors: practices and compliance with CMS and OPTN requirements.

We sought to assess how written informed consent practices for candidate living kidney donors have changed over the last 5 years and to assess compliance with Centers for Medicare and Medicaid (CMS) and Organ Procurement and Transplantation Network (OPTN) regulations that took effect in 2007. We requested evaluation consent forms from US centers that performed >5 living kidney transplants during the prior year (n = 184). We received 148 consent forms; each was reviewed for information provided and inclusion of CMS- and OPTN-required elements. We found that nearly all transplant centers now obtain written consent for living kidney donor evaluation. However, most centers' evaluation consent forms do not include all CMS and OPTN requirements. Multiple items balancing donor and recipient interests and confidentiality were omitted. In addition, information about payment for routine follow-up care, complications related to surgery and other health problems following surgery were highly variable and frequently ambiguous. As centers revise their consent forms to address the 2013 OPTN policies, our findings may help them identify areas of potential deficiency. We propose that UNOS develop a uniform donor evaluation consent form to improve the clarity, consistency and efficiency of living donor consent.

Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21.

Essential hypertension is a common multifactorial trait. The molecular basis of a number of rare diseases that after blood pressure in humans has been established, identifying pathways that may be involved in more common forms of hypertension. Pseudohypoaldosteronism type II (PHAII, also known as familial hyperkalaemia and hypertension or Gordon's syndrome; OMIM #145260), is characterized by hyperkalaemia despite normal renal glomerular filtration, hypertension and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis and suppressed plasma renin activity are variable associated findings. The pathogenesis of PHAII is unknown, although clinical studies indicate an abnormality in renal ion transport. As thiazide diuretics are among the most efficacious agents in the treatment of essential hypertension, understanding the pathogenesis of PHAII may be of relevance to more common forms of hypertension. Analysis of linkage in eight PHAII families showing autosomal dominant transmission demonstrates locus heterogeneity of this trait, with a multilocus lod score of 8.1 for linkage of PHAII to chromosomes 1q31-q42 and 17p11-q21. Interestingly, the chromosome-17 locus overlaps a syntenic interval in rat that contains a blood pressure quantitative trait locus (QTL). Our findings provide a first step toward identification of the molecular basis of PHAII.

Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.

Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function. Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelman's syndrome to the locus encoding the renal thiazide-sensitive Na-Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects. These findings demonstrate the molecular basis of Gitelman's syndrome. We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.

Multidetector CT angiography in living donor renal transplantation: accuracy and discrepancies in right venous anatomy.

Multidetector computed tomography (MDCT) angiography is a reliable technique for assessing pre-operative renal anatomy in living kidney donors. The method has largely evolved into protocols that eliminate dedicated venous phase and instead utilize a combined arterial/venous phase to delineate arterial and venous anatomy simultaneously. Despite adoption of this protocol, there has been no study to assess its accuracy. To assess whether or not MDCT angiography compares favorably to intra-operative findings, 102 donors underwent MDCT angiography without a dedicated venous phase with surgical interpretation of renal anatomy. Anatomical variants included multiple arteries (12%), multiple veins (7%), early arterial bifurcation (13%), late venous confluence (5%), circumaortic renal veins (5%), retroaortic vein (1%), and ureteral duplication (2%). The sensitivity and specificity of multiple arterial anomalies were 100% and 97%, respectively. The sensitivity and specificity of multiple venous anomalies were 92% and 98%, respectively. The most common discrepancy was noted exclusively in the interpretation of right venous anatomy as it pertained to the renal vein/vena cava confluence (3%). MDCT angiography using a combined arterial/venous contrast-enhanced phase provides suitable depiction of renal donor anatomy. Careful consideration should be given when planning a right donor nephrectomy whether the radiographic interpretation is suggestive of a late confluence.

Giant kidneys in Waldenström's macroglobulinemia.

A patient with Waldenström's macroglubulinemia had the unique feature of having one kidney infiltrated with malignant cells to such an extent as to produce a large palpable abdominal mass. Other unusual aspects of this case include the destruction of renal tubules by the invading cells that resulted in interstitial fibrosis and was probably responsible for the appearance of whole IgM in the urine.

The effect of dexamethasone on renal potassium excretion and acute potassium tolerance.

In order to further characterize the kaliuretic action of dexamethasone, the effect of the hormone on renal electrolyte excretion and potassium tolerance was evaluated. In the first set of experiments, dexamethasone was administered acutely to unreplaced adrenalectomized rats, to adrenalectomized rats replaced with a single daily injection of dexamethasone (10 micrograms/100 g X day), and to intact control rats. After dexamethasone injection (10 micrograms/100 g), urinary potassium excretion increased by 105% in unreplaced adrenalectomized rats (0.99 +/- 0.13 to 2.02 +/- 0.26 mueq/min, P less than 0.005) and by 59% in rats maintained on glucocorticoid (0.87 +/- 0.10 to 1.38 +/- 0.18 mueq/min, P less than 0.05). The kaliuresis in adrenalectomized rats was associated with a significant increase in phosphate excretion and by a tendency for urinary chloride excretion to rise. In contrast, potassium excretion was unchanged by dexamethasone in control rats. These results indicate that the kaliuretic effect of dexamethasone is influenced by the degree of glucocorticoid deficiency before hormone administration. An additional study with K loading was performed in these same three groups of rats to evaluate the effect of dexamethasone replacement on potassium tolerance. Adrenalectomized rats maintained in daily dexamethasone replacement received an additional dose of hormone (50 micrograms/100 g) before study. After KCl, plasma potassium concentration rose significantly higher in unreplaced adrenalectomized rats vs. control (2.2 +/- 0.2 vs. 1.3 +/- 0.4 meq/liter, P less than 0.05) and peak renal potassium clearance was significantly blunted (577 +/- 90 vs. 1104 +/- 120 microliter/min. P less than 0.001). This impairment in potassium tolerance could not be attributed to hypotension, acidemia, diminished urinary flow, or sodium delivery in the distal nephron in unreplaced adrenalectomized rats but may be explained by decreased renal perfusion since glomerular filtration rate at the end of study was lower than in controls. Dexamethasone replacement improved potassium tolerance (peak delta Pk = 1.7 +/- 0.1 meq/liter) and renal potassium clearance (942 +/- 60 microliter/min). These data demonstrate that dexamethasone, at the high dose employed during KCl loading, improves renal potassium tolerance by enhancing renal K clearance in adrenalectomized rats. These results explain our previous report of near normal potassium excretion in glucocorticoid replaced adrenalectomized rats.

Effect of cyclosporine on renal ischemic injury.

To determine whether cyclosporine exacerbated renal ischemic injury and whether or not the timing of cyclosporine administration was important, rats were subjected to 30 or 45 min of ischemia. Cyclosporine was administered either before or after the renal ischemic insult. A single intravenous dose of cyclosporine, 20 mg/kg, before ischemia had no additional deleterious effect on inulin clearance compared with rats subjected to ischemia alone. In contrast, a significant exacerbation of the diminished glomerular filtration rate (GFR) produced by ischemia occurred when a low dose of cyclosporine (5 mg/kg) was given after ischemia. With 30 min of ischemia, GFR was 160 +/- 40 microliter/min/100 g in rats receiving cyclosporine (5 mg/kg) after ischemia compared with 280 +/- 40 microliter/min/100 g in rats subjected to ischemia alone. After 45 min of ischemia, cyclosporine (5 mg/kg) markedly reduced GFR to 20 +/- 10 microliter/min/100 g, a value significantly lower (P less than 0.05) than that observed in rats subjected to 45 min of ischemia alone (290 +/- 100 microliter/min/100 g). Plasma potassium concentrations tended to be higher and urinary potassium and sodium excretion lower in rats subjected to ischemia plus cyclosporine compared with ischemia alone. These findings indicate that even a single low dose of parenteral cyclosporine can exacerbate renal ischemic injury if given immediately after the ischemic insult. This interaction may contribute to the acute renal failure observed with cyclosporine use. In contrast, the kidney appears to be relatively resistant to a single dose of cyclosporine injury when the drug is administered prior to ischemia. These data suggest that the administration of parenteral cyclosporine immediately after transplantation could have deleterious effects and should probably be avoided.

Evidence that calcium channel blockade prevents cyclosporine-induced exacerbation of renal ischemic injury.

The following study was performed to determine whether calcium channel blockers, delivered before or after an ischemic insult, were effective at reducing cyclosporine-induced exacerbation of renal ischemic injury. When cyclosporine (5 mg/kg) was administered intravenously to rats after 30 min of renal ischemia, GFR fell by 60% compared with values observed in rats subjected to ischemia alone (190 +/- 30 vs. 330 +/- 40 microliters/min/100 g; P less than 0.05). Pretreatment with verapamil (10 micrograms/kg/min delivered intravenously) prevented the fall in GFR (320 +/- 70 microliters/min 100 g), as did pretreatment with nitrendipine, 1 micrograms/kg/min (460 +/- 90 microliters/min/100 g). Verapamil was less effective if given after the ischemia-cyclosporine insult (GFR 260 +/- 90 microliters/min/100 g), and nitrendipine given at this time had no beneficial effect at all (GFR 180 +/- 10 microliters/min/100 g). The doses of calcium channel blockers used had no protective effect on renal ischemic injury alone. Blood pressure during study ranged between 105 and 119 mm Hg with minor differences between groups. Sodium and potassium excretion and urinary flow rates were similar in all groups, except for a slight increase in sodium excretion in verapamil-treated rats. These values demonstrate that calcium channel blockers ameliorate the exacerbation or renal ischemic injury induced by cyclosporine if given before but not after the ischemia-cyclosporine insult. The protective effect of these agents, used preischemia in cyclosporine-treated rats, is observed with intravenous use of the drugs at doses that have no protective effect on renal ischemic injury alone.

Effects of H2-receptor antagonists on renal function in cyclosporine-treated renal transplant patients.

H2-receptor antagonists have been frequently avoided in cyclosporine-treated transplant patients because of concern regarding possible exacerbation of nephrotoxicity. To determine whether the reported increase of serum creatinine levels in cyclosporine-treated transplant patients receiving H2-receptor antagonists was due to a true decrease in glomerular filtration rate or was secondary to altered renal tubular handling of creatinine, simultaneous inulin and creatinine clearances were analyzed in 11 cyclosporine-treated renal transplant recipients before and after H2-receptor antagonist administration. Seven patients received one week of cimetidine 300 mg p.o. four times daily and eight received one week of ranitidine 150 mg p.o. two times daily. Prior to study, all patients had stable renal function and were maintained on prednisone (mean dose 0.2 +/- 0.01 mg/kg/day) and cyclosporine (mean dose 5 +/- 0.6 mg/kg/day). Four patients were also receiving azathioprine (2 mg/kg/day). Cimetidine administration resulted in a significant increase (P less than 0.05) in mean serum creatinine concentration from 2.0 +/- 0.3 mg/dl to 2.4 +/- 0.3 mg/dl and a significant reduction (P less than 0.05) in mean creatinine clearance remained unchanged during this same period. Serum creatinine levels returned to baseline values for all patients following discontinuation of the drug. Ranitidine administration had no consistent effect on serum creatinine concentration, creatinine clearance or inulin clearance. Cyclosporine trough levels and BUN were unchanged by either drug. These results confirm previous observations demonstrating an increase in serum creatinine and a reduction in creatinine clearance following administration of H2 receptor antagonists, especially cimetidine. Failure to document a simultaneous reduction in inulin clearance is consistent with the hypothesis that H2-receptor antagonists do not exacerbate cyclosporine nephrotoxicity and lower GFR, but rather compete with creatinine for tubular secretion.

Microalbuminuria and hypertension in long-term renal donors.

In order to determine whether the proteinuria observed in some renal donors was glomerular or tubular in origin, and to determine whether creatinine clearance was an accurate index of glomerular filtration rate (GFR) in subjects with reduced nephron mass, 29 donors were evaluated 9-18 years after uninephrectomy. Results were compared with those in 31 age-, sex-, and race-matched controls evaluated at the same time. Mean creatinine clearance (Ccreat) in donor was 78% that of controls, which was similar to the 85% ratio of inulin clearance (Cin) in donors compared with that of controls. Furthermore, the ratio of Ccreat/Cin was similar in both donors and controls. One third of the renal donors had an elevated albumin excretion compared with controls (microalbuminuria [12-220 mg/24 hr] in seven patients; 301 and 1084 mg/24 hr in two patients). There was no correlation between albuminuria and blood pressure, nor was there a demonstrable clinical cause for the albuminuria in most patients. In contrast to these results, excretion of beta-2 microglobulin, an index of tubular proteinuria, was normal in all but one patient. The prevalence of hypertension was higher in donors compared with the expected prevalence adjusted for age, sex, and race. These results verify that creatinine clearance is a reliable measure of GFR in long-term renal donors. They also demonstrate an increased frequency of glomerular proteinuria and hypertension in renal donors. Despite these mild abnormalities, GFR is well preserved for up to 18 years postuninephrectomy.

Effect of treatment with cyclosporine versus azathioprine on incidence and severity of cytomegalovirus infection posttransplantation.

The incidence and severity of cytomegalovirus (CMV) infection were evaluated in 24 renal transplant patients treated with steroids and cyclosporine and compared with 40 patients treated with steroids and azathioprine: 58% of patients receiving azathioprine and 33% of patients receiving cyclosporine required additional therapy with antithymocyte globulin (ATG) to treat steroid-resistant rejections. CMV antibody titers and cultures of urine and saliva were determined monthly for 4-6 months following transplant in all patients. Both the frequency of CMV infection (occurring in 58% of patients on steroids and cyclosporine and in 48% of patients on steroids and azathioprine) and its severity (21% of cyclosporine-treated patients and 22% of azathioprine-treated patients with symptoms) were similar in both groups. Use of ATG was associated with an increased incidence of CMV disease, especially for patients in the azathioprine group. Both the incidence of CMV disease, and the number of patients with symptoms in the azathioprine group were significantly lower when patients who had received ATG were excluded from analysis. When results were analyzed in just the cadaveric recipients in each group, the incidence and severity of CMV infection tended to be higher in azathioprine-treated patients compared with those maintained on cyclosporine. This could have been explained by the more frequent use of ATG in 84% of azathioprine maintained patients compared with 35% of cyclosporine-treated patients (P less than 0.002) since other factors, such as risk for CMV infection and Solumedrol dose for rejection were similar in both groups. The data demonstrate that ATG has a deleterious influence on the incidence and severity of CMV infection in renal transplant patients, even when the dosage of other immunosuppressive drugs is decreased during ATG therapy. Since patients treated with steroids and azathioprine tend to require ATG to treat steroid-resistant rejection more frequently than do patients on cyclosporine, this effect of ATG must be taken into account when evaluating CMV infection in patients on these two drug regimens.

Posttransplant bone disease: evidence for a high bone resorption state.

Loss of bone is a significant problem after renal transplant. Although bone loss in the first post transplant year has been well documented, conflicting data exist concerning bone loss after this time. It is equally unclear whether bone loss in long-term renal transplant recipients correlates with bone turnover as it does in postmenapausal osteoporosis. To examine these issues, we conducted a cross-sectional study to define the prevalence of osteoporosis in long-term (> 1 year) renal transplant recipients with preserved renal function (mean creatinine clearance 73 +/- 23 ml/min). Bone mineral density (BMD) was measured at the hip, spine and wrist by DEXA in 69 patients. Markers for bone formation (serum osteocalcin) and bone resorption [urinary levels of pyridinoline (PYD) and deoxypyridinoline (DPD)] were also measured as well as parameters of calcium metabolism. Correlations were made between these parameters and BMD at the various sites. The mean age of the patients was 45 +/- 11 years. Eighty eight percent of patients were on cyclosporine (12% on tacrolimus) and all but 2 were on prednisone [mean dose 9 +/- 2 mg/day)]. Osteoporosis (BMD more than 2.5 SD below peak adult BMD) at the spine or hip was diagnosed in 44% of patients and osteopenia was present in an additional 44%. Elevated levels of intact parathyroid hormone (i PTH) were observed in 81% of patients. Elevated urinary levels of PYD or DPD were present in 73% of patients and 38% had elevated serum levels of osteocalcin. Levels of calcium, and of 25(OH) and 1,25(OH)2 vitamin D were normal. In a stepwise multiple regression model that included osteocalcin, PYD, DPD, intact PTH, age, years posttransplant, duration of dialysis, cumulative prednisone dose, smoking, and diabetes: urinary PYD was the strongest predictor of bone mass. These results demonstrate that osteoporosis is common in long-term renal transplant recipients. The data also suggest that elevated rates of bone resorption contribute importantly to this process.

Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) has been observed with increasing frequency consequent to the availability of more effective and potent immunosuppression. Prior work suggested that a peripheral blood monitoring strategy detecting peripheral B lymphoproliferation was effective in the early diagnosis of PTLD among 7 of 179 (3.9%) consecutive transplant recipients. Each of those seven patients received at least one course of antithymocyte globulin, Minnesota antilymphocyte globulin, or OKT3 before developing PTLD. METHODS: To determine whether antiviral prophylaxis might reduce the incidence of PTLD, a subsequent group of 198 consecutive recipients received either ganciclovir or acyclovir during antilymphocyte antibody administration. When the donor or recipient were cytomegalovirus-seropositive, ganciclovir was given; acyclovir was used when both were cytomegalovirus-seronegative. Baseline and protocol posttransplant cell surface profiles were obtained using immunofluorescence and flow cytometry to detect T cells, lymphocyte activation markers, and the CD19 B cell antigen. RESULTS: Demographic factors, including the incidence of recipients more than 50 years of age, non-Caucasians, previous transplantation, and diabetes mellitus, were similar in both groups. Additionally, the number of patients receiving antilymphocyte preparations was similar. However, only one patient (0.5%) from the latter group who received preemptive antiviral therapy developed PTLD. Although elevations in CD19+ B cells preceded clinical PTLD among each of the seven earlier patients, evidence of peripheral B cell proliferation was not demonstrated for the sole patient from the latter group, which suggests a possible effect of antiviral therapy. CONCLUSIONS: Prophylactic antiviral therapy may reduce the sensitivity of peripheral monitoring for B lymphoproliferation, but the dramatic reduction in PTLD incidence strongly supports its use among transplant recipients at risk.

Evaluation of living renal donors. The current practice of US transplant centers.

To examine practice patterns regarding how living donors are evaluated and selected in the U.S., a survey was sent to all 231 United Network of Organ Sharing (UNOS)-approved transplant centers. Respondents from 75% of centers completed the questionnaire, all of whom utilize living donors for renal transplantation. Although the use of living-unrelated donors is also widely accepted (in 92% of centers), only 31% of responding centers performed such transplants in 1992, indicating a discrepancy between acceptance and actual practice. Morbidity (0.23%) and mortality (0.03%) of kidney donation continue to be low. The long-term risk of renal insufficiency in kidney donors appears to be similar to, or lower than, that in the general population. There is substantial variability in how potential donors are evaluated and what they are told regarding the risk involved in renal donation. There is also variability in exclusion criteria such as the acceptance of older donors (> 55 years old); those with borderline-to-mild hypertension, and those with borderline low glomerular filtration rate. Larger centers tended to be less rigid in their exclusion criteria compared with smaller centers. While our results indicate widespread acceptance and use of living donors, they also highlight the need for future studies to examine the efficacy of tests used in the evaluation process and to determine the long-term risks of renal donation.

Parameters of high bone-turnover predict bone loss in renal transplant patients: a longitudinal study.

BACKGROUND: Osteoporosis is a serious complication of kidney transplantation. Various factors have been postulated to contribute to posttransplant bone loss, among them treatment with corticosteroids, the use of cyclosporine and cyclosporine-like agents, and persistent hyperparathyroidism. In a previous cross-sectional study of long-term renal transplant recipients, we observed that osteoporosis or osteopenia was present in 88% of patients. Because biochemical markers of bone formation (serum osteocalcin) and bone resorption (urine pyridinoline, PYD, and deoxypyridinoline, DPD) were elevated in the majority of study subjects, we hypothesized that elevated rates of bone-turnover contribute to posttransplant bone loss in long-term renal transplant patients. This study was performed to examine this hypothesis. METHODS: The study population was composed of 62 patients who were more than 1-year postrenal transplantation and who had preserved renal function. They were followed prospectively for 1 year. Biochemical markers of bone-turnover were measured at study entry, and patients were classified as having high bone-turnover based on elevated urinary levels of at least one marker of bone resorption (i.e., PYD or DPD) and/or serum osteocalcin (group 1). If none of these were present, they were classified as having normal bone-turnover (group 2). Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) at time of entry into the study and again after 1 year of follow-up. The changes in BMD at the lumbar spine, hip, and wrist over the period of the study were compared between the high and normal bone-turnover groups. RESULTS: Forty-three patients (69%) were classified as having high bone-turnover (Group 1), and 19 patients (31%) were classified as having normal bone-turnover (Group 2). There was a statistically significant difference in change in BMD between the two groups at the lumbar spine (-1.11+/-0.42%, high bone-turnover, vs. 0.64+/-0.54%, normal bone-turnover; P=0.02) and the hip (-0.69+/-0.38%, high bone-turnover, vs. 1.36+/-0.66%, normal bone-turnover; P=0.006). Whereas group 2 had stable bone mass, group 1 exhibited bone loss at these skeletal sites. CONCLUSIONS: Our results indicate that bone loss is greater in renal transplant recipients with elevated biochemical markers of bone-turnover, suggesting that these markers may be useful in identifying patients at risk for continued bone loss. These data support the hypothesis that continued bone loss in long-term renal transplant recipients is associated with high bone-turnover. If accelerated bone resorption does play a role in posttransplant bone loss, this would provide a strong rationale for use of antiresorptive therapy for the prevention and treatment of this complication.

ACE inhibitors do not induce recombinant human erythropoietin resistance in hemodialysis patients.

Angiotensin-converting enzyme (ACE) inhibitors may exacerbate anemia in patients with chronic renal failure, as well as in dialysis patients. To better answer this question, a prospective, crossover study was conducted to evaluate the effect of ACE inhibitors on recombinant human erythropoietin (rHuEPO) requirements in hemodialysis patients. Patients administered an ACE inhibitor when entering the study remained on this drug for the initial 4 months and were then switched to another antihypertensive agent for 4 more months. Patients not initially administered an ACE inhibitor were switched to lisinopril at 4 months. rHuEPO doses were adjusted using a sliding scale based on weekly laboratory hematocrit values. The inclusion criteria were met by 51 patients undergoing dialysis. Demographics were as follows: 61% were women, 64% were black, 46% had diabetes, average age was 53.2 +/- 13.3 years, and time on hemodialysis was 38.0 +/- 44.5 months. Thirty-three patients completed the study. Hematocrit averaged 32.7% +/- 1.9% while on ACE inhibitor therapy and 33.1% +/- 2.1% off ACE inhibitor therapy (P = 0.217). There was no difference in rHuEPO dose per treatment during each period (3,500 +/- 1,549 U on ACE inhibitor therapy versus 3,312 +/- 1,492 U off ACE inhibitor therapy; P = 0.300). No significant differences were found in degree of blood pressure control or various clinical and laboratory parameters that might be associated with rHuEPO resistance between the two periods. Similarly, no differences were found in hospitalization days, duration of infections, or transfusion requirements. These findings suggest that ACE inhibitors do not contribute to rHuEPO resistance in hemodialysis patients.

Mixed acid base disturbances: a clinical approach.

The analysis of a mixed acid-base disturbance begins with the history and physical examination from which data can be derived that make the clinician suspect a specific disturbance(s). The electrolytes are then evaluated with emphasis on the meaning of the values for serum bicarbonate, potassium and chloride concentration and on the level of the anion gap. Other laboratory data such as serum creatinine or glucose concentrations, blood cultures, and so forth, should also be reviewed for further clues to a possible disturbance(s). When it is clinically indicated, values for pH and Pco2 are obtained by blood gas determination. If the evidence up to this point indicates the presence of at least one disturbance, the data are examined to see if compensation for this disturbance is appropriate. If not, a mixed disturbance must be present. A normal pH in the setting of an abnormal serum HCO3(-) concentration or Pco2 also suggests a mixed disturbance since compensation rarely corrects the pH back to normal. Of course, a pH deviated in the opposite direction than that expected for a known primary disturbance makes the diagnosis of a mixed disturbance certain. The diagnosis of a mixed acid-base disturbance is therefore based on an analysis of all the clinical data and not just the blood gas measurements. Treatment of the disorders should be directed at maintaining a normal or near normal pH. Some combined acid-base disorders are important to recognize because they can result in a severe deviation in blood pH that demands immediate, specific therapy. Other mixed disturbances result in a pH which is near normal but are important to recognize since they can alert the clinician to the possibility of certain clinical derangements such as septic shock or drug ingestion. Careful analysis of mixed acid-base disturbances in this way is not peutic information to be used in caring for his (her) patients.

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers used for the treatment of hypertension appear to be safe in the early posttransplant period.

Angiotensin II converting enzyme inhibitors (ACE) and angiotensin II receptor blockers (ARB) are frequently avoided as treatment for hypertension in the early posttransplant period (0 to 90 days) for fear of nephrotoxicity. The following retrospective study was designed to explore the safety of these drugs in the early posttransplant period and determine appropriate clinical criteria for starting these medications. The records of all adult renal transplants performed between January 1997 and December 2000 (N = 290) were reviewed. All patients started on ACE or ARB for treatment of hypertension within 90 days of their transplant were included in the analysis (n = 17). Controls (n = 19) were patients who were treated with a calcium channel blocker (CCB) for hypertension. Cases and controls were matched for gender and type of transplant, living or cadaver. Patients were considered to be enrolled whey they met the following criteria: hypertension, serum creatinine < or =3.0 mg/dL, or falling 1 mg/dL/d and serum potassium < or =5.5 mEq/L. Exclusion criteria were coexistent pancreas transplant, anaphylaxis to ACE, and use of ACE or ARB for treatment of posttransplant erythrocytosis. There were no differences between cases and controls in hemoglobin or serum potassium concentrations or calculated glomerular filtration rate at 3, 6, and 9 months. In renal transplant patients with reasonable allograft function, administration of ACE and ARB to treat hypertension in the early posttransplant period appears to be well tolerated and not associated with excess hyperkalemia, anemia, or acute renal dysfunction.

Sirolimus-based immunosuppression with reduce dose cyclosporine or tacrolimus after renal transplantation.

Sirolimus (SRL), a fermentation product of Streptomyces hygroscopicus, complexes with the FKBP12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G(1)-S phase cell cycle arrest. Safety and efficacy have been documented in clinical renal transplantation, but concerns were raised due to important biologically relevant side effects. Hyperlipidemia was identified, beginning with early clinical experiences, and the unexpected findings that SRL may exacerbate CsA associated nephrotoxicity was observed during the pivotal phase III studies. This report details results of our experience using SRL (target trough concentration, 10-15 ng/mL) with low dose CsA (target trough concentration, 50-100 ng/mL), seeking to determine whether this approach might provide effective immunosuppression while reducing associated nephrotoxicity. Among 121 renal transplant recipients, 62 received the SRL based regimen and 59 received MMF with all patients receiving CsA and prednisone. Similar to earlier clinical experiences, hematopoeitic abnormalities and hyperlipidemia were observed among patients who received SRL, and those abnormalities were readily controlled. However, unlike observations from the phase III SRL studies, renal function was not adversely affected. These findings support the growing body of evidence indicating that SRL based immunosuppression in combination low dose calcineurin inhibitors and corticosteroids is safe, efficacious, and without associated renal toxicity.

The evolving experience using everolimus in clinical transplantation.

Everolimus is a derivative of sirolimus, a macrocyclic lactone, originally isolated from Streptomyces hygroscopicus. Both everolimus and sirolimus have a similar mechanism of action, exerting potent inhibition of growth factor-induced proliferation of lymphocytes, as well as other hematopoietic and nonhematopoietic cells of mesenchymal origin. Each agent complexes with the FK506 binding protein 12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G1-S phase cell cycle arrest. Safety and efficacy have been documented in large-scale, blinded, randomized, international clinical renal and cardiac transplant trials. Everolimus is more hydrophilic, exhibits a shorter elimination half-life (approximately 30 hours), and demonstrates greater relative bioavailability compared to sirolimus. However, similar to the calcineurin inhibitors and sirolimus, everolimus is biotransformed by the cytochrome P450, 3A4 isozyme. Also similar to sirolimus, clinical experiences identified biologically relevant side effects including hyperlipidemia and exacerbation of cyclosporine (CsA)-associated nephrotoxicity. However, also similar to sirolimus, accumulating evidence suggests that the hyperlipidemia can be controlled and the CsA-associated renal effects appear reduced with a low incidence of acute rejection when everolimus is administered in combination with reduced CsA doses. The experience using everolimus in cardiac transplantation has also provided potentially important insights into the consequences of antiproliferative effects on vascular smooth muscle cells and fibroblasts where reduction in intimal expansion was identified by intravascular coronary ultrasound examination among those patients receiving everolimus. Therefore, available results suggest that the introduction of everolimus as the newest TOR inhibitor should enhance therapeutic options for immunosuppression after organ transplantation.