A comparison between cyclosporine and tacrolimus-based immunosuppression for renal allografts: renal function and blood pressure after 5 years.

The choice of initial immunosuppressive therapy (IST) following solid organ transplant remains a source of some controversy. Cyclosporine A (CsA) has been the basis of most IST protocols over the past two decades but has recently been supplanted in many centers by the use of tacrolimus (TAC)-based protocols. Renal allograft recipients in London may receive either CsA or TAC based IST, along with prednisone and azathioprine or (since 1999) mycophenolate mofetil (MMF). The decision is based on criteria such as age, gender, diabetic status, and lipid levels, which are felt to be impacted by the delivery of CsA or TAC based IST. The present analysis focuses on the results of BP and renal function in renal transplant patients receiving CsA or TAC based initial therapy during the period January 1, 1996 to June 30, 2002. Patients receiving TAC based IST were significantly younger than those receiving CsA (44 +/- 13.9 vs 50.5 +/- 12.3 years; P < .004). Mean arterial pressure (MAP) was lower in the TAC patients at 1 month (97.8 +/- 13.1 vs 103.2 +/- 11.8 mm Hg; P = .035), but became equivalent to CsA-treated patients for the balance of the follow-up period of up to 60 m. Serum creatinine was not significantly different between groups at any time during up to 60 months of follow-up. Based on these results, it seems apparent that the choice of calcineurin inhibitor may not influence renal function or blood pressure in long-term renal allograft survivors.

Effect of valsartan on urinary protein excretion and renal function in patients with chronic renal allograft nephropathy.

Chronic allograft nephropathy (CAN) remains a significant cause of late renal allograft loss. Although many factors may be involved in pathogenesis, the hemodynamic and fibrogenic consequences of long-term therapy with cyclosporine (CsA) have been implicated as important potentially reversible causes. CsA's effect on CAN is mediated in part through increased renal expression of TGF-beta, which can be modified by administration of angiotensin receptor blockers (ARBs). A pilot study was undertaken to evaluate the safety and efficacy of the ARB valsartan on renal function and proteinuira in patients with CAN. Ten patients on CsA-based therapy with evidence of CAN received valsartan in an initial dose of 80 mg/d, force titrated to 160 mg/d after 4 weeks, for a total of 52 weeks. Renal function was evaluated by serum creatinine, 24-hour creatinine clearance (CrCl), and isotope, GFR and urinary protein by 24-hour protein excretion. The 10 patients were aged 20 to 71 years and had been transplanted for 88.2 +/- 64.8 months at the time of study. After 52 weeks of valsartan therapy mean blood pressure (BP) fell from 152/88 mm Hg to 138/77 mm Hg (P =.06); serum creatinine rose from 206 +/- 55 micromol/L to 238 +/- 81 micromol/L (P =.22.); GFR fell from 39.8 +/- 17.6 to 31.9 +/- 19 mL/min (P =.23); and urine protein fell from 2.16 +/- 2.7 to 1.12 +/-.095 g/24 hours (P =.13). Side effects of valsartan therapy were few and included transient hyperkalemia in 2/10 patients. The small rise in serum creatinine and fall in GFR observed were not statistically significant. Urine protein fell by more than 50%, though the small patient numbers in this pilot study prevent this from achieving statistical significance. It is concluded that valasartan reduces BP and proteinuria in CAN patients without inducing a serious worsening in renal function. Valsartan may have a role to play in the management of patients with CAN.

Acute interstitial nephritis due to omeprazole.

Omeprazole is a proton pump inhibitor that is used commonly in the treatment of acid-peptic disorders. Although omeprazole is generally well tolerated, serious adverse effects such as renal failure have been reported. Thus far, 17 cases of acute interstitial nephritis (AIN) secondary to omeprazole have been described. Another case of AIN is described in a 36-yr-old woman presenting with nausea, vomiting, weight loss, and a rising serum creatinine concentration. Omeprazole therapy had ceased 2 wk before admission. AIN was diagnosed by renal biopsy and corticosteroid therapy was initiated. After 4 wk of therapy the serum creatinine concentration had normalized. Among the reported cases in the literature, AIN was diagnosed after an average of 2.7 months of therapy with 20-40 mg of omeprazole daily. Recurrence was universal on rechallenge. Common symptoms included fatigue, fever, anorexia, and nausea. The classic triad of fever, rash, and eosinophilia was uncommon. Typical laboratory features included hematuria, proteinuria, pyuria, eosinophilia, and anemia. Management consisted of withdrawal of omeprazole and corticosteroid therapy in some patients. All but one patient recovered normal renal function. Corticosteroid therapy was well tolerated and may have been beneficial.

Long-term knowledge retention following predialysis psychoeducational intervention.

BACKGROUND/AIMS: Early identification and predialysis psychoeducation are gaining acceptance. Although research supports the immediate value of predialysis interventions, long-term benefits remain unknown. We examined long-term knowledge retention following a psychoeducational intervention. METHODS: 47 progressive renal failure patients completed the Kidney Disease Questionnaire at baseline and 18, 30, 42, and 54 months after initiating renal replacement therapy (RRT; the 'longitudinal' sample). A larger cohort provided data at one or more of these points (n = 132, 117, 101, and 70 at 18, 30, 42, and 54 months, respectively; the 'cross-sectional' sample). RESULTS: Initial knowledge gains among psychoeducation recipients were followed by a significant knowledge advantage for three groups throughout follow-up. Patients who received predialysis psychoeducation either before or after starting dialysis demonstrated superior Kidney Disease Questionnaire scores as compared with those identified before the initiation of RRT who received the usual standard of practice. Patients identified after the initiation of RRT and who received standard education, however, demonstrated the same level of knowledge retention as produced by psychoeducation. The results were identical across the longitudinal and cross-sectional samples. CONCLUSIONS: Patient education produces important benefits in end-stage renal disease, but the incremental value of early intervention remains to be demonstrated.

Live and learn: patient education delays the need to initiate renal replacement therapy in end-stage renal disease.

During a longitudinal study of the quality of life of end-stage renal disease, 204 patients with deteriorating renal function were identified before dialysis or transplantation was required to preserve their lives. These patients were randomly assigned to either an enhanced or a standard education condition. The enhanced education condition consisted of a specially prepared slide-lecture show concerning kidney diseases and their treatment that was delivered by a trained research assistant. The standard education condition consisted of whatever educational procedures were routinely available at the participating hospital. All but six patients have now started treatment by maintenance dialysis. Individuals in the enhanced education condition survived an average of 4.6 months longer than did those in the standard education group without requiring the initiation of renal replacement therapy. This effect could not be attributed to physical differences between the groups, to cohort effects, to delays in contacting the patients, or to when or where they were identified. Possible mechanisms for this effect are discussed.

Human mouse chimeric CD7 monoclonal antibody (SDZCHH380) for the prophylaxis of kidney transplant rejection.

mAb directed against CD7 have been shown to inhibit T cell proliferation in the allogeneic mixed lymphocyte reaction suggesting that CD7 may be an appropriate target for in vivo immunotherapy. We performed a prospective randomized clinical trial with a human-mouse chimeric CD7 mAb (SDZCHH380) and compared it with murine OKT3 for the prophylaxis of kidney transplant rejection. Twenty recipients of first cadaveric renal allografts were randomized to receive either SDZCHH380 or OKT3. SDZCHH380 was well tolerated. Rejection was delayed to day 35. No patients were sensitized to SDZCHH380. In contrast 7/10 OKT3 patients made anti-OKT3 antibodies. SDZCHH380 coated peripheral blood and lymph node T cells and, in contrast to OKT3, induced minimal release of IL-2, IL-6, TNF-alpha, and IFN-gamma. In addition, we showed that CD7-negative T cells mediated rejection in one of the SDZCHH380-treated patients. We conclude that the human-mouse chimeric CD7 mAb SDZCHH380 is well tolerated, is not immunogenic, and merits further study in the prophylaxis of transplant rejection.

Demand-side medical education: educating future physicians for Ontario.

Initiated by Associated Medical Services (AMS), Educating Future Physicians for Ontario is a 5-year collaborative project whose overall goal is to make medical education in Ontario more responsive to that province's evolving health needs. It is supported by AMS, the five universities with medical schools or academic health sciences centres and the Ontario Ministry of Health. The project's five objectives are to (a) define the health needs and expectations of the public as they relate to the training of physicians, (b) prepare the educators of future physicians, (c) assess medical students' competencies, (d) support related curricular innovations and (e) develop ongoing leadership in medical education. There are several distinctive features: a focus on "demand-side" considerations in the design of curricula, collaboration within a geopolitical jurisdiction (Ontario), implementation rather than recommendation, a systematic project-evaluation plan and agreement as to defined project outcomes, in particular the development of institutional mechanisms of curriculum renewal as health needs and expectations evolve.

The outcome of pregnancy following renal transplantation--the experience of a single center.

Many centers still recommend avoidance of pregnancy after renal transplantation because of fears for the safety of both mother and fetus. These fears are in part based on a lack of information concerning the effects of newer immunosuppressive drugs such as cyclosporine on the course and outcome of pregnancy. The present study examines the experience of first pregnancies following renal transplantation in a single center, with emphasis on the role of CsA. Data on the first pregnancies of 22 women transplanted between 1977 and 1988 were studied. The mean age of patients at the time of transplant was 23.4 +/- 3.1 years and interval from transplant to pregnancy was 34.5 +/- 24.5 months (range 1-75 months). Twelve patients received CsA alone or in combination with other immunosuppressives, while the remaining 10 patients received azathioprine and prednisone. Mean serum creatinine fell progressively during pregnancy in both CsA- and azathioprine-treated mothers. Mean CsA dose rose during pregnancy while mean CsA blood concentration fell during the 2nd trimester (P = 0.042). The gestation period ranged from 27 to 40 weeks (35.5 +/- 3.3) with 14 pregnancies ending prematurely prior to 37 weeks. Thirteen deliveries occurred by Caesarian section. Hypertension complicated 10 pregnancies. Birth weight correlated directly with both maternal weight gain (r = 0.57; P less than 0.02) and gestational age (r = 0.9; P less than 0.01). Ten of 23 offspring were below the 10th percentile for weight. Mean birth weight ranged from 0.72 to 3.7 kg (2.3 +/- 0.84 kg). The mean birth weight and gestational age of children born to mothers taking CsA were lower than those in azathioprine treated mothers but these differences were not statistically significant. Successful pregnancy is possible following renal transplantation, although there is a high rate of prematurity, low birth weight, and intrauterine growth retardation. CsA dose requirements may be increased. Maternal risks including hypertension require that such pregnancies be handled by a multidisciplinary team approach.

The role of aluminium and parathyroid hormone in erythropoietin resistance in haemodialysis patients.

Recombinant human erythropoietin (rHuEpo) is an effective therapy for anaemia in most patients with end-stage renal disease (ESRD). However, there remain a minority of patients with ESRD who are resistant to the effects of rHuEpo. The present study examined the role of aluminium overload and hyperparathyroidism of the biological effects of rHuEpo. Twenty-two patients aged 26-74 (mean 53 +/- SD 15.5) received rHuEpo 50-200 U/kg per week for 16.5 +/- 8.0 months (range 3-27). Haemoglobin was maintained at 11.5-13.0 g/dl by appropriate dose adjustment. Iron supplements were provided to maintain serum ferritin greater than 200 ng/ml. The mean time to rHuEpo response (Hb greater than 2 g/dl over baseline) was 6.1 +/- 2.6 weeks. Mean pretreatment serum aluminium correlated with time to Hb response (r = 0.48; P less than 0.05) and pretreatment mean corpuscular volume (r = 0.43; P less than 0.05) but not with eventual rHuEpo maintenance dose. PTH did not correlate with either Hb response or eventual maintenance rHuEpo dose. In summary, elevated serum aluminium concentrations were associated with an initial resistance to the biological effects of rHuEpo but had no effect on long-term dose requirements. In contrast, no impact of PTH on either immediate or long-term rHuEpo dose was evident.

The Kidney Disease Questionnaire: a test for measuring patient knowledge about end-stage renal disease.

Two studies report on the development of the Kidney Disease Questionnaire (KDQ) as a test for measuring patient knowledge about end-stage renal disease and its treatment. The KDQ is available in a 26-item version or as two parallel 13-item tests. Psychometric evaluations indicate that all versions show high levels of reliability. Initial validity tests are also promising. The KDQ is able to discriminate individuals well informed about kidney disease and its treatment from those who are not so well informed. It is also sensitive to the effects of an experimental education program and to ESRD-related knowledge that is acquired as a result of starting dialysis. Data and issues related to the administration, readability, demographic correlates, and a French translation of the KDQ are also presented and discussed.

Acute glomerular thrombosis with CsA treatment.

Cyclosporin A (CsA) is used widely as an immunosuppressive in organ transplantation. Although it is highly effective, acute and chronic nephrotoxicity of CsA are of continuing concern. A case of acute glomerular thrombosis secondary to CsA therapy in a renal transplant recipient is described. The course of the accompanying acute renal failure and its reversal following discontinuation of CsA and therapy with intra-arterial streptokinase is outlined. CsA-induced capillary thrombosis is rare but has been described in renal transplant recipients as well as in hepatic and bone marrow transplantation. It may give rise to diagnostic confusion in the early days following renal transplantation, where it may mimic acute rejection. The etiology of CsA-induced glomerular capillary thrombosis remains speculative.

Removal of aluminum during hemodialysis: effect of different dialyzer membranes.

Aluminum toxicity is now widely recognized as a major cause of morbidity in patients on maintenance hemodialysis. Desferrioxamine (DFO) chelation therapy has been suggested as a method of AI removal in such patients, though the most appropriate treatment schedule is yet to be established. In the present study, AI removal following DFO infusion was evaluated using two different dialyzer membranes to test the hypothesis that polyacrilonitrile (PAN) membranes permit better AI clearance. All patients studied had significantly elevated plasma AI concentrations (1.22 to 9.45 mumol/L; normal less than 0.56 mumol/L). Plasma AI did not correlate with estimated total AI intake. During hemodialysis with a cuprophane membrane, AI clearance ranged from 33.5 to 42.1 mL/min. Total AI removal was 192.2 +/- 90.4 mumol during cuprophane dialysis. During hemodialysis with a PAN membrane, AI clearance ranged from 35.7 to 54 mL/min. Total AI removal was 154.2 to 93.9 mumol during PAN dialysis. The differences in AI clearance and total AI removal were not statistically significant. It is concluded that use of a PAN membrane does not significantly enhance DFO-AI clearance.

Zinc metabolism in patients on maintenance hemodialysis.

Recent studies have focused attention on the possible role of zinc depletion in the pathogenesis of uremic symptoms such as dysgeusia and impotence. The present studies were undertaken to evaluate the prevalence of zinc deficiency and abnormalities of zinc metabolism in patients with end-stage renal disease. A total of 43 stable chronic hemodialysis patients were screened for evidence of zinc deficiency by measurement of fasting predialysis leukocyte and plasma zinc. The results were compared with those from 30 healthy volunteers. Seventeen of these 43 patients had 65Zn absorption measured, and in 9 the rate of disappearance of 65Zn from the body was also measured. The results were compared with those obtained in 20 healthy controls. The nutritional status of these 17 patients was estimated by global nutritional assessment and calculation of the Quetelet index while 9 of 17 had dietary zinc intake calculated from a diet history. The mean plasma zinc level was lower in the hemodialysis patients (11.7 +/- 2.3 mumol/l vs. 13.3 +/- 2.9 mumol/l in controls; p less than 0.05). The mean leukocyte zinc level was 0.81 +/- 0.27 mumol/g dry weight in dialysis patients and 0.81 +/- 0.22 mumol/g in controls (p greater than 0.2). The mean 65Zn absorption in the patients was 49 +/- 14% and in controls 53 +/- 12% (p greater than 0.2). Mean turnover of body 65Zn was 0.47 +/- 0.11%/day in patients and 0.43 +/- 0.18%/day in controls (p greater than 0.1). The mean 65Zn half-life was 154 +/- 29 days in patients and 187 +/- 75 days in controls (p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Transplantation and home hemodialysis: their cost-effectiveness.

Transplantation and home hemodialysis treatments have been available to treat patients with end stage renal disease for several years but it is not clear which approach is most cost-effective. This study compared the costs of hemodialysis and transplantation for comparable patients using the marginal cost methodology. Sixteen patients in a home program were matched with 16 patients in a transplantation program for sex, age, primary disease and other medical diseases. Questionnaires and a chart review allowed the accounting of all health services received in hospitals, offices or at home, and provided indicators of treatment effectiveness. The impact of the additional services generated by choosing one treatment over the other (difference between the two programs) was evaluated in terms of personnel, equipment and supplies. Survival and rehabilitation were similar in the two groups. However, for each year of follow-up, transplantation was considerably less expensive than home dialysis. These results suggest that transplantation is the most cost-effective way to treat end stage renal failure, at least for the subgroup of patients equally eligible for either transplantation or home dialysis.

Effects of high sodium dialysate during maintenance hemodialysis.

The effects of high sodium 144 mmol/l (mEq/l) dialysate were studied in normotensive, hypertensive and anephric chronic hemodialysis patients. Comparisons of blood pressures, weights and side effects associated with the hemodialysis procedure were made between two 6-month periods using dialysate sodium concentration of 133 mmol/l (mEq/l), followed by a high dialysate sodium of 144 mmol/l (mEq/l), each patient acting as his own control. No difference was found in the frequency of cramps or 'disequilibrium' side effects (nausea, vomiting, headache, restlessness). High sodium dialysate is beneficial for normotensive and anephric patients in reducing dialysis-induced hypotension and was not associated with any deleterious effects on long-term blood pressure control. In hypertensive patients, the benefit is less clear, and hypertension may increase.

Glomerular sclerosis in a renal isograft and identical twin donor. A family study.

Loss of renal mass has been associated with the development of glomerular sclerosis in animals and human beings. The pathophysiology of this renal injury is unknown, but glomerular sclerosis in animals can be aggravated or accelerated following exposure to nephrotoxic antibodies, puromycin aminoglycoside or renal irradiation. We describe here the outcome of the first renal transplant performed in the British Commonwealth. Glomerular sclerosis occurred in identical twins who were kidney donor and recipient, renal failure occurring 14 and 16 years after transplantation, respectively. Examination of these twins and all living immediate family members showed that six of the seven family members (both twins, their mother, and three sisters) had increased concentrations of circulating immune complexes, decreased total hemolytic complement, and low or borderline concentrations of C4. Only twins with single kidneys had detectable renal disease. Other preexisting causes of renal disease in these twins that would account for the glomerular sclerosis could not be identified. We suggest that a familial immune defect contributed to the development of glomerular sclerosis in these twins who were predisposed to renal disease due to loss of renal mass.

The clinical and pathological course of hepatitis B liver disease in renal transplant recipients.

A prospective study of the clinical and pathological sequelae of hepatitis B disease in 22 immunosuppressed renal transplant patients is reported. All patients had allografts that functioned for more than 1 year, and all were hepatitis B surface antigen (HBsAg)-positive following transplantation. None of the 18 patients who had serial HBsAg tests converted to HBsAg negative. Serial liver biopsies were performed in 19 patients and one liver biopsy was available in the remaining three patients. Follow-up ranged from 12 to 93 months. Seven patients ultimately developed cirrhosis, 6 developed chronic active hepatitis, 5 developed chronic persistent hepatitis, and in 4 the presence of HB virus in hepatocytes was the sole morphologic alteration. The initial liver biopsy was not an accurate predictor of ultimate severity of liver disease because 5 of the 12 patients with virus only or chronic persistent hepatitis subsequently developed chronic active hepatitis or cirrhosis. Clinical liver dysfunction occurred in 8 patients, all of whom had chronic active hepatitis or cirrhosis. Three patients died with hepatic failure and 2 with hepatoma. The risk of death from liver disease in HBsAg-positive renal transplant patients was 5% per patient-year. For comparison, 10 HBsAg-positive patients whose renal failure had been treated by hemodialysis were also studied over a comparable period. Biochemical evidence of persistent liver dysfunction recurred in 1 patient only; 4 patients converted to the HBsAg-negative state; and no patient has died from complications of liver disease. We conclude that in the immunosuppressed renal transplant patient HB infection often results in the development of chronic active hepatitis, leading to cirrhosis and death from hepatoma and hepatic failure.