Pharmacokinetics of rosuvastatin in patients with end-stage kidney disease undergoing peritoneal dialysis.

Patients undergoing dialysis treatment have a high incidence of dyslipidemia. Rosuvastatin is a potent statin drug that improves overall lipid profiles in dyslipidemic patients. However, the pharmacokinetics of rosuvastatin has not been studied in patients with end-stage kidney disease undergoing chronic peritoneal dialysis (PD). The goals of this study are to determine the pharmacokinetics and tolerability of a single oral dose of rosuvastatin in patients undergoing continuous ambulatory PD (CAPD). This was a nonrandomized, open-label, 1-week trial. Ten stable PD patients were given a single oral dose of rosuvastatin (10 mg). Serial blood samples were obtained over the next 48 hours, and the patients were followed for 1 week while they underwent CAPD. Rosuvastatin plasma concentration peaked (Cmax) at 3.68 +/- 2.3 ng/ml (geometric mean), 4.5 hours (median; range 2 - 6 hours) after oral dosing. The plasma concentration of rosuvastatin was 0.44 +/- 0.23 ng/ml at 24 hours (C24) and 0.14 +/- 0.07 ng/ml, with levels below the detectable range in 5 of 10 subjects, at 48 hours (C48). The area under the plasma concentration-time from 0 to 48 hours (AUC0-48) was 32.6 +/- 1.6 ng/ml/h. These pharmacokinetic profiles of rosuvastatin in CAPD patients are very similar to those observed in healthy volunteers, but different from patients with Stages 4 - 5 chronic kidney disease. A single oral dose of rosuvastatin was well tolerated in this small number of patients. We conclude that pharmacokinetic profiles of rosuvastatin in patients undergoing CAPD are similar to those observed in healthy volunteers. These findings suggest that a lower dose of rosuvastatin (<<= 10 mg) may be administered in CAPD patients without dose adjustment.

Urinary stones following renal transplantation.

BACKGROUND: The formation of urinary tract stones following renal transplantation is a rare complication. The clinical features of stones after transplantation differ from those of non-transplant patients. Renal colic or pain is usually absent and rarely resembles acute rejection. METHODS: We retrospectively studied 849 consecutive kidney transplant patients in The Rogosin Institute/The Weill-Cornell Medical Center, New York who were transplanted between 1980 and 1997 and had functioning grafts for more than 3 months, to determine the incidence of stone formation, composition, risk factors and patient outcome. RESULTS: At our center, urinary stones were diagnosed in 15 patients (1.8%) of 849 functioning renal grafts for 3 or more months. Of the 15 patients, 10 were males and 5 were females in their third and fourth decade. Eight patients received their transplant from living donors and 7 from cadaveric donors. The stones were first diagnosed between 3 and 109 months after transplantation (mean 17.8 months) and 5 patients had recurrent episodes. The stones were located in the bladder in 11 cases (73.3%), transplanted kidney in 3 cases and in multiple sites in one case. The size of stones varied from 3.4 mm to 40 mm (mean 12 mm). The composition of stones was a mixed form of calcium oxalate and calcium phosphate in 5 cases and 4 patients had infected stones consisting of struvite or mixed form of struvite and calcium phosphate. Factors predisposing to stone formation included tertiary hyperparathyroidism (n = 8), hypercalciuria (n = 5), recurrent urinary tract infection (n = 5), hypocitraturia (n = 4), and obstructive uropathy (n = 2). Many cases had more than one risk factor. Clinically, painless hematuria was observed in 6 patients and dysuria without bacteriuria in 5 patients. None had renal colic or severe pain at any time. There were no changes in graft function at diagnosis and after removal of stones. Five patients passed stones spontaneously and 8 patients underwent cystoscopy for stone removal. CONCLUSION: Urinary stone formation following kidney transplantation is a rare complication (1.8%). Hyperparathyroidism, hypercalciuria, recurrent urinary tract infection and hypocitraturia are the most common risk factors, but often there are multiple factors which predispose to stone formation. To detect stones and determine their location and size, ultrasonography appears to be the most useful diagnostic tool. Prompt diagnosis, the removal of stones and stone-preventive measures can prevent adverse effects on renal graft outcome.

Kidney transplantation in patients with type 1 diabetes mellitus: long-term prognosis for patients and grafts.

Kidney transplantation is the best therapeutic choice to improve survival and quality of life in patients with end-stage diabetic nephropathy. Long-term prognosis in diabetic patients who received kidney transplants, however, has not been delineated. We, therefore, studied patient and graft survival, graft function and cause of graft failure in 78 Type I diabetic kidney transplant recipients in The Rogosin Institute/The Weill-Cornell Medical Center, New York who had functioning grafts for more than one year. The results were compared with 78 non-diabetic patients who had functioning grafts for more than one year and were matched for age, gender, donor source, time of transplantation and immunosuppressive therapy protocol. Cumulative patient survival rates for diabetic patients were significantly lower than those of non-diabetic patients (86% vs. 97% at 5 years and 74% vs. 95% at 10 years, respectively; p < 0.05). The most common cause of death was cardiovascular disease. Graft survival rates for diabetic patients were also lower than that of non-diabetic patients (71% vs. 80% at 5 years and 58% vs. 72% at 10 years, respectively), but the differences did not reach statistical significance. Among the 22 failed grafts in diabetic patients, 7 (32%) were due to patient death rather than primary graft failure. If the patients who died with a functioning graft were censored, graft survival rates of diabetic patients approached those of non-diabetic patients (80% vs. 81% at 5 years and 65% vs. 73% at 10 years, respectively). Creatinine clearances in diabetic patients were lower than that in non-diabetic patients through the follow-up period, but the differences were significant only for the first few years. At no time was there a higher creatinine clearance for diabetic patients. Among the 16 patients who had transplant kidney biopsies two to seven years post-transplant, 6 showed morphological changes consistent with diabetic nephropathy. One patient lost graft function solely by recurrent diabetic nephropathy. We conclude that long-term patient survival for diabetic patients is significantly lower than that of non-diabetic patients, due primarily to cardiovascular disease. Graft survival is comparable between the two groups. Creatinine clearances of diabetic patients are lower than those of non-diabetic patients. There is no apparent glomerular hyperfiltration at any time in diabetic patients. Recurrence of diabetic nephropathy is a rare cause of graft failure in the first 10 year post-transplant period. Aggressive intervention to modify cardiovascular risk factors should improve patient and graft survival in diabetic kidney transplant recipients.

Renin system activation and delayed function of the renal transplant.

Delayed graft function (DGF), defined as persistent renal failure that requires dialysis within the first week after kidney transplantation, occurs commonly after cadaveric renal transplantation (CRT). This has important implications for long-term outcome because the 1-year allograft survival rate is significantly reduced when DGF occurs. The mechanisms contributing to the development of DGF are not well established. However, several lines of evidence indicate that excess renin system activity, in both the cadaver kidney donor and recipient, contributes importantly to the pathogenesis of DGF. If this hypothesis can be verified in clinical studies, then pharmacologic agents that interrupt the renin-angiotensin system (eg, type 1 angiotensin II receptor blockade, angiotensin converting enzyme inhibition, and beta-adrenergic blockade) in the donor and recipient might significantly improve the outcome of cadaveric renal transplants.

Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine.

OBJECTIVE: To describe a case of rhabdomyolysis in a cadaveric renal transplant (CRT) patient receiving atorvastatin and cyclosporine. CASE SUMMARY: A 40-year-old Asian woman with a history of systemic lupus erythematosus (SLE) presented with bilateral lower-extremity weakness and elevated concentrations of creatine kinase (CK), aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and alkaline phosphatase after two months of concomitant therapy with atorvastatin and cyclosporine. Her other medications were not known to cause rhabdomyolysis; neither was there evidence of an SLE flare. After atorvastatin was discontinued, her CK concentrations declined dramatically and her symptoms resolved. DISCUSSION: Rhabdomyolysis has been reported in patients treated with other 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors when used in combination with cyclosporine. Atorvastatin, a relatively new HMG-CoA reductase inhibitor, has not been reported to cause rhabdomyolysis when used concomitantly with cyclosporine. However, its pharmacologic and pharmacokinetic properties make an interaction with cyclosporine possible. CONCLUSIONS: Similar to other members of the HMG-CoA reductase inhibitor class, atorvastatin may interact with cyclosporine and potentially result in rhabdomyolysis. Clinicians should be aware of this possible drug interaction and carefully monitor patients receiving these two drugs concomitantly.

Hypertension in continuous ambulatory peritoneal dialysis patients: what do we know and what can we do about it?

Despite many advantages of CAPD in maintaining hemodynamic stability, approximately 50%-60% of CAPD patients have hypertension and require antihypertensive treatment. ACE inhibitors and beta-blockers are the preferred first-line antihypertensive drugs in these patients, but some patients may require additional long-acting calcium antagonists to enhance antihypertensive effects. Despite antihypertensive treatment, many patients often fail to maintain BP within optimal ranges, and this fact may contribute to the high incidences of cardiovascular morbidity and mortality. Vigilance is clearly desirable by the patient and the physician to maintain BP within target ranges most of the time. Because dialysis patients also have many other cardiovascular risk factors, the strategy to decrease cardiovascular mortality should be a combined effort targeting all potential risk factors at the same time.

Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients.

Low serum albumin and low serum cholesterol levels are among the most consistent predictors of mortality in patients with end-stage renal disease (ESRD) undergoing hemodialysis. Hypoalbuminemia is often interpreted as a marker of poor nutrition, but serum albumin and cholesterol levels can also be low as part of a cytokine-mediated acute-phase reaction to acute or chronic inflammation. Here we report the results from a 900-day prospective study designed to determine whether tumor necrosis factor-alfa (TNF-alpha) and interleukin-6 (IL-6) predict serum albumin and cholesterol levels and mortality in a group of 90 ambulatory, adult hemodialysis patients with no acute infection, hospitalization or surgery, and no known acquired immunodeficiency syndrome (AIDS), malignancy, or liver disease. Measurable levels of TNF-alpha and/or IL-6 were found in 89 of 90 patients. Significant relationships were found between TNF-alpha and IL-6 and the degree of hypoalbuminemia and dyslipoproteinemia. IL-6 was the strongest predictor of mortality in univariate and multivariate analysis, followed by age, albumin level, and body mass index (BMI). Although the cause of hypercytokinemia was not addressed in this study, the data support the view that hypoalbuminemia and hypocholesterolemia are negative acute-phase responses to inflammatory stimuli. These results suggest that efforts to identify the nature of the stimuli for cytokine production and to lower cytokine levels in hemodialysis patients might be effective in improving the survival of patients undergoing hemodialysis.

Effect of nifedipine on renal allograft function and survival beyond one year.

We previously reported that a calcium channel blocker supplemented immunosuppression produced excellent patient and graft survival rates in cadaveric kidney transplantation. We report here the long term outcome of patients treated with nifedipine-supplemented triple immunosuppression as compared with those of historical controls who were treated similarly without nifedipine. Study subjects included 111 patients transplanted in 1990-1994, treated with nifedipine and triple immunosuppression and with functioning grafts for more than one year (Nifedipine group). The results of cyclosporine (CyA) dose, blood pressure (BP), serum creatinine (Cr), and actuarial graft survival rate (GSR) up to 5 years posttransplant in these patients were compared with those of 52 patients transplanted in 1985-1990, treated similarly without calcium channel blockers (Control group). Donor sources, gender ratio, age distribution, causes of end stage renal disease, incidence of hypertension prior to transplantation and incidence of rejection in the first year between the groups were comparable. Throughout the study period the Nifedipine group had significantly lower serum Cr (1.5 +/- 0.7 vs. 1.8 +/- 0.7 mg/dl) and higher GSR (93.8% vs. 88% at 5 years) than the Control group. BP was comparable despite higher CyA doses in the Nifedipine group (4.3 +/- 1.1 vs. 3.3 +/- 1.1 mg/kg/day). We conclude that nifedipine is beneficial in improving long-term graft function and survival in kidney transplant recipients by mitigating CyA associated renal injury.

Long term results of subtotal parathyroidectomy in patients with end-stage renal disease.

This is a retrospective, clinical study evaluating the long-term outcome of subtotal parathyroidectomy (PTX) in 60 patients with chronic renal failure and severe secondary hyperparathyroidism. Patients were 41 +/- 2 years old (mean +/- SE) at the time of PTX, and followed for 69 +/- 6 months since the procedure. At the time of PTX, three patients had chronic renal failure, 53 had been on chronic hemodialysis, and four had received successful kidney transplants. In more than 80 per cent of patients, symptoms of hyperparathyroidism (bone pain and muscle weakness) resolved within weeks, and biochemical signs (hypercalcemia, and high plasma alkaline phosphatase and parathyroid hormone concentrations) returned to normal ranges within a year. Subperiosteal resorption, bone fractures, and soft tissue calcification frequently improved. Osteosclerosis (rugger-jersey spine), cystic bone changes, osteopenia, and vascular calcifications were, however, often unchanged or progressive. Five patients (8%) who had either persistent or recurrent hyperparathyroidism required additional surgical procedures, and two had subsequent improvement. Twelve patients who had aluminum associated bone disease diagnosed later continued to progress with a high incidence of bone fractures and severe osteopenia. Cystic bone changes, especially of the carpal bones, in association with carpal tunnel syndrome, probably representing amyloid bone disease, also did not respond to PTX. In conclusion, PTX is an effective surgical procedure to reverse complications of hyperparathyroidism in patients with end-stage renal disease, provided that other causes of osteodystrophy, such as aluminum or amyloid-associated bone diseases, are adequately excluded. We feel that subtotal PTX, leaving a small remnant in place, is the procedure of choice.

How well is hypertension controlled in CAPD patients?

UNLABELLED: To determine how well hypertension is controlled in continuous ambulatory peritoneal dialysis (CAPD) patients, we monitored the blood pressure of 31 hypertensive adult CAPD patients treated with antihypertensive agents. Blood pressure (BP) monitoring, using a noninvasive, ambulatory BP monitor, began in the morning and continued every 30-60 min for 24 h (mean 42 readings per patient). The mean BP of all patients over 24 h was 145.6/91.3 mm Hg. In these, 40.5% of systolic BP readings exceeded 150 mm Hg and 50.2% of diastolic readings exceeded 90 mm Hg, suggesting that hypertension was inadequately controlled for a considerable period of time. Diabetic patients had even worse control of BP. Mean BP, heart rates, and BP loads were not different, between daytime or nighttime. These findings suggest that CAPD patients do not preserve the normal circadian rhythm of BP and that their hypertension is not controlled any better during the night than during the day. We repeated BP monitoring after adjustment of antihypertensive medications in 8 patients who had poorly controlled hypertension. Systolic and diastolic BP loads in subsequent studies improved significantly from the first study. IN CONCLUSION: hypertension is suboptimally controlled in most CAPD patients; diabetic patients fare even worse in the control of hypertension; most patients do not preserve the circadian rhythm of BP and there is no difference in the adequacy of hypertension control during the day or at night; assessment of hypertension with ambulatory BP monitoring helps guide therapy and control of hypertension.

Excellent outcome with a calcium channel blocker-supplemented immunosuppressive regimen in cadaveric renal transplantation. A potential strategy to avoid antibody induction protocols.

Many transplant centers routinely utilize monoclonal antibody or polyclonal antibody based induction protocols in recipients of cadaver renal allografts. Given the potential complications associated with antibody-based immunosuppression regimens (e.g., CMV disease), we tested the hypothesis that a combination of a calcium antagonist and a triple drug protocol (cyclosporine + prednisone + azathioprine) would be an effective substitute for antibody-based induction protocols in ensuring excellent patient and graft survival rates. Our postulate was tested in a prospective study of 52 consecutive recipients of cadaver renal allografts (44 first, 5 second, and 3 third grafts) utilizing nifedipine as the first line calcium antagonist. Nifedipine was selected over verapamil or diltiazem due to its lack of interference with the metabolism of CsA. Some of the significant outcomes of our prospective trial were (A) a cumulative patient survival rate of 98.1% for the 52 recipients at 18 months posttransplantation; (B) a cumulative allograft survival rate of 92.1% for the 52 consecutive cadaver renal allografts at 18 months; (C) a cumulative allograft survival rate of 100% at 18 months for the 24 of 52 renal allografts without delayed graft function following transplantation; and (D) a cumulative allograft survival rate of 86% at 18 months for the 28 of 52 renal allografts with delayed graft function. Of the 4 of 52 who lost their grafts, 2 grafts were removed following discontinuation of immunosuppressive therapy while the remaining 2 had primary nonfunction; and (E) the lack of a requirement for monoclonal or polyclonal antibodies for the treatment of acute rejection episodes in this patient population. These gratifying results compare very favorably with (A) recent reports of the effects of long-term diltiazem therapy and of verapamil used in conjunction with an induction protocol that included Minnesota antilymphocyte globulin in recipients of cadaver renal allografts, and (B) the clinical outcome in many institutions with OKT3/ATG/ALG induction protocols. Whereas the mechanisms involved in the excellent clinical outcome found with the calcium antagonist remain undefined, our results strongly argue for a prospective, randomized and controlled study in which a calcium antagonist-supplemented immunosuppressive regimen is compared with antibody-based induction protocols.

End-stage renal disease in systemic lupus erythematosus.

The progression of lupus nephritis severe enough to require dialysis does not necessarily indicate that it is "end-stage." Ten percent to 28% of patients with lupus nephritis who develop renal failure requiring dialysis will recover enough function to come off dialysis. The clinical activity of systemic lupus erythematosus (SLE) is quiescent in most patients with end-stage lupus nephritis, regardless of the modality of dialysis treatment. Clinical and serologic remission of SLE permits judicious withdrawal of immunosuppressive therapy, as well as a favorable long-term outcome for patients that is comparable to that of nonlupus patients. The great majority of deaths in patients with end-stage lupus nephritis occur in the first 3 months of dialysis and most often result from infection. Later, infection and cardiovascular complications are common causes of death. Patients with lupus nephritis should wait at least 3 months on dialysis before receiving a kidney transplantation. Immunosuppressive therapy and graft survival rates for lupus patients are not different from those of nonlupus patients. Recurrence of lupus nephritis in the allograft is exceedingly rare.

Hypertension is not adequately controlled in hemodialysis patients.

To examine the adequacy of hypertension control, we monitored the blood pressure (BP) of 53 hemodialysis patients who received treatment for hypertension. BP measurement using an ambulatory BP monitor began 1 hour before dialysis and continued every 30 to 60 minutes for 48 hours until the next dialysis. Diet, medications including antihypertensive drugs, and hemodialysis prescription were not changed during this study. Each patient had a mean of 68 BP measurements during the monitoring period. Mean (+/- SD) systolic and diastolic BP levels of all patients over 48 hours were 158.6 +/- 22.7 mm Hg and 88.7 +/- 16.6 mm Hg, respectively, without diurnal variations. In these, BP loads (the percentage of systolic BP exceeding 150 mm Hg and diastolic BP exceeding 90 mm Hg) were 58.4% and 39.4%, respectively, suggesting that hypertension was inadequately controlled for more than half of the study period. Eight patients (15%) maintained BP within normal ranges at all times. All patients lost weight (2.9 +/- 0.9 kg) at the end of dialysis by ultrafiltration. However, only 27 patients (51%) had a greater than 5% decrease in mean arterial BP post-dialysis, which returned to predialysis levels within 12 to 24 hours. Reduction of BP postdialysis was significantly more common among black patients (72%) than white patients (30%) (P less than 0.01). However, there was no difference in age, cause of kidney disease, amount of ultrafiltration, and BP loads between those whose BP decreased and those whose did not. BP monitoring was repeated in eight patients, 2 to 3 months after adjustment of their antihypertensive regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytomegalovirus infection of renal allografts. Detection by polymerase chain reaction.

Early laboratory diagnosis of acute cytomegalovirus infection in renal transplant recipients is desirable but often difficult. The polymerase chain reaction (PCR) technique for detecting CMV DNA, although it promises a high sensitivity, risks the possibility of detecting latent CMV infection and leading to false-positive results. To address this issue and the feasibility of applying PCR to renal biopsy specimens, we analyzed 37 renal allografts by PCR. Formalin-fixed or Bouin-fixed paraffin-embedded materials were employed, and primers from the LA (late-antigen) region of CMV were used. Amplified products were detected by gel electrophoresis and ethidium bromide staining, followed by Southern blot analysis. Of 21 nephrectomy samples, three showed CMV-specific amplified products by PCR, but CMV inclusion bodies were detected histologically in only one of the three. Of 16 renal biopsies, three specimens were positive by PCR, with rare viral inclusions histologically identified in only one. All PCR-positive patients had clinically significant CMV disease as evidenced by positive CMV culture and/or seroconversion. In contrast, all CMV-seropositive patients without active viral disease had PCR-negative allografts. We conclude that PCR positivity in the renal allograft strongly correlates with active CMV disease but not latent infection. For the diagnosis of active CMV disease in patients with a renal allograft, PCR provides a means that is more sensitive and objective than histologic examination, more specific than serology, and faster than viral culture.

Minimal sensitization and excellent renal allograft outcome following donor-specific blood transfusion with a short course of cyclosporine.

UNLABELLED: A new protocol of donor-specific blood transfusion under cyclosporine coverage was developed and examined for immunologic consequences and clinical efficacy in recipients of one- or zero-HLA-haplotype-matched renal allografts. Between 1985 and 1989, 75 recipients were transfused with 100 ml of stored whole blood at 1, 8, and 15 days of its storage from either one-HLA-haplotype-matched related donors (n = 65, 33 from their parents, 30 from siblings, and 2 from offspring) or from zero-HLA-haplotype-matched donors (n = 10, 7 from spouses and 3 from siblings). During DST, all recipients received cyclosporine, 6 mg/kg/day, starting a day before and finishing a week after DST (23 days). Recipients were monitored by donor-specific mixed lymphocyte culture responses before and after DST, and serially for antibodies by fluorescence activated cell sorter analysis and by standard complement-dependent lymphocytotoxicity assay. Following DST with CsA, only 3 of 75 patients (4%) were sensitized against the blood donor. This rate is considerably lower, albeit statistically not significantly, compared with the 10% rate found in 30 recipients who had received DST without CsA in our previous study. Repeat MLC studied one to two months after DST (the day before transplant) were significantly increased compared with pre-DST (stimulation index: mean +/- SEM; 10.3 +/- 1.4 to 15.8 +/- 2.8, P = 0.004, and relative response: 40.9 +/- 5.1% to 49.8 +/- 5.5%, P = 0.003). Since the stimulation index with controls did not change after DST (23.4 +/- 2.9 to 26.2 +/- 3.3), enhanced MLC responses appear to be donor-specific. The changes in MLC responses did not correlate with the number of blood transfusion received prior to DST, the number of rejection episodes, or graft outcome. Fifty-seven recipients underwent a kidney transplant from their one-HLA-haplotype-matched blood donors within two to three months after DST. All 10 recipients of zero-haplotype-matched donors were also successfully transplanted from their respective blood donors. The graft survival rates were at least 90% at two years in both groups. IN CONCLUSION: (1) 100 ml of stored whole-blood DST, three times at weekly intervals with a short course of CsA is minimally sensitizing but effective in enhancing graft survival; (2) this protocol could be used in donor-recipient pairs who do not share a haplotype; and (3) DST with CsA elicits augmentation of donor-specific MLC responses.

Selection criteria for the evaluation of living related renal donors.

The documented long-term health of the living related renal donor is a tribute to careful preoperative selection and surgical technique. At our medical center 187 prospective donors were evaluated during a 6-year period and 91 underwent donor nephrectomy. Hypertension, renal artery anomalies and donor indecision were the most common reasons for donor rejection. Recipient health and/or death, or a positive crossmatch after pre-transplant donor specific transfusion were other post-arteriogram reasons not to proceed with transplantation. Women were more likely to undergo nephrectomy than men, and older or heavier donors were more likely to be rejected. Using the transcostal, extrapleural surgical approach for nephrectomy there were no deaths or major complications, and the mean postoperative length of stay was 6.4 days. The average postoperative increase in serum creatinine was 0.33 mg./dl. with an average creatinine at discharge of the patient from the hospital of 1.2 mg./dl. The latter creatinine values varied concordantly with donor age. Only 56% of fully evaluated donors (91 of 159) actually underwent donor nephrectomy. The minimal morbidity sustained by these patients re-emphasizes the importance of careful donor selection.