Kelly Weigel

Comparison of sirolimus vs. mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation.

Mycophenolate mofetil (MMF) and sirolimus impair wound healing. We compared sirolimus vs. MMF to determine the relative impact on surgical complications and wound healing in adult kidney transplant recipients. This retrospective, single center study of 235 adult kidney transplants performed between 1 January 2000 and 31 January 2002 identified 158 adult, kidney‐only recipients treated with tacrolimus and prednisone, from which two groups were defined: group 1 (n = 84) received MMF, group 2 (n = 74) received sirolimus. The incidence of fluid collections, wound problems, dehiscence, and urine leak were compared. A multivariate stepwise logistical regression analysis was performed to identify risk factors. The overall incidence of complications was 21.5%, with rates significantly lower in group 1 (2.4%) vs. group 2 (43.2%, p < 0.0001). Regression analysis showed only sirolimus (p < 0.001) and hypo‐albuminemia (p = 0.006) to independently correlate with complication occurrence. In subanalyses, lymphoceles correlated only with sirolimus (p = 0.003), while other wound problems also correlated with higher body mass index (p = 0.067). The use of sirolimus, tacrolimus and prednisone was associated with a greater incidence of lymphoceles, non‐lymphocele perinephric fluid collections and other consequences of poor wound healing, as compared to contemporary patients treated with MMF, tacrolimus and prednisone.

Factors associated with inadequate blood pressure control in hypertensive hemodialysis patients

Hypertension is common in hemodialysis patients and increases cardiovascular morbidity and mortality. We determined the prevalence of inadequate control of hypertension in 489 patients receiving hemodialysis and identified factors associated with uncontrolled hypertension. We interviewed the patients and abstracted demographic and clinical information from a computerized database. The prevalence of uncontrolled hypertension (average predialysis blood pressure, > or =160/90 mm Hg) was 62%. Ninety-one percent of patients with uncontrolled hypertension were receiving submaximal antihypertensive drug therapy, and 59% withheld their medications before dialysis. Uncontrolled hypertensives had a greater interdialytic weight gain (3.8% v 3.5%, P = 0.07) and a greater excess weight gain (3.1 +/- 1.6 kg v 2.5 +/- 1.4 kg; P < 0.05) compared with controlled hypertensives. Patients with uncontrolled hypertension showed higher interdialytic weight gain (2.7 +/- 0.06 kg v 2.2 +/- 0.13 kg; P < 0.05), were more likely to be black (94% v 81%; P < 0.05), were more likely to have hypertension as the cause of their end-stage renal disease (ESRD) (42% v 24%; P < 0.05), and had been receiving hemodialysis for a shorter time (4.3 +/- 2 yr v 6.1 +/- 0.9 yr; P < 0.05) compared with normotensive patients. There was significant correlation between diastolic blood pressure and both interdialytic weight gain (r = 0.31, P < 0.05) and percent weight gain (r = 0.34, P < 0.05) in the hypertensive but not in the normotensive patients (r = -0.21). Interdialytic weight gain and hypertension as a cause of ESRD were independent predictors of predialysis systolic blood pressure. We conclude that hypertension is uncontrolled in most patients undergoing hemodialysis. Submaximal antihypertensive therapy, excessive interdialytic weight gain, and withholding antihypertensive medication before dialysis are correctable factors potentially contributing to uncontrolled hypertension.

Prednisone Improves Renal Function and Proteinuria in Human Immunodeficiency Virus-associated Nephropathy

PURPOSE To determine if prednisone ameliorates the course of human immunodeficiency virus-associated nephropathy (HIV-AN). PATIENTS AND METHODS Twenty consecutive HIV-infected adults with biopsy-proven HIV-AN (n = 17) or clinical characteristics of HIV-AN (n = 3) with serum creatinine concentrations > 177 mumol/L (2 mg/dL) or proteinuria > 2.0 g/d or both were prospectively evaluated and treated with prednisone at a dose of 60 mg/d for 2 to 11 weeks, followed by a tapering course of prednisone over a 2- to 26-week period. Serum creatinine concentration, 24-hour protein excretion, serum albumin, and steroid-related adverse effects were assessed before and after treatment. RESULTS Nineteen patients had serum creatinine concentrations > 117 mumol/L (2 mg/dL). Two of them progressed to end stage renal disease (ESRD) in 4 to 5 weeks. In 17 patients serum creatinine levels decreased from 717 +/- 103 mumol/L (8.1 +/- mg/dL) (mean +/- SE) to 262 +/- 31 mumol/L (3.0 +/- 0.4 mg/dL) (P < 0.001). Five patients relapsed after prednisone was discontinued and were retreated. In these 5 the serum creatinine declined from 728 +/- 107 mumol/L (8.2 +/- 1.2 mg/dL) to 344 +/- 47 mumol/L (3.9 +/- 0.5 mg/dL) (P < 0.01) in response to the second course of prednisone. Twelve of 13 tested patients showed a reduction in 24-hour urinary protein excretion with an average decrement from 9.1 +/- 1.8 g/d to 3.2 +/- 0.6 g/d (P < 0.005). Serum albumin increased from 24.4 +/- 3.6 g/L to 29.3 +/- 2.6 g/L (P = NS) in the 11 patients with paired 24-hour urine collections for whom pre- and post-treatment determinations were available. In one non-azotemic patient with nephrotic syndrome, protein excretion declined from 15.2 to 2.2 g/day and the serum albumin increased from 4.0 g/L to 31.0 g/L. The 20 patients have been followed for a median of 44 weeks (range 8 to 107). Eight ultimately required maintenance dialysis. Eleven died from complications of HIV disease 14 to 107 weeks after institution of prednisone; none was receiving prednisone at the time of death. Seven are alive and free from ESRD a median of 25 weeks (range 8 to 81) from the initiation of prednisone therapy. Six patients developed a total of seven serious infections while receiving prednisone, including Mycobacterium avium-complex infection in 2 and CMV retinitis in 3. CONCLUSION Prednisone improves serum creatinine and proteinuria in a substantial proportion of adults with HIV-AN. Corticosteroid-related side effects are not prohibitive. A prospective, randomized controlled trial is required to confirm these preliminary results.

Withdrawal of steroid therapy in african american kidney transplant recipients receiving sirolimus and tacrolimus

Background. Withdrawal of corticosteroids from the immunosuppressive regimens of kidney transplant recipients has been associated with an increased risk of acute and chronic allograft rejection. Previous studies indicate that the risk of rejection is particularly high in African Americans. Methods. We prospectively enrolled 44 African American kidney transplant recipients to participate in an uncontrolled trial in which they were initially treated with sirolimus, tacrolimus, and corticosteroids. No patient received antibody induction therapy. Prednisone was withdrawn from eligible patients free of acute rejection beginning as early as 3 months posttransplant, and followed for a minimum of 9 months posttransplant. Patients were followed for acute rejection and for changes in blood pressure, body weight, and serum creatinine concentrations before and after withdrawal of steroids. Results. Thirty of 44 patients (68%) were weaned off of prednisone. Follow-up after withdrawal of prednisone ranged from 3 to 26 months (mean, 14.3±7.7 months). Two of 30 patients (6.7%) developed acute rejection. At last follow-up, 27 of 30 patients (90%) remain steroid-free. Steroid withdrawal was associated with significant reductions in blood pressure. Conclusions. Use of sirolimus and tacrolimus, without the use of induction antibody therapy, allows withdrawal of prednisone as early as 3 months posttransplant with low rates of subsequent acute rejection in African American kidney transplant recipients. Withdrawal of prednisone was associated with lower blood pressures and the need for fewer antihypertensive medications.

The Effects of Angiotensin II Receptor Blockade With Losartan on Systemic Blood Pressure and Renal and Extrarenal Prostaglandin Synthesis in Women With Essential Hypertension

The major antihypertensive effect of losartan, a nonpeptide angiotensin II antagonist, is thought to be due to inhibition of the pressor effects of angiotensin II. It is possible, however, that losartan alters the synthesis of vasodilator or vasoconstrictor prostaglandins (PG), thus contributing to its antihypertensive effect. Sixteen postmenopausal women with essential hypertension, with a mean age of 59 years and diastolic blood pressures of 95 to 115 mm Hg, were enrolled in a 12-week, single-blind study to determine the effects of losartan on blood pressure, renal and extrarenal PG production, plasma renin activity (PRA), plasma aldosterone, and routine biochemical parameters. The subjects received placebo during weeks 1 to 4, 50 mg losartan daily during weeks 5 to 8, and placebo during weeks 9 to 12. During the 4-week treatment period, there were no significant, sustained changes in renal or extrarenal synthesis of PGE2, PGI2, or thromboxane A2. Losartan significantly reduced systolic blood pressure from 155 +/- 11 mm Hg (mean +/- SD) to 139 +/- 13 mm Hg (P = .001) and diastolic blood pressure from 100 +/- 2 mm Hg to 87 +/- 5 mm Hg (P < .001) despite the fact that the majority of patients had low PRA. Plasma aldosterone concentration decreased from 9.7 +/- 6.5 ng/dL to 5.1 +/- 3.9 ng/dL (P = .002) and serum uric acid declined from 4.6 +/- 0.8 mg/dL to 4.2 +/- 0.8 mg/dL (P = .018) after 4 weeks of treatment with losartan. We conclude that 1) losartan decreases blood pressure in women with essential hypertension and low plasma renin activity; 2) the antihypertensive effect is not associated with sustained changes in renal or extrarenal PG production; and 3) losartan reduces plasma aldosterone and serum uric acid concentrations in patients with essential hypertension.

Long-term renal function in type I diabetics after kidney or kidney-pancreas transplantation: influence of number, timing, and treatment of acute rejection episodes.

BACKGROUND Previous studies comparing renal function in diabetic subjects receiving either a kidney or kidney-pancreas transplant generally have indicated no differences; however, these studies have been limited by inclusion of either a small number of patients or selected patients followed for relatively short periods of time. METHODS To compare long-term renal function and factors affecting renal function in type I diabetic patients receiving either kidney or kidney-pancreas transplants, the slopes of regression lines generated by plotting the reciprocal of serum creatinine (1/Cr) versus time were measured in 109 consecutive patients followed for at least 12 and up to 102 months after transplantation. Multivariate analyses included linear regression using the slope of 1/Cr versus time as the dependent variable and logistic regression using a positive or negative slope as the dependent variable. RESULTS Significant differences between kidney-pancreas (n=64) and kidney recipients (n=45) included a smaller proportion of African-Americans, lower rates of HLA matching, lower levels of panel-reactive antibodies, shorter cold ischemia times, a lower incidence of delayed graft function, and a higher incidence of acute renal allograft rejection episodes in the kidney-pancreas group. Trough cyclosporine blood levels were significantly higher in the kidney-pancreas group for the first 12 posttransplant months. The slopes of 1/Cr versus time were negative in each group with a trend toward a more negative slope in the kidney-pancreas group. Multivariate analyses indicated that a concomitant pancreas allograft did not influence long-term renal function. The total number of renal rejection episodes was the best independent predictor of a negative slope of 1/Cr versus time. However, use of OKT3 for the treatment of rejection within the first 3 months of transplantation exerted a surprisingly beneficial effect on long-term renal function, a phenomenon that was most apparent in the kidney-alone group. CONCLUSIONS The frequency and timing of acute rejection episodes are more important than the influence of a simultaneously transplanted pancreatic allograft in determining long-term function of the transplanted kidney. A concerning trend toward late deterioration of renal function in kidney-pancreas recipients suggests that the benefits of sustained euglycemia, shorter cold ischemia times, lower rates of sensitization, and early use of OKT3 ultimately may be outweighed by the negative effects of more frequent renal rejection episodes.

Thrombotic events and markers of oxidation and inflammation in hemodialysis.

The goal of this study was to determine whether antioxidant therapy with vitamin E would alter the rate of vascular access complications or other macrovascular complications in hemodialysis (HD) patients. A secondary goal of the study was to explore the relationship between baseline pretreatment markers of oxidative stress (the advanced glycation end product pentosidine and basal levels of vitamin Eα and γ) and the subsequent development of access failure. Thirty‐five stable patients treated by HD were recruited for the study. Patients were provided with vitamin E (800 IU) or placebo capsules to be taken daily. Clinical variables, vascular access function (flow meter access flow measurements), and circulating blood markers were obtained initially and every 3 months throughout the study. Vitamin Eα levels rose in treated patients from 12.7 ± 4.4 to 25.1 ± 15.1 µg/mL at 3 months and 28.6 ± 14.8 µg/mL at 6 months. Vitamin Eγ levels fell in treated patients from 3.9 ± 1.7 to 2.3 ± 1.5 µg/mL at 3 months and 1.7 µg/mL at 6 months. Patients who subsequently developed repeated thrombotic vascular access events were characterized by higher baseline pentosidine content of circulating proteins. Patients who developed a myocardial infarction had higher pentosidine, lower vitamin Eα, and much lower vitamin Eγ than patients who did not develop thrombotic events. These findings lead to the speculation that the anti‐inflammatory effects of vitamin Eγ may play a more important role in thrombotic vascular events than the antioxidant effects of vitamin Eα. Additional studies of these interactions are in progress.