Plasmapheresis treatment for recurrent focal sclerosis in pediatric renal allografts.

Recurrence of focal segmental glomerulosclerosis (FSGS) in pediatric renal allografts is associated with a poor graft survival. This study reports on plasmapheresis for the treatment of recurrent FSGS in pediatric renal transplant recipients. The records of 100 consecutive pediatric (age <21 years) renal transplants were reviewed. Twenty patients had FSGS as the cause of renal failure. Eight of these (40%) had a recurrence (proteinuria >1 g/m2 per day) within 1 month of transplantation. Five of six patients treated with plasmapheresis went into remission (<0.2 g/m2 per day), receiving a total of 42+/-26 (12-73) sessions, with the mean number of sessions required to achieve a remission being 24+/-17 (8-51). One patient had a second recurrence 1 year following cessation of plasmapheresis and responded to another course of plasmapheresis. The 1 patient who did not respond to plasmapheresis had a delay in initiation of therapy of 42 days. Plasmapheresis initiated within 48 h of recurrence resulted in earlier remissions and improved graft survival among our patients. Plasmapheresis appears to be effective in treating recurrent FSGS following kidney transplantation and should be started as soon as possible. The number of plasmapheresis sessions used to achieve remission should be adjusted according to response rather than adhering to a fixed protocol.

Mycophenolate mofetil treatment reduces atherosclerosis in the cholesterol-fed rabbit.

Immune/inflammatory responses of arterial vessel wall constituents to lipid metabolic disturbances have been postulated to contribute to the pathogenesis of atherosclerosis. Mycophenolate mofetil (MMF), an antiproliferative agent used in clinical transplantation, has been shown to inhibit smooth muscle cell (SMC) proliferation and decrease the recruitment of monocytes into sites of chronic inflammation. This study was conducted to determine the effect of MMF on atherosclerotic plaque development after cholesterol-induced injury. New Zealand white rabbits were fed a high-cholesterol diet containing 0.5% cholesterol and 8% peanut oil. The experimental group (n = 10) was given MMF (80 mg/kg/day subcutaneously); the control group (n = 10) received placebo injections. The aortas were harvested at 12 weeks for immunohistochemical analyses. SMCs were identified by reactivity with a monoclonal antibody (mAb) to alpha smooth muscle actin. Monocytes/macrophages were detected with mAb RAM 11. Cross-sectional areas of the media and neointima were measured using computer-assisted image analysis. The density of SMCs and macrophage/foam cells within the neointima was calculated by dividing the number of cells by the area of the plaque. Total cholesterol, triglyceride, high density lipoprotein, and low density lipoprotein were significantly increased compared with levels before the initiation of a high-cholesterol diet, but there were no significant differences between the MMF-treated and untreated groups. Neointimal area in aortic tissue sections of the MMF-treated group (0.586 +/- 0.602 mm(2)) was significantly lower when compared with that in control animals (1.082 +/- 0.621 mm(2)) (P < 0.05). The densities of neointimal SMCs and monocytes/macrophages in the control group were 778 +/- 293 and 341 +/- 90 cells/mm(2), respectively. MMF treatment significantly reduced the number of neointimal SMCs (506 +/- 185 cells/mm(2)) (P < 0.05). The number of monocytes/macrophages was also reduced after MMF treatment (260 +/- 124 cells/mm(2)) but not significantly. Our results demonstrate that the administration of MMF significantly reduced neointimal SMC accumulation and plaque development in a hypercholesterolemic model of atherosclerosis.

Renal transplantation in patients above 60 years of age in the modern era: a single center experience with a review of the literature.

A retrospective study was conducted of 797 patients receiving renal transplants from January 1985 to March 1997. Patient and graft survival was compared for patients above and below the age of 60. Sixty-nine patients < or =60 years old received 73 kidneys. Race: 73% Caucasian, 26% Black, 1% Other. Sex: 68% M. Hypertension (19) and PCKD (15) were the most common diagnoses. Mean peak panel reactive antibody (PRA) was 37.7%. Donor age was 2 to 66 years. Mean Cold ischemic time was 28.1 hours. Follow-up was until death or until 8/30/97. Patients <60 years included: 62% Caucasian, 34% Black, 4% Other; 60% male, Mean PRA 39.3. Of the 69 study patients, 27 died: 19 with a functioning graft, 8 within one year of transplantation. Cardiovascular causes (19 patients, 72%) and infection (7 patients, 24%) were most common. Common causes of graft loss were death with a functioning graft (19) and chronic rejection (15); other causes were acute rejection and primary non-function. Univariate analysis of 18 risk factors showed CHF and past history of vascular surgery significantly (p < 0.05) affected time of return to dialysis. Multi variate analysis did not show these independent variables to be significant. Abnormal ejection fraction and presence of q waves on EKG significantly affected time to death (p < 0.05) on uni- and multi-variate analysis. After censoring patients that died with functioning grafts, difference in graft survival between > or =60 and <59 years was not significant (p > 0.2). In this study, 68% of older patients had allografts functioning at 1 year. The fact that older patients succumb over time from natural causes should not keep patients from transplantation. Immunosuppressive agents need to be limited to reduce the incidence of infection. Criteria need to be refined to define those who are at prohibitive risk, who may not be candidates for transplantation.

Magnesium repletion therapy improved lipid metabolism in hypomagnesemic renal transplant recipients: a pilot study.

BACKGROUND: Hypomagnesemia has been associated with hypertension, abnormal glucose and lipid metabolism, and accelerated atherosclerosis in nontransplant patients. METHODS: In this prospective short-term pilot study, 14 hypomagnesemic renal transplant recipients with stable renal function were evaluated monthly over a 6-month interval. The first 3 months was the baseline observation period. During the second 3 months, MgO2 was administered to normalize the serum Mg level. Glucose tolerance, lipid levels, blood pressure, weight, and routine chemistries were assessed before and after Mg replacement. All others medications were held constant during the 6-month study. RESULTS: Serum Mg levels increased to normal range after MgO2 therapy, which was well tolerated. There were significant decreases in total cholesterol, low density lipoprotein, and total cholesterol/high density lipoprotein ratio after 3 months of MgO2 therapy. Only three patients had abnormal baseline glucose tolerance tests. All three patients showed improved glucose tolerance after MgO2, but this was not statistically significant. CONCLUSIONS: Mg repletion may be an important ancillary therapy in hypomagnesemic renal transplant patients with hyperlipidemia.

Use of spiral computerized tomography in lieu of angiography for preoperative assessment of living renal donors.

PURPOSE: We evaluate whether spiral computerized tomography (CT) can be used in lieu of renal angiography for preoperative assessment of living renal donors, with special attention to multiplicity of renal vasculature. MATERIALS AND METHODS: A total of 47 living renal donor candidates were evaluated with spiral CT and all but 2 underwent donor nephrectomy. Patients were divided into early and late groups because there was a learning curve with spiral CT. In the early group 18 donors underwent renal angiography as well as spiral CT and 10 underwent nephrectomy after spiral CT only. In the late group 5 had dual radiographic evaluation for ambiguities in spiral CT interpretation and 12 underwent nephrectomy after spiral CT only. Spiral CT was performed and interpreted blind to angiographic results, and vice versa. RESULTS: Spiral CT identified 50 of 52 renal arteries (96%) found at surgery overall and 23 of 25 (92%) found at surgery after spiral CT only. Two accessory arteries were missed in the 10 early group donors evaluated with spiral CT only, yielding an early negative predictive value of 80%. Renal angiography identified another accessory artery missed by spiral CT in the early group. All 3 missed vessels were identified retrospectively. No arteries found at surgery were missed in the late group (negative predictive value 100%), although there were 2 false-positive results detected by spiral CT relative to renal angiography in 1 candidate renal unit. Overall accuracy to predict early renal artery division relative to surgical findings was 93% for spiral CT and 91% for renal angiography. However, early renal artery division was clinically significant for only 1 of 11 vessels found at surgery. Spiral CT demonstrated 4 anomalous venous returns and renal angiography identified none. However, spiral CT missed 2 accessory veins and identified only 1 of 2 fibromuscular dysplasia cases. Total cost for spiral CT and renal angiography was $886 and $2,905, respectively. CONCLUSIONS: Spiral CT is a reasonably good alternative to renal angiography for living renal donor assessment but there is a profound learning curve for performance and interpretation. Renal angiography is still the gold standard with respect to the identification of arterial multiplicity and fibromuscular dysplasia, and it should be used adjunctively in cases with spiral CT ambiguity. Neither spiral CT nor renal angiography is ideal for the assessment of early renal artery division which is seldom an issue. The benefits of spiral CT over renal angiography are potentially lower morbidity, improved donor convenience and reduced cost.

Chronic renal allograft rejection: no response to mycophenolate mofetil.

BACKGROUND: Mycophenolate mofetil (MMF) has been previously shown to prevent functional deterioration in an experimental model of chronic renal allograft rejection. METHODS: In this retrospective case-control study, patients with chronic rejection who were receiving cyclosporine or tacrolimus and who had MMF added to their immunosuppressive regimen were compared with patients with chronic rejection who were not receiving MMF. Patients were matched for serum creatinine levels and transplant duration at the time MMF was begun. RESULTS: In the MMF group, the average dose of MMF was 1482 mg/day with an average duration of 19.3 months. Over 36 months, including 12 months before MMF and up to 24 months on MMF, there was no difference in serum creatinine levels between the two groups. Cyclosporine levels and dose were no different. CONCLUSIONS: In this small, retrospective, preliminary study, adding MMF to maintenance immunosuppression provided no clear benefit to renal allograft recipients with established chronic rejection. Larger prospective randomized studies are needed.

Nifedipine protects small intestine from cyclosporine-induced hemodynamic and functional impairment.

We have previously shown that cyclosporine (CsA) causes intestinal hemodynamic and functional impairments. In this study, we evaluated whether nifedipine protects the small intestine from such toxic side effects. Isogeneic small intestinal transplantation was performed in rats which then received one of the following two-week treatments: olive oil, 0.15 ml/kg/day i.m. as vehicle controls in group 1; nifedipine, 1 mg/kg/day i.m. in group 2; CsA, 15 mg/kg/day i.m. in group 3; and both nifedipine and CsA in group 4. Vascular resistance, whole tissue blood flow and its mucosal and serosal/muscularis distributions in both graft and recipient residual native intestines, and absorptive function were determined. The data showed that two-week treatment with CsA resulted in a marked elevation of vascular resistance from 51.0 +/- 6.8 to 72.4 +/- 11.1 U/g in the native whole tissue and from 53.7 +/- 7.2 to 78.2 +/- 12.1 U/g in the graft whole tissue, and decreases in blood flow from 1.59 +/- 0.26 to 1.11 +/- 0.17 ml/g/min in the native whole tissue and from 1.50 +/- 0.21 to 1.03 +/- 0.18 ml/g/min in the graft whole tissue and absorption from 227 +/- 36 to 166 +/- 26 mg glucose/dl. Mucosa was preferentially affected, while serosal/muscularis layers remained relatively unchanged. When nifedipine was concomitantly used with CsA, vascular resistance and blood flow values in the mucosal layer and whole intestinal tissue as well as absorptive function showed no significant differences from the baseline data. The changes observed in denervated grafts and recipient native intestines were similar. We conclude that nifedipine is effective in protecting both graft and native small intestines from CsA-induced toxicity in the rat.

Effect of tacrolimus on hemodynamics and absorption of experimental small intestinal transplants.

We have previously reported the adverse effects of cyclosporine on small intestine transplant physiology. In this study, we report for the first time the effect of tacrolimus (FK) on graft intestinal blood flow and intramural distribution, vascular resistance, and absorptive function. Isogeneic small intestine transplantation was performed in Lewis rats. Animals were grouped based upon the following treatment schedules: no treatment for 1 week in group 1; 0.6 ml/kg/day i.m. polyethylene glycol (PEG) for 1 week in group 2; 2 mg/kg/day i.m. FK for 1 week in group 3; 0.6 ml/kg/day PEG for 1 week and then 0.3 ml/kg/day for 5 weeks in group 4; 2 mg/kg/day FK for 1 week and then 1 mg/kg/day for 5 weeks in group 5. Group 6 was the same as in group 5 but FK was withdrawn for 1 week prior to assessment. Maltose absorption was measured to evaluate graft absorptive function. Blood flow and its intramural distribution to mucosal and serosal/muscularis layers were determined using the radioactive microsphere technique. Perfusion pressure was measured to calculate vascular resistance. One week of FK administration in group 3 did not change graft hemodynamics and absorption significantly. Prolonged FK treatment up to 6 weeks in group 5 resulted in a significant increase in mucosal vascular resistance (71.0 +/- 9.6 versus 47.7 +/- 6.7 U/g, P<0.01) and significant decreases in mucosal blood flow (1.14 +/- O.15 versus 1.69 +/- 0.24 ml/g/min, P<0.01) and maltose absorption (30 min after loading. 155.4 +/- 26.9 versus 216.4 +/- 29.6, P<0.01; 60 min after loading: 172.9 +/- 24.5 versus 229.1 +/- 32.6 glucose mg/dl P<0.01). The serosal/muscularis layer remained relatively unaffected. Withdrawal of FK for 1 week after prolonged treatment in group 6 resulted in restorations of all parameters measured to normal ranges. We conclude that a short course of FK is safe, but prolonged FK administration has harmful effects on the hemodynamics and function of small intestinal transplants. Complete recovery is achieved when FK is discontinued.

Improved small intestinal preservation after lazaroid U74389G treatment and cold storage in University of Wisconsin solution.

The small intestine (SI) is highly sensitive to oxygen free radical-induced injury. The most common preservation solution, University of Wisconsin (UW) solution, does not adequately prevent free radical-induced injury. Lazaroids, and U74389G in particular, are a new class of compound that are potent inhibitors of superoxide-mediated lipid peroxidation. We studied the added influence of U74389G to 18-hr cold preservation of rat SI in UW solution. Three groups of rats were studied. In group 1, SI was excised and reperfused immediately. In group 2, SI was stored in UW solution at 4 degrees C for 18 hr. In group 3, U74389G was given to the SI graft before storage and again before reperfusion. Blood reperfusion of the grafts was achieved via connection to the superior mesenteric artery and portal vein of support rats. Functional recovery was assessed using a maltose tolerance test. Weight changes were calculated and histologic studies done. After 30 and 60 min of reperfusion, maltose uptake in group 3 was significantly better than that of the group 2, and returned to control levels. Significantly more tissue swelling was noted in group 3 over control, but the magnitude was less than that of group 2. Less transmural necrosis and villous blunting were noted in group 3 versus group 2; the appearance of the mucosa in group 3 approached that of group 1. We conclude that the use of U74389G treatment in addition to cold storage in UW solution improves recovery of graft function and minimizes morphologic damage to the small intestinal mucosa.

Endourologic management of complications in renal allografts.

Because of the altered anatomy, the presence of immunosuppression, the possibility of graft rejection, and the serious implications of a problem involving a solitary kidney, the transplanted kidney presents unique challenges in the diagnosis and treatment of urologic complications. Historically, the mortality rate in these patients has been as high as 68%, and as many as 15% of the allografts have been lost. Today, endourologic procedures are used for prompt diagnosis, temporization, and even definitive management of many urologic complications, and many patients and allografts are being saved. The authors review present techniques and suggest others that may be available in the future.

Prolonged use of cyclosporine (CsA) produces reversible hemodynamic and absorptive alterations in the transplanted rat small intestine.

Cyclosporine (CsA)-induced alterations in organ blood flow (BF) and function have been studied in kidney and pancreatic transplants. In this study, we assessed the effect of prolonged CsA administration on graft tissue BF and absorption from transplanted rat small intestine (SI). Isogeneic SI transplantation was performed in Lewis rats. Animals were grouped based upon the following treatment schedules: no treatment for 1 week in group 1; 0.15 ml/kg/day im olive oil for 1 week in group 2; 0.15 ml/kg/day olive oil for 1 week and then 0.1 ml/kg/day for 5 weeks in group 3; 15 mg/kg/day im CsA for 1 week in group 4; and 15 mg/kg/day CsA for 1 week and then 10 mg/kg/day for 5 weeks in group 5. Group 6 was the same as group 5 but CsA was withdrawn for 1 week prior to assessment. Maltose absorption was measured to evaluate graft absorptive function. BF and its intramural distribution to mucosal and serosal/muscularis layers were determined using the radioactive microsphere technique. Perfusion pressure was measured to calculate vascular resistance (VR). One week of CsA of administration in group 4 resulted in a significant increase in mucosal VR (68.4 +/- 15.5 versus 46.9 +/- 8.7 U/g, P < 0.01) and significant decreases in mucosal BF (1.21 +/- 0.25 versus 1.80 +/- 0.38 ml/g/min, P < 0.01) and maltose absorption 30 min after loading (168.9 +/- 21.1 versus 214.4 +/- 28.4 glucose mg/dl, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Reassessment of the value of post-vascularization biopsy performed at renal transplantation: the effects of arteriosclerosis.

Between January 1, 1984 and December 31, 1991, 471 cadaver renal transplants were performed. We reviewed 130 transplants, which were biopsied 30 minutes to 1 hour after the establishment of renal allograft blood flow. Analysis showed a significant difference in 2-year graft survival rate between the groups with and without arteriosclerosis (71.8% versus 65.9%, p < 0.05). Arteriosclerotic changes were noted more frequently in biopsies from older donors (37 versus 28 years, p < 0.005). There was also a difference in ischemic time between the groups with and without tubular degeneration (30.1 hours versus 26.7 hours, p < 0.02), which did not correlate with the need for dialysis in the perioperative period (48% versus 49%, p > 0.8).