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Biomedical subjects

Judith Adams

Publications and source records attributed to Judith Adams.

16 recordsLinked to original sources
PubMed2006

Ureteric replacement with Meckel's diverticulum.

OBJECTIVE: To report on four patients with obstruction of the upper urinary tract due to severe ureteric strictures at different levels, in whom a Meckel's diverticulum was used for ureteric replacement. PATIENTS AND METHODS: The patients were aged 3-64 years at the time of operation. In every patient, a Meckel's diverticulum was used to bridge a ureteric defect after recurrent reconstructive procedures. RESULTS: The mean (range) follow-up was 36 (12-69) months. There were no surgical complications, apart from mucus production in one case and renal function was normal in all patients after surgery. In one case, the invaginated Meckel's diverticulum was used for reflux protection. CONCLUSIONS: A Meckel's diverticulum, if present, appears to be an ideal intestinal substitute for a ureteric defect. The advantages of its use are its unique blood supply, its mobility, and its minimization of functional bowel length resection.

Adult↗
PubMed2006

Accelerated partial-breast irradiation using proton beams: initial clinical experience.

PURPOSE: We present our initial clinical experience with proton, three-dimensional, conformal, external beam, partial-breast irradiation (3D-CPBI). METHODS AND MATERIALS: Twenty patients with Stage I breast cancer were treated with proton 3D-CPBI in a Phase I/II clinical trial. Patients were followed at 3 to 4 weeks, 6 to 8 weeks, 6 months, and every 6 months thereafter for recurrent disease, cosmetic outcome, toxicity, and patient satisfaction. RESULTS: With a median follow-up of 12 months (range, 8-22 months), no recurrent disease has been detected. Global breast cosmesis was judged by physicians to be good or excellent in 89% and 100% of cases at 6 months and 12 months, respectively. Patients rated global breast cosmesis as good or excellent in 100% of cases at both 6 and 12 months. Proton 3D-CPBI produced significant acute skin toxicity with moderate to severe skin color changes in 79% of patients at 3 to 4 weeks and moderate to severe moist desquamation in 22% of patients at 6 to 8 weeks. Telangiectasia was noted in 3 patients. Three patients reported rib tenderness in the treated area, and one rib fracture was documented. At last follow-up, 95% of patients reported total satisfaction with proton 3D-CPBI. CONCLUSIONS: Based on our study results, proton 3D-CPBI offers good-to-excellent cosmetic outcomes in 89% to 100% of patients at 6-month and 12-month follow-up and nearly universal patient satisfaction. However, proton 3D-CPBI, as used in this study, does result in significant acute skin toxicity and may potentially be associated with late skin (telangiectasia) and rib toxicity. Because of the dosimetric advantages of proton 3D-CPBI, technique modifications are being explored to improve acute skin tolerance.

Aged↗
PubMed2006

Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations.

SCN1B, the gene encoding the sodium channel beta 1 subunit, was the first gene identified for generalized epilepsy with febrile seizures plus (GEFS+). Only three families have been published with SCN1B mutations. Here, we present four new families with SCN1B mutations and characterize the associated phenotypes. Analysis of SCN1B was performed on 402 individuals with various epilepsy syndromes. Four probands with missense mutations were identified. Detailed electroclinical phenotyping was performed on all available affected family members including quantitative MR imaging in those with temporal lobe epilepsy (TLE). Two new families with the original C121W SCN1B mutation were identified; novel mutations R85C and R85H were each found in one family. The following phenotypes occurred in the six families with SCN1B missense mutations: 22 febrile seizures, 20 febrile seizures plus, five TLE, three other GEFS+ phenotypes, two unclassified and ten unaffected individuals. All individuals with confirmed TLE had the C121W mutation; two underwent temporal lobectomy (one with hippocampal sclerosis and one without) and both are seizure free. We confirm the role of SCN1B in GEFS+ and show that the GEFS+ spectrum may include TLE alone. TLE with an SCN1B mutation is not a contraindication to epilepsy surgery.

Adolescent↗
PubMed2006

Dosimetric comparison of proton and photon three-dimensional, conformal, external beam accelerated partial breast irradiation techniques.

PURPOSE: To compare the dosimetry of proton and photon-electron three-dimensional, conformal, external beam accelerated partial breast irradiation (3D-CPBI). METHODS AND MATERIALS: Twenty-four patients with fully excised, Stage I breast cancer treated with adjuvant proton 3D-CPBI had treatment plans generated using the mixed-modality, photon-electron 3D-CPBI technique. To facilitate dosimetric comparisons, planning target volumes (PTVs; lumpectomy site plus 1.5-2.0 cm margin) and prescribed dose (32 Gy) were held constant. Plans were optimized for PTV coverage and normal tissue sparing. RESULTS: Proton and mixed-modality plans both provided acceptable PTV coverage with 95% of the PTV receiving 90% of the prescribed dose in all cases. Both techniques also provided excellent dose homogeneity with a dose maximum exceeding 110% of the prescribed dose in only one case. Proton 3D-CPBI reduced the volume of nontarget breast tissue receiving 50% of the prescribed dose by an average of 36%. Statistically significant reductions in the volume of total ipsilateral breast receiving 100%, 75%, 50%, and 25% of the prescribed dose were also observed. The use of protons resulted in small, but statistically significant, reductions in the radiation dose delivered to 5%, 10%, and 20% of ipsilateral and contralateral lung and heart. The nontarget breast tissue dosimetric advantages of proton 3D-CPBI were not dependent on tumor location, breast size, PTV size, or the ratio of PTV to breast volume. CONCLUSIONS: Compared to photon-electron 3D-CPBI, proton 3D-CPBI significantly reduces the volume of irradiated nontarget breast tissue. Both approaches to accelerated partial breast irradiation offer exceptional lung and heart sparing.

Aged↗
PubMed2006

Accelerated partial breast irradiation using proton beams: Initial dosimetric experience.

PURPOSE: The unique dosimetric features of proton radiotherapy make it an attractive modality for normal tissue sparing. We present our initial experience with protons for three-dimensional, conformal, external-beam accelerated partial breast irradiation (3D-CPBI). METHODS AND MATERIALS: From March 2004 to June 2005, 25 patients with tumors < or =2 cm and negative axillary nodes were treated with proton 3D-CPBI. The prescribed dose was 32 Cobalt Gray Equivalents (CGE) in 4 CGE fractions given twice daily. One to three fields were used to provide adequate planning target volume (PTV) coverage and dose homogeneity. RESULTS: Excellent PTV coverage and dose homogeneity were obtained in all patients with one to three proton beams. The median PTV receiving 95% of the prescribed dose was 100%. Dose inhomogeneity exceeded 10% in only 1 patient (4%). The median volume of nontarget breast tissue receiving 50% of the prescribed dose was 23%. Median volumes of ipsilateral lung receiving 20 CGE, 10 CGE, and 5 CGE were 0%, 1%, and 2%, respectively. The contralateral lung and heart received essentially no radiation dose. Cost analysis suggests that proton 3D-CPBI is only modestly more expensive (25%) than traditional whole-breast irradiation (WBI). CONCLUSION: Proton 3D-CPBI is technically feasible, providing both excellent PTV coverage and normal tissue sparing. It markedly reduces the volume of nontarget breast tissue irradiated compared with photon-based 3D-CPBI, addressing a principle disadvantage of external-beam approaches to PBI. As proton therapy becomes more widely available, it may prove an attractive tool for 3D-CPBI.

Aged↗
PubMed2005

Proton radiotherapy for orbital rhabdomyosarcoma: clinical outcome and a dosimetric comparison with photons.

BACKGROUND: Over 85% of pediatric orbital rhabdomyosarcoma (RMS) are cured with combined chemotherapy and radiation. However, the late effects of photon radiation compromise function and cosmetic outcome. Proton radiation can provide excellent tumor dose distributions while sparing normal tissues better than photon irradiation. METHODS AND MATERIALS: Conformal 3D photon and proton radiotherapy plans were generated for children treated with proton irradiation for orbital RMS at Massachusetts General Hospital. Dose-volume histograms (90%, 50%, 10%) were generated and compared for important orbital and central nervous system structures. Average percentages of total dose prescribed were calculated based on the 3 dose-volume histogram levels for normal orbital structures for both the proton and photon plans. The percent of normal tissue spared by using protons was calculated. RESULTS: Seven children were treated for orbital rhabdomyosarcoma with proton irradiation and standard chemotherapy. The median follow-up is 6.3 years (range, 3.5-9.7 years). Local and distant controls compare favorably to those in other published accounts. There was an advantage in limiting the dose to the brain, pituitary, hypothalamus, temporal lobes, and ipsilateral and contralateral orbital structures. Tumor size and location affect the degree of sparing of normal structures. CONCLUSIONS: Fractionated proton radiotherapy is superior to 3D conformal photon radiation in the treatment of orbital RMS. Proton therapy maintains excellent tumor coverage while reducing the radiation dose to adjacent normal structures. Proton radiation therapy minimizes long-term side effects.

Brain↗
PubMed2005

Differences in peak bone mass in women of European and South Asian origin can be explained by differences in body size.

There are few data concerning the occurrence of peak bone mass in women of South Asian origin. The aim of this study was to determine the level of peak bone mass in South Asian women in the UK and to determine whether any observed differences could be explained by differences in body size. Two groups of South Asian women, those of (1) Pakistani Muslim and (2) Gujarati Hindu origin, together with a European group aged 18 to 36 years, were recruited from primary-care population age-sex registers in the Greater Manchester area. They were invited to attend for a detailed interview-assisted lifestyle questionnaire and assessment of height and weight. Bone mass density (BMD) at the hip and lumbar spine was measured by dual energy X-ray absorptiometry (DEXA) scan (Hologic QDR 4500). Volumetric bone density was measured at the distal radius using pQCT (Norland Stratec XCT 2000). Linear regression was used to determine whether any observed differences in the level of bone mass could be explained by differences in body size. A total of 119 European women with a mean age of 30.4 years, 98 Pakistani Muslim women with a mean age of 29.2 years and 20 Gujarati Hindu women with a mean age of 29.2 years had bone density measurements performed. The Europeans were taller and heavier than either South Asian group. Peak BMD was greater among the European than the Pakistani women at all three measuring sites, with the Gujarati women having intermediate values at the hip and lumbar spine. Observed differences disappeared, however, after adjusting for height and weight. There were no differences in volumetric density at the lumbar spine or distal radius between the groups. In summary, there are differences in the level of bone mass between European and South Asian women, though these can be explained by differences in bone size, height or weight.

Absorptiometry, Photon↗
PubMed2005

13-cis retinoic acid inhibits development and progression of chronic allograft nephropathy.

Chronic allograft nephropathy is characterized by chronic inflammation and fibrosis. Because retinoids exhibit anti-proliferative, anti-inflammatory, and anti-fibrotic functions, the effects of low and high doses of 13-cis-retinoic acid (13cRA) were studied in a chronic Fisher344-->Lewis transplantation model. In 13cRA animals, independent of dose (2 or 20 mg/kg body weight/day) and start (0 or 14 days after transplantation) of 13cRA administration, serum creatinine was significantly lower and chronic rejection damage was dramatically reduced, including subendothelial fibrosis of preglomerular vessels and chronic tubulointerstitial damage. The number of infiltrating mononuclear cells and their proliferative activity were significantly diminished. The mRNA expression of chemokines (MCP-1/CCL2, MIP-1alpha/CCL3, IP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-beta1, and collagens I and III) were strikingly lower in treated allografts. In vitro, activated peritoneal macrophages of 13cRA-treated rats showed a pronounced decrease in protein secretion of inflammatory cytokines (eg, tumor necrosis factor-alpha, interleukin-6). The suppression of the proinflammatory chemokine RANTES/CCL5 x 13cRA in fibroblasts could be mapped to a promoter module comprising IRF-1 and nuclear factor-kappaB binding elements, but direct binding of retinoid receptors to promoter elements could be excluded. In summary, 13cRA acted as a potent immunosuppressive and anti-fibrotic agent able to prevent and inhibit progression of chronic allograft nephropathy.

Animals↗
PubMed2005

Reduced bone mineral density in adults treated with high-dose corticosteroids for childhood nephrotic syndrome.

BACKGROUND: Children with minimal change nephrotic syndrome (MCNS) receive repeated courses of high dose oral prednisolone. No previous study has investigated the impact of this on final bone mineral density (BMD). Young adults previously reported in a large follow-up study of children with MCNS were invited to participate in a cross-sectional study. Areal BMD (aBMD) of the spine (L1-4), left femoral neck, and total left hip was measured using dual x-ray absorptiometry (DXA), and volumetric BMD (vBMD) of the distal radius was measured by pQCT. BMD results were compared with reference data provided by the manufacturers of the densitometers. METHODS: Thirty-four (24 male) of the original cohort of 62 participated in the study. The mean (SD) final height Z score of the cohort was -0.45 (0.92) (P = 0.007) and mean BMI Z score 1.62 (1.53) (P < 0.0001). RESULTS: There was a highly significant reduction in distal radial trabecular vBMD; the mean Z score was -0.95 (0.99) and T score -1.04 (1.01) (both P < 0.0001); however, there was no reduction in distal radial total vBMD, the mean Z score being 0.00 (0.95) and T score -0.08 (0.99), (P = 0.99 and 0.66, respectively). The aBMD of the lumbar spine and femoral neck also showed a reduction in T scores [-0.45 (1.27), P = 0.045 and -0.49 (0.86), P = 0.002, respectively], but not Z scores [-0.37 (1.28) and -0.15 (0.87), respectively, both P = NS]. Total hip aBMD was not different from the control population. CONCLUSION: Adult survivors of childhood MCNS have a significant reduction in forearm trabecular vBMD, placing them at increased fracture risk at this site.

Adrenal Cortex Hormones↗
PubMed2004

Low magnitude mechanical loading is osteogenic in children with disabling conditions.

UNLABELLED: The osteogenic potential of short durations of low-level mechanical stimuli was examined in children with disabling conditions. The mean change in tibia vTBMD was +6.3% in the intervention group compared with -11.9% in the control group. This pilot randomized controlled trial provides preliminary evidence that low-level mechanical stimuli represent a noninvasive, non-pharmacological treatment of low BMD in children with disabling conditions. INTRODUCTION: Recent animal studies have demonstrated the anabolic potential of low-magnitude, high-frequency mechanical stimuli to the trabecular bone of weight-bearing regions of the skeleton. The main aim of this prospective, double-blind, randomized placebo-controlled pilot trial (RCT) was to examine whether these signals could effectively increase tibial and spinal volumetric trabecular BMD (vTBMD; mg/ml) in children with disabling conditions. MATERIALS AND METHODS: Twenty pre-or postpubertal disabled, ambulant, children (14 males, 6 females; mean age, 9.1 +/- 4.3 years; range, 4-19 years) were randomized to standing on active (n = 10; 0.3g, 90 Hz) or placebo (n = 10) devices for 10 minutes/day, 5 days/week for 6 months. The primary outcomes of the trial were proximal tibial and spinal (L2) vTBMD (mg/ml), measured using 3-D QCT. Posthoc analyses were performed to determine whether the treatment had an effect on diaphyseal cortical bone and muscle parameters. RESULTS AND CONCLUSIONS: Compliance was 44% (4.4 minutes per day), as determined by mean time on treatment (567.9 minutes) compared with expected time on treatment over the 6 months (1300 minutes). After 6 months, the mean change in proximal tibial vTBMD in children who stood on active devices was 6.27 mg/ml (+6.3%); in children who stood on placebo devices, vTBMD decreased by -9.45 mg/ml (-11.9%). Thus, the net benefit of treatment was +15.72 mg/ml (17.7%; p = 0.0033). In the spine, the net benefit of treatment, compared with placebo, was +6.72 mg/ml, (p = 0.14). Diaphyseal bone and muscle parameters did not show a response to treatment. The results of this pilot RCT have shown for the first time that low-magnitude, high-frequency mechanical stimuli are anabolic to trabecular bone in children, possibly by providing a surrogate for suppressed muscular activity in the disabled. Over the course of a longer treatment period, harnessing bone's sensitivity to these stimuli may provide a non-pharmacological treatment for bone fragility in children.

Bone Density↗
PubMed2004

Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebo-controlled 3-year study.

UNLABELLED: The efficacy of oral clodronate 800 mg daily to reduce vertebral fractures was studied in 593 women with postmenopausal or secondary osteoporosis. The incidence of vertebral fractures was significantly reduced by 46%. The effect was not modified by the underlying cause of osteoporosis or other baseline factors including bone mineral density, QUS, weight, and smoking. INTRODUCTION: This study aimed to determine if the bisphosphonate, clodronate (Bonefos), reduced the incidence of vertebral fractures in osteoporotic women. MATERIALS AND METHODS: Women fulfilling the WHO criteria for osteoporosis at the lumbar spine (T-score </= -2.5) and/or with at least one prevalent vertebral fracture were recruited to a 3-year double-blind, placebo-controlled study. A total of 593 patients were randomized to two strata comprised of women with postmenopausal osteoporosis (I, n = 483) and secondary osteoporosis (II, n = 110). They received either clodronate 800 mg daily orally (n = 292) or an identical placebo (n = 301). All patients received a calcium supplement of 500 mg daily. BMD was measured at 6, 12, 24, and 36 months, and lateral spine radiographs were obtained at baseline and annually thereafter for vertebral morphometry. RESULTS: Treatment with clodronate was associated with a significant increase in mean spine BMD over 3 years (percent change from baseline, 4.35 +/- 6.34% versus 0.64 +/- 6.02% in the placebo group, p < 0.0001). At the hip, clodronate maintained total BMD, whereas a significant decrease was observed in the placebo group (percent change from baseline 0.70 +/- 5.67% versus -3.03 +/- 6.32% in the placebo group, p < 0.0001). The changes at the spine and hip were similar in both strata. Incident vertebral fractures at 3 years were observed in 63 women in the placebo group and 33 patients receiving clodronate (relative risk, 0.54; 95% CI, 0.37-0.80; p = 0.001). Clodronate significantly reduced vertebral fracture risk in both strata and in women with or without prior vertebral fracture at baseline. Nonvertebral osteoporosis-associated fractures occurred in 21 women in the placebo group and in 14 women treated with clodronate. Treatment was well tolerated, with no significant difference in adverse event rates, including esophagitis, during clodronate treatment. CONCLUSION: We conclude that clodronate 800 mg daily is a safe and effective treatment to reduce fracture risk in women with osteoporosis, regardless of causation.

Aged↗
PubMed2003

Isotretinoin ameliorates renal damage in experimental acute renal allograft rejection.

BACKGROUND: Retinoic acids, derivatives of vitamin A, act through retinoid receptors that are expressed in renal and immunocompetent cells (B and T cells; monocytes and macrophages). In experimental models of glomerulonephritis and renal interstitial disease, retinoids were shown to reduce both glomerular and tubular damage and inflammation. We therefore examined whether retinoids reduce cellular rejection and renal damage in a model of acute renal allograft rejection. METHODS: Kidneys of Fisher rats (F344, RT11v1) were orthotopically grafted to Lewis rats (RT11). Animals were killed 7 or 14 days after transplantation. Rats undergoing transplantation were treated with isotretinoin (13 cis-retinoic acid) at a low dose of 2 mg/kg body weight per day (LD isotretinoin) or at a high dose of 20 mg/kg body weight per day (HD isotretinoin) or with vehicle. RESULTS: At day 14, albuminuria was reduced by approximately 70% (vehicle: 1.1+/-0.2 mg/24 hr vs. LD isotretinoin: 0.32+/-0.1 mg/24 hr; P<0.001). At days 7 and 14 serum creatinine levels were significantly higher in the vehicle-treated group than in the LD and HD isotretinoin-treated rats (P<0.05). Both LD and HD isotretinoin significantly reduced acute vascular injury compared with vehicle-treated rats (score at day 14: LD isotretinoin 20.1+/-5.1 vs. vehicle 57.8+/-9.9, P<0.01), acute glomerular injury (score: LD isotretinoin 6.8+/-1.0 vs. vehicle 10.6+/-0.9 P<0.05), and the number of glomerular monocytes and macrophages and cytotoxic T cells. Isotretinoin also significantly lessened tubulointerstitial damage, tubulointerstitial cell proliferation, and the number of cells infiltrating the tubulointerstitium. CONCLUSIONS: Isotretinoin significantly ameliorated functional, vascular, glomerular, and tubulointerstitial lesions in acute graft rejection. Although the current study did not definitely eliminate the possibility that isotretinoin only delayed the rejection process, retinoic acid derivatives may provide a new approach in the treatment of acute rejection injury.

Albuminuria↗
PubMed2003

Proton beams to replace photon beams in radical dose treatments.

With proton beam radiation therapy a smaller volume of normal tissues is irradiated at high dose levels for most anatomic sites than is feasible with any photon technique. This is due to the Laws of Physics, which determine the absorption of energy from photons and protons. In other words, the dose from a photon beam decreases exponentially with depth in the irradiated material. In contrast, protons have a finite range and that range is energy dependent. Accordingly, by appropriate distribution of proton energies, the dose can be uniform across the target and essentially zero deep to the target and the atomic composition of the irradiated material. The dose proximal to the target is lower compared with that in photon techniques, for all except superficial targets This resultant closer approximation of the planning treatment volume (PTV) to the CTV/GTV (grossly evident tumor volume/subclinical tumor extensions) constitutes a clinical gain by definition; i.e. a smaller treatment volume that covers the target three dimensionally for the entirety of each treatment session provides a clinical advantage. Several illustrative clinical dose distributions are presented and the clinical outcome results are reviewed briefly. An important technical advance will be the use of intensity modulated proton radiation therapy, which achieves contouring of the proximal edge of the SOBP (spread out Bragg peak) as well as the distal edge. This technique uses pencil beam scanning. To permit further progressive reductions of the PTV, 4-D treatment planning and delivery is required. The fourth dimension is time, as the position and contours of the tumor and the adjacent critical normal tissues are not constant. A potentially valuable new method for assessing the clinical merits of each of a large number of treatment plans is the evaluation of multidimensional plots of the complication probabilities for each of 'n' critical normal tissues/ structures for a specified tumor control probability. The cost of proton therapy compared with that of very high technology photon therapy is estimated and evaluated. The differential is estimated to be approximately 1.5 provided there were to be no charge for the original facility and that there were sufficient patients for operating on an extended schedule (6-7 days of 14-16 h) with > or = two gantries and one fixed horizontal beam.

Dose-Response Relationship, Radiation↗
PubMed2003

Association between vertebral fracture and increased mortality in osteoporotic patients.

UNLABELLED: Determinants of mortality were studied in a prospective study of 677 women and men with primary or secondary osteoporosis. Prevalent vertebral fractures were associated with increased mortality, but other known predictors of mortality explain a significant proportion of the excess risk. INTRODUCTION: In population studies, prevalent vertebral fractures are associated with increased mortality. It is unknown whether this excess mortality is related to low bone mineral density or its determinants or whether there is an additional component associated with fracture itself. METHODS: We studied 677 women and men with osteoporosis, 28-88 years old, of whom 352 had morphometrically determined vertebral fracture, to examine the risk and causes of mortality in patients with osteoporosis (defined densitometrically as a spine bone mineral density T-score < -2.5 and -3.0 for women and men, respectively, and/or one or more prevalent vertebral fractures without a history of significant trauma). The participants had enrolled in a double-blind placebo-controlled study in osteoporosis and were comprised of 483 women with postmenopausal osteoporosis, 110 women with secondary osteoporosis, and 84 men with osteoporosis of any cause. Demographics, medical history, and other measures of skeletal and nonskeletal health status were assessed at entry. RESULTS: During a median follow-up of 3.2 years, 37 (5.5%) participants died, with 31 of these deaths occurring in those with prevalent vertebral fractures. Compared with participants who did not have a prevalent vertebral fracture, those with one or more fractures had a 4.4-fold higher (95% CI, 1.85, 10.6) mortality rate. After adjustment for predictors for poor health--including number of medications, number of diseases, use of oral corticosteroids, alcohol intake, serum albumin and erythrocyte sedimentation rate (ESR), renal function, height, weight, gender, and age--the point estimate of risk remained elevated but was no longer statistically significant (hazard ratio, 2.4; 95% CI, 0.93, 6.23). CONCLUSIONS: Prevalent vertebral fractures in osteoporotic patients are associated with increased mortality. Other known predictors of mortality can explain a significant proportion of the excess risk.

Adult↗
PubMed2002

Combination treatment with an ET(A)-receptor blocker and an ACE inhibitor is not superior to the respective monotherapies in attenuating chronic transplant nephropathy in a 'Fisher-to-Lewis' rat model.

BACKGROUND: Specific endothelin A (ET(A))-receptor blockade and ACE inhibition attenuate chronic transplant nephropathy (CTN) in the 'Fisher-to-Lewis' rat model. It is unknown (i) which of both pharmacological interventions attenuates CTN more effectively and (ii) whether combination therapy exerts additive nephroprotection. METHODS: We compared (i) the effects of specific ET(A)-receptor blockade with LU 302146 (30 mg/kg bw/day) and ACE inhibition with trandolapril (0.3 mg/kg bw/day) and (ii) the effect of a combination therapy of both drugs on the development of CTN. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Untreated 'Fisher-to-Lewis' allografts served as controls (TX). All animals received low-dose cyclosporin A (1.5 mg/kg body weight) for 10 days post-transplant to inhibit early acute rejection episodes. The duration of the experiment was 36 weeks. Blood pressure (BP) was measured every other week by tail plethysmography. Indices of glomerulosclerosis (GS), tubulointerstitial and vascular damage, number of glomeruli, total glomerular volume and mean glomerular volume were measured using morphometric and stereological techniques, respectively. Albuminuria, blood chemistry and haematology were measured at the end of the experiment. RESULTS: LU 302146 did not affect systolic BP. In contrast, trandolapril and combination treatment significantly reduced systolic BP. Histological signs of CTN were almost completely prevented by LU 302146 and trandolapril as compared to TX, e.g. GS=0.8+/-0.08 and 0.9+/-0.20 vs 1.8+/-0.21* (arbitrary unit; *P<0.001 vs treated groups). Allograft weight was significantly lower in treated vs TX animals. Trandolapril and combination therapy, but not LU 302146 alone, abrogated glomerular hypertrophy, i.e. mean glomerular volume: TX 2.22+/-0.43, trandolapril 1.61+/-0.38**, LU 302146 2.22+/-0.11, trandolapril+LU 302146 1.78+/-0.28* (microm(3); *P<0.05 vs control and LU 302146, **P<0.01 vs control and LU 302146). Albuminuria was lower in treated compared to TX animals. Combination therapy did not confer additional benefit compared to the respective monotherapies. CONCLUSIONS: We conclude that ET(A)-receptor blockade abrogates GS, tubulointerstitial and vascular damage in the 'Fisher-to-Lewis' model of CTN to a similar extent as ACE inhibition. However, only ACE inhibition inhibits glomerular hypertrophy. In contrast to ACE inhibition, the effect of ET(A)-receptor blockade is independent of BP. This finding is consistent with the notion that ET(A)-receptor mediated events play a partly BP-independent role in the genesis of CTN. Combination therapy exerts no additive nephroprotection.

Angiotensin-Converting Enzyme Inhibitors↗