Development of an outpatient finger-prick glomerular filtration rate procedure suitable for epidemiological studies.

Development of an outpatient finger-prick glomerular filtration rate (GFR) procedure suitable for epidemiological studies. In clinical practice, reference GFR procedures are rarely used; in large-scale research studies, a great deal of effort and experience is required to obtain them, which is a considerable disincentive to using GFR as an end point. The major problem for both clinical staff and the subject is the length of time that the procedure takes, requiring continuous attendance in the outpatient clinic or its vicinity. Using iohexol as a marker, we therefore propose an alternative approach, which addresses this fundamental deterrent to a more widespread use of GFR measurement. Eighty-two GFR measurements were performed in a mixture of healthy subjects and patients with differing degrees of renal impairment with a wide range of GFRs. Serum was obtained from blood samples to enable a reference GFR to be calculated. Blood spots were collected on filter paper at the same intervals (120, 180, and 240 min), allowed to dry, and then sent through the post. Serum and blood spots were analyzed simultaneously for each individual by automated reverse-phase high-pressure liquid chromatography. Standard linear regression analyses confirmed a good agreement (r2 = 0.953) between the iohexol serum GFR and iohexol blood spots GFR. Bland-Altman analysis confirmed that there was no concentration bias. Paired comparisons (Wilcoxon's paired signed rank test) showed no significant difference between the two measurements. Capillary sampling is simple, effective, and significantly reduces the time and costs of performing plasma clearance GFR measurements. This approach will make the GFR measurement more accessible for clinical practice and large-scale epidemiological studies may become feasible.

Prevalence and causes of low bone density and fractures in kidney transplant patients.

Osteoporosis is known to occur in patients with kidney transplants, but limited information is available about the prevalence and causes of this complication. We asked all 330 patients with kidney transplants in our unit to participate in this study of whom 165 (50%) agreed to do so. The characteristics of the participating patients were similar to the remaining 165 nonparticipants. Seventy of 165 (42%) of the participants were women of whom 40 were postmenopausal in contrast to the men of whom only one was hypogonadal. Bone mineral density (BMD) was significantly reduced at the radius (Z score, -1.5) and femoral neck (Z score, -0.7), but the lumbar spine was normal. BMD was lower in women than men at all skeletal sites. Osteoporosis was found in 10-44% and osteopenia was found in 35-50% of women depending on the site. BMD was related inversely to time since transplantation and cumulative prednisolone dose. Twenty-seven of the 165 (16%) patients had either vertebral deformities or a history of a low trauma fracture after transplantation. This fracture group consisted of 10/27 (37%) men and 17/27 (63%) women, of whom 14 were postmenopausal. Fracture patients tended to be older and have a longer duration of renal failure, dialysis, transplantation, greater cumulative steroid dose, and higher bone resorption markers than the nonfracture group. No differences were found for cumulative doses of cyclosporin or tacrolimus. Logistic regression showed that only duration of dialysis and time since transplantation significantly increased fracture risk, with odds ratio (OR) for each year of dialysis or transplantation being 1.21 (CI, 1.00-1.48) and 1.14 (CI, 1.05-1.23), respectively. These data show that low bone density and fractures are common in patients with kidney transplant and are determined by both pre- and posttransplant variables. Fracture risk was greatest in women, particularly if they were postmenopausal and we recommend that this subgroup is targeted for assessment and treatment.

European randomised trial of dual versus triple tacrolimus-based regimens for control of acute rejection in renal allograft recipients.

Two large multicentre studies have shown superiority of tacrolimus-based immunosuppressive regimens compared with standard cyclosporine-based therapy in renal transplantation. In these studies, tacrolimus was used in a triple drug regimen of tacrolimus, corticosteroids, and azathioprine. The present study aimed to determine whether a tacrolimus-based dual regimen achieves a similar efficacy and safety profile compared with conventional triple therapy. In this prospective, open, multicentre trial, 249 patients were randomised to receive either dual therapy (n = 125) of oral tacrolimus (initial daily dose of 0.2 mg/kg) and oral prednisone or additionally, as a triple therapy (n = 124), oral azathioprine. The primary endpoint was the incidence of acute rejection at month 3. In addition, all patients were included into a follow-up evaluation at 1 year after transplantation. Both treatment groups had similar baseline characteristics. At month 3, patient survival was 97.6 % (dual) and 96.7 % (triple); graft survival was 92.7 % (dual) and 91.7 % (triple). The incidence of treated acute rejection confirmed by biopsy was 27.4 % (dual) and 24.8 % (triple); difference 2.6 %, 95 % CI [-9.4 %-12.9 %], P = 0.755. The incidence of corticosteroid-resistant rejection (biopsy-confirmed) was 9.7 % (dual) and 10.7 % (triple). The overall adverse events profile was similar; leukopenia (1.6 % vs 11.6 %, P = 0.002) was more frequent with triple therapy. Between months 4 and 12, six (dual) and eight (triple) patients had a rejection. At month 12, patient survival was 95.6 % (dual) and 93.6 % (triple); graft survival was 91.8 % (dual) and 90.7 % (triple). Tacrolimus proved to be efficacious and safe with both dual and triple low-dose regimens. The addition of azathioprine to a tacrolimus/corticosteroid-based therapy did not result in an increased efficacy.

The use of optical sensors to understand cellular interactions with renal cells.

Optical biosensor technology has revolutionized the assessment of receptor binding, enabling the characterization of low affinity interactions in real time. We report the application of the LAsys Optical Biosensor to the investigation of the affinity and specificity of the putative proximal tubular scavenging receptor for protein reabsorption and the specificity of AGE-modified protein interactions with primary human mesangial cells. Using the LLCPK cell line, the carboxy-methyl dextran cuvette surface and five different proteins (ranging in size and charge), we have shown that there is evidence to support the existence of a single scavenging receptor for all the proteins tested. The proteins competed with each other differing only in their relative binding affinity for the common receptor. We have also shown that human mesangial cells can bind to AGE-modified human serum albumin (AGE-HSA) immobilized onto the carboxylate surfaced planar cuvette and that binding can be inhibited using increasing concentrations of soluble AGE-HSA. However, increasing concentrations of soluble Non-AGE modified HSA can also inhibit binding to a similar extent which implies that there is relatively little AGE-receptor (RAGE) expression on cultured primary human mesangial cells. These results demonstrate the exciting potential of this technology as a tool to explore cellular interactions with renal cells.

Monocyte expression of tissue factor and adhesion molecules: the link with accelerated coronary artery disease in patients with chronic renal failure.

OBJECTIVE: To investigate the expression of monocyte tissue factor (MTF) and adhesion molecules in patients with chronic renal failure (CRF) and to look for any correlation with thrombin generation and Lp(a) lipoprotein. DESIGN: A study of MTF expression and adhesion molecules, prothrombin fragments 1+2 (PTf1+2), an index of thrombin generation, and lipoproteins in patients with CRF and in normal control subjects. BACKGROUND: Patients with end stage renal failure have an increased risk of coronary artery disease despite advances in therapy. Stimulated monocytes are potent activators of blood coagulation through the generation of MTF, which was recently implicated in the aetiology of acute coronary ischaemic syndromes. METHODS: MTF expression and adhesion molecules were measured in whole blood using immunofluorescence of monocytes labelled with anti-tissue factor antibody and CD11b and c by flow cytometry. PTf1+2 and Lp(a) lipoprotein in plasma were measured by enzyme linked immunosorbent assay (ELISA). PATIENTS: 70 patients with CRF without documented coronary artery disease (30 patients with CRF undialysed, 20 patients undergoing chronic ambulatory peritoneal dialysis (CAPD), and 20 undergoing haemodialysis (HD)), together with 20 normal controls, were studied. RESULTS: The (mean (SD)) increased MTF of CRF (48.0 (29) v 33.3 (7.2) mesf unit/100 monocytes in controls, p = 0.04) was more pronounced in patients undergoing dialysis (HD 73.1 (32.8) (p < 0.003) and CAPD 62.8 (28.9) mesf unit/100 monocytes, p < 0.04). MTF activity showed a positive correlation with both PTf1+2 and serum creatinine (p < 0.003) but not with Lp(a) lipoprotein. Lp(a) lipoprotein was significantly increased in both dialysis groups compared with controls (p < 0.005) and non-dialysis CRF groups (p < 0.02). Monocyte adhesion molecule (CD11b) was significantly higher in all three CRF groups than in the controls (p = 0.006). CONCLUSION: This study has demonstrated a hypercoagulable state in patients with CRF. This was especially pronounced in the dialysis patients. These findings provide a possible explanation for the increased cardiovascular and cerebrovascular morbidity and mortality in these patients.

Membranous nephropathy complicating adenolymphoma of the parotid (Warthin's tumour).

Membranous nephropathy has been described in association with many malignancies including various lymphomas. However, it has not been previously described as a complication of benign solid adenolymphoma of the parotid, also called Warthin's tumour. We describe a patient who presented with an adenolymphoma of the parotid, and developed a severe nephrotic syndrome due to membranous nephropathy 6 months after the parotid swelling. The nephrotic syndrome resolved following parotidectomy and a short course of immunosuppression with prednisolone and cyclophosphamide. The possible pathophysiologic mechanisms are discussed.

Reversible renal failure due to the antiphospholipid antibody syndrome, pre-eclampsia and renal thrombotic microangiopathy.

A 27-year-old Caucasian female, with a past history of recurrent spontaneous abortions, was admitted with pre-eclampsia at 26 weeks' gestation during her sixth pregnancy. She was previously known to have antiphospholipid antibodies since her fifth abortion, but had no clinical or serological evidence of systemic lupus erythematosus. A small-for-dates infant was delivered by emergency Caesarean section at 27 weeks for poor placental blood flow and fetal distress. She was transferred to the renal unit on the sixth post partum day with pulmonary edema, hypertension, disseminated intravascular coagulation and acute renal failure. Renal biopsy showed lesions compatible with thrombotic microangiopathy with diffuse glomerular necrosis. She was plasma exchanged and remained dialysis dependent for 7 months. Antiphospholipid antibodies were present in high titres and were the presumed cause of her acute renal failure. The patient now has stable renal function with a creatinine clearance of 30 ml/min for over two years. The late recovery of renal function is unique in the above circumstances.

Increased prevalence of dysplastic and malignant lip lesions in renal-transplant recipients.

BACKGROUND: Renal-transplant recipients are known to have increased rates of skin cancer associated with exposure to the sun. Little is known, however, about the prevalence and histologic features of lesions of the lips in these patients, or about risk factors for such lesions. METHODS: We examined the lips of 160 renal-transplant recipients (105 men and 55 women; mean [+/- SD] age, 48 +/- 13 years) and 160 normal subjects matched with the transplant recipients for age, sex, and skin type. The mean length of time between transplantation and the examination was 69 +/- 52 months; 58 percent of the recipients had received their grafts more than 60 months earlier. RESULTS: Among the 160 renal-transplant recipients, 21 (13 percent) had leukoplakia; in 2 (1.2 percent) the leukoplakia contained squamous-cell carcinoma. In contrast, only one normal subject (0.6 percent) had leukoplakia. Histologically, 13 of the 21 leukoplakias (62 percent) in the renal-transplant recipients who underwent biopsy were dysplastic, and 2 (10 percent) contained squamous-cell carcinoma. Actinic change was evident in 91 percent of the dysplastic lesions but not in the nondysplastic lesions (P < 0.001). Exposure to the sun and smoking were risk factors for dysplastic and malignant lip lesions in the renal-transplant recipients (P < 0.001 and P = 0.003, respectively). Among these recipients, only men had dysplastic or malignant lip lesions (P = 0.006); lipstick was used frequently by 73 percent of the women. The clinical appearance of lip lesions did not predict the presence of dysplasia or cancer. CONCLUSIONS: Renal-transplant recipients have an increased prevalence of leukoplakia, dysplasia, and cancer of the lip.

Prevalence and risk factors associated with leukoplakia, hairy leukoplakia, erythematous candidiasis, and gingival hyperplasia in renal transplant recipients.

The aims of this study were to determine the prevalence of intraoral lesions in renal transplant recipients and to identify possible risk factors. The oral mucosa of 159 renal transplant recipients and 160 control patients was examined. The most common lesion in renal transplant recipients was cyclosporin-induced gingival hyperplasia (prevalence 22%) and patients with gingival hyperplasia were found to be taking significantly more cyclosporin-A than those without (p < 0.001). The prevalence of hairy leukoplakia and leukoplakia in renal transplant recipients was 11.3% and 10.7%, respectively, compared with 0% and 5.6% in the controls. Oral candidiasis was observed in 9.4% of renal transplant recipients compared with 2.5% of the controls; 3.8% of renal transplant recipients exhibited erythematous candidiasis, but this was not seen in the controls. Renal transplant recipients had a significantly increased risk of developing gingival hyperplasia (p < 0.0001), oral candidiasis (p < 0.0005), and two other conditions that have a well-established association with the immune suppression accompanying HIV infection, hairy leukoplakia (p < 0.0001) and erythematous candidiasis (p < 0.01).

Non-melanoma skin cancer in renal transplant recipients: the extent of the problem and a strategy for management.

Over the past 2 years, we have examined all patients with a functioning renal allograft attending a regional nephrology unit. A total of 291 patients were examined. 172 (59%) were found to have cutaneous warts, and 64 (21.9%) had non-melanoma skin cancer (NMSC). The proportion of patients with both warts and NMSC increased with time from transplantation: 40% of patients who had been transplanted for more than 9 years had NMSC. Fifteen patients had extensive dysplastic change in all sun-exposed areas, particularly the dorsal aspect of the hands. This subgroup of patients develop large numbers of tumours, particularly squamous cell carcinomas (SCC), and require close surveillance and frequent surgery. One patient has died as a result of rapidly evolving metastases from an SCC on the dorsum of the hand. Excision and grafting of the backs of the hands in four patients, and long term etretinate therapy in 6 patients have led to a marked reduction in the frequency of surgery to remove tumours. The very high rate of NMSC, frequently multiple, found in this study of UK residents is a source of concern and indicates the need for close dermatological monitoring of allograft recipients, with intensive surveillance of patients with extensive dysplasia, who may develop tumours requiring surgery every few weeks.

Loss of regional bone mineral density in the first 12 months following renal transplantation.

A high incidence of osteopenia is likely in renal transplant recipients in whom pre-existing uraemic osteodystrophy, persisting hyperparathyroidism and glucocorticoids constitute a formidable array of risk factors. The correction of some biochemical and hormonal abnormalities, an increase in body weight and an increase in physical activity following transplantation could favour improvements in skeletal integrity. Using dual energy X-ray absorptiometry (DEXA), we studied prospectively the regional bone mineral density (BMD) of 34 consecutive cadaveric renal allograft recipients who were already established on dialysis. BMD of these patients was measured at the time of transplantation and was repeated at 3, 6 and 12 months following the transplantation. Immunosuppression was achieved using triple therapy: azathioprine, cyclosporin-A and prednisolone. At baseline, total BMD and BMD at the lumbar spine and femoral neck did not differ from age- and sex-matched controls. Females experienced marked and progressive bone loss at the lumbar spine, with less marked changes at the femoral neck. Males, in contrast, experienced substantial reduction of BMD at the femoral neck at 6 months and a recovery at 12 months without significant change at the lumbar spine. Whole body bone mineral content fell transiently in males, with partial recovery by 6 months. No significant correlation was found with the cumulative doses of either corticosteroids or cyclosporin-A, the duration of hospitalisation, the function of the transplant, patient age or menopausal status.(ABSTRACT TRUNCATED AT 250 WORDS)