B. J. R. Junor

Hypercalcaemic osteomalacia due to aluminium toxicity.

In 16 patients with chronic renal failure and osteomalacia resistant to vitamin-D therapy, aluminium was demonstrated in bone biopsy specimens at the interface between thickened osteoid and calcified bone by means of both X-ray microanalysis and a specific histochemical stain. 14 patients also had hypercalcemia. It is suggested that this is due to the blocking by aluminium of additional calcium uptake into bone coupled with the availability of additional calcium from dialysis fluid and vitamin-D therapy. This study provides more aetiological evidence linking aluminium and the development of osteomalacia in chronic renal failure. Further, if hypercalcaemia develops in such patients it is important that aluminium toxicity be excluded as the cause to prevent unnecessary parathyroidectomy.

Ultrasound changes in sclerosing peritonitis following continuous ambulatory peritoneal dialysis

Sclerosis of the peritoneum, with encapsulation of the small bowel is one of the most serious complications of continuous ambulatory peritoneal dialysis (CAPD), and carries a high mortality. The abnormalities seen on ultrasound are described for 14 patients and comprise increased small bowel peristalsis, tethering of the bowel to the posterior abdominal wall, intraperitoneal echogenic strands and, in the late stages of the disease, membrane formation. Optimal visualization of these features in the early stages of the disease was obtained by examining the patients with dialysis fluid present in the abdomen. Sclerosing peritonitis should be suspected in patients being treated by CAPD who develop abdominal pain and progressive loss of ultrafiltration and subsequent investigation should include the use of ultrasound.

The impact of late acute rejection after cadaveric kidney transplantation

Background: Acute graft rejection (AR) following renal transplantation results in reduced graft survival. However, there is uncertainty regarding the definition, aetiology and long‐term graft and patient outcome of AR occurring late in the post‐transplant period. 
Aim: To determine if rejection episodes can be classified by time from transplantation by their impact on graft survival into early acute rejection (EAR) and late acute rejection (LAR). 
Materials and methods: 687 consecutive adult renal transplant recipients who received their first cadaveric renal transplant at a single centre. All received cyclosporine (CyA)‐based immunosuppression, from 1984 to 1996, with a median follow‐up of 6.9 yr. Details were abstracted from clinical records, with emphasis on age, sex, co‐morbid conditions, HLA matching, rejection episodes, patient and graft survival. 
Analysis: Patients were classified by the presence and time to AR from the date of transplantation. Using those patients who had no AR (NAR) as a baseline, we determined the relative risk of graft failure by time to rejection. The characteristics of patients who had no rejection, EAR and LAR were compared. 
Results: Compared with NAR, the risk of graft failure was higher for those patients who suffered a rejection episode. A much higher risk of graft failure was seen when the first rejection episode occurred after 90 d. Thus, a period of 90 d was taken to separate EAR and LAR (relative risk of 3.06 and 5.27 compared with NAR as baseline, p<0.001). Seventy‐eight patients (11.4%) had LAR, 271 (39.4%) had EAR and 338 (49.2%) had NAR. The mean age for each of these groups differed (LAR 39.6 yr, EAR 40.8 yr compared with NAR 44 yr, p<0.003). The 5‐yr graft survival for those who had LAR was 45% and 10‐yr survival was 28%. HLA mismatches were more frequent in those with EAR vs. NAR (zero mismatches in HLA‐A: 36 vs. 24%, HLA‐B: 35 vs. 23% and HLA‐DR: 63 vs. 41%, p<0.003). There was no difference in mismatching frequency between NAR and LAR. 
Conclusions: AR had a deleterious impact on graft survival, particularly if occurring after 90 d. AR episodes should therefore be divided into early and late phases. In view of the very poor graft survival associated with LAR, it is important to gain further insight into the main aetiological factors. Those such as suboptimal CyA blood levels and non‐compliance with medication should be further investigated with the aim of developing more effective immunosuppressive regimens in order to reduce the incidence of LAR.

Long-term outcome of a prospective randomized trial of conversion from cyclosporine to azathioprine treatment one year after renal transplantation.

BACKGROUND Since the introduction of cyclosporine (CsA), 1-year renal allograft survival has improved, but concern persists about the long-term adverse effects of CsA, especially with respect to renal function and blood pressure. This randomized controlled trial was set up to establish whether withdrawal of CsA would alter long-term outcome. METHODS Adult patients who, at 1 year after renal transplantation, had a stable serum creatinine of less than 300 micromol/L and who had not had acute rejection within the last 6 months were eligible for entry. Patients were randomized either to continue on CsA (n=114) or to stop CsA and start azathioprine (Aza, n=102). All patients remained on prednisolone. Median follow-up was 93 months after transplantation (range: 52-133 months). RESULTS There was no significant difference in actuarial 10-year patient or graft survival (Kaplan-Meier), despite an increased incidence of acute rejection within the first few months after conversion. Median serum creatinine was lower in the Aza group (Aza: 119 micromol/L; CsA. 153 micromol/L at 5 years after randomization, P=0.0002). The requirement for antihypertensive treatment was also reduced after conversion to Aza; 75% of patients required antihypertensive treatment at the start of the study, decreasing to 55% from 1 year after randomization in the Aza group and increasing to >80% in the CsA group (55% (Aza) and 84% (CsA) at 5 years after randomization, P<0.005). CONCLUSIONS Conversion from CsA to Aza at 1 year after renal transplantation results in improvement in both blood pressure control and renal allograft function, and is not associated with significant adverse effects on long-term patient or graft survival.

Histological and electron microprobe studies of mineralisation in aluminium-related osteomalacia.

AIMS: To determine a possible mechanism to explain the presence of aluminium lines within fully calcified bone in aluminium-related osteomalacia. METHODS: Fifty five bone cases shown by bone biopsy to be aluminium-related osteomalacia were studied. In 38 specimens aluminium lines were identified within calcified bone by means of the Aluminon stain and a characteristic form of patchy mineralisation was seen within thickened osteoid seams. Five representative examples were analysed quantitatively by histomorphometry and electronprobe X-ray microanalysis and compared with five cases of vitamin D deficiency-related osteomalacia which also had patchy mineralisation. RESULTS: The patchy calcification occupied 40 +/- 8% (mean +/- SEM) of the osteoid and consisted of small focal deposits (less than 40 microns diameter), often (52%) around osteoid osteocytes (probably an underestimate of the association), and larger areas that extended to the aluminium lines at the underlying mineralisation front. Small and large mineralisation nuclei were seen ultrastructurally in the patchy calcification. Quantitative electronprobe X-ray microanalysis showed that calcium concentrations and calcium:phosphorus ratios in the mineralisation nuclei and in the superficial layer of the fully calcified bone of the aluminium-related osteomalacia cases were significantly less than values measured at similar sites in the vitamin D deficiency-related osteomalacia cases. Furthermore, aluminium could not be detected by means of this technique at the mineralisation front or along cement lines in these specimens. CONCLUSIONS: Calcification can occur in thickened osteoid seams in osteomalacia. It can begin around osteoid osteocytes as small deposits that enlarge within the osteoid and extend to the underlying mineralisation front or cement line where aluminium lines may become trapped. Complete calcification of osteoid could account for the presence of aluminium lines within fully calcified bone. The Aluminon stain appears to be a more sensitive method for the detection of aluminium in bone than electronprobe X-ray microanalysis.

Osteonecrosis and fractures following renal transplantation

Skeletal radiological surveys in 161 renal transplant recipients identified 36 patients with 115 lesions of osteonecrosis. A further two patients with osteonecrosis found at autopsy had had no radiographic abnormality. The total incidence of osteonecrosis was, therefore, 38 (24%) out of 161. The lesions were frequently multiple and bilateral with structural failure being the most common initial abnormality and the femoral head the most frequent site. Lesions also occurred in the femoral condyles, the talus, the humeral heads and the metatarsals, many being symptom-free. Calcification was demonstrated in the femoral and tibial shafts. The initial radiological abnormality appeared at a mean interval of 19 months after transplant but could occur as late as 75 months. Significantly fewer patients, three (7%) out of 41, developed osteonecrosis following a low-dose prednisolone regimen (0.8 g) compared with a high-dose group (2.8 g) where 35 (29%) out of 120 were affected. More females than males developed osteonecrosis, but no correlation could be demonstrated with regard to age, primary renal disease, number and type of transplant and duration of dialysis prior to transplant. Osteonecrosis is a complication which can be reduced with a low-dose prednisolone regimen. Most lesions will be demonstrated by radiological survey undertaken during the second and fourth years after transplantation.

Randomized study comparing cyclosporine with azathioprine one year after renal transplantation-15-year outcome data

Background. The introduction of cyclosporine (CsA) improved 1-year graft survival and reduced the incidence of acute rejection episodes after renal transplantation compared to azathioprine (Aza). However, CsA has many side effects and reducing exposure of this drug after the first year may benefit long-term patient and graft survival. Methods. We report 15-year outcome data from a single center, randomized controlled study comparing CsA withdrawal and conversion to Aza with continuation of CsA 1-year posttransplant. Results. Two hundred sixteen patients who showed a serum creatinine less than 300 &mgr;mol/L with no acute rejection episodes in the preceding 6 months were enrolled (CsA 114, Aza 102). There was no difference in patient survival at 15 years: 62.4% in the CsA group and 64.4% in the Aza group (P=0.6). Fifteen-year transplant survival was 41.9% for the CsA group and 48.8% for the Aza group (P=0.8). Fifteen-year graft survival censoring for death with a functioning graft was 58% in the CsA group and 72% in the Aza group (P=0.5). Predictors of patient survival were younger recipient age (P<0.001) and lower systolic blood pressure at randomization (P=0.01). Predictors of graft survival were older recipient age (P<0.001) and better renal function at randomization (P=0.01). Assigned drug showed no effect on graft or patient survival. Patients assigned to CsA showed significantly worse renal function up to 10 years posttransplantation and required more anti-hypertensive treatment throughout the study period. Conclusion. In a selected group of patients, either Aza or low-dose CsA is safe and effective. Despite lower estimated glomerular filtration rate (eGFR) up to 10 years posttransplantation and increased use of anti-hypertensive agents, low-dose CsA was not associated with a worse patient or graft survival.

Correlation between high-molecular-weight Fcγ-receptor-blocking factors in serum and renal allograft survival

In this study, we have demonstrated the occurrence of IgG class noncytotoxic, lymphocyte Fc gamma-receptor-blocking antibodies in a proportion of sera obtained from transfused uremic patients. The presence of these antibodies was not found to correlate with subsequent renal allograft survival. Serum fractionation studies did however reveal a striking correlation between graft survival and Fc gamma-receptor blocking mediated by a serum factor(s) with a sedimentation coefficient of greater than 19S. The precise nature of this factor remains to be clarified.

Does osteomalacia contribute to development of oral complications of oxalosis

Two renal dialysis patients with oral manifestations of oxalosis had undecalcified sections of iliac and alveolar bone and teeth examined histologically in an attempt to explain the development of tooth mobility and tooth loss. Osteomalacia was detected in all bone specimens and attributed to aluminum toxicity after the histochemical localization of aluminum at the calcification front between osteoid and calcified matrix. Aluminum was also detected histochemically in the cementum of teeth. Calcium oxalate crystals were present in bone marrow, teeth, and gingiva. It is proposed that tooth mobility and tooth loss in oxalosis result from the combined effects of osteomalacia and oxalate crystal deposition within the periodontium. To prevent avoidable tooth loss it is suggested that patients with oxalosis who develop tooth mobility should have aluminum toxicity and osteomalacia excluded as causal factors.

Persistent dipstick haematuria following renal transplantation.

Abstract:  Despite widespread testing for dipstick haematuria following renal transplantation, there are no published series describing the prevalence and possible causes of this complication in an adult population. A cross‐sectional study of 640 renal transplant recipients under review at our follow‐up clinic was performed. Persistent haematuria was defined as a minimum of 1+ of blood on urinalysis stick testing detected at not fewer than 75% of clinic visits since its onset, or since the start of routine testing, present over a period of at least 4 weeks. The prevalence of persistent dipstick haematuria was 13.3%. Median serum creatinine was higher in patients with persistent haematuria but age, gender and length of time since transplantation were not significantly different. Potential explanations for persistent haematuria in 21 of 85 affected patients were chronic infection, ureteric stent without chronic infection, regular or intermittent self‐catheterization, persistent menstrual bleeding, anticoagulant therapy, graft calculus, and allograft renal cell carcinoma. Recurrent or de novo glomerular disease was confirmed by graft biopsy in 10 of 85 patients. Among the 41 recipients whose original cause of renal failure was IgA nephropathy (IgAN), the prevalence of persistent haematuria was 31.7% compared with 12% in the remaining patients (relative risk 2.6, 95% CI: 1.6–4.3). Persistent haematuria in IgAN patients was not associated with gender, age or time since transplantation. After 29 months of follow‐up, 20% of patients with haematuria had progressed to graft failure or death compared with 11.6% of the unaffected group (p = 0.029). However, despite the association with earlier graft failure, haematuria did not predict this endpoint independently of renal function.