C. B. Brown

Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure

Abstract Objective: To determine whether alfacalcidol—used in management of overt renal bone disease—may safely prevent renal bone disease when used earlier in course of renal failure. Design: Double blind, prospective, randomised, placebo controlled study. Setting: 17 nephrology centres from Belgium, France, the Netherlands, and the United Kingdom. Subjects: 176 patients aged 18–81 with mild to moderate chronic renal failure (creatinine clearance 15–50 ml/min) and with no clinical, biochemical, or radiographic evidence of bone disease. Interventions: Alfacalcidol 0.25 μg (titrated according to serum calcium concentration) or placebo given for two years. Main outcome measures: Quantitative histology of bone to assess efficacy of treatment and renal function to assess safety. Results: 132 patients had histological evidence of bone disease at start of study. Biochemical, radiographic, and histological indices of bone metabolism were similar for the 89 patients given alfacalcidol and the 87 controls given placebo. After treatment, mean serum alkaline phosphatase activity and intact parathyroid hormone concentration had increased by 13% and 126% respectively in controls but had not changed in patients given alfacalcidol (P<0.001). Hypercalcaemic episodes occurred in 10 patients given alfacalcidol (but responded to decreases in drug dose) and in three controls. Histological indices of bone turnover significantly improved in patients given alfacalcidol and significantly deteriorated in controls: among patients with abnormal bone histology before treatment, bone disease resolved in 23 (42%) of those given alfacalcidol compared with two (4%) of the controls (P<0.001). There was no difference in rate of progression of renal failure between the two groups. Conclusion: Early administration of alfacalcidol can safely and beneficially alter the natural course of renal bone disease in patients with mild to moderate renal failure. Key messages Key messages Treating such patients with alfacalcidol (up to 1 μg/day for two years) significantly improved their osteomalacia and hyperparathyroid disease Treatment had no apparent adverse effect on renal function Hypercalcaemic episodes were uncommon and readily responded to decreases in drug dose Alfacalcidol might be used more widely for patients with moderate renal failure not yet needing dialysis

Immunosuppressive treatment of idiopathic focal segmental glomerulosclerosis : A five-year follow-up study

Background/Aims: Focal segmental glomerulosclerosis (FSGS) is a common type of glomerular disease that can lead to chronic renal failure. Various therapeutic regimens have been used in nephrotic FSGS patients. The effect of treatment with prednisolone alone or its combination with azathioprine and cyclosporin and parameters related to a poor outcome are studied. Methods: Fifty-one patients with idiopathic FSGS and a follow-up period of 5 years were included. Twenty-five were treated with prednisolone alone (1 mg/kg BW/day) or combination of prednisolone (0.5 mg/kg BW/day) with azathioprine (2 mg/kg BW/day) or cyclosporine (3 mg/kg BW/day) in gradually reduced doses whereas 26 patients received no immunosuppressive drugs. Lower prednisolone dose regimens were used as initial treatment in obese, borderline diabetics or patients with bone disease. The clinical course was estimated using the end-points of 50% or doubling of baseline serum creatinine and/or end-stage renal failure. The contribution of clinical and histological parameters in the clinical outcome was estimated by univariate and multivariate analyses. Results: Increase of baseline serum creatinine by 50% during the follow-up period was observed in 2 treated and 9 untreated patients (8% vs. 35%, p = 0.03) whereas doubling of serum creatinine in 2 and 5 patients respectively (8% vs. 19%, p = NS). End-stage renal failure developed in 4 of 51 patients (8%), 2 treated and 2 untreated (p = NS). Parameters related to a poor outcome were baseline serum creatinine and severity of glomerulosclerosis (multivariate analysis OR = 1.08, p = 0.01). Most of patients (68%) who reached end-points had persistent nephrotic syndrome during the follow-up. Remission of nephrotic syndrome was observed more frequently among treated (75 vs. 30.7%, p = 0.05). Prednisolone alone was followed by remission of nephrotic syndrome in 62.5% whereas combination of lower prednisolone dose with azathioprine and cyclosporin in 80 and 85.7% of patients. No serious side-effects were observed. Conclusion: This and previous studies suggest that steroid and/or immunosuppressive therapy have a role in amelioration of the clinical course and remission of nephrotic syndrome in patients with FSGS A combination of low predisolone dose with cyclosporine could be used as initial treatment in patients with higher risk for side-effects from the usual prednisolone dose.

Plasma Levels of the Anaphylatoxins C3a and C4a in Patients with IgA Nephropathy/Henoch-Schönlein Nephritis

Measurements of plasma anaphylatoxins C3a and C4a were carried out as an indicator of in vivo complement activation in 46 patients suffering from IgA nephropathy/Henoch-Schönlein nephritis. There was a significant correlation between plasma levels of C4a and plasma creatinine and urea. We also found a significant correlation of plasma levels of C3a with plasma creatinine. We propose that the measurement of anaphylatoxin levels provides a sensitive indicator of in vivo complement activation and may serve as an additional method for monitoring the progress of disease in these patients.

Prednisolone and Azathioprine in IgA Nephropathy

Background: Immunoglobulin A nephropathy (IgAN) is one of the most common primary glomerular diseases. Although its clinical course is usually benign, some patients develop end-stage renal failure (ESRF). The role of immunosuppressive drugs in the treatment of IgAN remains controversial. The effect of treatment with prednisolone and azathioprine and the clinical and histological parameters related to a poor outcome are examined retrospectively in this analysis. Methods: Seventy-four patients with IgAN and a follow-up period of 10 years were included in this study. Forty-one were treated with prednisolone (initially 60 mg/day) and azathioprine (initially 2 mg/kg BW/day) in gradually reduced doses for 24 ± 9 months, whereas 33 patients received no immunosuppressive drugs. The clinical course was estimated using the end-points of doubling of baseline serum creatinine and/or ESRF. The contribution of clinical and histological parameters in the clinical outcome was estimated by univariate and multivariate analyses. Results: The overall clinical courses of both groups of patients showed a rather similar pattern. Doubling of serum baseline creatinine was observed in 9 of 41 treated (22%) and in 10 of 33 untreated (30%), whereas ESRF developed in 6 treated (15%) and 6 untreated patients (18%) (p = NS). However, treated patients with heavy proteinuria (>3 g/24 h) had a significantly better outcome compared to untreated (doubling of serum creatinine in 29 vs. 78% and ESRF in 17 vs. 55%, p < 0.05). Proteinuria (p < 0.01), mean blood pressure (p < 0.02), baseline serum creatinine (p = 0.02) and severity of interstitial myofibroblast expression (p = 0.02) were identified as independent risk factors related to a poor outcome by multivariate analysis. Side effects of treatment were not uncommomn and observed in 10 (24%) patients. Conclusion: Treatment with prednisolone and azathioprine is beneficial in ameliorating the clinical course of a subset of IgAN patients with heavy proteinuria or impaired renal function. Patients with advanced renal failure and severe chronic histological lesions should not be treated by this regimen as no benefit is expected and there is a risk of side effects.

Prednisolone and azathioprine in membranous nephropathy: a 10-year follow-up study.

BACKGROUND Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Although its clinical course is usually benign, some patients develop chronic renal failure. Combination of corticosteroids with cytotoxic drugs and cyclosporin have been used in the treatment of the disease. Conflicting results are reported with the use ofprednisolone and azathioprine. In this study, the effect of treatment with prednisolone and azathioprine and the parameters related to a poor outcome over a follow-up period of 10 years is estimated. METHODS 50 patients were included in this study; 33 were treated with prednisolone (initially 60 mg/day) and azathioprine (initially 2 mg/kg body weight/day) in gradually reduced doses for 26 +/- 9 months, whereas 17 patients received no immunosuppressive drugs. The clinical course was estimated using the end-points of doubling of baseline serum creatinine and/or end-stage renal failure (ESRF). The contribution of clinical and histological parameters in the clinical outcome was examined by univariate and multivariate analyses. RESULTS Doubling of baseline serum creatinine was observed in 20 of 50 patients (40%), 14 from treated and 6 from the untreated group (42% vs. 35%, p=NS). ESRF developed in 10 of 50 patients (20%), 7 from treated and 3 from the untreated group (21% vs. 18%, p=NS). Most patients from both groups who reached the end-points had impaired renal function at presentation and persistent nephrotic syndrome during the follow-up period. Both parameters were identified as independent risk factors related to an unfavorable clinical outcome. No difference in the remission rate of nephrotic syndrome was observed between treated and untreated patients (51% vs. 58%, p=NS). CONCLUSION Treatment with prednisolone and azathioprine seems to be of no long-term benefit in ameliorating the clinical course of nephrotic patients with membranous nephropathy. Thus, other therapeutic regimens including cyclophosphamide, chlorambucil or cyclosporin should be used in nephrotic IMN patients with poor prognostic features.

Does immunosuppression with prednisolone and azathioprine alter the progression of idiopathic membranous nephropathy

The role of immunosuppressive drugs in the treatment of idiopathic membranous nephropathy (IMN) remains controversial. The effect of treatment with prednisolone and azathioprine in patients with nephrotic-range proteinuria and biopsy-proven IMN from a single center (Sheffield Kidney Institute, Sheffield, UK) is described. In this retrospective study, 58 patients with IMN and nephrotic-range proteinuria were followed up for 4 years. Thirty-eight patients were treated with prednisolone (1 mg/kg body weight/d) and azathioprine (2 mg/kg body weight/d) orally for a median period of 26 months (range, 6 to 48 months). Twenty patients received no specific treatment for IMN and served as a control group. Clinical, biochemical, and histopathologic features at presentation were similar between the groups. Renal function (RF), measured by serum creatinine (Scr) level, deteriorated in both treated and control groups during the follow-up period. The median initial and final Scr levels (at the end of follow-up) in the treated group were 1.6 and 2. 1 mg/dL, respectively, and in the control group were 1.3 and 1.7 m/dL, respectively (P = not significant). Neither the rate of RF decline (measured by the slope of reciprocal of Scr against time) nor the proportion of patients with deteriorating RF differed significantly between the groups (37%, treated group; 30%, control group). A significant reduction in proteinuria was observed in both groups (P < 0.01, either group). Also, the rate of remission of nephrotic-range proteinuria was not significantly different between groups (55%, treated group; 65%, control group). The only prognostic factor that correlated with RF outcome (expressed by final Scr level) in a given patient was the mean proteinuria during follow-up in either group (r = 0.493; P < 0.01, treated group; r = 0.651; P < 0.01, control group). Adverse effects of immunosuppressive treatment were observed in nine patients (24%). These were serious in four patients (10%) and included squamous cell carcinoma (two patients), bacterial meningitis (one patient), and septicemia (one patient). In conclusion, treatment with prednisolone and azathioprine for patients with IMN did not show significant beneficial effects on the progression of disease. Furthermore, this treatment was associated with frequent and serious adverse effects.

Nutritional Profile of Continuous Ambulatory Peritoneal Dialysis Patients

Undernutrition in dialysis patients contributes to their morbidity and mortality. This is a cross-sectional study of the nutritional status of 61 patients treated with continuous ambulatory peritoneal dialysis (CAPD). They were studied with emphasis on assessment of their nutritional intake, anthropometric measurements, and evaluation of biochemical parameters. The correlation between the rate of CAPD peritonitis and these measurements was also examined. The majority of the patients (63.1%) had inadequate protein intake ( < or = 1.2 g/kg/day). A comparable percentage had a low energy intake ( < or = 30 kcal/kg/day). Moderate malnutrition, as assessed by a low triceps skinfold thickness (TST) or a reduced midarm muscle circumference (MAMC) of < or = 20th percentile, was detected in 52% and 39% of the patients, respectively. Severe malnutrition (TST or MAMC < or = 10th percentile) was present in 36% of the patients. The serum insulin-like growth factor I (IGF-I) proved to be the most useful biochemical marker of malnutrition. It showed a positive correlation with TST (r = 0.325; p < 0.05). No significant correlation was observed with other short-life proteins such a transferrin or prealbumin. However, stepwise regression analysis showed the predictive value of serum IGF-I for anthropometric values to be low (adjusted R2 = 34.6%). Wasted patients did not appear to have more infections when compared to their healthier counterparts. However, a weak correlation was observed between TST and the number of peritonitis episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue transglutaminase: a mediator and predictor of chronic allograft nephropathy?

Background. The precise mechanisms underlying the development of chronic allograft nephropathy (CAN) and the associated renal fibrosis remain uncertain. The protein-crosslinking enzyme, tissue transglutaminase (tTg), has recently been implicated in renal fibrosis. Methods. We investigated the involvement of tTg and its crosslink product, ε-(γ-glutamyl) lysine, in 23 human kidney allografts during the early posttransplantation period and related these to changes of CAN that developed in 8 of them. Sequential biopsies were investigated using immunohistochemical, immunofluorescence, and in situ enzyme activity techniques. Results. From implantation, tTg (+266%) and ε-(γ-glutamyl) lysine crosslink (+256.3%) staining increased significantly (P <0.001) in a first renal biopsy performed within 3 months from transplantation. This was paralleled by elevated tTg in situ activity. The eight patients who developed CAN had further increases in immunostainable tTg (+197.2%, P <0.001) and ε-(γ-glutamyl) lysine bonds (+465%, P <0.01) that correlated with interstitial fibrosis (r=0.843, P =0.009 and r=0.622, P =0.05, respectively). The staining for both was predominantly located within the mesangium and the renal interstitium. Both implantation and first biopsies showed tTg and ε-(γ-glutamyl) lysine crosslinking levels in patients who developed CAN to be twice the levels of those with stable renal function. Cox regression analysis suggested the intensity of the early tTg staining was a better predictor of inferior allograft survival that other histologic markers (hazard ratio=4.48, P =0.04). Conclusions. tTg and ε-(γ-glutamyl) lysine crosslink correlated with the initiation and progression of scarring on sequential biopsies from renal-allograft recipients who experienced CAN. Elevated tTg may offer an early predictor of the development of CAN, whereas tTg manipulation may be an attractive therapeutic target.

Early human renal allograft fibrosis: cellular mediators.

Background: The development of early renal interstitial fibrosis (IF) in renal allografts is likely to depend on multiple factors. We studied retrospectively renal biopsies from cadaveric human renal allografts, transplanted from 1996 to 1998, with the intention of detecting early fibrotic changes and determining the underlying cellular mediators. We studied 23 transplant patients whose 46 renal biopsies were analysed, including a donor biopsy taken routinely at implantation from each patient and 23 follow-up biopsies, taken as clinically indicated over a period of 3 months following transplantation. Methods: Histological evaluation of induction and progression of fibrosis relied on point count analysis of conventional (Masson’s trichrome/MT) and immunohistochemical staining for collagen III and IV, and alpha-smooth muscle actin (α-SMA) as a marker of myofibroblast differentiation. Mast cells (MC) were counted in sections stained with an anti-human mast cells tryptase monoclonal antibody. Activated macrophages as well as total, helper and cytotoxic T-lymphocytes were identified on frozen sections by direct immunofluorescence using mouse anti-CD71, CD3, CD4 and CD8 antibodies respectively. Eosinophils (E) were counted in hematoxylin and eosin (HE)-stained sections. Changes in interstitial fibrosis (IF) scores were evaluated and correlated with myofibroblasts, MC, E and lympho-monocytic cells. Results: We noted a significant increase in IF over a 3 months period following transplantation. There was also a significant increase in α-SMA+ cells, MC and E counts from implantation to follow-up biopsies. Similarly, there was a significant increase in interstitial infiltration by T-lymphocytes (modal category = 2 versus 0, p = 0.012) but not by macrophages. MC at implantation and follow-up were found to be predictive of IF (immunostainable collagen III) at follow-up (R2 = 0.510, p = 0.023 and p = 0.030). Further, the predictive value for total T-lymphocyte infiltration at follow-up was also significant (R2 = 0.617, p = 0.036). A strong correlation was found between α-SMA+ cells and MC counts at implantation (r = 0.7259, p < 0.001) and in follow-up biopsies (r = 0.5183, p < 0.01). However, there was no correlation between E counts and either α-SMA+ cells or MC either at implantation or in follow-up biopsies. Based on changes in interstitial immunostainable α-SMA, our patients were divided arbitrarily into 2 groups; group 1 (n = 12) with >100% increase in α-SMA and group 2 (n = 11) with <100% increase. Group 1 patients differed significantly from group 2 regarding the degree of MC infiltration at follow-up (t = 0.4519, p < 0.05) with the mean increase in MC count from implantation to follow-up biopsies being +5.1 cells/high power field (HPF) in group 1 and +0.8 cell/HPF in group 2 (p = 0.0237). MC counts in group 1 were associated with a higher modal category (greater than one) of cytotoxic: helper T-lymphocytes ratio compared to group 2 (2:1 versus 1:1 respectively). Conclusion: Multiple cells may contribute to early interstitial fibrosis in a subgroup of human renal allograft recipients with MC playing a major role.

Sarcomatoid renal cell carcinoma arising in hemodialysis-associated acquired cystic kidney disease presenting with disseminated bone marrow infiltration

A 51-year-old man with a 23-year history of hemodialysis-dependant end-stage renal failure presented with pyrexia, malaise, and progressive pancytopenia. Investigations revealed acquired cystic kidney disease, with one cyst being interpreted as showing evidence of recent hemorrhage, and a malignant sarcomatoid bone marrow infiltrate. The patient rapidly deteriorated and died. At autopsy a seminecrotic and cystic sarcomatoid renal cell carcinoma was identified, with metastases in the adrenals, bone marrow, liver, lungs, and abdominal lymph nodes. The case is reviewed with regard to epithelial membrane antigen- and cytokeratin-negative bone marrow immunohistology as well as the immunophenotype of acquired cystic kidney disease and that expected in renal carcinoma, with reference to the literature on acquired cystic kidney disease.