Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein.

INTRODUCTION: Fibrinogen A alpha chain amyloidosis is an autosomal dominant disease associated with mutations in the fibrinogen A alpha chain (FGA) gene, and it is the most common cause of hereditary renal amyloidosis in the UK. Patients typically present with kidney impairment and progress to end-stage renal disease over a median time of 4.6 years. METHODS: Six patients presented with proteinuria, hypertension, and/or lower limb edema and underwent detailed clinical and laboratory investigations. RESULTS: A novel FGA gene mutation was identified in each case: 2 frameshift mutations F521Sfs*27 and G519Efs*30 and 4 single base substitutions G555F, E526K, E524K, R554H. In 5 subjects, extensive amyloid deposits were found solely within the glomeruli, which stained specifically with antibodies to fibrinogen A alpha chain, and in one of these cases, we found coexistent fibrinogen A alpha chain amyloidosis and anti-glomerular basement membrane antibody disease. One patient was diagnosed with light-chain amyloidosis after a bone marrow examination revealed a small clonal plasma cell population, and laser microdissection of the amyloid deposits followed by liquid chromatography and tandem mass spectrometry identified kappa light chain as the fibril protein. DISCUSSION: We report 6 novel mutations in the FGA gene: 5 were associated with renal fibrinogen A alpha chain amyloidosis and 1 was found to be incidental to light-chain amyloid deposits discovered in a patient with a plasma cell dyscrasia. Clinical awareness and suspicion of hereditary amyloidosis corroborated by genetic analysis and adequate typing using combined immunohistochemistry and laser microdissection and mass spectrometry is valuable to avoid misdiagnosis, especially when a family history of amyloidosis is absent.

Transperitoneal water transport before, during, and after episodes with infectious peritonitis in patients treated with CAPD.

BACKGROUND: Peritonitis is considered to change peritoneal permeability and influences the long-term change in permeability during peritoneal dialysis. The objective of this study is to evaluate water transport across the peritoneum, expressed as drained ultrafiltration volume, before, during, and after episodes of peritonitis. METHODS: A retrospective analysis of data from a group of patients was performed in which drained ultrafiltration volume and glucose concentration in dialysis fluid were recorded for each dwell time every day during time on continuous ambulatory peritoneal dialysis treatment as a part of the clinical routine performed. Days with peritonitis and average of daily measurements 1 month before and after each peritonitis episode were evaluated separately for day and night exchanges. In all, 64 episodes of peritonitis in 30 patients were included in this study. Approximately 15,000 exchanges were recorded. Paired t-test and repeated-measures analysis of variance were performed. RESULTS: Compared with the average for the previous month, there was a significant decrease in ultrafiltration volume for day exchanges occurring 2 days before the appearance of other clinical symptoms of peritonitis (P = 0.029). For night exchanges, the decrease in ultrafiltration volume occurred 24 hours before diagnosis (P < 0.001). Ultrafiltration volume was at its minimum the day of diagnosis for both the day (P < 0.001) and night (P < 0.001) exchanges compared with average volume for the previous month. Ultrafiltration volumes remained low for 2 days after diagnosis during both the day (P = 0.009) and night (P = 0.017) exchanges. Relative to the previous month, glucose concentration on the day of clinical diagnosis of peritonitis did not differ significantly (P = 0.328 and P = 0.963 for day and night shifts, respectively). Overall, no significant changes in ultrafiltration volumes or glucose concentrations from the month before to the month after the peritonitis episode were found (P = 0.99 and P = 0.27 for measurements during the day, respectively). CONCLUSION: Osmotic forced ultrafiltration decreased during infectious peritonitis, most significantly for a long dwell time, consistent with an increase in both functional peritoneal surface area and hydraulic conductivity. This finding appeared 2 days before other clinical symptoms and remained significantly low 2 days after diagnosis.

Changes in water transport across the peritoneum during treatment with continuous ambulatory peritoneal dialysis in selected patients with and without peritonitis.

BACKGROUND: The natural course of longitudinal changes in peritoneal permeability and membrane area has been studied mostly by performing single-dwell studies in selected patients during treatment with peritoneal dialysis. PURPOSE: To evaluate the permeability characteristics of the peritoneal membrane by measuring drained ultrafiltration volume relative to initial glucose concentration in dialysis fluid from the start to the end of continuous ambulatory peritoneal dialysis (CAPD) treatment in a selected cohort of patients with and without peritonitis. DESIGN: A retrospective analysis of a group of patients whose peritoneal function was prospectively followed by recording drained ultrafiltration volume and glucose concentration in dialysis fluid for each dwell time, every day, during the time in CAPD treatment. Mean values from a 1-month period starting after the first 3 weeks of CAPD treatment were compared with the mean values from the last month of treatment. Approximately 11 500 exchanges were analyzed. Evaluations were done separately for short (day) and long (night) dwell times. PATIENTS AND STATISTICS: Of 132 patients commencing CAPD treatment in the time period selected for inclusion, 51 had enough data to be included in this study. Of these, 29 patients experienced one or more episodes of successfully treated peritonitis. The selection of patients was not based upon patient characteristics, but upon criteria to satisfy predefined demands, such as number of measurements in each period, time since an episode of peritonitis, and time on CAPD treatment. Data were analyzed in three different groups: patients with episodes of peritonitis, patients without peritonitis, and both groups together. To assess changes between monthly mean at the start and at the end of CAPD, paired t-test was performed. Patients were also stratified into two groups according to low and high glucose in dialysis fluid at the start of CAPD (cutoff = 2 g/dL). Additionally, we used linear regression analyses to predict the level of drained ultrafiltration volume for a given level and change in glucose concentration. Mean treatment time for the entire group was 20 months (median 14.3 months), ranging from 6 to 69 months. RESULTS: No statistical differences in glucose concentrations were found between the periods compared. In the entire group there was an increase in ultrafiltration volume from the start to the end of CAPD treatment, for both day (p = 0.009) and night (p = 0.013) exchanges. Also, for patients without peritonitis, an increase appeared for day (p = 0.046) and night exchanges (p = 0.053). However, for the cohort with peritonitis, only an insignificant increase was indicated. Patient characteristics, diabetic patients, the need for glucose in dialysis fluid when commencing CAPD treatment, the number of episodes of peritonitis, and time on CAPD did not influence the change in ultrafiltration. Regression analyses showed higher ultrafiltration response to a given level and change in glucose concentration at the end of CAPD treatment compared to the start values, also for the cohort with peritonitis. The regression coefficient between these variables was also significantly changed for both day (p < 0.0001) and night (p = 0.027) exchanges. CONCLUSION: A significant change in the regression coefficient between glucose in dialysis fluid and ultrafiltration volume reflects an increase in ultrafiltration response to a given level and change in glucose concentration during time on CAPD treatment. A parallel change after 5- and 9-hour dwells can be explained by a decrease in peritoneal surface area combined with a lesser decrease in peritoneal conductivity. However, changes in Starling forces across the peritoneal membrane are possible even in the absence of changes in peritoneal membrane characteristics.