Anders Fernström

Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy

The Fc-α receptor (FcαR/CD89) is involved in IgA complex formation and may affect the development of IgA nephropathy (IgAN). In this study, we tested the genetic variations of the CD89 gene in relation to disease susceptibility in IgAN and the expression of soluble CD89 (sCD89) in sera of patients with IgAN and in controls. There was a significant difference between the levels of sCD89-IgA complexes, measured by sandwich enzyme-linked immunosorbent assay (ELISA), in 177 patients with IgAN with and without disease progression at the time of first diagnosis. No such difference was found in 42 patients with other renal diseases. The patients with IgAN without disease progression had stable but high levels of sCD89 over 5-15 years of follow-up in contrast to stable but low levels of sCD89 in the disease progression group. Moreover, levels of sCD89 complexes were correlated with one of the five CD89 genetic variants in 212 patients with IgAN and 477 healthy Caucasians; the single-nucleotide polymorphism (SNP) rs11084377 was significantly associated with a lower expression of sCD89. However, no association between CD89 gene polymorphisms and susceptibility to IgAN was detected. Thus, we found an association between the levels of sCD89-IgA complexes in serum and the severity of IgAN, and a possible genetic component in regulating the production or expression of sCD89.

New treatment for IgA nephropathy: enteric budesonide targeted to the ileocecal region ameliorates proteinuria

BACKGROUND Systemic corticosteroid treatment has been shown to exert some protection against renal deterioration in IgA nephropathy (IgAN) but is not commonly recommended for long-term use due to the well-known systemic side effects. In this study, we investigated the efficacy and safety of a new enteric formulation of the locally acting glucocorticoid budesonide (Nefecon®), designed to release the active compound in the ileocecal region. The primary objective was to evaluate the efficacy of targeted release budesonide on albuminuria. METHODS Budesonide 8 mg/day was given to 16 patients with IgAN for 6 months, followed by a 3-month follow-up period. The efficacy was measured as change in 24-h urine albumin excretion, serum creatinine and estimated glomerular filtration rate (eGFR). RESULTS The median relative reduction in urinary albumin excretion was 23% during the treatment period (interquartile range: -0.36 to -0.04, P = 0.04) with pretreatment values ranging from 0.3 to 6 g/24 h (median: 1.5 g/24 h). The median reduction in urine albumin peaked at 40% (interquartile range: -0.58 to -0.15) 2 months after treatment discontinuation. Serum creatinine was reduced by 6% (interquartile range: -0.12 to -0.02; P = 0.003), and eGFR [Modification of Diet in Renal Disease (MDRD)] increased ∼8% (interquartile range: 0.02-0.16, P = 0.003) during treatment. No major corticosteroid-related side effects were observed. CONCLUSIONS In the present pilot study, enteric budesonide targeted to the ileocecal region had a significant effect on urine albumin excretion, accompanied by a minor reduction of serum creatinine and a modest increase of eGFR calculated by the MDRD equation, while eGFR calculated from Cockcroft-Gault equation and cystatin C was not changed. Enteric budesonide may represent a new treatment of IgAN warranting further investigation.

Genetic variation in the transforming growth factor-β1 gene is associated with susceptibility to IgA nephropathy

Background. There is growing evidence of genetic risk for susceptibility to IgA nephropathy. Among several candidate genes related to immunological regulation in renal tissue, TGFB1 is known to be a contributor to proliferation and the development of fibrosis. Methods. We analysed several SNPs in a region of this gene using 212 DNA samples from biopsy-proven IgA nephropathy patients, 146 men and 66 women and 477 healthy age-matched controls (321 men and 156 women) from the same population in Sweden. Results. Frequencies of four out of five selected SNPs (rs6957, rs2241715, rs1800471, rs1982073 and rs1800469) were found to significantly differ between male patients and male controls in a co-dominant model (corrected P ≤ 0.05) and of two SNPs (rs1982073 and rs1800469) in the allelic model (P ≤ 0.05 in 100 000 permutation test). Haplotype analysis for five selected SNPs revealed a significant association of TGGCG with protective effect (P = 0.0012, empirical P = 0.006, 100 000 permutations) and of CTGTA with susceptibility effect (P = 0.0018, empirical P = 0.008, 100 000 permutations). In our study, no association with TGFB1 variations was found when comparing female patients and female controls. No association was found for TGFB1 markers with disease progression for selected individuals from the patients group. In addition, meta-analysis performed for SNP rs1982073 for combined patients and controls from our study together with published data from two independent studies showed a significant association. Conclusions. Our experimental data together with the meta-analysis suggest TGFB1 as an important candidate gene for further biological studies of IgA nephropathy and as a possible target for therapy. Our data also indicate a possibility of a gender effect in the genetic background of IgA nephropathy.

Clinical significance of bone alkaline phosphatase isoforms, including the novel B1x isoform, in mild to moderate chronic kidney disease

BACKGROUND Mineral bone disorder (MBD) is a common complication of chronic kidney disease (CKD) even during the early stages. Bone alkaline phosphatase (BALP) is a marker of bone formation and plays a pivotal role in the mineralization process. Three BALP isoforms (B/I, B1 and B2) have been identified in healthy individuals and a fourth isoform (B1x) has been discovered in serum from dialysis patients. We investigated these BALP isoforms, type I procollagen intact amino-terminal propeptide (PINP), carboxy-terminal telopeptide of type I collagen (CTX) and tartrate-resistant acid phosphatase isoform 5b (TRACP5b), as well as bone mineral density (BMD) in predialysis CKD patients. METHODS PINP, CTX, TRACP5b and BALP isoforms were analysed in serum from 46 patients within CKD stages 3-5. BMD was determined by dual-energy x-ray absorptiometry. RESULTS PINP, TRACP5b and the BALP isoforms, B/I, B1 and B2, were independent predictors of total hip BMD in all patients. Furthermore, B/I predicted osteopaenia in the hip and in the distal 1/3 of the radius in CKD stage 3. The B1x isoform was detected in nine patients (20%), who had lower GFR, higher phosphate and calcium x phosphate product. CONCLUSION We found an association of BALP isoforms and other markers of bone turnover with total hip BMD, which predominantly comprises trabecular bone. The association of the new BALP isoform B1x with risk factors for vascular calcification leads us to hypothesize a possible role for B1x in this process. The significance of the BALP isoforms in CKD remains to be further explored in experimental and clinical settings in conjunction with bone histomorphometry.

Genetic Risk Factors in Lupus Nephritis and IgA Nephropathy – No Support of an Overlap

Background IgA nephropathy (IgAN) and nephritis in Systemic Lupus Erythematosus (SLE) are two common forms of glomerulonephritis in which genetic findings are of importance for disease development. We have recently reported an association of IgAN with variants of TGFB1. In several autoimmune diseases, particularly in SLE, IRF5, STAT4 genes and TRAF1-C5 locus have been shown to be important candidate genes. The aim of this study was to compare genetic variants from the TGFB1, IRF5, STAT4 genes and TRAF1-C5 locus with susceptibility to IgAN and lupus nephritis in two Swedish cohorts. Patients and Methods We genotyped 13 single nucleotide polymorphisms (SNPs) in four genetic loci in 1252 DNA samples from patients with biopsy proven IgAN or with SLE (with and without nephritis) and healthy age- and sex-matched controls from the same population in Sweden. Results Genotype and allelic frequencies for SNPs from selected genes did not differ significantly between lupus nephritis patients and SLE patients without nephritis. In addition, haplotype analysis for seven selected SNPs did not reveal a difference for the SLE patient groups with and without nephritis. Moreover, none of these SPNs showed a significant difference between IgAN patients and healthy controls. IRF5 and STAT4 variants remained significantly different between SLE cases and healthy controls. In addition, the data did not show an association of TRAF1-C5 polymorphism with susceptibility to SLE in this Swedish population. Conclusion Our data do not support an overlap in genetic susceptibility between patients with IgAN or SLE and reveal no specific importance of SLE associated SNPs for the presence of lupus nephritis.

Optical Online Monitoring of Uric Acid Removal during Dialysis

This study estimates the total removal of uric acid (TRUA) by online UV absorbance measurements in the spent dialysate in two different dialysis centers in Estonia and Sweden. Sixteen dialysis patients were included. All dialysate was collected that gave the reference for TRUA. Two regression models were investigated: one for each patient (UV1) and one for the entire material (UV2). TRUA from the three methods was in the same order but showed a statistically significant difference when the UV2 model was built on data from both centers together. TRUA, (n = 56) was (mean ± SD, µmol): 5,854 ± 1,377 for reference, 6,117 ± 1,795 for UV1 and 5,762 ± 1,591 for UV2. Six patients were monitored 1 year after the first study session, using the same models as the previous year, still having a nonsignificant difference. The results show the possibility of estimating TRUA by using UV absorbance. The method appeared to be reliable also in long-term patient monitoring.

Evaluation of an individual sleep intervention programme in people undergoing peritoneal dialysis treatment

AIMS AND OBJECTIVES This study aimed to evaluate effects of a non-pharmacological intervention on sleep, activity and fatigue in patients receiving peritoneal dialysis by the use of both actigraphy registration and self-assessed questionnaires. BACKGROUND Insomnia is estimated to affect up to 60% of haemo- and peritoneal dialysis patients. It is associated with two common uremic symptoms, pruritus and restless legs syndrome. To our knowledge, no interventions have been evaluated by actigraphy. DESIGN A prospective multiple baseline single-case experimental design. METHODS Two women and seven men with sleep problems, 48-77 years, treated with PD participated in a 17-week study from January 2009 to February 2011. Two interventions were separately implemented. First, a pressure-relieving mattress and second, a four week individual sleep hygiene and sleep scheduling intervention. The two interventions were evaluated both objectively by actigraphy and subjectively by questionnaires. RESULTS A total of 315 sleep-wake cycles from nine individuals were evaluated. Three patients improved clinically significantly in five or more of the nine outcomes, i.e. sleep onset latency, nocturnal sleep duration, numbers and duration of napping, movement and fragmentation index, number of steps, metabolic equivalent unit, sleep efficiency and fatigue. The other six patients also showed improvements but to a lesser degree. Physical activity advice was the intervention that yielded most sleep improvements. CONCLUSIONS This study illuminates the need for regular assessment of sleep and tiredness. It also demonstrates how a non-pharmacological treatment and self-management can be applied with renal supportive care to improve sleep quality. RELEVANCE TO CLINICAL PRACTICE This study is a clinical example of a non-pharmacological intervention with supportive care and self-management. This model can improve health and reduce the pharmacological burden because hypnotics can be replaced by sleep hygiene self-care activities.

Determinants of Fibroblast Growth Factor-23 and Parathyroid Hormone Variability in Dialysis Patients

Background/Aims: Treatment strategies for abnormal mineral metabolism in chronic kidney disease are largely based on achieving target ranges of biomarkers that vary considerably over time, yet determinants of their variability are poorly defined. Methods: Observational study including 162 patients of three dialysis cohorts (peritoneal dialysis, n = 78; hemodialysis, n = 49; hemodiafiltration, n = 35). Clinical and biochemical determinants of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) variability were analyzed in the peritoneal dialysis cohort. All cohorts were used for comparison of PTH and FGF23 intra-subject variability (intra-class correlation), and their intra-subject variability in different modes of dialysis was explored. Results: High PTH variability was independently associated with lower 25-hydroxyvitamin D concentration and factors of lipid and glucose metabolism, whereas high FGF23 variability was mainly associated with lower baseline serum phosphorous. These results were consistent in multivariate and sensitivity analyses. The intra-subject variability of FGF23 was lower than for PTH irrespective of dialysis mode. Conclusions: Baseline vitamin D status and serum phosphorous are independent determinants of the longitudinal variation in PTH and FGF23, respectively. The clinical utility of FGF23 measurement remains unknown, yet it appears favorable based on its greater temporal stability than PTH in dialysis patients.

Utilization of UV Absorbance for Estimation of Phosphate Elimination during Hemodiafiltration

Background: Phosphate is an important factor in explaining the high progress of vascular calcification among dialysis patients. Today, phosphate concentration is measured in plasma on a regular basis. The aim of this study was to find out if it is possible to estimate total removed phosphate (TRp) in spent dialysate utilizing UV absorbance during hemodiafiltration. Methods: Eleven patients were monitored online with UV absorbance at 297 nm, three times during one week each (n = 33). Dialysate samples were taken at different times during treatment and from a collection tank to chemically determine phosphate concentrations. Two mathematical models (UVIND and UVGROUP) were tested to estimate TRp with supervision by UV absorbance and compared with TRp measured in the tank (reference). Results: High correlation between UV absorbance and phosphate concentration for each single patient and lower for the whole group together was found. TRp was (mean ± SD) 30.7 ± 7.3 mmol for the reference and 30.8 ± 8.2 and 29.1 ± 5.2 mmol for UVIND and UVGROUP, respectively (p > 0.05). Conclusion: This study demonstrates a novel possibility to estimate TRp based on linear relationship between online monitoring of UV absorbance and concentration of phosphate in spent dialysate.

In the backwater of convective dialysis : decreased 25-hydroxyvitamin D levels following the switch to online hemodiafiltration.

BACKGROUND/AIMS Vitamin D deficiency and elevated serum fibroblast growth factor-23 (FGF23) levels are hallmark features and surrogate markers of adverse clinical outcomes in patients with chronic kidney disease (CKD). Convection of molecules over the dialysis membrane during online hemodiafiltration (ol-HDF) increases the removal of larger waste molecules compared with traditional high-flux hemodialysis (HD). The primary aim of this study was to explore the long-term impact of ol-HDF on serum 25(OH)D and FGF23. METHOD An observational, prospective, noncomparator study including 35 patients who were switched from HD to ol-HDF. Serum 25(OH)D and FGF23 were measured at baseline (i.e., time of switch to ol-HDF) and at 6, 12, and 24 months. RESULTS At follow-up time points, there was a significant reduction in serum 25(OH)D compared with baseline (p<0.0001) whereas FGF23 was unaltered (p>0.05). The decrease in 25(OH)D was more prominent in individuals with higher baseline 25(OH)D levels. CONCLUSION Ol-HDF may lower systemic 25(OH)D levels by convective mechanisms although the clinical significance remains unknown. Further controlled studies are warranted to replicate these findings in larger patient cohorts.