Genetic evidence for involvement of adaptive immunity in the development of IgA nephropathy: MHC class II alleles are protective in a Caucasian population.

There is evidence suggesting that IgA nephropathy (IgAN) is an immunological disease. The role of HLA class II DR beta 1 (DRB1) has previously not been well studied. The aim of our study was to investigate the association of HLA-DRB1 variants with IgAN in a Swedish Caucasian cohort. Our study consisted of 213 patients with biopsy proven IgAN, all of self-reported Caucasian ancestry. As a control cohort, 1569 healthy subjects from the same population in Sweden were included. HLA-DRB1 low-resolution genotyping was performed and odds ratios were calculated to assess the risk. In an allelic model the HLA-DRB1(*)03 and (*)10, demonstrated association for IgAN after correction for multiple comparison, with subsequent OR=0.54 (95% CI 0.37-0.78) and 3.44 (95% CI 1.67-7.07). When the influence of risk allelic groups was adjusted for protective allelic groups and vice versa, only a protective effect of HLA-DRB1(*)03 remained significant. In conclusion, the variants of HLA-DRB1 were associated with IgAN of which the HLA-DRB1(*)03 revealed a strong protective effect for IgAN. Our data replicates finding from other Caucasian populations and suggest that involvement of adaptive immunity may be of importance in the development of the disease.

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.

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.

Genetic variation in the transforming growth factor-beta1 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

Incidence of end-stage renal disease among live kidney donors.

BACKGROUND: The increasing use of living kidney donors requires knowledge about long-term effects, especially number and causes of donors with end-stage renal disease (ESRD). METHODS: A retrospective data analysis of 1,112 consecutive living kidney donors who underwent nephrectomy from 1965 until 2005 at Sahlgrenska University Hospital. Case reports were sought with help from nephrologists in the region and data from Swedish Registry of Active Uremic Treatment (SRAU). RESULTS: The number of cases with end stage kidney failure among living kidney donors was 6/1112, that is 0.5%. The donors had reached ESRD during the years 2001-2006, that means 36-41 years after start of the living donor program. The donors were 45-89 years old, median 77 years, and five of six were males. Time since donation was 14-27 years, median 20 years, for the donors developing ESRD. The diagnoses were nephrosclerosis (4 cases), postrenal failure (1 case), and renal carcinoma (1 case). The expected incidence for development of ESRD according to incidence in the general population would have been two donors but we found six. However, considering the high age of the donors in this follow up, the age-matched incidence is calculated to be closer to six donors due to higher incidence in the aged. CONCLUSION: In all 0.5% of the donors developed ESRD. Due to high age of the uremic donors, there seems to be no increased incidence.

Macrovascular disease after simultaneous pancreas and kidney transplantation.

The objective of this study was to evaluate the outcome of simultaneous pancreas and kidney transplantation (SPK) with focus on cardiovascular mortality and morbidity in relation to graft function. From January 1985 through 1999, 87 SPK were performed in the unit. Sixty recipients were males, median age at diabetes onset 13 yr (1-40) and age at transplantation 39 yr (29-54). No case was lost to follow-up. Morbidity and mortality during median 8 yr of follow-up (range 1-15 yr) were recorded. Major macrovascular disease (MVD) was defined as myocardial infarction or sudden death (AMI), stroke or peripheral gangrene requiring amputation of leg, foot or fingers. At the evaluation, 26 of 87 patients (30%) had died, 19 after loss of the pancreas graft and 20 after loss of the kidney. MVD was the dominant cause of death. Non-lethal MVD had previously been recorded in 62%. Of the 61 patients alive, 22 had lost their pancreas graft and 12 the concomitant kidney. MVD had occurred in 32%. Whereas 89% of the concomitant kidneys functioned when the pancreas graft did so, only 37% of the kidneys functioned if the pancreas had been lost, p < 0.0001. The mortality rate was significantly higher among patients who lost both grafts (16/26) than in those who lost only the pancreas graft (3/15), p = 0.01. Progressive MVD is a major clinical problem for SPK transplant patients, particularly if the kidney fails.

Impaired kidney graft survival is associated with the TNF-alpha genotype.

BACKGROUND: The TNF2 allele at position -308 of the tumor necrosis factor (TNF)-alpha gene is associated with high TNF production. The purpose was to study the association of this gene polymorphism with rejection episodes and graft survival after kidney transplantation. METHODS: A retrospective analysis of transplant outcomes of patients who only had been treated with one single form of immunosuppression consisting of cyclosporine, azathioprine, and prednisolon was performed. RESULTS: We found that 115 (73%) patients had the TNF1/TNF1 genotype, whereas 42 (27%) were TNF2 positive. There was no difference in the overall acute rejection frequency between these two groups (50% in each), but our data showed a non-significant tendency towards a higher frequency of steroid resistant rejections in the TNF2 positive group (57% vs. 40%). There was no significant difference in graft survival between the two genotype groups, although an early tendency towards worse survival was seen in TNF2 recipients. However, the TNF2 positive recipients with rejection episodes had far worse graft survival compared with the TNF1/TNF1 recipients with rejection episodes (P<0.02). No difference was seen between the two genotype groups in patients without rejection episodes. CONCLUSION: Our data propose that potentially high TNF producers with the TNF2 allele do not have an increased risk for rejection episodes, but if rejection episodes occur, they have a significantly increased risk for early graft loss. TNF production may intensify rejection, but is not a primary factor for the induction of such acute immune activation.

Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients.

Sirolimus and cyclosporine (CsA) prevent acute rejection in man when used as primary therapies in triple drug regimens. Sirolimus does not act via the calcineurin pathway and therefore is not expected to produce the same renal side-effects. This paper presents the pooled 2-year data analysis of renal function parameters from two open-label, randomized, multicenter studies. Patients (18-68 years) receiving a primary renal allograft were randomized to receive concentration-controlled sirolimus (n = 81) or CsA (n = 80), in combination with azathioprine and steroids (n = 83), or mycophenolate mofetil (MMF) and steroids (n = 78). From week 10 through year 2, calculated glomerular filtration rate (GFR) was significantly higher in sirolimus--than in CsA-treated patients (69.3 vs. 56.8 mL/min, at 2 years, p = 0.004). Serum uric acid was significantly higher in the CsA-treated patients and magnesium was significantly lower; these parameters were more likely to be within normal limits in the sirolimus group. Mean serum potassium and phosphorus were lower in sirolimus-treated patients. In conclusion, sirolimus, when administered as primary therapy in combination with azathioprine or MMF, has a favorable safety profile compared to CsA with regards to renal function.