Refinement of the critical region for MCKD1 by detection of transcontinental haplotype sharing

BACKGROUND: Autosomal-dominant medullary cystic kidney disease type 1 (MCKD1) [OMIM 174000] is a hereditary nephropathy that leads to renal salt wasting and end-stage renal failure at a median age of 62 years. In a Welsh MCKD1 kindred we have recently demonstrated linkage to the MCKD1 locus on chromosome 1q23.1 and refined the critical MCKD1 region to <3.3 Mb. METHODS: In order to refine the candidate gene region for MCKD1, high-resolution haplotype analysis in three large kindreds with MCKD1 was performed. RESULTS: We report here on high-resolution haplotype analysis in this Welsh kindred, as well as in the Arizona kindred, which was used for the first definition of MCKD as a disease entity, and in a kindred from the Dutch/German border. We detected extensive haplotype sharing among all affected individuals of all three kindreds. Scrutinization of the genealogy of the Arizona kindred revealed an origin from Germany in the 17th century, thereby providing historical data for haplotype sharing by descent at the MCKD1 locus. CONCLUSION: Under the hypothesis of haplotype sharing by descent, we refined the critical genetic interval to <650 kb, thus enabling candidate gene analysis.     

Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and an important cause of ESRD. Familial clustering of cases suggests genetic predisposition to this disease. Two recent genome-wide studies in IgAN have identified a major susceptibility locus on chromosome 6q22 (IGAN1) and two additional loci with suggestive linkage signals on chromosomes 4q26-31 and 17q12-22. A large four-generation family with 14 affected individuals has been clinically ascertained and excluded from linkage to these loci. A genome-wide linkage scan was performed on this family with GeneChip Mapping 10K 2.0 Arrays using an "affected-only" strategy. By nonparametric analysis, two regions of suggestive linkage (multipoint logarithm of odds [LOD] scores >2) were identified on chromosomes 2q36 and 13p12.3. By parametric analysis (assuming an autosomal dominant inheritance, a disease allele frequency of 0.001, phenocopy rate of 0.01, and penetrance of 75%), a significant linkage to chromosome 2q36 (maximum multipoint LOD score 3.47) was found. Nine simple sequence repeat markers then were genotyped in 21 members (included all of the affected individuals), and significant linkage to chromosome 2q36 over a region of 12.2 cM (maximum multipoint LOD score 3.46) was confirmed. Recombination events in two affected individuals, as detected by haplotype analysis, delineated a critical interval of approximately 9 cM (equivalent to approximately 7 Mb) between D2S1323 and D2S362. Taken together, these data provide strong evidence for a novel disease susceptibility locus for familial IgAN.     

Familial vesicoureteral reflux: testing replication of linkage in seven new multigenerational kindreds

Vesicoureteral reflux (VUR) (OMIM %193000), a common cause of childhood renal failure, is strongly influenced by hereditary factors. Familial VUR most closely conforms to autosomal-dominant inheritance, but because of variable penetrance and expressivity, large multigenerational pedigrees tractable to linkage analysis have been difficult to ascertain. A single genome-wide study of familial VUR has demonstrated linkage to chromosome 1p13, with 78% locus heterogeneity. Previous studies in humans have also suggested loci on chromosomes 6p21, 10q26, and 19q13, whereas mutations in ROBO2 were recently reported in some patients with VUR. Replication of these studies was attempted in seven previously undescribed families from Italy and the United States. Simulation studies, assuming 50% locus heterogeneity, showed that these kindreds had 85% power to replicate linkage and 53% power to achieve genome-wide significance at candidate intervals. Thirty-five markers on chromosomes 1p13, 3p12, 6p21, 10q26, and 19q13 were genotyped and analysis of linkage under a variety of models was performed. Parametric analysis excluded linkage to all candidate loci under genetic homogeneity; moreover, the data did not support statistically significant linkage under models of locus heterogeneity. Similarly, nonparametric, allele-sharing analysis did not reveal any evidence of linkage at any of the loci tested. Thus, despite sufficient power, linkage of familial VUR to previously reported candidate intervals could not be replicated. These data demonstrate substantial genetic heterogeneity of VUR and suggest that mapping strategies relying on a large number of kindreds or single "loaded" pedigrees will be most effective to achieve replication or detection of linkage.     

IgA肾病合并肾小球基底膜弥漫性变薄的临床特点及COL4A3/COL4A4的基因连锁分析

目的 对IgA肾病合并肾小球基底膜弥漫性变薄(TGBM-IgAN)患者的临床病理情况进行系统研究；并在TGBM-IgAN患者的家系中，初步探讨同薄基底膜肾病(TGBMD)相关基因COL4A3/COL4A4的关系。方法 根据透射电镜下GBM的厚度，以GBM的平均厚度小于250 nm及GBM变薄的范围至少达到50%为诊断GBM变薄的标准，明确GBM弥漫性变薄在散发性IgA肾病患者及肾脏病家族史阳性的患者中所占的比例。将234例IgA肾病患者分成合并GBM弥漫性变薄组(n=30)及正常GBM厚度组(n=204)，比较两组患者的临床和病理特点。应用2号染色体长臂分别与COL4A3/COL4A4基因连锁的微卫星体PAX3及HaeⅢ-酶切限制性多态性片段(RFLP)位点作为多态性遗传标记，对其中3个TGBM-IgAN的家系进行COL4A3/COL4A4基因连锁分析。结果 本研究中IgA肾病GBM正常厚度为(352.43±32.11) nm，TGBM-IgAN的GBM厚度为(205.56±23.48) nm。(1)在家族性IgA肾病患者中，TGBM-IgAN患者所占比例为31.8%(21/66)，明显高于其在散发性IgA肾病中所占比例11%(24/219)；(2)30例TGBM-IgAN患者临床特点:女性为主(20/30)，合并肾脏病家族史比例高，均有血尿，尿蛋白量少，预后较好；(3)3个TGBM-IgAN家系中，2个家系与COL4A3/COL4A4的连锁分析提示与COL4A3/COL4A4基因连锁，LOD值为1.53(θ=0)。结论 家族性TGBM-IgAN明显高于散发性患者，合并GBM弥漫变薄的呈家族聚集性发病的IgA肾病患者家系可能为薄基底膜肾病家系，建议在家族性IgA肾病的定义中应强调电镜下GBM形态和厚度的观察。     

Telomeric refinement of the MCKD1 locus on chromosome 1q21

BACKGROUND: Autosomal-dominant medullary cystic kidney disease type 1 (MCKD1) is a tubulointerstitial nephropathy that causes renal salt wasting and end-stage renal failure in the sixth decade of life. The chromosomal locus for MCKD1 was localized to chromosome 1q21 in a Cyprotic kindred. In this report we describe further refinement of the critical genetic region by a recombination in a Belgian kindred. METHODS: Clinical data and blood samples of 33 individuals from a large Belgian kindred were collected and high-resolution haplotype analysis was performed. RESULTS: In the Belgian kindred linkage to the MCKD1 locus on chromosome 1q21 was found with a logarithm of odds (LOD) score significant for linkage. A recombination in individual III:7 for marker D1S2624 refines the critical genetic region to 2.1 Mb. In this kindred a wide variety of clinical symptoms and age of onset of renal failure was detected. CONCLUSION: We confirm the MCKD1 locus on chromosome 1q21 and show further refinement of the MCKD1 locus to 2.1 Mb. This allowed us to exclude another 17 genes as positional candidate genes.     

Persistent dipstick haematuria following renal transplantation

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.     

Familial ureteral abnormalities syndrome: genomic mapping, clinical findings

Abnormal development of the ureter during embryogenesis, when occurring in multiple family members, appears to be a genetically determined defect with autosomal dominant inheritance and high penetrance, which can lead to significant kidney damage, renal failure, and death. We have studied 48 individuals within a large kindred in which ureteral-related abnormalities (including vesicoureteral reflux, ureteropelvic junction obstruction, duplicated ureters, and medullary sponge kidney) were segregated. Family members who had not had previous diagnostic studies were evaluated for presence or absence of ureteral abnormalities and we attempted to map the locus for this familial ureteral abnormalities syndrome (FUAS). These studies identified 11 asymptomatic individuals, previously assumed to be unaffected, with minor abnormalities. When linkage analysis between the inheritance of ureteral abnormalities and six marker loci glyoxalase I (GLO-1), major histocompatibility antigens (HLA-A, B, and DR/DQ), D6S288, and factor XIII antigen (F13A1) on the short arm of chromosome 6 was performed, the lod scores significantly rejected linkage over a 77.1-cM distance. These findings are in contrast to previous data suggesting linkage between the presence of ureteral abnormalities and HLA, and indicate the possibility of genetic heterogeneity of FUAS. Received April 29, 1997; received in revised form September 15, 1997; accepted September 22, 1997     

家族性局灶节段性肾小球硬化一家系相关基因连锁分析

目的 对1个家族性局灶节段性肾小球硬化（FFSGS）家系的临床表型进行连锁分析,并对国内外已知的4个基因进行排除性定位。 方法 调查该家系成员的临床资料。应用两点连锁分析方法,在已知的FFSGS遗传的相关基因WT1、TRPC6、CD2AP、NPHS2所在染色体区域,选取9个微卫星遗传标记（STR）进行连锁分析。 结果 该FFSGS家系的遗传方式为常染色体显性遗传。19名家系成员中1例已进展至终末期肾病（ESRD）;4例尿检异常成员中2例病理明确诊断为FSGS;Ⅲ9和Ⅲ15患者发病年龄较早,分别为10岁和13岁;第Ⅰ和第Ⅱ代的患者均为25岁以后发病。用D1S196、D1S218、D1S238、11S935、D11S898、D11S908、D11S1986、D6S936、D6S1566等9个STR对该家系进行NPHS2、CD2AP、TRPC6和WT1基因的两点连锁分析,测得各个标记位点在重组率θ=0时,最大优势对数（LOD） 值为0.32 (D11S1986),不支持连锁。 结论 该FFSGS家系遗传方式为常染色体显性遗传。已知基因NPHS2、WT1、TRPC6、CD2AP不是该家系的致病基因。     

一个中国汉族家族性IgA肾病家系致病基因的排除性定位

目的 对一个中国汉族家族性IgA肾病（FIgAN）家系进行遗传连锁分析,并对目前国内外已知的5个致病位点进行排除性定位,从而初步定位该家系致病基因的染色体位点。 方法 判断FIgAN的遗传方式。采集家系成员外周血提取基因组DNA。在已报道的FIgAN致病区域（2q36、3p23-24、4q26-31、6q22-23、17q12-22）选取微卫星遗传标记（STR）,进行基因组扫描,应用两点间连锁分析方法对基因分型数据进行分析。结果 该FIgAN家系的遗传方式为常染色体显性遗传。对该家系5个已知致病区域内计26个STR的两点间连锁分析结果显示,最大优势对数（LOD）值为0.39（D17S1868）,不支持与上述5个染色体区域的连锁关系。 结论 该家系致病基因所在染色体区域非目前已报道的5个FIgAN致病位点,提示FIgAN存在新的致病区域,并进一步证明了该病的遗传异质性。     

Localization of susceptibility to familial idiopathic scoliosis

STUDY DESIGN: Genome-wide linkage surveys in large multiplex families with apparent inherited idiopathic scoliosis. OBJECTIVE: To identify chromosomal loci encoding genes involved in susceptibility to idiopathic scoliosis by positional cloning. SUMMARY OF BACKGROUND DATA: Although the inheritance of idiopathic scoliosis most often exhibits a complex pattern, autosomal dominant inheritance can be identified in some families. Families exhibiting such an inheritance pattern present an opportunity to identify the predisposing gene(s) by positional cloning. METHODS: Probands having clinically relevant idiopathic scoliosis (50 degrees Cobb angle) from large multiplex families were identified. A curve of 15 degrees, made from standing posteroanterior radiographs, was required for a positive diagnosis. A genome-wide search in one large family (seven affected members) was conducted with 385 polymorphic microsatellite markers spaced at an approximate 10-cM resolution. Hot spots identified in this family were subsequently tested in a second large kindred. RESULTS: Maximum evidence of allele-sharing in affected individuals from the first family was detected for three loci on chromosomes 6p, distal 10q, and 18q with nonparametric lod scores of 1.42 (P = 0.020), 1.60 (P = 0.019), and 8.26 (P = 0.002), respectively. Evidence of allele-sharing was also detected in the second family at distal chromosome 10q (nonparametric lod score = 2.02; P = 0.033). CONCLUSIONS: These data indicate a limited number of genetic loci predisposing to idiopathic scoliosis.     

Familial Paget's disease of bone: patterns of inheritance and frequency of linkage to chromosome 18q

Paget’s disease of bone is a common disorder characterized by focal abnormalities of bone turnover which are associated with bone pain bone deformity and an increased risk of pathological fracture. Genetic factors play an important role in the pathogenesis of Paget’s disease, and recent genetic linkage studies have shown that in some families the disease is linked to a candidate locus on chromosome 18q21-22, which also harbors the gene for the related inherited condition, familial expansile osteolysis. In this study we characterized the patterns of inheritance in a series of 269 individuals from a further 50 kindreds with familial Paget’s disease and sought to determine how frequently the disease was linked to chromosome 18q. Segregation analysis showed that 54% of individuals had developed Paget’s disease by the age of 55, with an equal distribution in men in women, consistent with an autosomal dominant mode of inheritance with high penetrance. In families where parental data were available, there was no difference in the frequency of disease transmission between paternal or maternal sources. Linkage studies with nine polymorphic markers spread across the candidate region did not support linkage to 18q under models of homogeneity or heterogeneity. Indeed, the summated multipoint lodscores were consistently below −2.0 across the region, providing strong evidence against linkage. These studies confirm the presence of genetic heterogeneity in familial Paget’s disease but show that linkage of the disease to the previously identified candidate locus on chromosome 18q21-22 is relatively uncommon.     

HLA Has Strongest Association with IgA Nephropathy in Genome-Wide Analysis

Demographic and family studies support the existence of a genetic contribution to the pathogenesis of IgA nephropathy, but results from genetic association studies of candidate genes are inconsistent. To systematically survey common genetic variation in this disease, we performed a genome-wide analysis in a cohort of patients with IgA nephropathy selected from the UK Glomerulonephritis DNA Bank. We used two groups of controls: parents of affected individuals and previously genotyped, unaffected, ancestry-matched individuals from the 1958 British Birth Cohort and the UK Blood Service. We genotyped 914 affected or family controls for 318,127 single nucleotide polymorphisms (SNPs). Filtering for low genotype call rates and inferred non-European ancestry left 533 genotyped individuals (187 affected children) for the family-based association analysis and 244 cases and 4980 controls for the case-control analysis. A total of 286,200 SNPs with call rates >95% were available for analysis. Genome-wide analysis showed a strong signal of association on chromosome 6p in the region of the MHC (P = 1 × 10⁻⁹). The two most strongly associated SNPs showed consistent association in both family-based and case-control analyses. HLA imputation analysis showed that the strongest association signal arose from a combination of DQ loci with some support for an independent HLA-B signal. These results suggest that the HLA region contains the strongest common susceptibility alleles that predispose to IgA nephropathy in the European population.IgA nephropathy (IgAN) is the most common form of glomerulonephritis and is an important cause of ESRD. Clinical presentation is usually with hematuria with a variable degree of proteinuria; progression to ESRD occurs in ∼25% of those affected in the 20 years after diagnosis.¹ Pathologically, IgAN is characterized by deposition of polymeric IgA1 in the renal mesangium, accompanied by mesangial hypercellularity, mesangial matrix expansion, and varying degrees of glomerulosclerosis and interstitial fibrosis. The pathogenesis is unclear, and diversity in the clinico-pathologic disease spectrum has suggested etiologic heterogeneity.A number of observations suggest that there is a significant genetic contribution to the pathogenesis of IgAN. These include differences in the prevalence of IgAN across ancestry groups, increased disease prevalence in relatives of affected individuals, and reports of large pedigrees containing multiple affected individuals.² To date, the strongest direct evidence for the existence of genetic factors in the development and/or progression of IgAN has been provided by linkage analyses in such families.^3–5 A major disease locus designated IGAN1 on chromosome 6q22–23 was defined in a study of white families.⁶ However, only 60% of the families in the study were linked to this locus, and, to date, no disease-specific genes associated with disease/susceptibility have been identified within the linkage interval. This locus was excluded by linkage analysis in a Japanese family,⁷ whereas in Italian families, linkage has been reported at two different IgAN loci on 4q26–31 and 17q12–22.⁸ A Canadian family study has localized another IgAN susceptibility locus to chromosome 2q36,⁹ whereas analysis of a large Lebanese kindred did not provide evidence for linkage at 6q22–23, 2q36, or 4q22–31.¹⁰These studies therefore suggested that at least part of the genetic basis of IgAN is specified by variants that are confined to specific families or discrete populations (and therefore might not be fundamental to the disease process as a whole), and it is unclear whether there are common IgAN susceptibility haplotypes that operate across large populations. This led to increasing interest in defining the existence and extent of IgAN susceptibility loci in large populations using genetic association. Most studies conducted to date examined small numbers of candidate genes, although some surveyed candidate genes more extensively¹¹ or conducted limited genome-wide analyses.¹² Although a number of potential associations with polymorphisms at candidate gene loci were reported (reviewed in references ^2,13,14), these associations have not all been reproduced, and there is no systematic genome-wide analysis of susceptibility to IgAN.To evaluate evidence for genetic association with IgAN, we undertook a genome-wide analysis in patients with European ancestry using a panel of ∼300,000 tagging single nucleotide polymorphisms (SNPs), designed to maximize coverage of common human haplotypes based on linkage disequilibrium intervals.¹⁵We performed both family-based and case-control association studies, using cases and nuclear families ascertained from the UK MRC/Kidney Research UK National DNA Bank for Glomerulonephritis and controls from the 1958 British Birth Cohort and the UK National Blood Service. Strong signals of association were observed in the MHC on chromosome 6p but not other loci, indicating that, in the UK population, the MHC contains the strongest common susceptibility alleles for IgAN.     

Autosomal dominant progressive nephropathy with deafness: linkage to a new locus on chromosome 11q24

Focal segmental glomerulosclerosis (FSGS) and Alport syndrome (AS) are two major causes of end-stage renal disease (ESRD). A few families with autosomal dominant FSGS have been reported with linkage to chromosome 19q13 or 11q22, while AS is usually linked to mutations in type IV collagen (COL4) subunit genes. A phenotype resembling AS may also be seen with myosin heavy chain-9 (MYH9) gene mutations. This study ascertained a multigeneration family (CHP-177) with clinical aspects of both FSGS and AS where we identified a new locus for the trait. A genome-wide scan was performed with 400 markers, and fine mapping was performed for chromosome 11 markers. Data were analyzed by GENEHUNTER and VITESSE under various models. CHP-177 is a 39-member kindred residing near New Delhi, India, with seven affecteds and showed male-to-male transmission. Two members had ESRD. Renal biopsies showed both FSGS lesions and thin glomerular basement membranes. Five of the affecteds also had sensorineural deafness, which involved both low and high frequency in some members. The AS loci, i.e., COL4A3/COL4A4 and MYH9 (LOD scores: -6.1 and -4.3, respectively) and FSGS loci, on 19q13 and 11q22, were excluded from linkage. A significant evidence of linkage was observed for 11q24 region, with a multipoint LOD (z-score) of 3.2 for marker D11S4464 at theta = 0. The z-1 confidence interval for the linked region spans a genetic distance of 7 cM. This study thus reports an autosomal dominant nephropathy with features of both FSGS and AS in which linkage to currently known loci for such phenotypes was excluded and a new locus on 11q24 was identified. The findings suggest further locus heterogeneity for the autosomal dominant nephropathy phenotype.     

Clinicopathological features of paediatric renal biopsies in Shanghai over a 31 year period

Aim: To identify the variations in paediatric renal biopsy pathology and clinicopathological features during the past 31 years. Methods: A retrospective analysis of paediatric renal biopsies performed at a single institution in Shanghai from January 1979 to December 2009 was conducted. Results: The major pathologies included minor glomerular abnormalities (MGA, 26.1%), IgA nephropathy (IgAN, 17%) and mesangial proliferative glomerulonephritis (MsPGN) without IgA deposition (11.3%). The major clinical presentations included nephrotic syndrome (NS, 39.4%), haematuria with proteinuria (24.4%) and persistent microscopic haematuria (15.1%). MGA accounted for 46.9% of the cases in NS. IgAN and HSN accounted for 24% and 28.9% of patients with concomitant haematuria and proteinuria, and thin basement membrane nephropathy accounted for 51.2% of cases with persistent microscopic haematuria. The frequency of IgAN (78.6%) was much higher than that of TBMN (29.0%) in patients with persistent microscopic haematuria with abnormal urinary albumin. Conclusion: Minor glomerular abnormalities and IgAN were the major renal diseases in our study population, and the focus of our paediatric nephrologists. The high proportion of TBMN suggested that there should be limited use of renal biopsy for patients with persistent microscopic haematuria and renal biopsy should be performed in the presence of proteinuria or abnormal levels of urinary albumin.     

Linkage of a gene causing familial membranoproliferative glomerulonephritis type III to chromosome 1

Membranoproliferative glomerulonephritis (MPGN) type III is a chronic progressive renal disease of unknown cause. The diagnosis is based on renal pathologic features (specifically immunofluorescence staining patterns and ultrastructural appearance). Mesangial cell proliferation and subendothelial and subepithelial deposits characterize the renal disease. Although the actual prevalence of this disease is not known, the disease is rare and usually sporadic. The clinical features of MPGN include the nephrotic syndrome and hematuria, with renal dysfunction occurring in approximately 50% of patients. Progression to end-stage renal disease is variable, and some patients exhibit stabilization or even improvement. Here is presented an Irish family in which there are eight affected members in four generations, suggesting autosomal dominant inheritance. This is the only reported family with an inherited form of MPGN type III. To evaluate the disease in this family, a genome-wide scan was performed with a panel of 402 polymorphic microsatellite markers, defining a grid with an average resolution of 10 cM (centimorgans). Significant evidence for linkage was observed on chromosome 1q31-32, with a maximal logarithm of the odds score of 3.86 at theta = 0.00 for microsatellite marker GATA135F02. Recombination events among affected individuals, as detected by haplotype analysis, established a 22-cM minimal candidate region flanked by markers D1S3470 and GATA124F08. The data provide evidence for a gene for familial MPGN on chromosome 1q.     

Néphropathie associée à une vascularite urticarienne hypocomplémentémique : présentation d’un cas clinique et revue de la littérature

Hypocomplementemic urticarial vasculitis is a rare systemic vasculitis, affecting small vessels, characterised by chronicle urticaria, hypocomplementemia, and systemic manifestations. Renal involvement, whose prevalence varies between 9% and 60%, is mainly glomerular. We here report the case of a 59 years old woman presenting kidney failure, associated with chronicle urticaria and arthralgias. Laboratory investigation showed haematuria, proteinuria, hypocomplementemia and anti-SSa antibody positivity. A percutaneous kidney biopsy revealed focal and segmental glomerulonephritis associated with an acute interstitial nephritis. Hypocomplementemic urticarial vasculitis diagnosis was established after identifying anti-C1q antibodies. The lack of a dry syndrome, the negativity of a Schirmer test and the lack of sialadenitis on a salivary gland biopsy excluded an associated Gougerot–Sjögren Syndrome. The patient was treated with hydroxychloroquine and low-dose steroids, enabling a clinical and biological recovery. Of the 82 cases in the literature describing hypocomplementemic urticarial vasculitis associated nephropathies, 72 (88%) were a glomerular impairment, most frequently secondary to membranoproliferative glomerulonephritis. Only 6 (7%) tubulo-interstitial nephritis have been reported, 4 of them being associated with a glomerulonephritis. Patients were more likely to be women, aged in their third decade. The most frequent renal manifestations were haematuria (60%), and proteinuria (52%). Kidney failure was rarely observed (22%), with a fairly good renal prognosis. Hypocomplementemic urticarial vasculitis was associated with a systemic disease in 11 (13%) patients. In the absence of recommendations, the treatment strategy remains to be defined.     

Renal transplantation in patients with primary immunoglobulin A nephropathy.

BACKGROUND: Opinions on the clinical course and outcome of renal transplantation in patients with primary immunoglobulin A nephropathy (IgAN) have been controversial. METHODS: We conducted a retrospective single-centre study on 542 kidney transplant recipients over the period 1984-2001. Long-term outcome and factors affecting recurrence in recipients with primary IgAN were analysed. RESULTS: Seventy-five patients (13.8%) had biopsy-proven IgAN as the cause of renal failure, and their mean duration of follow-up after transplantation was 100 +/- 5.8 months. Fourteen (18.7%) of the 75 patients had biopsy-proven recurrent IgAN, diagnosed at 67.7 +/- 11 months after transplantation. The risk of recurrence was not associated with HLA DR4 or B35. Graft failure occurred in five (35.7%) of the 14 patients: three due to IgAN and two due to chronic rejection. Three (4.9%) of the 61 patients without recurrent IgAN had graft failure, all due to chronic rejection. Graft survival was similar between living-related and cadaveric/living-unrelated patients (12-year graft survival, 88 and 72%, respectively, P = 0.616). Renal allograft survival within the first 12 years was better in patients with primary IgAN compared with those with other primary diseases (80 vs 51%, P = 0.001). Thereafter, IgAN patients showed an inferior graft survival (74 vs 97% in non-IgAN patients, P = 0.001). CONCLUSIONS: Our data suggested that around one-fifth of patients with primary IgAN developed recurrence by 5 years after transplantation. Recurrent IgA nephropathy in allografts runs an indolent course with favourable outcome in the first 12 years. However, the contribution of recurrent disease to graft loss becomes more significant on long-term follow up.     

Frequency of renal diseases and clinical indication for renal biopsy in children (Report of the Italian National Registry of Renal Biopsies in Children)

Background. Children's renal biopsy data were gathered for 3 consecutive years (1992-1994) by the Group of Renal Immunopathology of the Italian Society of Pediatric Nephrology, which opened a paediatric section of the Italian Registry of Renal Biopsies. Materials. The Registry recorded the histological diagnosis and the clinical data at renal biopsy of 432 children ⩽15 years old (mean age 8.96±3.7 years). Results. The most common glomerulonephritis (GN) at renal biopsy was idiopathic IgAGN (18.8%) and the most frequent secondary GN was Henoch-Schonlein purpura (HSP) nephritis (11.6%). Minimal-change disease (MCD) accounted for 11.6%, focal and segmental sclerosis (FSG) 8.5%, mesangial proliferative GN (MPGN) 9.5%, membranoproliferative GN 5.5%, and thin-membrane disease 5%. Lupus nephritis was diagnosed in 5% and Alport's GN in 3.9% of the cases. The annual incidence of primary GN in Italian children was 11.1 cases per million children population (p.m.c.p.), IgAN accounting for 3.1 cases, MCD 2.3, and HSP nephritis 1.9 cases p.m.c.p. respectively. Italian children underwent renal biopsy because of isolated microscopic haematuria in 19.3% of the cases, non-nephrotic proteinuria with or without microscopic haematuria in 31.2%, and nephrotic-range proteinuria in 34.2%, less frequently (15.3%) because of acute or chronic renal failure. Children with persistent isolated microscopic haematuria had most frequently IgAN (34.9%) or thin-membrane disease (25.3%), while those with non-nephrotic proteinuria had IgAN (30.4%) and HSP nephritis (23%). In cases with nephrotic proteinuria renal biopsy showed MCD in 34.5% of the cases, FSG in 16.9%, and MPGN in 12.2%. When renal biopsy was performed in chronic renal failure chronic interstitial renal disease was detected in 62.5% of the cases. Conclusions. This National Registry provides data on the indications for performing renal biopsy in Italian children and on the frequency and annual incidence of histological lesions detected. IgAN, primary or related to HSP, was the most common nephritis in Italian children undergoing renal biopsy.     

Human immunodeficiency virus and IgA nephropathy

Summary: IgA nephropathy (IgAN) in human immunodeficiency virus (HIV)-infected patients has been described with increasing frequency. In contrast to HIV-associated nephropathy, with collapsing variant of focal and segmental glomerulosclerosis and prominent tubular cell changes, a disorder which is more common in black persons, IgAN is a disease mainly of white patients. Most are asymptomatic carriers of HIV although few have acquired immunodeficiency syndrome (AIDS) or ARC at the time the renal disorder is discovered. The clinical manifestations are generally of haematuria, sometimes with proteinuria. In some patients, the finding of IgA reactive with anti-HIV IgG or IgM in circulating immune complexes and in glomerular eluates strongly suggests this glomerulopathy to be an HIV-associated immune complex disorder. Because of the demographic factors, IgAN may evolve to be an important renal lesion in HIV infection.