Clinical features and outcomes of renal amyloidosis in Hong Kong.

AIM: Early symptoms of primary (AL) amyloidosis are non-specific. Any delay in diagnosis and treatment results in poor outcome despite increasing treatment options. We aimed to determine baseline risk factors that identify patients with poor kidney outcomes and overall survivals. METHODS: We recruited all patients aged 18 years or above with biopsy-proven renal amyloidosis between years 2000 and 2019 in three Hong Kong regional hospitals. Patients' clinical and pathological parameters, treatment response, kidney outcomes and overall survivals were recorded and analysed. RESULTS: Thirty-six cases of renal amyloidosis were recruited. Four cases were diagnosed to have multiple myeloma. Edema was the most common presenting symptom. The mean estimated glomerular filtration rate (eGFR) was 98.8 ml/min/1.73 m2 at presentation. Autologous stem cell transplant conferred the best renal outcomes as well as patients' survival. Twenty-two patients had 50% decrease in eGFR, 12 patients developed end-stage kidney disease (ESKD) and 22 patients died. Hypertension, diabetes mellitus, proteinuria and low eGFR were identified as independent baseline risk factors for ESKD. Proteinuria, hyperlipidemia, and cardiac involvement were independent baseline risk factors for death. CONCLUSION: Amyloidosis, a rare disease with poor prognosis without treatment. Hypertension, diabetes mellitus, heavy proteinuria and low eGFR at diagnosis were associated with poor kidney outcome.

Relatives in silent kidney disease screening (RISKS) study: A Chinese cohort study.

AIM: Family members of patients with end-stage renal disease (ESRD) have higher risk for chronic kidney disease (CKD). Limited study has examined the risk of developing CKD in relatives of patients in earlier stages of CKD. METHODS: From January 2008 to June 2009, the Hong Kong Society of Nephrology studied first-degree relatives of stage 1-5 CKD patients from 11 local hospitals. A total of 844 relatives of 466 index CKD patients (stages 1-2: 29.6%; stage 3: 16.7%; stage 4: 10.9%; stage 5: 42.7%) were reviewed for various risk factors of CKD. We also defined a composite marker of kidney damage by the presence of one or more following features: (i) positive urine protein, (ii) spot urine protein-to-creatinine ratio ≥0.15 mg/mg, (iii) hypertension and (iv) estimated glomerular filtration rate (eGFR) ≤60 mL/min per 1.73 m2 and determine its association with participant and index patient factors. RESULTS: Among these 844 relatives, 23.1%, 25.9% and 4.4% of them had proteinuria (urine protein ≥1+), haematuria (urine red blood cell ≥1+) and glycosuria (urine glucose ≥1+), respectively. Proteinuria (P = 0.10) or glycosuria (P = 0.43), however, was not associated with stages of CKD of index patients. Smoking participants had a significantly lower eGFR (102.7 vs. 107.1 mL/min per 1.73 m2 ) and a higher prevalence of proteinuria (33.6% vs. 21.4%). Multivariate analysis showed that older age, male gender, obesity, being parents of index patients and being the relatives of a female index patient were independently associated with a positive composite marker. CONCLUSION: First-degree relatives of all stages of CKD are at risk of developing CKD and deserve screening. Parents, the elderly, obese and male relatives were more likely to develop markers of kidney damage.

Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations.

OBJECTIVES: Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility. METHODS: The study involved a total of 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction. RESULTS: Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets. CONCLUSIONS: Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases.

Gene-based meta-analysis of genome-wide association study data identifies independent single-nucleotide polymorphisms in ANXA6 as being associated with systemic lupus erythematosus in Asian populations.

OBJECTIVE: Previous genome-wide association studies (GWAS), which were mainly based on single-variant analysis, have identified many systemic lupus erythematosus (SLE) susceptibility loci. However, the genetic architecture of this complex disease is far from being understood. The aim of this study was to investigate whether using a gene-based analysis may help to identify novel loci, by considering global evidence of association from a gene or a genomic region rather than focusing on evidence for individual variants. METHODS: Based on the results of a meta-analysis of 2 GWAS of SLE conducted in 2 Asian cohorts, we performed an in-depth gene-based analysis followed by replication in a total of 4,626 patients and 7,466 control subjects of Asian ancestry. Differential allelic expression was measured by pyrosequencing. RESULTS: More than one-half of the reported SLE susceptibility loci showed evidence of independent effects, and this finding is important for understanding the mechanisms of association and explaining disease heritability. ANXA6 was detected as a novel SLE susceptibility gene, with several single-nucleotide polymorphisms (SNPs) contributing independently to the association with disease. The risk allele of rs11960458 correlated significantly with increased expression of ANXA6 in peripheral blood mononuclear cells from heterozygous healthy control subjects. Several other associated SNPs may also regulate ANXA6 expression, according to data obtained from public databases. Higher expression of ANXA6 in patients with SLE was also reported previously. CONCLUSION: Our study demonstrated the merit of using gene-based analysis to identify novel susceptibility loci, especially those with independent effects, and also demonstrated the widespread presence of loci with independent effects in SLE susceptibility genes.

Meta-analysis of two Chinese populations identifies an autoimmune disease risk allele in 22q11.21 as associated with systemic lupus erythematosus.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms, ranging from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, detailed information for SLE association and the underlying functional mechanism(s) is still lacking. METHODS: Through meta-analysis of two genome-wide association studies (GWAS) on Han Chinese populations, comprising a total of 1,659 cases and 3,398 controls matched geographically, we closely examined the 22q11.21 region, especially on the reported single-nucleotide polymorphisms (SNPs) associated with different autoimmune diseases and their relationships. We further replicated the most significant associations of SNPs with SLE using 2,612 cases and 2,323 controls of Asian ancestry. RESULTS: All reported SNPs in the 22q11.21 region with different autoimmune diseases were examined using the two GWAS data and meta-analysis results, and supportive evidence of association with SLE was found (meta-analysis: P_meta ≤ 7.27E-05), which might require further investigation. SNP rs2298428 was identified as the most significant SNP associated with SLE in this region (P_meta =2.70E-09). It showed independent effects through both stepwise and conditional logistic regression, and there is no evidence of other independent association signals for SLE in this region. The association of rs2298428 was further replicated in three cohorts from Hong Kong, Anhui and Thailand comprising a total of 2,612 cases and 2,323 controls (joint analysis of GWAS and replication result: P_all =1.31E-11, odds ratio =1.23). SNP rs2298428 was shown to be an expression quantitative locus for UBE2L3 gene in different cell types, with the risk allele (T) being correlated with higher expression of UBE2L3. This is consistent with earlier reports on higher expression of UBE2L3 in patients with SLE. CONCLUSIONS: Association with distinct autoimmune diseases highlights the significance of this region in autoreactive responses and potentially shared functional mechanisms in these diseases.

Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease.

Three SNPs in chromosome 11q23.3 are independently associated with systemic lupus erythematosus in Asians.

Systemic lupus erythematosus (SLE) has a complex etiology and is affected by both genetic and environmental factors. Although more than 40 loci have shown robust association with SLE, the details of these loci, such as the independent contributors and the genes involved, are still unclear. In this study, we performed meta-analysis of two existing genome-wide association studies (GWASs) on Chinese Han populations from Hong Kong and Anhui, China, and followed the findings by further replication on three additional Chinese and Thailand cohorts with a total of 4254 cases and 6262 controls matched geographically and ethnically. We discovered multiple susceptibility variants for SLE in the 11q23.3 region, including variants in/near PHLDB1 (rs11603023, P(_combined) = 1.25E-08, OR = 1.20), DDX6 (rs638893, P(_combined) = 5.19E-07, OR = 1.22) and CXCR5 (rs10892301, P(_combined) = 2.51E-08, OR = 0.85). Genetic contributions from the newly identified variants were all independent of SNP rs4639966, whose association was reported from the previous GWAS. In addition, the three newly identified variants all showed independent association with the disease through modeling by both stepwise and conditional logistic regression. The presence of multiple independent variants in this region emphasizes its role in SLE susceptibility, and also hints the possibility that distinct biological mechanisms might be involved in the disease involving this genomic region.

Relationship between autoantibody clustering and clinical subsets in SLE: cluster and association analyses in Hong Kong Chinese.

OBJECTIVE: This study aims to identify the existence of, and relationship between autoantibody clusters and clinical subsets in Chinese SLE patients. METHODS: Data from 1928 SLE patients from Hong Kong were analysed. Using cluster analysis, patients were grouped by autoantibodies into clusters. The frequencies of various clinical manifestations were then compared between each cluster. Separate association analyses between individual autoantibodies and clinical manifestations as well as between clinical manifestations were also performed without any prior clustering. RESULTS: Three separate autoantibody clusters were identified, each with significantly different clinical manifestations. Cluster 1 was characterized by anti-dsDNA and the greatest prevalence of renal disorder but the lowest frequencies of other clinical manifestations. Cluster 2 was represented by the predominance of anti-Smith, anti-RNP and aPL, with greater prevalence of malar rash, oral ulcers, arthritis and serositis. Cluster 3 was characterized by anti-Ro and anti-La with greater prevalence of discoid rash, photosensitivity and haematological involvement. Individual association analysis also revealed similar findings. Patients of clusters 2 and 3 were more closely related, while cluster 1 was more distinct, associated with renal disorder only and negatively associated or not associated with other manifestations. CONCLUSION: We conclude that autoantibody clustering and clinical subsets exist in SLE patients of our locality. These clusters may be viewed as a bipolar spectrum of related autoantibody and clinical manifestations. At one end are patients with over-representation of anti-dsDNA and renal disorder, while at the other end are two distinct autoantibody clusters (anti-Sm/anti-RNP/aPL and anti-Ro/anti-La) with overlapping of other clinical manifestations.

Prospective study on dialysis patients after total parathyroidectomy without autoimplant.

AIM: Secondary hyperparathyroidism is common in chronic kidney disease. When medical treatment fails, subtotal or total parathyroidectomy with autoimplant is done but both are associated with a high recurrence rate. The third surgical strategy is total parathyroidectomy without autoimplant. We evaluate the outcomes of patients who had total parathyroidectomy with no autoimplant. METHODS: Thirteen patients who had total parathyroidectomy without autoimplant were prospectively studied from 1998-2002. Intact parathyroid hormone, biochemistry and bone mineral densities were measured at baseline and serially. All patients had bone biopsies done preoperatively and seven had repeat bone biopsies at a mean of 37.7 months postoperatively. Histomorphometric studies were done for all bone biopsies. Patients were observed for fractures. RESULTS: Five patients were on haemodialysis and eight on peritoneal dialysis. Mean duration of follow up was 68 months. Postoperatively, mean intact parathyroid hormone decreased precipitously and remained within or just above normal. Mean serum calcium phosphate product decreased and remained normal. Out of seven patients who had repeat bone biopsies, two showed reversal of hyperparathyroid bone disease to normal, two had mild hyperparathyroidism, while three had adynamic bone disease. One patient with adynamic bone disease subsequently developed biochemical recurrence of hyperparathyroidism. Serial bone densitometry showed remarkable improvement. There was no fracture. CONCLUSION: In the studied series of total parathyroidectomy without autoimplant, adynamic bone disease occurred in three out of seven repeat bone biopsies while improvement occurred in the rest. Bone mineral density was much improved and there was no fracture.

Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-blind, randomized, placebo-controlled study.

BACKGROUND: Previous studies showed that angiotensin-receptor blocker (ARB) therapy decreased proteinuria and possibly slowed the rate of renal function decline in patients with chronic proteinuric nephropathies. We performed a double-blind, randomized, placebo-controlled, multicenter study on the ARB valsartan in the treatment of patients with immunoglobulin A (IgA) nephropathy. METHODS: From 6 centers, we recruited 109 patients with IgA nephropathy who had either: (1) proteinuria with protein greater than 1 g/d and serum creatinine level less than 2.8 mg/dL (< 250 micromol/L), or (2) serum creatinine level of 1.4 to 2.8 mg/dL (120 to 250 micromol/L) regardless of degree of proteinuria. Patients were randomly assigned to administration of either valsartan, 80 mg/d (titrated up to 160 mg/d for blood pressure control), or placebo for 104 weeks. Additional antihypertensive therapy was allowed to achieve a target blood pressure of 140/90 mm Hg. The primary end point was doubling of serum creatinine level or dialysis-dependent renal failure. Secondary outcomes included change in proteinuria and decrease in glomerular filtration rate (GFR). RESULTS: There were 54 patients in the treatment group and 55 patients in the placebo group. Baseline clinical characteristics were similar between groups, although the treatment group had a marginally greater baseline GFR (87 +/- 36 versus 78 +/- 38 mL/min/1.73 m2 [1.45 +/- 0.60 versus 1.30 +/- 0.63 mL/s/1.73 m2];P = 0.29) and less proteinuria (protein, 1.8 +/- 1.2 versus 2.3 +/- 1.7 g/d; P = 0.21) than the placebo group. Average blood pressures during the study were 92.7 +/- 10.6 mm Hg in the treatment group and 100.9 +/- 9.1 mm Hg in the placebo group (P < 0.001). During the study period, 4 patients in the placebo group and 1 patient in the treatment group reached the primary end point (log-rank test, P = 0.18). Proteinuria decreased significantly in the treatment group (protein, 1.8 +/- 1.2 to 1.2 +/- 1.2 g/d; P = 0.03), but did not change in the placebo group. With multiple linear regression models, valsartan treatment resulted in a 33.0% decrease in proteinuria (95% confidence interval, 10.9 to 55.1) after adjusting for other confounding factors. There was a significant decrease in mean rate of GFR decrease in the valsartan-treated group (-5.62 +/- 6.79 mL/min/y [-0.09 +/- 0.11 mL/s/y]) compared with the placebo group (-6.98 +/- 6.17 mL/min/y [-0.12 +/- 0.10 mL/s/y]) throughout the study period after adjustment for average blood pressure and proteinuria (P = 0.014). CONCLUSION: Valsartan significantly decreases proteinuria and slows renal deterioration in patients with IgA nephropathy after adjustment for confounding factors, notably blood pressure. The long-term benefit of valsartan needs to be confirmed with additional studies.