Changes in metabolic parameters and adverse kidney and cardiovascular events during glomerulonephritis and renal vasculitis treatment in patients with and without diabetes mellitus

Background@#Cardiovascular disease causes significant morbidity and mortality in patients with glomerulonephritis, which is increasingly diagnosed in older individuals who may have diabetes mellitus (DM). We evaluated the impact of DM on metabolic profile, renal and cardiovascular outcomes during treatment and follow-up of individuals with glomerulonephritis. @*Methods@#We performed a retrospective cohort study of 601 consecutive adults with biopsy-proven glomerulonephritis for factors associated with kidney failure, hospitalization for cardiovascular events, and death. Biopsies with isolated diabetic nephropathy were excluded. @*Results@#The median patient age was 49.8 years (36.7–60.9 years) with estimated glomerular filtration rate of 56.7 mL/min/1.73 m2 (27.7–93.2 mL/min/1.73 m2). DM was present in 25.4%. The most frequent diagnoses were minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) (29.5%), lupus nephritis (21.3%), immunoglobulin A (IgA) nephropathy (19.1%), and membranous nephropathy (12.1%). The median follow-up was 38.8 months (interquartile range [IQR], 26.8–55.8 months). Among 511 individuals with lupus nephritis, anti-neutrophil cytoplasmic antibody-associated vasculitis, MCD/FSGS, membranous nephropathy, and IgA nephropathy, 52 (10.2%) developed kidney failure at a median 16.4 months (IQR, 2.3–32.2 months), while 29 (5.7%) had cardiovascular-related hospitalizations at 12.9 months (IQR, 4.8–31.8 months) and 31 (6.1%) died at 13.5 months (IQR, 2.5–42.9 months) after diagnosis. Cox regression analysis found that baseline DM was independently associated with kidney failure (adjusted hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.06–4.05, p = 0.03) and cardiovascular-related hospitalization (adjusted HR, 2.69; 95% CI, 1.21–5.98, p = 0.02) but not with mortality. @*Conclusion@#DM was strongly associated with kidney failure and hospitalization for cardiovascular events in patients with biopsy-proven glomerulonephritis.

Changes in metabolic parameters and adverse kidney and cardiovascular events during glomerulonephritis and renal vasculitis treatment in patients with and without diabetes mellitus

Background@#Cardiovascular disease causes significant morbidity and mortality in patients with glomerulonephritis, which is increasingly diagnosed in older individuals who may have diabetes mellitus (DM). We evaluated the impact of DM on metabolic profile, renal and cardiovascular outcomes during treatment and follow-up of individuals with glomerulonephritis. @*Methods@#We performed a retrospective cohort study of 601 consecutive adults with biopsy-proven glomerulonephritis for factors associated with kidney failure, hospitalization for cardiovascular events, and death. Biopsies with isolated diabetic nephropathy were excluded. @*Results@#The median patient age was 49.8 years (36.7–60.9 years) with estimated glomerular filtration rate of 56.7 mL/min/1.73 m2 (27.7–93.2 mL/min/1.73 m2). DM was present in 25.4%. The most frequent diagnoses were minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) (29.5%), lupus nephritis (21.3%), immunoglobulin A (IgA) nephropathy (19.1%), and membranous nephropathy (12.1%). The median follow-up was 38.8 months (interquartile range [IQR], 26.8–55.8 months). Among 511 individuals with lupus nephritis, anti-neutrophil cytoplasmic antibody-associated vasculitis, MCD/FSGS, membranous nephropathy, and IgA nephropathy, 52 (10.2%) developed kidney failure at a median 16.4 months (IQR, 2.3–32.2 months), while 29 (5.7%) had cardiovascular-related hospitalizations at 12.9 months (IQR, 4.8–31.8 months) and 31 (6.1%) died at 13.5 months (IQR, 2.5–42.9 months) after diagnosis. Cox regression analysis found that baseline DM was independently associated with kidney failure (adjusted hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.06–4.05, p = 0.03) and cardiovascular-related hospitalization (adjusted HR, 2.69; 95% CI, 1.21–5.98, p = 0.02) but not with mortality. @*Conclusion@#DM was strongly associated with kidney failure and hospitalization for cardiovascular events in patients with biopsy-proven glomerulonephritis.

Perspectives of patients, families, and health care professionals on decision-making about dialysis modality--the good, the bad, and the misunderstandings!

OBJECTIVES: This study explored the factors influencing decision-making about dialysis modality, integrating the perspectives of patients, their families, and health care professionals within an Asian population. The study further sought to understand the low penetration rate of peritoneal dialysis (PD) in Singapore. ♢ METHODS: A sample of 59 participants comprising pre-dialysis patients, dialysis patients, caregivers, and health care professionals (HCPs) participated in semi-structured interviews to explore the decision-making process and their views about various dialysis modalities. Data were thematically analyzed using NVivo9 (QSR International, Doncaster, Australia) to explore barriers to and facilitators of various dialysis modalities and decisional support needs. ♢ RESULTS: Fear of infection, daily commitment to PD, and misperceptions of PD emerged as barriers to PD. Side effects, distance to dialysis centers, and fear of needling and pain were barriers to hemodialysis (HD). The experiences of other patients, communicated informally or opportunistically, influenced the preferences and choices of patients and family members for a dialysis modality. Patients and families value input from HCPs and yet express strong needs to discuss subjective experiences of life on dialysis (PD or HD) with other patients before making a decision about dialysis modality. ♢ CONCLUSIONS: Pre-dialysis education should expand its focus on the family as the unit of care and should provide opportunities for interaction with dialysis patients and for peer-led learning. Barriers to PD, especially misperceptions and misunderstandings, can be targeted to improve PD uptake.

Genomics and disease progression in IgA nephritis

Apart from clinical, histological and biochemical indices, genomics are now being employed to unravel the pathogenetic mechanisms in the disease progression of IgA nephritis (IgAN). The results of angiotensin converting enzyme (ACE) gene polymorphism have been controversial. Those patients with the DD genotype seem to have a poorer prognosis. However, with high dose angiotensin receptor blocker (ARB) therapy, the ACE gene polymorphism status of a patient may no longer be a matter for concern as those with the DD genotype would also respond favourably to high dose ARB therapy. Association studies with gene sequencing and haplotypes have suggested that multiple genes are involved in the pathogenesis of IgAN. Some workers have reported a synergistic effect in the combined analysis of AGT-M235T and ACE I/D polymorphism. With the use of deoxyribo nucleic acid (DNA) microarray, tens of thousands of gene expressions genome-wide can be examined together simultaneously. A locus of familial IgAN has been described with strong evidence of linkage to IgAN1 on chromosome 6q22-23. Two other loci were reported at 4q26-31 and 17q12-22. DNA microarray techniques could also help in the identification of specific pathogenic genes that are up- or down-regulated and this may allow genome wide analyses of these genes and their role in the pathogenesis and progression of IgAN. Recently, using genome-wide association studies (GWAS) more loci for disease susceptibility for IgAN have been identified at 17p13, 8p23, 22q12, 1q32 and 6p21.

National Health Survey on the prevalence of urinary abnormalities in the population: then and now (1975 to 2012)

<p><b>INTRODUCTION</b>This paper presents the results of a community survey on urinary abnormalities which covered 1/80th of the population of Singapore in 1975. These findings were compared with the data from the Singapore National Service Registrants in 1974 as well as data from a recent survey in Singapore and that of other Asian and Western countries.</p><p><b>MATERIALS AND METHODS</b>The study covered 18,000 persons aged 15 years and above, representing a sampling fraction of 1/80th of the population. A total of 16,808 respondents attended the field examination centres, of whom 16,497 had their urine sample tested representing 92.7% of the sample population.</p><p><b>RESULTS</b>In the dipstick urine testing at the field examination centres, 769 subjects (4.6%) were found to have urinary abnormalities. Two hundred and eighty-two (36.7%) of these 769 subjects were found to have urinary abnormalities based on urine microscopy constituting a prevalence of 1.71%. The prevalence of proteinuria was 0.63% and for both haematuria and proteinuria was 0.73%. The prevalence for hypertension was 0.43% and renal insufficiency was 0.1%.</p><p><b>DISCUSSION</b>The consensus is that routine screening for chronic kidney disease (CKD) in the general population is not cost effective as the yield is too low. Whilst, most studies showed that screening of the general population was not cost effective, it has been suggested that screening for targeted groups of subjects could help to identify certain risk groups who may benefit from early intervention to prevent or retard the progression of CKD.</p><p><b>CONCLUSION</b>The prevalence of urinary abnormalities in Singapore has remained the same, now and three decades ago.</p>

How can we improve clinical research in clinical practice with better research outcome?

This paper explains some of the difficulties doctors face when taking up a career in research. It describes the efforts by the government and the Ministry of Health (MOH) to nurture the Clinician Scientist Programme. The nature of research and the mindset of clinicians who are passionate about research are explored and the reasons which drive some of them to pursue a research career. It discusses the need to have structured training for research and how continuing research education is necessary for the researcher. The paper discusses the goals for research and how we can achieve better research outcomes and the importance of good mentorship. It suggests ways to engage more doctors in research in the restructured hospitals by overcoming some of the problems they encounter. Finally, it relates the Biomedical Science initiative of the government through the National Research Foundation and the various programmes in Translational Clinical Research available for clinicians who are keen on a research career.

Urotensin 2 and retinoic acid receptor alpha (RARA) gene expression in IgA nephropathy

<p><b>INTRODUCTION</b>IgA nephropathy is a disease where the pathogenesis is still poorly understood. Deoxyribonucleic acid (DNA) microarray technique allows tens of thousands of gene expressions to be examined at the same time. Commercial availability of microarray genechips has made this powerful tool accessible for wider utilisation in the study of diseases.</p><p><b>MATERIALS AND METHODS</b>Seven patients with IgA nephropathy, 6 with minimal change nephrotic syndrome (MCNS) as patient controls and 7 normal healthy subjects were screened for the differential expression of genes, genome-wide. The Human Genome U133 Plus 2.0 Arrays (Affymetrix, USA) were used to quantitate the differential expression of 38,500 well-characterised human genes.</p><p><b>RESULTS</b>A total of 7761 gene expressions were identified that have an IgAN/Normal gene expression ratio of 0.06-fold to 5.58-fold. About 35% of the altered gene expressions have no gene title or just a hypothetical protein label such as FLJ30679. Most of the remaining 65% are identified proteins where their importance to IgAN is not immediately apparent at this time. Among the 30 most upregulated and 30 most downregulated genes are Urotensin 2 (upregulated 3.09-fold, P <0.05) and Fatty-acid binding protein 6 (downregulated to 0.12-fold, P <0.05). Retinoic acid receptor alpha (vitamin A receptor) was also found downregulated to 0.41-fold (P <0.005). Taqman realtime polymerase chain reaction (PCR) for urotensin 2 and retinoic acid receptor alpha (RARA) were performed on 20 patients with IgA nephropathy and 11 with Minimal Change Disease and the data correlated with various clinical indices.</p><p><b>CONCLUSIONS</b>The findings suggest that there may be a therapeutic role for retinoic acid receptor alpha (RARA) in IgA nephropathy and a clinical monitoring role for Urotensin 2 in Minimal Change Disease.</p>

Parallel genotyping of 10,204 single nucleotide polymorphisms to screen for susceptible genes for IgA nephropathy

<p><b>INTRODUCTION</b>IgA nephritis (IgAN) is the most common glomerulonephritis worldwide. We aim to genotype SNPs (single nucleotide polymorphisms) genomewide in patients with IgAN to search for genetic clues to its aetiology.</p><p><b>MATERIALS AND METHODS</b>Genotyping for 10,204 SNPs genomewide was done with the Gene Chip Human Mapping 10K Microarray (Affymetrix). Twenty-eight patients with IgAN and 30 normal subjects were screened and analysed for differences in genotype frequency, allele frequency and heterozygosity reduction.</p><p><b>RESULTS</b>Among the most significantly associated SNPs, 48 SNPs were found mapping directly to the intron of 42 genes that localised in 13 somatic chromosomes and chromosome X. Genotype distribution of these SNPs did not deviate from the Hardy-Weinberg equilibrium in normal subjects. The most significantly associated gene, glial cells missing homolog 1 (GCM, 2 =13.05, P = 0.000) is a transcription factor mapped to 6p12.2. GCM1 reported decreased in placenta of patients with pre-eclampsia. The second gene, Tenascin-R (TNR, 2 = 9.85, P = 0.002) is a glycoprotein and extra-cellular matrix component mapped to 1q25.1. Tenascin-R was associated with motor coordination impairment and enhanced anxiety profile in deficient mice. Interestingly, Triadin (TRDN, 2 = 9.16, P = 0.01) is an integral membrane protein mapped to 6q22.31 within the IgAN1 locus. Triadin was shown to participate in cardiac myocyte arrhythemia. However, there is no published study of these genes in IgAN.</p><p><b>CONCLUSION</b>Forty-two associated genes (particularly GCM1, TNR and TRDN) are identified as possible susceptibility or marker genes for IgAN. Knowledge of their mesangial expression and binding capacity for IgA-containing complexes may help elucidate the pathogenesis of IgAN.</p>

Angiotensin-converting enzyme inhibitor versus angiotensin 2 receptor antagonist therapy and the influence of angiotensin-converting enzyme gene polymorphism in IgA nephritis

<p><b>INTRODUCTION</b>In this study of 109 patients with IgA nephritis (IgAN), we compared the longterm effects on patients treated with angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ATRA) alone with respect to renal outcome in terms of ESRF from 1995 to 2006. The renal outcome is also correlated with the ACE gene ID polymorphism to study its influence on response to ACEI/ATRA therapy.</p><p><b>MATERIALS AND METHODS</b>Seventy-seven patients were on treatment with ACEI/ATRA (22 on ACEI alone, 47 on ATRA alone and 8 on both). The other 32 patients were on no treatment (control group).</p><p><b>RESULTS</b>Compared to controls, treated patients had lower serum creatinine (P <0.001), lower proteinuria (P <0.001) and fewer number progressing to ESRF (P <0.001). For those with the II and ID genotype there were significantly fewer patients with ESRF in the treatment group. With the DD genotype, treatment did not change the poor renal outcome with regard to ESRF. Patients on ACEI therapy had a higher incidence of ESRF compared to those on ATRA (P <0.001). For the control group, the projected number of years-to-ESRF was 10 years. For those on ACEI therapy it was 11 years, and for those on ATRA therapy it was 24 years. Among patients with the II genotype, those treated with ATRA had significantly less incidence of ESRF compared to those treated with ACEI (P <0.001).</p><p><b>CONCLUSION</b>ATRA therapy was found to be effective in retarding disease progression to ESRF in IgAN compared to ACEI therapy. Genotyping showed better response to ATRA therapy only for those with the II genotype.</p>