North Asian population relationships in a global context.

Population genetic studies of North Asian ethnic groups have focused on genetic variation of sex chromosomes and mitochondria. Studies of the extensive variation available from autosomal variation have appeared infrequently. We focus on relationships among population samples using new North Asia microhaplotype data. We combined genotypes from our laboratory on 58 microhaplotypes, distributed across 18 autosomes, on 3945 individuals from 75 populations with corresponding data extracted for 26 populations from the Thousand Genomes consortium and for 22 populations from the GenomeAsia 100 K project. A total of 7107 individuals in 122 total populations are analyzed using STRUCTURE, Principal Component Analysis, and phylogenetic tree analyses. North Asia populations sampled in Mongolia include: Buryats, Mongolians, Altai Kazakhs, and Tsaatans. Available Siberians include samples of Yakut, Khanty, and Komi Zyriane. Analyses of all 122 populations confirm many known relationships and show that most populations from North Asia form a cluster distinct from all other groups. Refinement of analyses on smaller subsets of populations reinforces the distinctiveness of North Asia and shows that the North Asia cluster identifies a region that is ancestral to Native Americans.

Ancestry inference of 96 population samples using microhaplotypes.

Microhaplotypes have become a new type of forensic marker with a great ability to identify and deconvolute mixtures because massively parallel sequencing (MPS) allows the alleles (haplotypes) of the multi-SNP loci to be determined directly for an individual. As originally defined, a microhaplotype locus is a short segment of DNA with two or more SNPs defining three or more haplotypes. The length is short enough, less than about 300 bp, that the read length of current MPS technology can produce a phase-known sequence of each chromosome of an individual. As part of the discovery phase of our studies, data on 130 microhaplotype loci with estimates of haplotype frequency data on 83 populations have been published. To provide a better picture of global allele frequency variation, we have now tested 13 more populations for 65 of the microhaplotype loci from among those with higher levels of inter-population gene frequency variation, including 8 loci not previously published. These loci provide clear distinctions among 6 biogeographic regions and provide some information distinguishing up to 10 clusters of populations.

52 additional reference population samples for the 55 AISNP panel.

Ancestry inference for a person using a panel of SNPs depends on the variation of frequencies of those SNPs around the world and the amount of reference data available for calculation/comparison. The Kidd Lab panel of 55 AISNPs has been incorporated in commercial kits by both Life Technologies and Illumina for massively parallel sequencing. Therefore, a larger set of reference populations will be useful for researchers using those kits. We have added reference population allele frequencies for 52 population samples to the 73 previously entered so that there are now allele frequencies publicly available in ALFRED and FROG-kb for a total of 125 population samples.

Mongolians in the Genetic Landscape of Central Asia: Exploring the Genetic Relations among Mongolians and Other World Populations.

Genetic data on North and Central Asian populations are underrepresented in the literature, especially for autosomal markers. In the present study we used 812 single nucleotide polymorphisms (SNPs) distributed across all the human autosomes and extensively studied at Yale to examine the affinities of two recently collected samples of populations: rural and cosmopolitan Mongolians from Ulaanbaatar and nomadic, Turkic-speaking Tsaatan from Mongolia near the Siberian border. We compare these two populations with each other and with a global set of populations and discuss their relationships to New World populations. Specifically, we analyze data on 521 autosomal loci (single SNPs and multi-SNP haplotypes) studied in 57 populations representing all the major geographical regions of the world. We conclude that these North and Central Asian populations are genetically distinct from all other populations in our study and may be close to the ancestral lineage leading to the New World populations.

MgCaCO3 versus CaCO3 in peritoneal dialysis patients--a cross-over pilot trial.

BACKGROUND: Despite adverse effects such as constipation, vascular calcification, and hypercalcemia, calcium-based salts are relatively affordable and effective phosphate binders that remain in widespread use in the dialysis population. We conducted a pilot study examining whether the use of a combined magnesium/calcium-based binder was as effective as calcium carbonate at lowering serum phosphate levels in peritoneal dialysis (PD) patients. METHODS: This was a cross-over, investigator-masked pilot study in which prevalent PD patients received calcium carbonate alone (200 mg calcium per tablet) or calcium magnesium carbonate (100 mg calcium, 85 mg magnesium per tablet). Primary outcome was serum phosphate level at 3 months. Analysis was as per protocol. RESULTS: Twenty patients were recruited, 17 completed the study. Mean starting dose was 11.35 ± 7.04 pills per day of MgCaCO3 and 9.00 ± 4.97 pills per day of CaCO3. Mean phosphate levels fell from 2.13 mmol/L to 2.01 mmol/L (95% confidence interval (CI): 1.76 - 2.30, p = 0.361) in the MgCaCO3 group, and 1.81 mmol/L (95% CI: 1.56 - 2.0, p = 0.026) in the CaCO3 alone group. Six (35%) patients taking MgCaCO3 and 9 (54%) taking CaCO3 alone achieved Kidney Disease Outcomes Quality Initiative (KDOQI) serum phosphate targets at 3 months. Diarrhea developed in 9 patients taking MgCaCO3 and 3 taking CaCO3. Serum magnesium exceeded 1.4 mmol/L in 5 patients taking MgCaCO3 while serum calcium exceeded 2.65 mmol/L in 3 patients receiving CaCO3. When compared to the initial dose, the prescribed dose at 3 months was reduced by 44% (to 6.41 tablets/day) in the MgCaCO3 group and by 8% (to 8.24 pills per day) in the CaCO3 alone group. CONCLUSION: Compared with CaCO3 alone, the preparation and dose of MgCaCO3 used in this pilot study was no better at lowering serum phosphate levels in PD patients, and was associated with more dose-limiting side effects.

Variability in CKD stage in outpatients followed in two large renal clinics.

OBJECTIVE: Chronic kidney disease (CKD) is staged by glomerular filtration rate (GFR). CKD stages sometimes vary between routine office visits, and it is unknown if this impacts renal and patient survival separately from a cross-sectional CKD stage value. We quantified and categorized CKD stage variability in a large group of outpatients and correlated this with clinical and demographic features and with renal and patient survival. METHODS: All estimated GFRs were staged in the first observation period. CKD stages were then categorized as static, improving, worsening, or fluctuating. Logistic regression analysis was performed to identify clinical variables associated with CKD stage variability. Death and dialysis progression rates were then collected and analyzed using Cox proportional regression. RESULTS: During a 1.1-year observation period, 1,262 patients (mean age 71.25 years) had a mean 5 eGFR's. CKD stages were static in 60.4%, worsened in 14.4%, improved in 7.4%, and fluctuated in 17.2% of patients. Secondary analysis revealed heavy proteinuria and East Asian ethnicity to be negatively, and diabetes mellitus and previous acute kidney injury to be positively associated with improving CKD stages. Cox proportional regression of 902 patients analyzed 2.3 years later revealed a negative association with improving CKD stage and subsequent need for dialysis. CONCLUSIONS: CKD stage changed in 40% of 1,262 elderly patients when determined 5 times in just over 1 year. Improving CKD stage was the only variability pattern significantly associated with any of the clinical outcomes when assessed 2.3 years later, being unlikely to be linked with subsequent need for dialysis.

A randomized controlled trial comparing mupirocin and polysporin triple ointments in peritoneal dialysis patients: the MP3 Study.

BACKGROUND AND OBJECTIVES: Infectious complications remain a significant cause of peritoneal dialysis (PD) technique failure. Topical ointments seem to reduce peritonitis; however, concerns over resistance have led to a quest for alternative agents. This study examined the effectiveness of applying topical Polysporin Triple ointment (P(3)) against mupirocin in a multi-centered, double-blind, randomized controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: PD patients routinely applied either P(3) or mupirocin ointment to their exit site. Patients were followed for 18 months or until death or catheter removal. The primary study outcome was a composite endpoint of exit-site infection (ESI), tunnel infection, or peritonitis. RESULTS: Seventy-five of 201 randomized patients experienced a primary outcome event (51 peritonitis episodes, 24 ESIs). No difference was seen in the time to first event for P(3) (13.2 months; 95% confidence interval, 11.9-14.5) and mupirocin (14.0 months; 95% confidence interval, 12.7-15.4) (P=0.41). Twice as many patients reported redness at the exit site in the P(3) group (14 versus 6, P=0.10). Over the complete study period, a higher rate per year of fungal ESIs was seen in patients using P(3) (0.07 versus 0.01; P=0.02) with a corresponding increase in fungal peritonitis (0.04 versus 0.00, respectively; P<0.05). CONCLUSIONS: This study shows that P(3) is not superior to mupirocin in the prophylaxis of PD-related infections. Colonization of the exit site with fungal organisms is of concern and warrants further study. As such, the use of P(3) over mupirocin is not advocated in the prophylaxis of PD-related infections.

Peritoneal dialysis in the nursing home.

UNLABELLED: The mean age of patients with end-stage renal disease increases steadily. The elderly on dialysis have significant comorbidity and require extra attention to meet their dialysis, dietary, and social needs, and some may need to be treated at a long-term care facility such as a nursing home (NH). Providing dialysis and caring for elderly patients in a nursing home (NH) presents a number of challenges. Few data are available in the literature about elderly patients on peritoneal dialysis (PD) in an NH. This paper describes our experience of starting and maintaining a peritoneal dialysis program in three community-based nursing homes. RESULTS: During the period 2004-2008, after the nursing home personnel had received appropriate training, we established a PD program in three community-based nursing homes and admitted 38 patients on peritoneal dialysis. We educated 112 NH staff over the three-year period. Mean age of the patients at entry was 77.3 + or - 8.5(18.4%) were male. The main causes of end-stage renal disease were diabetes mellitus (DM) 21 (55.8%) and hypertension 13 (34.2%). Comorbid conditions included DM (27, 71.1%), hypertension (26, 68.4%), coronary artery disease (18.5%), chronic heart failure (11, 28.9%), cerebrovascular event (12, 31.6%), and cancer(3, 7.9%). The average total time on chronic peritoneal dialysis was 36.5 + or - 29.8 months, (median 31, range: 1-110 months) of which the average time in the NH program, as of the time of this report, was 18.4 + or - 13.1 months (median 15.5, range: 1-45 months). During the study period, 16 (42.1%) of the patients died, 2 (5.3%) transferred to HD, 2 (5.3%) stopped treatment, and 18 (47.4%) are still in the program. Actuarial patient survival from entry into the NH program was 89.5% at six months, 60.5% at 12 months, 39.5% at 24 months and 13.2% at 36 months. Patient survival from initiation of chronic dialysis was 89.5% at six months, 76.3% at 12 months, 63.1% at 24 months, and 39.5% at 36 months. We observed 28 episodes of peritonitis with a rate of one episode every 40.3 treatment-months. Two PD catheters had to be replaced, giving a rate of one in every 362.5 patient months. CONCLUSION: Our results with elderly patients in a nursing home show an excellent patient and technique survival and a low peritonitis rate. With appropriate training of the NH nursing staff, peritoneal dialysis could be performed successfully in these nursing homes. Successful peritoneal dialysis in a nursing home requires a close collaboration between the nursing home staff and PD dialysis unit.

Improvement in eGFR in patients with chronic kidney disease attending a nephrology clinic.

BACKGROUND: The adverse effects arising from late referral to a nephrologist of patients with chronic kidney disease (CKD) are well known. Retrospectively we examined the initial characteristics of patients referred in various stages of CKD to our nephrology division and tried to identify potential baseline factors associated with subsequent changes in estimated glomerular filtration rate (eGFR). PATIENTS AND METHODS: Between September 1997 and June 2006 1,443 patients (909 male, 534 female) with CKD, with eGFRs ranging from 15 to 89 ml/min, were referred to our nephrology division and categorized using the National Kidney Foundation classification for CKD based on eGFR. The slope of eGFR change (ml/min-1/1.73/m2-1/year-1) was determined by linear regression analysis and the patients were divided into five groups: (1) significantly progressive slope (deterioration) (more negative than -5 ml/min/year); (2) mildly progressive slope (>-5 to -1 to +1 to or=+5). RESULTS: At the first nephrology referral, 5.8% of the patients were on CKD stage 2 (eGFR: 90-60 ml/m), 46.7% on CKD stage 3 (eGFR: 59-30 ml/m), and 47.5% on CKD stage 4 (eGFR: 29-15 ml/m) CKD. Significantly improved slope was detected in 48.2% of CKD stage 2 patients, 29.3% of CKD stage 3 patients, and only 14.7% of CKD stage 4 patients (P<0.05). Being in stage 4 or stage 3 versus being in stage 2 significantly reduced the likelihood of an improved slope in logistic regression analysis whereas age, gender, presence of hypertension, and diabetes mellitus did not reach the level of significance. CONCLUSION: Referral to a nephrology clinic can lead not only to arrest of progression of CKD but also to regression/improvement. Early referral is a positive predictive factor for improvement in eGFR, which emphasizes the importance of such referral. The previously held idea that, once established, CKD progresses invariably is not valid anymore.

Differential impairment of psychomotor efficiency and processing speed in patients with chronic kidney disease.

BACKGROUND: Cognitive impairment has been documented in patients with chronic kidney disease. In a recent paper, improvements in cognitive function were seen in hemodialysis (HD) patients switched from conventional HD to nocturnal HD, in two of three domains of cognitive function. Based on these findings, we hypothesized that functional decline may occur differentially in some domains more than others. METHODS: Using a cross-sectional study design, patients optimized on medical treatment at a predialysis clinic were tested using a battery of neuropsychological (NP) tests measuring three domains of cognitive functioning-attention & working memory skills; psychomotor efficiency & processing speed; and learning efficiency. Clinical subjective symptoms for cognitive functioning and depression were measured using the Patient's Assessment of Own Functioning (PAOF) inventory and the Beck Depression Inventory (BDI). RESULTS: One hundred and three patients aged 64.6+/-12.4 years were recruited. Of these, 40% were diabetic, with a mean Charlson comorbidity score of 4.4+/-2.1. Depression (defined as >16 on the BDI score) was seen in 11 patients. After adjustment for comorbid diseases, hemoglobin, the use of neurodepressor medication, and parathyroid hormone (PTH) values, renal function was negatively correlated with psychomotor efficiency & processing speed, but not with attention & working memory or learning efficiency scores. CONCLUSION: Chronic kidney disease is associated with a decline in psychomotor efficiency & processing speed, but not with attention & working memory or learning efficiency.

Kidney transplantation in the elderly: a decision analysis.

Transplantation offers superior life expectancy and quality of life compared with dialysis in young patients with end-stage renal failure. However, the initial risks of mortality and morbidity are high. This study used a decision analysis model to evaluate the costs and benefits of kidney transplantation versus continued dialysis for older patients with renal failure. A decision analytic model comparing cadaveric renal transplantation to continued hemodialysis treatment was developed. The base case considered a theoretical cohort of patients aged 65 yr without known comorbidity or contraindications to transplantation who would have to wait 2 yr for a cadaveric transplant. Separate models were constructed for patients with diabetes or cardiovascular disease and for patients receiving an organ after a variety of wait-list times. Probability, utility, and survival data were obtained from published reports and renal registries. For 65-yr-old patients, quality-adjusted life expectancy increased by 1.1 quality-adjusted life years (QALY) at an incremental cost of $67,778 per QALY. Assuming a 2-yr wait-listed time, transplantation remained economically attractive for 70-yr-old patients (incremental cost effectiveness [ICE], $79,359 per QALY) but was less economically attractive for those over 75 yr of age (ICE, $99,553) or for 70-yr-olds with either cardiovascular disease or diabetes (ICE, $126,751 and $161,090 per QALY, respectively). The analytic results were sensitive only to the time spent waiting for the graft. The cost-effectiveness reduced such that the costs associated with one QALY were in excess of $100,000/yr when the probability of a complication was > or = 50% per 3-mo cycle and when the utility of transplantation fell below 0.62. If available within a timely period, transplantation may offer substantial clinical benefits to older patients at a reasonable financial cost. Prolonged waiting times dramatically decrease the clinical benefits and economic attractiveness of transplantation, suggesting that living donor transplantation may be of particular benefit in this population.