Quantifying infection risks in incompatible living donor kidney transplant recipients

Desensitization has enabled incompatible living donor kidney transplantation (ILDKT) across HLA/ABO barriers, but added immunomodulation might put patients at increased risk of infections. We studied 475 recipients from our center from 2010 to 2015, categorized by desensitization intensity: none/compatible (n = 260), low (0-4 plasmaphereses, n = 47), moderate (5-9, n = 74), and high (≥10, n = 94). The 1-year cumulative incidence of infection was 50.1%, 49.8%, 66.0%, and 73.5% for recipients who received none, low, moderate, and high-intensity desensitization (P < .001). The most common infections were UTI (33.5% of ILDKT vs. 21.5% compatible), opportunistic (21.9% vs. 10.8%), and bloodstream (19.1% vs. 5.4%) (P < .001). In weighted models, a trend toward increased risk was seen in low (wIRR = _0.771.40_2.56,P = .3) and moderately (wIRR = _0.881.35_2.06,P = .2) desensitized recipients, with a statistically significant 2.22-fold (wIRR = _1.332.22_3.72,P = .002) increased risk in highly desensitized recipients. Recipients with ≥4 infections were at higher risk of prolonged hospitalization (wIRR = _2.623.57_4.88, P < .001) and death-censored graft loss (wHR = _1.154.01_13.95,P = .03). Post–KT infections are more common in desensitized ILDKT recipients. A subset of highly desensitized patients is at ultra-high risk for infections. Strategies should be designed to protect patients from the morbidity of recurrent infections, and to extend the survival benefit of ILDKT across the spectrum of recipients.     

Induction of follicular growth and production of a normal hormonal milieu in spite of using a constant low dose of luteinizing hormone in women with hypogonadotrophic hypogonadism

This study was designed to examine ovarian performance, i.e.follicular growth, normal steroidogenesis and luteal phase function,following the administration of multiple increasing doses ofhuman follicle stimulating hormone (FSH) with a constant lowdose of luteinizing hormone (LH) in women with isolated hypogonadotrophichypogonadism. Human meno–pausal gonadotrophin (HMG) wasused in the first treatment cycle, starting with 150 IU of LHand 150 IU of FSH per day, for 7 days. The dose was increaseddaily with 75 IU of LH and 75 IU of FSH for another 7 days ifno response was detected by serial ultrasound measurements andserumoestradiol determinations. In the second treatment cycle,a constant dose of 75 IU of LH (using HMG) was administeredper day and up to 150 IU of FSH (using urofollitrophin) wassupplemented. If no response was detected after 7 days of treatment,the dose of FSH was increased. For the final stage of ovulationinduction, human chorionic gonadotrophin (HCG) was administeredin the presence of at least one follicle >17 mm in diameterbut with no more than three follicles >16mm in diameter.To verify the adequacy of the luteal phase, a pharmacokinetic/pharmacodynamicstudy of -HCG, oestradiol and progesterone was performed followingthe second treatment cycle only. Ovarian stimulation using aconstant dose of 75 IU of LH and increasing doses of FSH upto 225 IU, resulted in normal follicular growth and hormonalmilieu. Both women showed normal luteal phase oestradiol andprogesterone production and both women conceived following thesecond treatment cycle     

Progesterone support in IVF: is evidence-based medicine translated to clinical practice? A worldwide web-based survey

This worldwide web-based survey compared the clinical practice for luteal-phase supplementation (LPS) in stimulated IVF cycles to the current evidence-based literature. Eighty-four treatment centres in 35 countries, representing a total of 51,155 IVF cycles/year, responded. Vaginal progesterone alone was used for LPS in 64% of cycles and in another 16% of cycles in combination with either i.m. (15%) or oral progesterone (1%). As a single agent, i.m. progesterone was used in 13% of cycles, oral progesterone in another 2% and human chorionic gonadotrophin (HCG) was still used in 5% of cycles. Progesterone was administered until 10–12 weeks’ gestation in 67% of cycles and in 22% and 12% it was discontinued when fetal heart pulsations are recognized or until βHCG was positive, respectively. In conclusion, in almost two-thirds of the assisted cycles represented in this survey, vaginal administration of progesterone is preferred for LPS. Nevertheless, despite the available literature on the disadvantages of oral progesterone, i.m. progesterone and HCG for LPS, these agents are still used routinely by many practitioners. Furthermore, although there is no firm evidence to support the continuation of LPS until 10–12 weeks’ gestation, this practice is used in the majority of IVF cycles worldwide.This worldwide web-based survey assessed the clinical practice for luteal-phase support in stimulated cycles in comparison to the current evidence-based literature. The survey included the following questions: (i) ‘What is the progesterone you use for luteal support?’; and (ii) ‘How long does progesterone needs to be administered in an IVF cycle if the patient becomes pregnant?’. Eighty-four units from 35 countries representing a total of 51,155 treated IVF cycles/year were included. Vaginal progesterone alone was used for luteal-phase supplementation in 64% of cycles. In another 16% of cycles, vaginal progesterone was used in combination with either intramuscular (15%) or oral progesterone (1%). As a single agent, intramuscular progesterone was used in 13% of cycles, oral progesterone in another 2%, and human chorionic gonadotrophin (HCG) was still used in 5% of cycles. Progesterone was administered until 10–12 weeks’ gestation in 67% of cycles, in 22% of cycles it was discontinued when fetal heart pulsations are recognized, and in 12% it was administered until a positive pregnancy test. In conclusion, in agreement with the currently available literature, in almost two-thirds of assisted cycles worldwide, the vaginal route of progesterone administration is preferred for luteal-phase supplementation. Nevertheless, despite the described disadvantages of oral progesterone, intramuscular progesterone and HCG for LPS, these agents are still used routinely in clinical practice by many practitioners. Furthermore, although there is no firm evidence to support the continuation of LPS until 10–12 weeks of gestation, this practice is used in the majority of IVF cycles worldwide.     

Antibody responses to endemic coronaviruses modulate COVID-19 convalescent plasma functionality

SARS-CoV-2 (CoV2) antibody therapies, including COVID-19 convalescent plasma (CCP), monoclonal antibodies, and hyperimmune globulin, are among the leading treatments for individuals with early COVID-19 infection. The functionality of convalescent plasma varies greatly, but the association of antibody epitope specificities with plasma functionality remains uncharacterized. We assessed antibody functionality and reactivities to peptides across the CoV2 and the 4 endemic human coronavirus (HCoV) genomes in 126 CCP donations. We found strong correlation between plasma functionality and polyclonal antibody targeting of CoV2 spike protein peptides. Antibody reactivity to many HCoV spike peptides also displayed strong correlation with plasma functionality, including pan-coronavirus cross-reactive epitopes located in a conserved region of the fusion peptide. After accounting for antibody cross-reactivity, we identified an association between greater alphacoronavirus NL63 antibody responses and development of highly neutralizing antibodies against CoV2. We also found that plasma preferentially reactive to the CoV2 spike receptor binding domain (RBD), versus the betacoronavirus HKU1 RBD, had higher neutralizing titer. Finally, we developed a 2-peptide serosignature that identifies plasma donations with high anti-spike titer, but that suffer from low neutralizing activity. These results suggest that analysis of coronavirus antibody fine specificities may be useful for selecting desired therapeutics and understanding the complex immune responses elicited by CoV2 infection.     

Low income,community poverty and risk of end stage renal disease

Background

The risk of end stage renal disease (ESRD) is increased among individuals with low income and in low income communities. However, few studies have examined the relation of both individual and community socioeconomic status (SES) with incident ESRD.

Methods

Among 23,314 U.S. adults in the population-based Reasons for Geographic and Racial Differences in Stroke study, we assessed participant differences across geospatially-linked categories of county poverty [outlier poverty, extremely high poverty, very high poverty, high poverty, neither (reference), high affluence and outlier affluence]. Multivariable Cox proportional hazards models were used to examine associations of annual household income and geospatially-linked county poverty measures with incident ESRD, while accounting for death as a competing event using the Fine and Gray method.

Results

There were 158 ESRD cases during follow-up. Incident ESRD rates were 178.8 per 100,000 person-years (10⁵ py) in high poverty outlier counties and were 76.3 /10⁵ py in affluent outlier counties, p trend?=?0.06. In unadjusted competing risk models, persons residing in high poverty outlier counties had higher incidence of ESRD (which was not statistically significant) when compared to those persons residing in counties with neither high poverty nor affluence [hazard ratio (HR) 1.54, 95% Confidence Interval (CI) 0.75-3.20]. This association was markedly attenuated following adjustment for socio-demographic factors (age, sex, race, education, and income); HR 0.96, 95% CI 0.46-2.00. However, in the same adjusted model, income was independently associated with risk of ESRD [HR 3.75, 95% CI 1.62-8.64, comparing the?<?$20,000 income group to the?>?$75,000 group]. There were no statistically significant associations of county measures of poverty with incident ESRD, and no evidence of effect modification.

Conclusions

In contrast to annual family income, geospatially-linked measures of county poverty have little relation with risk of ESRD. Efforts to mitigate socioeconomic disparities in kidney disease may be best appropriated at the individual level.

     

Cumulative Systolic BP and Changes in Urine Albumin-to-Creatinine Ratios in Nondiabetic Participants of the Multi-Ethnic Study of Atherosclerosis

Background and objectives

Cumulative exposure to elevated systolic BP (cumSBP) may affect progression of urine albumin excretion in the absence of diabetes. The objective of this study was to examine the association between cumSBP exposure and progression of spot urine albumin-to-creatinine ratio (UACR) in a multi-ethnic cohort of adults without diabetes.

Design, setting, participants, & measurements

The analysis included 3789 participants without severely increased urine albumin excretion or diabetes in the Multi-Ethnic Study of Atherosclerosis, a cohort of 6814 adults aged 45–84 years. UACR was measured at baseline and approximately 1.6, 3.1, and 9.4 years after the baseline examination. cumSBP was calculated as the summed average systolic BP (SBP; mmHg) between two consecutive examinations multiplied by the time between the two examinations (mmHg×year) and categorized as ≤1128 (SBP<120 mmHg), 1129–1222 (SBP≥120–129 mmHg), 1223–1316 (SBP≥130–130 mmHg), and >1316 (SBP≥140 mmHg). Baseline UACR was categorized as normal, mildly increased, or moderately increased, and definite progression of UACR was defined as a persistently higher UACR category at subsequent examinations. No UACR progression was defined as remaining in the same UACR category across all examinations or regressing.

Results

In fully adjusted models, compared with cumSBP≤1128 mmHg, cumSBP 1223–1316 and >1316 mmHg was associated with a 85% and 130% significantly higher odds of definite UACR progression (95% confidence interval, 24% to 178% and 56% to 243%, respectively) versus no UACR progression. Every 100-mmHg higher level of cumSBP was associated with a 1.23-fold higher odds of definite UACR progression (95% confidence interval, 1.13 to 1.34) versus no UACR progression.

Conclusion

Exposure to higher cumSBP was associated with increased UACR progression among adults without diabetes.     

Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment

Strategies that increase homing to the bone marrow and engraftment efficacy of ex?vivo expended CD34(+) cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34(+) cells cultured with cytokines. In the presence of NAM, the fraction of CD34(+)CD38(-) cells increased and the fraction of differentiated cells (CD14(+), CD11b(+), and CD11c(+)) decreased. CD34(+) cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD(+)-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34(+) cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not?inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest?a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the?clinical utility of NAM for ex?vivo expansion of functional CD34(+) cells.