Fasting Blood Glucose-A Missing Variable for GFR-Estimation in Type 1 Diabetes?

Objective

Estimation of glomerular filtration rate (eGFR) is one of the current clinical methods for identifying risk for diabetic nephropathy in subjects with type 1 diabetes (T1D). Hyperglycemia is known to influence GFR in T1D and variability in blood glucose at the time of eGFR measurement could introduce bias in eGFR. We hypothesized that simultaneously measured blood glucose would influence eGFR in adults with T1D.

Methods

Longitudinal multivariable mixed-models were employed to investigate the relationships between blood glucose and eGFR by CKD-EPI eGFR_{CYSTATIN C} over 6-years in the Coronary Artery Calcification in Type 1 diabetes (CACTI) study. All subjects with T1D and complete data including blood glucose and cystatin C for at least one of the three visits (n = 616, 554, and 521, respectively) were included in the longitudinal analyses.

Results

In mixed-models adjusting for sex, HbA1c, ACEi/ARB, protein and sodium intake positive associations were observed between simultaneous blood glucose and eGFR_{CYSTATIN C} (β±SE:0.14±0.04 per 10 mg/dL of blood glucose, p<0.0001), and hyperfiltration as a dichotomous outcome (OR: 1.04, 95% CI: 1.01–1.07 per 10 mg/dL of blood glucose, p = 0.02).

Conclusions

In our longitudinal data in subjects with T1D, simultaneous blood glucose has an independent positive effect on eGFR_{CYSTATIN C}. The associations between blood glucose and eGFR_{CYSTATIN C} may bias the accurate detection of early diabetic nephropathy, especially in people with longitudinal variability in blood glucose.     

Comparisons between the 2012 New CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) Equations and Other Four Approved Equations

Objective

The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) reported two equations in 2012: one based on cystatin C concentration (CKD-EPI_2012cys) and the other using both serum creatinine and cystatin C concentrations (CKD-EPI_2012Scr-cys). We compared the adaptability of new formulae with other four equations.

Methods

Participants (n = 788; median age, 54 [range, 19–94] years) were recruited from the First Affiliated Hospital of Nanjing Medical University. The reference glomerular filtration rate (rGFR) was measured by a ⁹⁹mTc-DTPA renal dynamic imaging method, and the estimated glomerular filtration rate (eGFR) was calculated separately by the Chinese adapted Modification of Diet in Renal Disease equation (C-MDRD), MacIsaac, Ma, serum creatinine-based CKD-EPI equation (CKD-EPI_2009Scr), CKD-EPI_2012cys and CKD-EPI_2012Scr-cys equations. We compared the performance of six equations with rGFR.

Results

Median rGFR was 76.35 (interquartile range, 59.03–92.50) mL/min/1.73 m². Compared with CKD-EPI_2009Scr, CKD-EPI_2012Scr-cys formula had better diagnostic value with larger area under the receiver operating characteristic curve (ROC^AUC, 0.879, p = 0.006), especially in young participants (ROC^AUC, 0.883, p = 0.005). CKD-EPI_2012cys equation did not perform better than other available equations. Accuracy (the proportion of eGFR within 30% of rGFR [P₃₀]) of the CKD-EPI_2012Scr-cys equation (77.03%) was inferior only to MacIsaac equation (80.2%) in the entire participants, but performed best in young participants with normal or mildly-injured GFR. Neither of the two new CKD-EPI equations achieved any ideal P₃₀ in the elderly participants with moderately-severely injured GFR. Linear regression analysis demonstrated a consistent result. In this study, CKD-EPI_2012Scr-cys had a relatively better diagnosis consistency of GFR stage between the eGFR and rGFR in the whole cohort.

Conclusion

CKD-EPI_2012Scr-cys appeared less biased and more accurate in overall participants. Neither of the new CKD-EPI equations achieved ideal accuracy in senior participants with moderately-severely injured GFR. A large-scale study with more subjects and cooperating centers to develop new formulae for the elderly is assumed to be necessary.     

Multicenter Study of Creatinine- and/or Cystatin C-Based Equations for Estimation of Glomerular Filtration Rates in Chinese Patients with Chronic Kidney Disease

Objective

To establish equations for the estimation of glomerular filtration rates (eGFRs) based on serum creatinine (SCr) and/or serum cystatin C (SCysC) in Chinese patients with chronic kidney disease (CKD), and to compare the new equations with both the reference GFR (rGFR) and the literature equations to evaluate their applicability.

Methods

The 788 Chinese CKD patients were randomly divided into two groups, the training group and the testing group, to establish new eGFR-formulas based on serum CysC and to validate the established formulas, respectively. ^99mTc-DTPA clearance (as the rGFR), serum Cr, and serum CysC were determined for all patients, and GFR was calculated using the Cockcroft-Gault equation (eGFR1), the MDRD formula (eGFR2), the CKD-EPI formulas (eGFR3, eGFR4), and the Chinese eGFR Investigation Collaboration formulas (eGFR5, eGFR6). The accuracy of each eGFR was compared with the rGFR.

Results

The training and testing groups'' mean GFRs were 50.84±31.36 mL/min/1.73 m² and 54.16±29.45 mL/min/1.73 m², respectively. The two newly developed eGFR formulas were fitted using iterative computation: and . Significant correlation was observed between each eGFR and the rGFR. However, proportional errors and constant errors were observed between rGFR and eGFR1, eGFR2, eGFR4, eGFR5 or eGFR6, and constant errors were observed between eGFR3 and rGFR, as revealed by the Passing & Bablok plot analysis. The Bland-Altman analysis illustrated that the 95% limits of agreement of all equations exceeded the previously accepted limits of <60 mL/min •1.73 m², except the equations of eGFR7 and eGFR8.

Conclusion

The newly developed formulas, eGFR7 and eGFR8, provide precise and accurate GFR estimation using serum CysC detection alone or in combination with serum Cr detection. Differences in detection methods should be carefully considered when choosing literature eGFR equations to avoid misdiagnosis and mistreatment.     

Association between Kidney Function and Framingham Global Cardiovascular Disease Risk Score: A Chinese Longitudinal Study

Background

Chronic kidney disease (CKD) is generally considered an independent risk factor for cardiovascular disease (CVD) development, but rates in individuals with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m² are uncertain. The Framingham global CVD risk score (FRS) equation is a widely accepted tool used to predict CVD risk in the general population. The purpose of the present study was to examine whether an association exists between eGFR and FRS in a Chinese population with no CKD or CVD.

Methods

A total of 333 participants were divided into three groups based on FRS. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and CKD-EPI equation for Asians (CKD-EPI-ASIA) were used to measure eGFR.

Results

A significant inverse association between eGFR and FRS was confirmed with Pearson correlation coefficients of –0.669, –0.698 (eGFR_CKD-EPI, P<0.01) and –0.658, –0.690 (eGFR_CKD-EPI-ASIA, P<0.01). This association gradually diminished with progression from the low- to high-risk groups (eGFR_CKD-EPI, r = –0.615, –0.282, –0.197, P<0.01, P<0.01, P>0.05; similar results according to the CKD-EPI-ASIA equation). In the low- or moderate-risk new-groups, this association became stronger with increased FRS (eGFR_CKD-EPI-ASIA, r = –0557, –0.622 or –0.326, –0.329, P<0.01). In contrast to the results from 2008, eGFR was independently associated with FRS following adjustment for traditional cardiovascular risk factors (P<0.05).

Conclusion

Renal function has multiple influences on predicting CVD risk in various populations. With increasing FRS and decreasing eGFR, it is also independently associated with CVD, even in individuals with eGFR >60 ml/min/1.73 m².     

Comparison of Various Equations for Estimating GFR in Malawi: How to Determine Renal Function in Resource Limited Settings?

Background

Chronic kidney disease (CKD) is a probably underrated public health problem in Sub-Saharan-Africa, in particular in combination with HIV-infection. Knowledge about the CKD prevalence is scarce and in the available literature different methods to classify CKD are used impeding comparison and general prevalence estimates.

Methods

This study assessed different serum-creatinine based equations for glomerular filtration rates (eGFR) and compared them to a cystatin C based equation. The study was conducted in Lilongwe, Malawi enrolling a population of 363 adults of which 32% were HIV-positive.

Results

Comparison of formulae based on Bland-Altman-plots and accuracy revealed best performance for the CKD-EPI equation without the correction factor for black Americans. Analyzing the differences between HIV-positive and –negative individuals CKD-EPI systematically overestimated eGFR in comparison to cystatin C and therefore lead to underestimation of CKD in HIV-positives.

Conclusions

Our findings underline the importance for standardization of eGFR calculation in a Sub-Saharan African setting, to further investigate the differences with regard to HIV status and to develop potential correction factors as established for age and sex.     

Factors Other than the Glomerular Filtration Rate That Determine the Serum Beta-2-Microglobulin Level

Background

β2-microglobulin has been increasingly investigated as a diagnostic marker of kidney function and a prognostic marker of adverse outcomes. To date, non-renal determinants of β2-microglobulin levels have not been well described. Non-renal determinants are important for the interpretation and appraisal of the diagnostic and prognostic value of any endogenous kidney function marker.

Methods

This cross-sectional analysis was performed within the framework of the www.seniorlabor.ch study, which includes subjectively healthy individuals aged ≥60 years. Factors known or suspected to have a non-renal association with kidney function markers were investigated for a non-renal association with serum β2-microglobulin. As a marker of kidney function, the Berlin Initiative Study equation 2 for the estimation of the estimated glomerular filtration rate (eGFR_BIS2) in the elderly was employed.

Results

A total of 1302 participants (714 females and 588 males) were enrolled in the study. The use of a multivariate regression model adjusting for age, gender and kidney function (eGFR_BIS2) revealed age, male gender, and C-reactive protein level to be positively associated with β2-microglobulin levels. In addition, there was an inverse non-renal relationship between systolic blood pressure, total cholesterol and current smoking status. No association with markers of diabetes mellitus, body stature, nutritional risk, thyroid function or calcium and phosphate levels was observed.

Conclusions

Serum β2-microglobulin levels in elderly subjects are related to several non-renal factors. These non-renal factors are not congruent to those known from other markers (i.e. cystatin C and creatinine) and remind of classical cardiovascular risk factors.     

Renal Function Can Improve at Any Stage of Chronic Kidney Disease

Introduction

Even though renal function decline is considered relentless in chronic kidney disease (CKD), improvement has been shown in patients with hypertensive nephropathy. Whether this can occur in any type of nephropathy and at any stage is unknown as are the features of patients who improve.

Methods

We identified 406 patients in the NephroTest cohort with glomerular filtration rates (mGFR) measured by ⁵¹Cr-EDTA clearance at least 3 times during at least 2 years of follow-up. Individual examination of mGFR trajectories by 4 independent nephrologists classified patients as improvers, defined as those showing a sustained mGFR increase, or nonimprovers. Twelve patients with erratic trajectories were excluded. Baseline data were compared between improvers and nonimprovers, as was the number of recommended therapeutic targets achieved over time (specifically, for systolic and diastolic blood pressure, proteinuria, and use of renin angiotensin system blockers).

Results

Measured GFR improved over time in 62 patients (15.3%). Their median mGFR slope was +1.88[IQR 1.38, 3.55] ml/min/year; it was −2.23[−3.9, −0.91] for the 332 nonimprovers. Improvers had various nephropathies, but not diabetic glomerulopathy or polycystic kidney disease. They did not differ from nonimprovers for age, sex, cardiovascular history, or CKD stage, but their urinary albumin excretion rate was lower. Improvers achieved significantly more recommended therapeutic targets (2.74±0.87) than nonimprovers (2.44±0.80, p<0.01). They also had fewer CKD-related metabolic complications and a lower prevalence of 25OH-vitamin-D deficiency.

Conclusion

GFR improvement is possible in CKD patients at any CKD stage through stage 4–5. It is noteworthy that this GFR improvement is associated with a decrease in the number of metabolic complications over time.     

Serologic Responses to Recombinant Pneumocystis jirovecii Major Surface Glycoprotein among Ugandan Patients with Respiratory Symptoms

Background

Little is known about the serologic responses to Pneumocystis jirovecii major surface glycoprotein (Msg) antigen in African cohorts, or the IgM responses to Msg in HIV-positive and HIV-negative persons with respiratory symptoms.

Methods

We conducted a prospective study of 550 patients, both HIV-positive (n = 467) and HIV-negative (n = 83), hospitalized with cough ≥2 weeks in Kampala, Uganda, to evaluate the association between HIV status, CD4 cell count, and other clinical predictors and antibody responses to P. jirovecii. We utilized ELISA to measure the IgM and IgG serologic responses to three overlapping recombinant fragments that span the P. jirovecii major surface glycoprotein: MsgA (amino terminus), MsgB (middle portion) and MsgC1 (carboxyl terminus), and to three variations of MsgC1 (MsgC3, MsgC8 and MsgC9).

Results

HIV-positive patients demonstrated significantly lower IgM antibody responses to MsgC1, MsgC3, MsgC8 and MsgC9 compared to HIV-negative patients. We found the same pattern of low IgM antibody responses to MsgC1, MsgC3, MsgC8 and MsgC9 among HIV-positive patients with a CD4 cell count <200 cells/µl compared to those with a CD4 cell count ≥200 cells/µl. HIV-positive patients on PCP prophylaxis had significantly lower IgM responses to MsgC3 and MsgC9, and lower IgG responses to MsgA, MsgC1, MsgC3, and MsgC8. In contrast, cigarette smoking was associated with increased IgM antibody responses to MsgC1 and MsgC3 but was not associated with IgG responses. We evaluated IgM and IgG as predictors of mortality. Lower IgM responses to MsgC3 and MsgC8 were both associated with increased in-hospital mortality.

Conclusions

HIV infection and degree of immunosuppression are associated with reduced IgM responses to Msg. In addition, low IgM responses to MsgC3 and MsgC8 are associated with increased mortality.     

Prevalence of kidney disease in HIV-infected and uninfected Rwandan women

Background

In the United States, HIV-related kidney disease disproportionately affects individuals of African descent; however, there are few estimates of kidney disease prevalence in Africa. We evaluated the prevalence of kidney disease among HIV-infected and uninfected Rwandan women.

Methods

The Rwandan Women''s Interassociation Study and Assessment prospectively enrolled 936 women. Associations with estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m² and proteinuria were assessed in separate logistic regression models.

Results

Among 891 non-pregnant women with available data, 2.4% had an eGFR<60 mL/min/1.73 m² (calculated by the Modification of Diet in Renal Disease equation, MDRD eGFR) and 8.7% had proteinuria ≥1+. The prevalence of decreased eGFR varied markedly depending on the estimating method used, with the highest prevalence by Cockcroft-Gault. Regardless of the method used to estimate GFR, the proportion with decreased eGFR or proteinuria did not differ significantly between HIV-infected and -uninfected women in unadjusted analysis. After adjusting for age and blood pressure, HIV infection was associated with significantly higher odds of decreased MDRD eGFR but not proteinuria.

Conclusion

In a well-characterized cohort of Rwandan women, HIV infection was associated with decreased MDRD eGFR. The prevalence of decreased eGFR among HIV-infected women in our study was lower than that previously reported in African-Americans and in other Central and East African HIV populations, although there was substantial variability depending on the equation used to estimate GFR. Future studies are needed to optimize GFR estimates and to determine the impact of antiretroviral therapy on kidney disease in this population.     

Time to Complete Wound Healing in HIV-Positive and HIV-Negative Men following Medical Male Circumcision in Kisumu,Kenya: A Prospective Cohort Study

Background

While voluntary medical male circumcision (VMMC) has been shown to be protective against HIV-acquisition, the procedure may place men and their partners at risk of HIV infection in the period following circumcision if sex is resumed before the wound is healed. This prospective cohort study evaluates post-circumcision wound healing to determine whether the 42-day post-circumcision abstinence period, recommended by the World Health Organization and adopted by VMMC programs, is optimal.

Methods and Findings

Men were circumcised by forceps-guided method and their post-circumcision wounds examined weekly for seven weeks and at 12 weeks. Time to complete healing was recorded in completed weeks since circumcision, and its associations with baseline covariates were assessed by Kaplan-Meier methods and Cox Proportional Hazard Models. A total of 215 HIV-negative and 108 HIV-positive men aged 18–35 years (median 26, IQR 23–30) were enrolled. 97.1% of scheduled follow-up visits were completed. At week 4, 59.3% of HIV-positive men and 70.4% of age-matched HIV-negative men were healed. At week 6, these percentages rose to 93.4% in HIV-positive men and 92.6% in age-matched HIV-negative men. There was no difference in the hazard of healing between 108 HIV-positive and 108 age-matched HIV-negative men (HR 0.91 95% CI 0.70–1.20). Early post-operative infection was associated with delayed healing in both HIV-positive and HIV-negative men (HR 0.48 95% CI 0.23–1.00).

Conclusions

Our results indicate that the WHO recommendation for 42-days post-circumcision sexual abstinence should be maintained for both HIV-positive and HIV-negative men. It is important to stress condom use upon resumption of sex in all men undergoing circumcision.     

Comparison and Temporal Trends of Three Groups with Cryptococcosis: HIV-Infected, Solid Organ Transplant, and HIV-Negative/Non-Transplant

Background

The Infectious Disease Society of America (IDSA) 2010 Clinical Practice Guidelines for the management of cryptococcosis outlined three key populations at risk of disease: (1) HIV-infected, (2) transplant recipient, and (3) HIV-negative/non-transplant. However, direct comparisons of management, severity and outcomes of these groups have not been conducted.

Methodology/Principal Findings

Annual changes in frequency of cryptococcosis diagnoses, cryptococcosis-attributable mortality and mortality were captured. Differences examined between severe and non-severe disease within the context of the three groups included: demographics, symptoms, microbiology, clinical management and treatment. An average of nearly 15 patients per year presented at Duke University Medical Center (DUMC) with cryptococcosis. Out of 207 study patients, 86 (42%) were HIV-positive, 42 (20%) were transplant recipients, and 79 (38%) were HIV-negative/non-transplant. HIV-infected individuals had profound CD4 lymphocytopenia and a majority had elevated intracranial pressure. Transplant recipients commonly (38%) had renal dysfunction. Nearly one-quarter (24%) had their immunosuppressive regimens stopped or changed. The HIV-negative/non-transplant population reported longer duration of symptoms than HIV-positive or transplant recipients and 28% (22/79) had liver insufficiency or underlying hematological malignancies. HIV-positive and HIV-negative/non-transplant patients accounted for 89% of severe disease cryptococcosis-attributable deaths and 86% of all-cause mortality.

Conclusions/Significance

In this single-center study, the frequency of cryptococcosis did not change in the last two decades, although the underlying case mix shifted (fewer HIV-positive cases, stable transplant cases, more cases with neither). Cryptococcosis had a relatively uniform and informed treatment strategy, but disease-attributable mortality was still common.     

Estimating Kidney Function in HIV-Infected Adults in Kenya: Comparison to a Direct Measure of Glomerular Filtration Rate by Iohexol Clearance

Background

More than two-thirds of the world''s HIV-positive individuals live in sub-Saharan Africa, where genetic susceptibility to kidney disease is high and resources for kidney disease screening and antiretroviral therapy (ART) toxicity monitoring are limited. Equations to estimate glomerular filtration rate (GFR) from serum creatinine were derived in Western populations and may be less accurate in this population.

Methods

We compared results from published GFR estimating equations with a direct measure of GFR by iohexol clearance in 99 HIV-infected, ART-naïve Kenyan adults. Iohexol concentration was measured from dried blood spots on filter paper. The bias ratio (mean of the ratio of estimated to measured GFR) and accuracy (percentage of estimates within 30% of the measured GFR) were calculated.

Results

The median age was 35 years, and 60% were women. The majority had asymptomatic HIV, with median CD4+ cell count of 355 cells/mm³. Median measured GFR was 115 mL/min/1.73 m². Overall accuracy was highest for the Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) equation. Consistent with a prior report, bias and accuracy were improved by eliminating the coefficient for black race (85% of estimates within 30% of measured GFR). Accuracy of all equations was poor in participants with GFR 60–90 mL/min/1.73 m² (<65% of estimates within 30% of measured GFR), although this subgroup was too small to reach definitive conclusions.

Conclusions

Overall accuracy was highest for the CKD-EPI equation. Eliminating the coefficient for race further improved performance. Future studies are needed to determine the most accurate GFR estimate for use in individuals with GFR <90 mL/min/1.73 m², in whom accurate estimation of kidney function is important to guide drug dosing. Direct measurement of GFR by iohexol clearance using a filter paper based assay is feasible for research purposes in resource-limited settings, and could be used to develop more accurate GFR estimates in African populations.     

Using Mathematical Algorithms to Modify Glomerular Filtration Rate Estimation Equations

Background

The equations provide a rapid and low-cost method of evaluating glomerular filtration rate (GFR). Previous studies indicated that the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease-Epidemiology (CKD-EPI) and MacIsaac equations need further modification for application in Chinese population. Thus, this study was designed to modify the three equations, and compare the diagnostic accuracy of the equations modified before and after.

Methodology

With the use of ^{99 m}Tc-DTPA renal dynamic imaging as the reference GFR (rGFR), the MDRD, CKD-EPI and MacIsaac equations were modified by two mathematical algorithms: the hill-climbing and the simulated-annealing algorithms.

Results

A total of 703 Chinese subjects were recruited, with the average rGFR 77.14±25.93 ml/min. The entire modification process was based on a random sample of 80% of subjects in each GFR level as a training sample set, the rest of 20% of subjects as a validation sample set. After modification, the three equations performed significant improvement in slop, intercept, correlated coefficient, root mean square error (RMSE), total deviation index (TDI), and the proportion of estimated GFR (eGFR) within 10% and 30% deviation of rGFR (P₁₀ and P₃₀). Of the three modified equations, the modified CKD-EPI equation showed the best accuracy.

Conclusions

Mathematical algorithms could be a considerable tool to modify the GFR equations. Accuracy of all the three modified equations was significantly improved in which the modified CKD-EPI equation could be the optimal one.     

The Impact of HIV Infection and CD4 Cell Count on the Performance of an Interferon Gamma Release Assay in Patients with Pulmonary Tuberculosis

Background

The performance of the tuberculosis specific Interferon Gamma Release Assays (IGRAs) has not been sufficiently documented in tuberculosis- and HIV-endemic settings. This study evaluated the sensitivity of the QuantiFERON TB-Gold In-Tube (QFT-IT) in patients with culture confirmed pulmonary tuberculosis (PTB) in a TB- and HIV-endemic population and the effect of HIV-infection and CD4 cell count on test performance.

Methodology/Principal Findings

161 patients with sputum culture confirmed PTB were subjected to HIV- and QFT-IT testing and measurement of CD4 cell count. The QFT-IT was positive in 74% (119/161; 95% CI: 67–81%). Sensitivity was higher in HIV-negative (75/93) than in HIV-positive (44/68) patients (81% vs. 65%, p = 0.02) and increased with CD4 cell count in HIV-positive patients (test for trend p = 0.03). 23 patients (14%) had an indeterminate result and this proportion decreased with increasing CD4 cell count in HIV-positive patients (test for trend p = 0.03). Low CD4 cell count (<300 cells/µl) did not account for all QFT-IT indeterminate nor all negative results. Sensitivity when excluding indeterminate results was 86% (95% CI: 81–92%) and did not differ between HIV-negative and HIV–positive patients (88 vs. 83%, p = 0.39).

Conclusions/Significance

Sensitivity of the QFT-IT for diagnosing active PTB infection was reasonable when excluding indeterminate results and in HIV-negative patients. However, since the test missed more than 10% of patients, its potential as a rule-out test for active TB disease is limited. Furthermore, test performance is impaired by low CD4 cell count in HIV-positive patients and possibly by other factors as well in both HIV-positive and HIV-negative patients. This might limit the potential of the test in populations where HIV-infection is prevalent.     

Deferred Pre-Emptive Switch from Calcineurin Inhibitor to Sirolimus Leads to Improvement in GFR and Expansion of T Regulatory Cell Population: A Randomized,Controlled Trial

Background

Measures to prevent chronic calcineurin inhibitor (CNI) toxicity have included limiting exposure by switching to sirolimus (SIR). SIR may favorably influence T regulator cell (T_reg) population. This randomized controlled trial compares the effect of switching from CNI to SIR on glomerular filtration rate (GFR) and T_reg frequency.

Methods

In this prospective open label randomized trial, primary living donor kidney transplant recipients on CNI-based immunosuppression were randomized to continue CNI or switched to sirolimus 2 months after surgery; 29 were randomized to receive CNI and 31 to SIR. All patients received mycophenolate mofetil and steroids. The main outcome parameter was estimated GFR (eGFR) at 180 days. T_reg population was estimated by flowcytometry.

Results

Baseline characteristics in the two groups were similar. Forty-eight patients completed the trial. At six months, patients in the SIR group had significantly higher eGFR as compared to those in the CNI group (88.94±11.78 vs 80.59±16.51 mL/min, p = 0.038). Patients on SIR had a 12 mL/min gain of eGFR of at the end of six months. Patients in the SIR group showed significant increase in T_reg population at 30 days, which persisted till day 180. There was no difference in the adverse events in terms of number of acute rejection episodes, death, infections, proteinuria, lipid profile, blood pressure control and hematological parameters between the two groups. Four patients taking SIR developed enthesitis. No patient left the study or switched treatment because of adverse event.

Conclusions

A deferred pre-emptive switch over from CNI to SIR safely improves renal function and T_reg population at 6 months in living donor kidney transplant recipients.Registered in Clinical Trials Registry of India (CTRI/2011/091/000034)     

Triglyceride Levels Are Closely Associated with Mild Declines in Estimated Glomerular Filtration Rates in Middle-Aged and Elderly Chinese with Normal Serum Lipid Levels

Objective

To investigate the relationship between lipid profiles [including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)] and a mild decline in the estimated glomerular filtration rate (eGFR) in subjects with normal serum lipid levels.

Design and Methods

In this study, we included 2647 participants who were ≥40 years old and had normal serum lipid levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the GFR. A mildly reduced eGFR was defined as 60–90 mL/min/1.73 m². First, multiple linear regression analysis was used to estimate the association of lipid profiles with the eGFR. Then, the levels of each lipid component were divided into four groups, using the 25th, 50th and 75th percentiles as cut-off points. Finally, multiple logistic regression analysis was used to investigate the association of different lipid components with the risk of mildly reduced eGFR.

Results

In the group with a mildly reduced eGFR, TG and LDL-C levels were significantly increased, but HDL-C levels were significantly decreased. After adjusting for age, gender, body mass index (BMI), systolic blood pressure (SBP), glycated hemoglobin (HbA_1c), smoking and drinking, only TC and TG were independently related to the eGFR. Additionally, only TG showed a linear relationship with an increased risk of a mildly reduced eGFR, with the highest quartile group (TG: 108–150 mg/dl [1.22–1.70 mmol/L]) having a significantly increased risk after adjusting for the above factors.

Conclusions

Triglyceride levels are closely associated with a mildly reduced eGFR in subjects with normal serum lipid levels. Dyslipidemia with lower TG levels could be used as new diagnostic criteria for subjects with mildly reduced renal function.     

An autopsy study describing causes of death and comparing clinico-pathological findings among hospitalized patients in Kampala, Uganda

Background

Information on causes of death in HIV-infected patients in Sub-Saharan Africa is mainly derived from observational cohort and verbal autopsy studies. Autopsy is the gold standard to ascertain cause of death. We conducted an autopsy study to describe and compare the clinical and autopsy causes of death and contributory findings in hospitalized HIV-infected and HIV-uninfected patients in Uganda.

Methods

Between May and September 2009 a complete autopsy was performed on patients that died on a combined infectious diseases gastroenterology ward in Mulago Hospital in Kampala, Uganda. Autopsy cause of death and contributing findings were based on the macro- and microscopic post-mortem findings combined with clinical information. Clinical diagnoses were reported by the ward doctor and classified as confirmed, highly suspected, considered or not considered, based on information derived from the medical chart. Results are reported according to HIV serostatus.

Results

Fifty-three complete autopsies were performed in 66% HIV-positive, 21% HIV-negative and 13% patients with an unknown HIV serological status. Infectious diseases caused death in 83% of HIV-positive patients, with disseminated TB as the main diagnosis causing 37% of deaths. The spectrum of illness and causes of death were substantially different between HIV-positive and HIV-negative patients. In HIV-positive patients 12% of postmortem diagnoses were clinically confirmed, 27% highly suspected, 16% considered and 45% not considered. In HIV-negative patients 17% of postmortem diagnoses were clinically highly suspected, 42% considered and 42% not considered.

Conclusion

Autopsy examination remains an important tool to ascertain causes of death particularly in settings with limited access to diagnostic testing during life. HIV-positive patients continue to die from treatable and clinically undiagnosed infectious diseases. Until rapid-point of care testing is available to confirm common infections, empiric treatment should be further investigated.     

Plasma Lipidomic Profiling of Treated HIV-Positive Individuals and the Implications for Cardiovascular Risk Prediction

Background

The increased risk of coronary artery disease in human immunodeficiency virus (HIV) positive patients is collectively contributed to by the human immunodeficiency virus and antiretroviral-associated dyslipidaemia. In this study, we investigate the characterisation of the plasma lipid profiles of treated HIV patients and the relationship of 316 plasma lipid species across multiple lipid classes with the risk of future cardiovascular events in HIV- positive patients.

Methods

In a retrospective case-control study, we analysed plasma lipid profiles of 113 subjects. Cases (n = 23) were HIV-positive individuals with a stored blood sample available 12 months prior to their diagnosis of coronary artery disease (CAD). They were age and sex matched to HIV-positive individuals without a diagnosis of CAD (n = 45) and with healthy HIV-negative volunteers (n = 45).

Results

Association of plasma lipid species and classes with HIV infection and cardiovascular risk in HIV were determined. In multiple logistic regression, we identified 83 lipids species and 7 lipid classes significantly associated with HIV infection and a further identified 74 lipid species and 8 lipid classes significantly associated with future cardiovascular events in HIV-positive subjects. Risk prediction models incorporating lipid species attained an area under the receiver operator characteristic curve (AUC) of 0.78 (0.775, 0.785)) and outperformed all other tested markers and risk scores in the identification of HIV-positive subjects with increased risk of cardiovascular events.

Conclusions

Our results demonstrate that HIV-positive patients have significant differences in their plasma lipid profiles compared with healthy HIV-negative controls and that numerous lipid species were significantly associated with elevated cardiovascular risk. This suggests a potential novel application for plasma lipids in cardiovascular risk screening of HIV-positive patients.     

CD4 Cell Levels during Treatment for Tuberculosis (TB) in Ethiopian Adults and Clinical Markers Associated with CD4 Lymphocytopenia

Background

The clinical correlations and significance of subnormal CD4 levels in HIV-negative patients with TB are unclear. We have determined CD4 cell levels longitudinally during anti-tuberculosis treatment (ATT) in patients, with and without HIV co-infection, and their associations with clinical variables.

Method

Adults diagnosed with TB (maximum duration of ATT for 2 weeks, and with no history of antiretroviral therapy (ART) in HIV-positive subjects) were included consecutively in eight out-patient clinics in Ethiopia. Healthy individuals were recruited for comparison at one of the study health centers. Data on patient characteristics and physical findings were collected by trained nurses following a structured questionnaire at inclusion and on follow-up visits at 2 and 6 months. In parallel, peripheral blood CD4 cell levels were determined. The evolution of CD4 cell levels during ATT was assessed, and the association between clinical characteristics and low CD4 cell levels at baseline was investigated using regression analysis.

Results

In total, 1116 TB patients were included (307 HIV-infected). Among 809 HIV-negative patients, 200 (25%) had subnormal CD4 cell counts (<500 cells/mm³), with <350 cells/mm³ in 82 (10%) individuals. CD4 cell levels increased significantly during the course of ATT in both HIV+ and HIV- TB-patients, but did not reach the levels in healthy subjects (median 896 cells/mm³). Sputum smear status, signs of wasting (low mid upper arm circumference (MUAC)), and bedridden state were significantly associated with low CD4 cell counts.

Conclusion

A high proportion of Ethiopian TB patients have subnormal CD4 cell counts before starting treatment. Low CD4 cell levels are associated with smear positive disease and signs of wasting. The continuous increase of CD4 cell counts during the course of ATT suggest a reversible impact of active TB on CD4 cell homeostasis, which may be considered in interpretation of CD4 cell counts in HIV/TB co-infected subjects.