CLN Article

The Sample

Kidney Recipients Fare Better With HLA-Incompatible Donations Than Waiting for HLA-Compatible Organs

A 22-center study found that kidney transplant recipients who received organs from human leukocyte antigen (HLA)-incompatible living donors after undergoing desensitization had significantly better 1- 3- and 8-year survival rates than controlled matches who either remained on a transplant waiting list, received a transplant, or remained on a transplant waiting list and did not receive a transplant (N Engl J Med 2016;374:940–9). The findings have “revolutionary” implications for kidney transplant protocols, according to the authors of an accompanying editorial.

Researchers at Johns Hopkins University in Baltimore led the effort, based on their own experience showing survival benefit for patients who received kidneys from HLA-incompatible living donors after undergoing desensitization. Since the Johns Hopkins kidney transplant program has a very high volume, the researchers wanted to determine whether other transplant centers could achieve similar results.

An enduring imbalance between the supply of and demand for HLA-matching kidney donations prompted Johns Hopkins’ initial research as well as the broader investigation. More than 32,000 people awaiting kidney transplants in the United States have anti-HLA antibodies, making it “very difficult” to find a match with a compatible donor, according to the authors. 

The study involved 1,025 patients who received kidney transplants from HLA-incompatible live donors, and two control groups each comprised of 5,125 patients and matched with the intervention group on a variety of factors, including panel-reactive antibody level. The first control group included individuals who remained on a transplant waiting list and/or received a kidney transplant, while the other included patients who remained on a transplant waiting list and did not receive a new kidney.

The investigators used three methods to detect and define the degree of anti-HLA activity: cytotoxic cross-match, flow-cytometric cross-match, and Luminex antibody testing. They defined low donor-specific antibody level as a positive Luminex result and negative flow-cytometric cross-match, moderate as a positive flow-cytometric assay and negative cytotoxic cross-match, and high as a positive cytotoxic cross-match. The authors cited this heterogeneity in antibody testing as a limitation of their study.

Overall, kidney recipients from HLA-incompatible donors had a higher survival rate than either control group at 1 year, 3 years, and 8 years of follow-up. This survival benefit at 8 years extended across low, moderate, and high donor-specific antibody levels.

The authors of the accompanying editorial opined that the findings underscore “the numerous contradictory opinions raised by the transplant community.” HLA desensitization involves “extremely powerful immunosuppressive regimens,” putting them at risk for opportunistic infections and cancer. This regimen also costs about $30,000, while transplants cost around $100,000. In contrast, dialysis costs approximately $70,000 annually for life. “The differing opinions about who should undergo transplantation and the risks involved call for a certain degree of caution,” according to the editorial.

Familial Hyper-cholesterolemia More Common in U.S. Than Generally Recognized

Familial hypercholesterolemia (FH) is much more common in the U.S. than previously thought, with approximately 1.5 million people affected (Circulation 2016;133:1067–72). These findings should be a clarion call for providing state-of-the-art care for patients with FH to prevent the coronary heart disease it causes, according to an accompanying editorial.

According to the investigators, published estimates of FH have varied widely, from 1 in 500 to 1 in 137, depending on the populations assessed and the criteria for defining FH. In their analysis, the authors included 36,949 participants in 1999 to 2012 National Health and Nutrition Examination Surveys (NHANES) who were at least 20 years old, along with a secondary analysis of 13,343 adolescents between ages 12 and 19.

The authors also used a modified version of the Dutch Lipid Clinic (DLC) criteria to define FH. The DLC assigns points based on low-density lipoprotein-cholesterol (LDL-C) levels. DLC also assigns 8 points for having a known gene defect for FH, but the authors were unable to consider this criteria as well as several others that were not collected as part of NHANES.

The authors found that the overall U.S. prevalence of probable or definite FH based on NHANES participants was 0.40%, which equates to about 1 in 250 individuals. They found a similar rate in adolescents, 0.42%, or about 1 in 237. The rates varied by race and ethnicity, ranging from 1 in 414 for Mexican Americans to 1 in 174 in other Hispanics.

Comprehensive Molecular Testing for CAP Outperforms Culture in Detecting Causative Pathogens

Comprehensive molecular testing for community-acquired pneumonia (CAP) using a combination of multiplex, rapid, real-time PCR assays identified causative pathogens in 87% of cases, compared with 39% in culture-based methods (Clin Infect Dis 2016;62:817–23). “The significantly greater sensitivity in pathogen detection could make this technology the standard approach for microbiological diagnosis in hospitalized CAP patients,” according to an accompanying editorial (Clin Infect Dis 2016:62:824–5).

The Edinburgh, U.K.-based investigators conducted the study to explore whether a comprehensive molecular diagnostic approach examining 26 respiratory bacterial and viral pathogens along with bacterial quantification would provide better information for clinical decision-making around CAP. Quantitative molecular assays for respiratory bacteria have been used in patients with pneumonia, but they often lack key targets, use targets with sub-optimal specificity, or are only semi-quantitative, according to the authors.

Culture-based testing identified a bacterial pathogen in 39.3% of patients, all of which were positive by PCR for the human target gene GAPDH. Molecular testing methods detected bacteria in 81.1% of samples. Considering respiratory virus results as well, the molecular methods detected pathogens in 86.7% of cases.

The researchers found that molecular testing could enable physicians to scale back initial empirical antibiotic therapy for 77.2% of patients. They concluded that their findings show “the feasibility of providing the physician with significantly more information on which to base treatment decisions than is currently available.”

HbA1c Plus Glycated Albumin Identifies Nearly 80% of Africans With Prediabetes

A study of equatorial African immigrants living in the U.S. found that as individual tests hemoglobin A1c (HbA1c), fructosamine, and glycated albumin (GA) identified no more than 50% of individuals with prediabetes. However, combining results for HbA1c and GA increased the sensitivity for detecting prediabetes significantly, to 78% (Diabetes Care 2016; 39:271–7).

The authors conducted the study because of the burgeoning diabetes epidemic in sub-Saharan Africa, where prediabetes and diabetes prevalence is expected to rise within the next 20 years by more than 100%, the highest anticipated globally. At the same time, the transition from prediabetes to diabetes can be delayed with effective treatment, yet screening for prediabetes in Africa is underfunded and inadequately studied. In addition, HbA1c cannot be used in homozygous hemoglobinopathies common in Africans, such as sickle cell anemia.

This led the researchers to explore how well not only HbA1c but also fructosamine—a measure of all glycated proteins in plasma—and GA—a subfraction of fructosamine—detected prediabetes in Africans living in the U.S.

The researchers used oral glucose tolerance testing (OGTT) as the gold standard test for prediabetes, while also measuring fasting plasma glucose, insulin, HbA1c, fructosamine, GA, and hemoglobin electrophoresis. OGTT identified 34% of subjects as having prediabetes. As independent tests HbA1c, fructosamine, and GA identified prediabetes in 50%, 41%, and 42% of subjects, respectively. Combining either fructosamine or GA with HbA1c improved sensitivity, but only the combination of GA and HbA1c was statistically significant in contrast to HbA1c alone, with sensitivity 78% versus 50% and P value <0.001.