Kidney News April 2017 9#4 : Page 1

April 2017 | Vol. 9, Number 4 Donor-Recipient Weight and Sex Mismatch May Contribute to Kidney Transplant Failure By Tracy Hampton Research has also shown that male re-cipients of female kidneys are at increased risk of graft loss, presumably due to size mismatch and nephron number. (Studies indicate that female kidneys have an aver-age of 12% to 17% fewer total nephrons than male kidneys.) Female recipients of male kidneys also experience reduced graft survival, but to a lesser extent. The mecha-nisms involved are likely immunologic in nature, owing to mismatch between H-Y minor histocompatibility antigens (on the Y chromosome in male donors). To explore the potentially additive ef-fect of size mismatch and sex mismatch, a team led by Amanda Miller, MD, and Karthik Tennankore, MD, of Dalhousie University and the Nova Scotia Health Authority, in Canada, examined wheth-er receiving a kidney transplant from a smaller donor of the opposite sex would impact a recipient’s transplant outcomes. The researchers analyzed information on a cohort of US deceased donor trans-plant recipients between 2000 and 2014 who were listed in the Scientific Registry Continued on page 3 Inside Kidney Transplantation 2017 Breaking down barriers and building bridges Detective Nephron Twists and turns in a case of metabolic acidosis Fellows Corner Referring the preventable before it becomes the inevitable Findings Switching to Spanish-speaking providers improves diabetes control in Latinos N ew research indicates that the success of a kidney transplant may rely in part on how the re-cipient and donor compare in terms of weight and sex. The findings, which are published in the Clinical Journal of the American Society of Nephrology , suggest that changes may be needed to current immunology-based protocols that match donors and recipients. Several kidney transplantation studies have demonstrated that a smaller donor size relative to recipient is associated with a higher risk of graft loss, perhaps due to increased strain on the relatively smaller transplanted kidney. Very few studies have investigated the outcomes associated with donor-recipient weight mismatch-ing as determined by body mass in isola-tion, however. Innovation Summit Co-sponsors ASN, VA gather experts to talk about advancing innovation in kidney disease care Industry Spotlight Fresenius partners with insurers Variability in Parathyroid Hormone Assays: Better Standardization on the Way? By Eric Seaborg C linicians worried about bone dis-ease developing in patients with chronic kidney disease (CKD) lean on parathyroid hormone (PTH) measurements as a marker for skeletal and mineral disorders. But the utility of PTH assays is controversial—mainly because the variability among analytical techniques makes the interpretation of results difficult. A working group from the Interna-tional Federation of Clinical Chemis-try and Laboratory Medicine (IFCC) is working to standardize the assays and establish protocols for issues such as pre-analytical variables. The group has the support of many stakeholders, includ-ing testing manufacturers, and expects to show progress within the next couple of years. In the meantime, nephrologists can consult the literature to aid in the interpretation of the assays used by their laboratories. “There can be differences up to four-fold in the results reported with different methods from the same samples,” said the chair of the IFCC group, Catherine M. Sturgeon, PhD, who is consultant clinical scientist at the Royal Infirmary of Edinburgh and director of one of the Continued on page 5

Donor-Recipient Weight And Sex Mismatch May Contribute To Kidney Transplant Failure

Tracy Hampton

New research indicates that the success of a kidney transplant may rely in part on how the recipient and donor compare in terms of weight and sex. The findings, which are published in the Clinical Journal of the American Society of Nephrology, suggest that changes may be needed to current immunology-based protocols that match donors and recipients.

Several kidney transplantation studies have demonstrated that a smaller donor size relative to recipient is associated with a higher risk of graft loss, perhaps due to increased strain on the relatively smaller transplanted kidney. Very few studies have investigated the outcomes associated with donor-recipient weight mismatching as determined by body mass in isolation, however.

Research has also shown that male recipients of female kidneys are at increased risk of graft loss, presumably due to size mismatch and nephron number. (Studies indicate that female kidneys have an average of 12% to 17% fewer total nephrons than male kidneys.) Female recipients of male kidneys also experience reduced graft survival, but to a lesser extent. The mechanisms involved are likely immunologic in nature, owing to mismatch between H-Y minor histocompatibility antigens (on the Y chromosome in male donors).

To explore the potentially additive effect of size mismatch and sex mismatch, a team led by Amanda Miller, MD, and Karthik Tennankore, MD, of Dalhousie University and the Nova Scotia Health Authority, in Canada, examined whether receiving a kidney transplant from a smaller donor of the opposite sex would impact a recipient’s transplant outcomes.

The researchers analyzed information on a cohort of US deceased donor transplant recipients between 2000 and 2014 who were listed in the Scientific Registry Of Transplants Recipients. The team excluded living donors, patients <18 years of age, those receiving multiple organs, en bloc or sequential transplants, and patients without a documented donor or recipient weight.

The analysis included 115,124 kidney transplant recipients, and 59.4% and 61.6% of donors and recipients were male, respectively. Over a median followup of 3.8 years, 21,261 of the recipients (18. 5%) developed transplant failure.

After accounting for other transplant variables, the investigators found that if a kidney transplant recipient was >30 kg (66 pounds) heavier than the donor, there was a 28% higher risk of transplant failure compared with equally weighted donors and recipients. If the kidney was from a smaller donor of the opposite sex, the relative risk of transplant failure was further elevated to 35% for a male receiving a kidney from a female donor and 50% for a female receiving a kidney from a male donor. This risk is similar to that observed when a recipient receives a kidney transplant from a donor who has diabetes, a known risk factor for kidney failure. It is also comparable to other risk factors for graft loss that historically influence organ allocation, including dialysis vintage >4 years and expanded vs. standard criteria donors.

The study is the first large scale analysis to demonstrate that worse kidney transplant outcomes associated with donor and recipient weight mismatch—as determined by absolute differences in body weight, and donor and recipient sex mismatch— are additive.

“This study is extremely important because we have shown that when all else is considered, something as simple as the combination of a kidney donor’s weight and sex is associated with a marked increase in kidney transplant failure,” Miller said. “While more research is required before including these variables in a recipient matching strategy, this study highlights the importance of donor and recipient matching above and beyond current immunology-based protocols.” It will be important to determine the extent to which any benefit derived from weight and sex matching would offset the potential risk of longer times on the transplant wait list for individual candidates.

Jane Tan, MD, PhD, a transplant nephrologist at Stanford University Medical Center who was not involved with the study, noted that the results lend support to previous research as well as provide insights that will be useful when looking toward the future.

“These findings build upon prior studies that demonstrate the long-term risks of low nephron dose for metabolic demand in kidney transplantation, as well as the potential impact of non–human leukocyte antigen immune responses to allograft survival,” she said. “With a continued increase in obesity among kidney transplant candidates, donor-recipient weight mismatch may factor into clinical decision-making, especially among recipients with increased metabolic demand.”

In an accompanying editorial, Bethany Foster, MD, MSCE. And Indra Gupta, MD, of McGill University, stressed that while matching for sex and body size in organ allocation algorithms deserves consideration, this idea must be approached with a great deal of caution. It would require complex matching, and special care would have to be taken to avoid disadvantaging larger recipients. “Restricting transplant options by prioritizing sex matching may also lead to longer waiting times,” they wrote. “Females with a large body size would be particularly disadvantaged by an approach that favoured allocation of sexand body-size matched kidneys.”

Article: “Donor-Recipient Absolute Weight and Sex Mismatch and the Risk of Graft Loss in Renal Transplantation.”

Read the full article at http://onlinedigeditions.com/article/Donor-Recipient+Weight+And+Sex+Mismatch+May+Contribute+To+Kidney+Transplant+Failure/2754537/397340/article.html.

Variability In Parathyroid Hormone Assays: Better Standardization On The Way?

Eric Seaborg

Clinicians worried about bone disease developing in patients with chronic kidney disease (CKD) lean on parathyroid hormone (PTH) measurements as a marker for skeletal and mineral disorders. But the utility of PTH assays is controversial—mainly because the variability among analytical techniques makes the interpretation of results difficult.

A working group from the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) is working to standardize the assays and establish protocols for issues such as preanalytical variables. The group has the support of many stakeholders, including testing manufacturers, and expects to show progress within the next couple of years. In the meantime, nephrologists can consult the literature to aid in the interpretation of the assays used by their laboratories.

“There can be differences up to fourfold in the results reported with different methods from the same samples,” said the chair of the IFCC group, Catherine M. Sturgeon, PhD, who is consultant clinical scientist at the Royal Infirmary of Edinburgh and director of one of the national External Quality Assessment Service proficiency testing centers in the U.K. “The bigger and more complicated a molecule is, the more difficult it can be to measure consistently.”

PTH is one of those complicated molecules. It is an 84-amino-acid peptide protein that breaks down in the body into a large variety of peptide fragments. The fragments are generally considered not biologically active, although there is some controversy about how active some might be.

“Intact” PTH and molecular fragments

Most laboratories use what are called second-generation immunoassays that were originally billed as detecting “intact” PTH, but that in fact detect and include in their quantitation fragments as well. For most patients, the fragments are not an issue because a normally functioning kidney clears them. However, the fragments may accumulate in patients with impaired kidney function and especially in those on dialysis.

The assays measure the fragments to varying degrees, which makes them problematic for monitoring patients with chronic kidney disease–mineral bone disorder (CKD–MBD) and difficult to standardize. Although the assay may have originated more as a tool for the diagnosis of patients with primary hyperparathyroidism or hypoparathyroidism, “in many laboratories the majority of PTH measurements are now performed in patients with CKD,” according to an article e-published by the IFCC working group in Clinica Chimica Acta in October 2016 (Sturgeon CM, Sprague S, Almond A, et al. Perspective and priorities for improvement of parathyroid hormone (PTH) measurement–a view from the IFCC Working Group for PTH. Clin Chim Acta 2016 doi: 10.1016/j.cca.2016.10.016. [Epub ahead of print]) “The average clinician takes the results as gospel.

They don’t understand the nuances behind the tests,” said Stuart M. Sprague, DO, clinical professor of medicine at the University of Chicago Pritzker School of Medicine and chair of the division of nephrology and hypertension at NorthShore University HealthSystem in Evanston, IL.

Assay calibration

A major effort of the IFCC working group is to overcome the variability among test platforms through assay calibration. The World Health Organization has established an international standard of recombinant PTH, but none of the commercially available assays is calibrated to it, Sturgeon said. The IFCC group is working to get the assay manufacturers to recalibrate their tests using this standard.

“Manufacturers are absolutely critical, so we are very lucky that they are very enthusiastic and supportive of this effort,” Sturgeon said. “For the manufacturers, it is quite a lot of trouble and expense to change the calibration of an assay. For one thing, they have to change all their documentation.” It will take at least two years for manufacturers to standardize their methods and change their kit inserts. Sturgeon said that a standard introduced for prostate specific antigen tests cut those tests’ variation in half.

While they wait for that to happen, nephrologists can improve their test interpretation by finding out which manufacturer’s assay their laboratory is using, according to Kevin J. Martin, MD, director of the division of nephrology at Saint Louis University in Missouri.

Particular assays are consistent in their results, so by knowing which assay a laboratory is using, a clinician can get a better idea of the meaning of the results. Information on the performance of specific assays can be found in the literature, including the IFCC working group’s Clinica Chimica Acta article and in a National Kidney Foundation publication that can be found online www.kidney.org/sites/default/files/12-10-0202_LBA_PTH_CKD-MBD_Tool_feb4.pdf ).

But clinicians need to stay aware because laboratories can change suppliers without telling physicians. Martin said: “You might notice that followup PTH measurements appear higher than prior values and upon checking with the lab learn that they have changed the supplier of the PTH assay reagents. This has happened in our own hospital.”

Handling of samples

The working group is also developing evidencebased recommendations for the handling of PTH samples prior to analysis. For example, for blood samples taken in tubes containing EDTA, the group recommends the plasma be separated within 24 hours, the samples should be stored at 4 ºC, and the samples should be analyzed within 72 hours. For samples taken in dry tubes, the serum must be separated as soon as possible and analyzed within 4 hours or stored at -20 ºC for later analysis. For consistency within and between individuals, samples should be collected from the same sample site—central or peripheral—and clinical guidelines should state whether targets refer to peripheral or central venous concentrations.

The experts who write clinical treatment guidelines for CKD are aware of the lack of standardization and variation in assays and have tried to take them into account.

“KDIGO [Kidney Disease: Improving Global Outcomes] guidelines have widened the limits for the target levels for renal patients with advanced disease, because they were aware the assays couldn’t cope with the tighter limits,” Sturgeon said.

The KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease suggests that for patients with CKD stage 5D, PTH levels should be maintained “in the range of approximately two to nine times the upper normal limit for the assay. We suggest that marked changes in PTH levels in either direction within this range prompt an initiation or change in therapy to avoid progression to levels outside of this range.”

Because of the lack of faith in a single test or number, the guidelines also recommend that in patients with CKD stages 3–5D, therapeutic decisions should “be based on trends rather than on a single laboratory value, taking into account all available CKD–MBD assessments.”

Another avenue the working group is exploring is the development of a mass spectrometry-based reference method. Several mass spectrometry methods have been published that can provide accurate PTH measurements as well as identify and quantify PTH fragments—which could increase the understanding of the clinical relevance of these fragments. But these methods can involve difficult sample preparation steps and are much less sensitive—by a factor of 10—than the immunoassays.

Optimal PTH values for patients on dialysis less certain

Even the overall usefulness of PTH measurements is somewhat controversial and unclear.

“There is considerable uncertainty as to what range of PTH values would be desirable for patients on dialysis,” Martin said. “PTH is one marker of bone turnover and bone metabolism, but it is not the only one. And the correlation between these various PTH values and what’s happening in the bone is rather weak.”

The KDIGO guidelines note the lack of solid research in the area of CKD and bone metabolism: “The evidence on which existing recommended guideline treatment targets for serum concentrations of calcium, phosphate, and parathyroid hormone, and the strategies to achieve those targets, is exclusively observational and thus problematic for that reason.”

Just the same, the IFCC working group notes: “Most nephrologists consider there is already sufficient evidence linking high or very low PTH levels with adverse outcomes in patients with CKD–MBD. However, better understanding of the complex disease processes and biological interactions involved would be expected to help improve clinical outcomes for CKD–MBD patients and further research is highly desirable.”

But some things are known. “Hyperparathyroidism is common in CKD and results in significant morbidity and mortality if left untreated,” Sprague said. Better assays for detecting it would be a big step forward in both research and treatment, and the IFCC group posits that its goal of “improving the standardization of PTH methods is clearly feasible.”

Read the full article at http://onlinedigeditions.com/article/Variability+In+Parathyroid+Hormone+Assays%3A+Better+Standardization+On+The+Way%3F/2754545/397340/article.html.

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