December 2019: Abstract Round Up

ADPKD

Automated Measurement of TKV and TLV in Patients with ADPKD

Journal of the American Society of Nephrology. 2019;30(8):1514-1522

In patients with autosomal dominant polycystic kidney disease (ADPKD), the formation and growth of cysts in the kidney and the liver result in progressive increases in total kidney volume (TKV) and total liver volume (TLV). Manual tracing of kidneys and livers is laborious and time-consuming. Maatje D. A. van Gastel, MD, and colleagues developed a fully automated segmentation method for measurement of TKV and TLV; the method utilizes a deep learning network optimized to perform semantic segmentation of kidneys and liver.

To train the network, the researchers used 80% of a set of 440 abdominal magnetic resonance images (T2-weighted HASTE coronal sequences) from patients with ADPKD. The remaining 20% were used for validation. Kidneys and livers were also segmented manually. An additional test set of images from 100 patients was used to evaluate the method’s performance; of those patients, 45 were also involved in longitudinal analyses.

There was high correlation between TKV and TLV measured by the automated approach and manually traced TKV and TLV (intraclass correlation coefficients, 0.998 and 0.996, respectively), with low bias and high precision (<0.1% for TKV and –1.6% for TLV). The findings were comparable with inter-reader variability of manual tracing (<0.1% for TKV and –1.5% for TLV). For longitudinal analysis, bias and precision were <0.1% for TKV and 1.4% for TLV growth.

The researchers said, “These findings demonstrate a fully automated segmentation method that measures TKV, TLV, and changes in these parameters as accurately as manual tracing. This technique may facilitate future studies in which automated and reproducible TKV and TLV measurements are needed to assess disease severity, disease progression, and treatment response.”

DIABETES

Baseline Kidney Function and Decline in Kidney Function

Nephrology Dialysis Transplantation. 2019;34(8):1328-1335

The available data on the effects of uric acid on diabetes concentrate on patients with preserved kidney function. Ko Hanai, MD, PhD, and colleagues in Japan conducted a study to test the hypothesis that among patients with diabetic kidney disease, the effects of serum uric acid levels on the decline in kidney function differ depending on baseline kidney function.

The historical cohort study included 7033 patients with type 2 diabetes; the patients were divided into two groups: those with nonchronic kidney disease (non-CKD), with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (n=4994), and those with CKD, with an eGFR <60 mL/min/1.73 m2 (n=2039). The composite end point was a ≥30% decrease in eGFR from baseline or initiation of renal replacement therapy. Multivariate Cox proportional hazards models were used to estimate the hazard ratio (HR) of serum uric acid levels at baseline.

With respect to the end point, there was a significant interaction between uric acid levels and baseline eGFR (P<.001). The HRs of 1 mg/dL increase in uric acid levels were 1.13 (95% confidence interval [CI], 1.05-1.22; P=.002) in the non-CKD group and 0.93 (95% CI, 0.88-0.99; P=.02) in the CKD group. When patients were classified by quintile of levels of uric acid, the HRs of those in the fifth quintile versus the first quintile were 1.64 (95% CI, 1.23-2.18; P<.001) in the non-CKD group and 0.76 (95% CI, 0.58-0.99; P=.05) in the CKD group.

“The effects of uric acid on kidney function decline might differ depending on baseline kidney function in type 2 diabetic patients,” the researchers said. “High uric acid levels are the prognostic factor only in patients with preserved kidney function.”

DIALYSIS

Differences in Technique Failure and Mortality Rates among Peritoneal Systems

Nephrology Dialysis Transplantation. 2019;34(6):1035-1044

Neil Boudville, DMed, and colleagues conducted a study to compare peritoneal dialysis systems. The researchers sought to examine differences in technique failure and patient survival among different peritoneal company systems.

Participants were all patients who initiated peritoneal dialysis in Australia and New Zealand between 1995 and 2014. The groups were identified according to the initial peritoneal dialysis company system they received. The primary outcome of interest was a composite of peritoneal dialysis technique failure and death.

The total cohort included 16,575 patients; the study groups were patients using systems manufactured by (1) Baxter (n=13,438; 81%); (2) Fresenius Medical Care (n=2848; 17%); and (3) Gambro (n=289; 2%). Of those, 11,870 (72%) developed technique failure, including 5421 (33%) who died.

For all patients, median time to technique failure or death was 625 days: 629.5 days with Baxter systems, 620.5 days with Fresenius Medical Care systems, and 538 days with Gambro systems. Compared with patients with Baxter systems, there was a statistically significant increase in technique failure or mortality rates in patients on Gambro systems (adjusted incidence rate ratio [IRR], 1.46; 95% confidence interval [CI], 1.33-1.62) and Fresenius Medical Care systems (adjusted IRR, 1.10; 95% CI, 1.01-1.19).

There were no differences among the three systems in patient survival.

The researchers said, “Peritoneal dialysis systems manufactured by different companies may be associated with important differences in peritoneal dialysis technique survival. This needs to be confirmed with adequately powered, prospective randomized controlled clinical trials.”

Effects of Gender Differences in Healthcare Access among Hemodialysis Patients

Nephrology Dialysis Transplantation. 2019;34(6):1026-1035

Women have a higher prevalence of chronic kidney disease than men, yet more men start renal replacement therapy (RRT) compared with women. Researchers, led by Alexander Kainz, PhD, conducted a study to test the hypothesis that there are gender differences in access to healthcare. The researchers sought to examine whether characteristics and outcomes of hemodialysis patients differ by sex over time.

The study cohort included 28,323 adults in the Austrian Dialysis Registry who initiated hemodialysis from 1965 to 2014. The researchers used Cox regression models to analyze trends in patient characteristics by sex and decade with mortality; those trends were compared with mortality among the general population in Austria.

More men than women initiated hemodialysis: 60.1% men versus 39.3% women overall. There were minor differences among decades and age groups. In the general population, the male-female mortality rate ratio ranged from 1.2 to 2.4 for age groups >18 years; in hemodialysis patients, the range was from 0.80 to 1.3 (closer to 1 than in the general population, but consistently >1 in decades 3 to 5).

In earlier decades, glomerulonephritis was the primary cause of end-stage renal disease (ESRD) in both men and women. In recent decades, diabetes and hypertension were the leading causes of ESRD in both sexes.

In interaction analyses, the mortality risk associated with hemodialysis access type (recorded only in decade 5) was significantly lower for men than for women.

In conclusion, the researchers said, “The male-female mortality rate ratio and the proportion of women starting hemodialysis were remarkably stable, which does not support the hypothesis of gender differences in healthcare/hemodialysis access, or could imply that such differences might have persisted over decades. Future research should expand to other countries and other forms of RRT.”

PEDIATRIC KIDNEY DISEASE

Association of Higher versus Lower eGFR at Dialysis Initiation and Survival

Journal of the American Society of Nephrology. 2019;30(8):1505-1513

In adults with end-stage renal disease (ESRD), there is no improvement in survival associated with initiating dialysis at a higher level of estimated glomerular filtration rate (eGFR). There are few available data on the association between starting dialysis at higher eGFR and survival in children with chronic kidney disease. Erica Winnicki, MD, and colleagues conducted a study to examine whether there is a survival benefit of dialysis initiation at a higher eGFR among pediatric patients.

The retrospective cohort study included pediatric patients 1 to 18 years of age who initiated dialysis between 1995 and 2015, according to the US Renal Data System. The primary predictor was eGFR at time of initiation of dialysis, categorized as higher (eGFR >10 mL/min/1.73 m2) versus lower eGFR (eGFR ≤10 mL/min/1.73 m2).

Of 15,170 children identified, 29% (n=4327) had a higher eGFR (median eGFR, 12.8 mL/min/1.73 m2) at time of dialysis initiation. Compared with children with a lower eGFR (median, 6.5 mL/min/1.73 m2), those with higher eGFR at initiation of dialysis were more often white, girls, underweight or obese, and more likely to have glomerulonephritis as the cause of ESRD.

Among children with higher versus lower eGFR at dialysis initiation, the risk of death was 1.36 times higher (95% confidence interval [CI], 1.24-1.50). There were differences by treatment modality (hemodialysis versus peritoneal dialysis) in the association between timing of dialysis and survival: (P<.001 for interaction). The association was stronger among children initially treated with hemodialysis (hazard ratio [HR], 1.56; 95% CI, 1.39-1.75 versus HR, 1.07; 95% CI, 091-1.25; respectively).

“In children with ESRD, a higher eGFR at dialysis initiation is associated with lower survival, particularly among children whose initial treatment modality is hemodialysis,” the researchers said.

TRANSPLANTATION

Identifying Heterogeneity of Transplant Glomerulopathy

Journal of the American Society of Nephrology. 2019;30(4):625-639

To date, there is no precise characterization of the heterogeneity of transplant glomerulopathy, a glomerular lesion commonly observed following kidney transplant. The lesion, associated with poor prognosis, is not a specific entity but the end stage of overlapping disease pathways.

Olivier Aubert, MD, PhD, and colleagues conducted a study of consecutive kidney transplant recipients from three centers in France and one in Canada who presented with a diagnosis of transplant glomerulopathy, diagnosed by Banff cg score ≥1 by light microscopy; the biopsies were performed from January 2004 through December 2014.

There were 8207 post-transplant allograft biopsies performed during the inclusion period. Of those, the researchers identified 552 biopsy samples (from 385 patients) with transplant glomerulopathy (incidence of 6.7%). Median time from transplant to transplant glomerulopathy was 33.18 months. Kidney allograft survival rates at 3, 5, 7, and 10 years after diagnosis were 69.4%, 57.1%, 43.3%, and 25.5%, respectively.

An unsupervised learning method that integrated clinical, functional, immunologic, and histologic parameters revealed five transplant glomerulopathy archetypes characterized by distinct functional, immunologic, and histologic features and associated causes and distinct allograft survival profiles. Among the five archetypes, there were significant differences in allograft outcomes; allograft survival rates 5 years after diagnosis ranged from 88% to 22%.

The researchers said, “A probabilistic data-driven archetype analysis approach applied in a large, well defined multicenter cohort refines the diagnostic and prognostic features associated with cases of transplant glomerulopathy. Reducing heterogeneity among such cases can improve disease characterization, enable patient-specific risk stratification, and open new avenues for archetype-based treatment strategies and clinical trials optimization.”

Diagnosing Subclinical Clinical Acute Rejection

Journal of the American Society of Nephrology. 2019;30(8):1481-1494

In kidney transplant recipients with stable graft function, surveillance biopsies can reveal histologic features of acute rejection and borderline changes associated with adverse graft outcomes. Weijia Zhang, PhD, and colleagues conducted an analysis designed to identify noninvasive biomarkers of subclinical acute rejection in an effort to avoid the risks and costs associated with repeated biopsies.

The researchers utilized data on subclinical histologic and functional changes in kidney transplant recipients from the prospective GoCar (Genomics of Chronic Allograft Rejection) study. Eligible participants underwent surveillance biopsies over 2 years. Those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant were identified. RNA sequencing on whole blood collected from 88 individuals at the time of 3-month surveillance biopsy was performed to identify transcripts associated with ACR-3. A novel sequencing-based targeted expression assay was then developed; the gene signature was validated in an independent cohort.

The risk of clinical acute rejection at 12 and 24 months was significantly higher in those with ACR-3 than in those without ACR-3. In adjusted Cox analysis, participants with ACR-3 were also at higher risk of faster decline in graft function and decreased graft survival.

The researchers identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3; the gene signature was validated using microarray expression profiles of blood samples from 65 transplant recipients in the GoCar cohort and three public microarray datasets. Tests of the targeted expression assay on the basis of the 17-gene set in an independent cohort of 110 transplant recipients demonstrated that the gene set identified individuals at increased risk of ongoing acute rejection and future graft loss.

The researchers said, “Our targeted expression assay enabled noninvasive diagnosis of subclinical acute rejection and inflammation in the graft and may represent a useful tool to risk-stratify kidney transplant recipients.”

Everolimus-Based Immunosuppression versus Standard of Care

Transplantation. 2019;103(8):1705-1713

There are few available data on the long-term efficacy of everolimus-based immunosuppression for kidney transplant recipients. Previous randomized controlled trials are limited by short duration of follow-up, making it difficult to assess the impact on graft and patient survival. Tracey Ying, FRACP, and colleagues linked individual trial participants to the Australian and New Zealand Dialysis and Transplant Registry. The researchers used a one-step meta-analysis approach to examine the 10-year risk of graft loss, mortality, and graft function in participants from five randomized trials of everolimus-based immunosuppression.

A total of 242 patients were randomized to everolimus and 107 control patients were followed for a median of 9 years. There were no significant differences between the two groups in the risk of all-cause graft loss (adjusted hazard ratio [HR], 1.16; 95% confidence interval [CI], 0.69-1.94), mortality (adjusted HR, 1.51; 95% CI, 0.78-0.93), or death-censored graft loss in the everolimus group versus the control group (adjusted HR, 1.00; 95% CI, 0.50-2.01).

For the 279 patients in the early initiation (de novo or <6-month conversion) everolimus trials, there was no significant difference between the intervention group and controls in decline in estimated glomerular filtration rate (eGFR) (mean difference in the slope of eGFR 0.01 mL/min/1.73 m2).

“This registry-based analysis with long-term follow-up found no differences in graft and recipient survival or graft function for everolimus over current standard of care,” the researchers said.