According to the results of two 12-year studies, levels of circulating tumor necrosis factor receptor 1 and 2 (TNFR1 and TNFR2) predicts kidney disease in both type 1 and type 2 diabetes….
Andrzej S. Krolewski, MD, PhD, from the Joslin Diabetes Center in Boston, and colleagues reported that, the cumulative incidence of end-stage renal disease (ESRD) among those with type 2 diabetes who had the highest quartile of TNFR1 at baseline was 54% at 12 years, compared with only 3% for the other quartiles (P< 0.001).
Among those with type 1 diabetes, the cumulative incidence of estimated glomerular filtration rate less than 60 mL/min per 1.73 m2 for those in the highest quartile of TNFR2 was 60% after 12 years, compared with 5% to 19% in the other quartiles. Both studies were published online ahead of print in the Journal of the American Society of Nephrology.
The Joslin Study of the Genetics of Type 2 Diabetes and Kidney Complications enrolled 410 people between 1991 and 1995. At the end of 2004, 267 (65.1%) were still alive. ESRD had developed in 59 patients, of whom 51 had died.
The patients in the type 1 diabetes study were drawn from two different Joslin studies with a total enrollment of 628. All had high normal GFR at baseline. The researchers used progression to chronic kidney disease stage 3 or above (CKD³) over the 12-year observation period as the primary outcome. In both instances, several dozen possible markers for inflammation in blood and urine were obtained at baseline. The subjects’ kidney function and status were then followed during the course of 12 years.
The impact on kidney function in those with both types of diabetes is well-known, and the researchers wanted to examine the TNF pathway as a possible predictive marker for renal disease.
In the type 2 diabetes study, concentrations of markers for endothelial dysfunction and systemic inflammation were similar in all three groups. Concentration of markers for the TNF pathway (free TNF alpha, total TNF alpha, TNFR1 and TNFR2) were highest among those developing end-stage renal disease, and intermediate for those who died from non-kidney-related causes. There also was a high intercorrelation among the pathway markers, particularly TNFR1 with TNFR2 (Spearman correlation r=0.90, P<0.001). This was not related to cross-reactivity between the antibodies used for the assay, according to the researchers.
When they looked at those patients with proteinuria at baseline, the cumulative risk of renal disease in the highest quartile of TNFR1 rose steeply and at a constant rate throughout the study. Among those without proteinuria, the first cases of ESRD did not begin to show up for six years.
A Cox proportional hazard analysis controlling for influential clinical characteristics found that each of the TNF pathway markers remained significant. The effects of both TNF receptor markers were similar to that of total TNF alpha, but were much stronger. When both TNFR1 and TNFR2 were entered into the model, the effect of TNFR1 remained significant but TNFR2 did not.
Among those with type 1 diabetes, patients with the highest quartile of TNFR2 values were three times more likely to have renal decline than those in the other quartiles (HR 3.0, 95% CI 1.7 to 5.5). The risk associated with high TNFR1 values was slightly less than that seen in those with elevated TNFR2.
As with type 2 diabetes, the risk was higher over time among those with higher TNF markers. For patients in the highest quartile of TNFR2, the cumulative risk of being in CKD class 3 or better increased steeply at a constant rate from the beginning. Among those in the lower quartiles, cases were fewer and occurred later.
When entered into the Cox models with the influential characteristics, the effect of TNFR2 was strongest with TNFR1 close behind, while total and free TNF alpha no longer was significant. In pair wise comparisons across the TNF pathway makers, TNFR2 was dominant.
One of the limitations was the use of less-than-certain documentation among the 19 patients who had indications of kidney-related death on death certificates but were not registered. There also was some concern with miscalculation of patients due to biologic variation in the assessment of baseline characteristics. There was also a high concentration of Caucasians among the participants that might limit its usefulness among other racial/ethnic groups.
Despite the limitations, “(our) findings in type 1 and type 2 diabetes point to the specific involvement of TNFR-mediated pathway rather a general inflammation in the development of renal function decline and progression to ESRD,” the authors concluded.
Results from the two studies may help speed the search for new therapeutic agents to prevent or slow the kidney decline seen in diabetes, they wrote.
- Among those with type 1 diabetes, patients with the highest quartile of TNFR2 values were three times more likely to have renal decline than those in the other quartiles, and the risk associated with high TNFR1 values was slightly less than that seen in those with elevated TNFR2.
- These studies found that levels of circulating tumor necrosis factor receptor 1 and 2 (TNFR1 and TNFR2) predict kidney disease in both type 1 and type 2 diabetes.
Godha T, et al “Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes” J Am Soc Nephrol 2012; 23: DOI: 10.1681/ASN.2011060628