Weight of Evidence versus Weight of Speculation to Evaluate the a2u-Globulin Hypothesis

whereas the severity of spontaneous chronic nephropathy in treated male rats relative to controls increased from 52 and 104 weeks. As a result of the current discussion in the literature (3), the kidney specimens were reanalyzed for the hallmarks of x2u-globulin nephropathy sequelae, namely the presence of granular casts and linear mineralization (8). These changes were not observed in male rats receiving 250, 1,000, or 2,000 mg/kg of gabapentin for 2 years. In terms of proliferative effects, there were 3 foci of atypical hyperplasia of renal tubules: 2/50 were found in male rats at 1,000 mg/kg and 1/50 male rats at 2,000 mg/kg of gabapentin. These kidney examinations in the 2-year study included four sections (two from each kidney) from every animal in the group (50/sex/group), amounting to 1,600 kidney sections in the 2-year rat study. This standard procedure seems to adequately sample the kidney. Reference was made to renal accumulation of gabapentin and to its ability to bind a2u-globulin. Metabolic disposition data revealed no differences in the accumulation of gabapentin in the kidney of male and female rats. Gabapentin distributes rapidly to the kidney in both sexes, and approximately 10-12% of the dose is found at 2hr post-dose. The elimination decay is rapid, and 0.20-0.14 gabapentin radioequivalents in micrograms per gram are found at 12 hr post-dose. Full profile toxicokinetic studies have shown linear kinetics without accumulation, and elimination follows rapid clearance from the plasma and organ compartments. Recoveries in the mass balance studies yielded 99% or more of the administered dose. Why such a diverse series of chemicals causes a putatively similar microglobulin nephropathy with (i.e., unleaded gasoline) and without (i.e., gabapentin) nephrocarcinogenesis is intriguing. Evaluation of the gabapentin data does not prove or disprove that a2u-globulin accumulation precedes, promotes, or causes renal cancer in rats over a 2-year constant exposure at toxicity-limiting doses. We propose that although morphofunctional features may appear similar for all documented cases of this xenobioticinduced nephropathy, different mechanisms may be operative. Alternatively, a structural comparison of the x2u microglobulin species would assert this microglobulin not to be the same in all cases when induced by the diverse chemicals. The work by Hildebrand et al. (9) would indicate some support to this notion. In the case of gabapentin, in which we have substantial data on hand, it is difficult to advocate existing mechanisms because of the drug's lack of metabolism or biotransformation, lack of serum protein binding, or lack of significant organ accumulation. It remains unanswered whether data on cell proliferation or specific 4x2uglobulin binding to renal tubule proteins would substantiate current mechanisms. Clearly new data, rather than new assumptions, will give fresh insight to our understanding of the a2u nephropathy puzzle.