Proximal tubular dysfunction as an indicator of chronic graft dysfunction

New strategies are being devised to limit the impact of renal sclerosis on graft function. Individualization of immunosuppression, specifically the interruption of calcineurin-inhibitors has been tried in order to promote better graft survival once chronic graft dysfunction has been established. However, the long-term impact of these approaches is still not totally clear. Nevertheless, patients at higher risk for tubular atrophy and interstitial fibrosis (TA/IF) development should be carefully monitored for tubular function as well as glomerular performance. Since tubular-interstitial impairment is an early event in TA/IF pathogenesis and associated with graft function, it seems reasonable that strategies directed at assessing tubular structural integrity and function would yield important functional and prognostic data. The measurement of small proteins in urine such as α-1-microglobulin, N-acetyl-beta-D-glucosaminidase, alpha/pi S-glutathione transferases, β-2 microglobulin, and retinol binding protein is associated with proximal tubular cell dysfunction. Therefore, its straightforward assessment could provide a powerful tool in patient monitoring and ongoing clinical assessment of graft function, ultimately helping to facilitate longer patient and graft survival associated with good graft function.

Prior Ischemic Treatment Renders Kidney Resistant to Subsequent Ischemia

Prior ischemia leads to resistance against subsequent ischemic insults. The mechanisms that underlie this adaptive response remain unidentified. Thus, we studied whether the reduced susceptibility of mice previously subjected to the ischemia to ischemia/ reperfusion injury is related with altered inflammatory responses. Thirty minutes of bilateral kidney ischemia results in significantly increased plasma creatinine and blood urea nitrogen levels in BALB/c male mice. There is severe disruption of actin cytoskeleton of proximal tubular cells in the outer stripe of the outer medulla 24 hours post-ischemia. When mice are subjected to 30 minutes of bilateral ischemia 8 days later, there is no increase in plasma creatinine and blood urea nitrogen levels and the post-ischemic disruption of actin cytoskeleton of proximal tubular cells is much less. Inflammatory responses have highly implicated with ischemia/reperfusion injury. Ischemia results in the increased tissue myeloperoxidase (MPO) activity that is a marker of leukocyte infiltration. There is, however, no the post-ischemic increase of MPO activity in kidneys previously subjected to ischemia. Post-ischemic expression of tissue intercellular adhesion molecule-1 (ICAM-1) is greater in the kidney previously sham-operated than in the kidneys previously subjected to ischemia. In conclusion, prior ischemia protects kidney function and morphology against subsequent ischemia 8 days later. The resistance is associated with the reduced post-ischemic leukocyte infiltration due to the reduced post-ischemic ICAM-1 expression.

Impairment of the renal tubular acidification kinetics by lithium

We studied the kinetics of HCO-3 reabsorption in the middle proximal (MPT) and distal convoluted tubules (DCT) by measuring continuously intratubular pH with Sb-microelectrodes in stopped-flow microperfusion (HCO-3, 30 mM Ringer) experiments. Male Wistar rats (240-280 g) were injected ip with LiCl (4mEqkg-1 day-1) for 4 days (Li) and were compared to controls (C). Steady-state pH increased in MPT from 6.64 + or - 0.02(57) to 6.89 + or - 0.02(45), mean + or - SEM (number of measurements) on tissue from 13 rats in each group, and from 6.87 + or - 0.5(30) to 7.08 + or - 0.01(63) in DCT. HCO-3 reabsorption decreased from 1.32 + or - 0.08(57) to 0.96 + or - 0.4(45) nmol cm-2 s-1 in MPT and from 0.85 + or - 0.07(30) to 0.45 + or - 0.04(63) in DCT. These data indicate that lithium affected the acidification mechanism in MPT and DCT, probably through an impairment of the Na+ -H+ antiport in both tubular segments