chuckle.... Mike, I used to work at SyStemix, very early. Don't know him, but I regard this (Perry on the Board) as a strong positive........
Kidney Int 1999 Feb;55(2):674-85
Nature and mediators of renal lesions in kidney transplant patients given
cyclosporine for more than one year.
Benigni A, Bruzzi I, Mister M, Azzollini N, Gaspari F, Perico N, Gotti E, Bertani T, Remuzzi G
Department of Immunology, Ospedali Riuniti Bergamo-Mario Negri Institute for Pharmacological Research, Italy.
[Medline record in process]
BACKGROUND: Cyclosporine (CSA) has improved patients and organ-graft survival rates, but its chronic nephrotoxicity is
still an issue. Although prolonged vasoconstriction could contribute to chronic CsA tubulointerstitial changes by producing
chronic ischemia, this relationship has been difficult to demonstrate thus far, and cellular origin and mediators of these structural
alterations remain ill-defined. METHODS: As a part of a clinical trial in kidney transplant recipients on triple
immunosuppressive therapy (CsA, azathioprine and steroid), which includes renal biopsy as "per protocol," 22 patients enrolled
between 12 and 24 months posttransplantation underwent renal hemodynamic evaluation by measuring glomerular filtration rate
and renal plasma flow by the plasma clearance of unlabeled iohexol and the renal clearance of para-aminohippuric acid,
respectively. In parallel, the CsA pharmacokinetic profile was also determined. A week later, a protocol biopsy of kidney graft
was performed. Light microscopy examination and localization of endothelin-1, RANTES, monocyte chemoattractant protein-1
gene expression by in situ hybridization in the graft specimens were evaluated and related to the pattern of histologic lesions.
RESULTS: Ten out of 22 kidney transplant recipients who underwent the protocol biopsy had CsA nephrotoxicity, eight had
chronic rejection, and four had no lesions at histological examination. The total daily exposure to CsA was higher in patients
with CsA nephrotoxicity than in those with chronic rejection or no lesions at biopsy. Renal function was preserved in the CsA
toxicity group as compared with the chronic rejection group, despite some degree of renal hypoperfusion. Tubular atrophy and
striped interstitial fibrosis were found in all patients with light microscopical evidence of CsA nephrotoxicity, whereas glomerular
and arteriolar lesions were less frequent. Intense staining for endothelin-1, RANTES, and monocyte chemoattractant protein-1
mRNAs selectively localized at tubular epithelial cells was found in biopsies taken from patients with CsA nephrotoxicity, but
not in the chronic graft rejection group, whose tubuli had only minimal staining for RANTES mRNA on a few occasions.
CONCLUSION: Long-term CsA administration to kidney allograft recipients leads to tubulointerstitial injury independently of
its vascular effect. The possible contribution to the development of interstitial fibrosis of inflammatory and growth factors
released by tubular cells in which CsA accumulates is proposed.
Am J Kidney Dis 1999 Jan;33(1):11-20
Unique changes in interstitial extracellular matrix composition are associated
with rejection and cyclosporine toxicity in human renal allograft biopsies.
Abrass CK, Berfield AK, Stehman-Breen C, Alpers CE, Davis CL
Department of Medicine, University of Washington School of Medicine, and the Veterans Affairs Puget Sound Health Care
System, Seattle 98108, USA. cabrass@u.washington.edu
Renal allograft loss from chronic rejection or cyclosporine toxicity (CsAT) is characterized by progressive interstitial fibrosis,
yet the protein composition of these lesions is unknown. The normal tubular basement membrane (TBM) contains laminin
(LM), collagen IV (containing collagen IV alpha chain 1 [COL4A1] and COL4A2), thrombospondin (TSP), and fibronectin
(FN). Only TSP and FN extend beyond the TBM into the interstitial space. Very scanty amounts of interstitial collagens (I and
III) are detected in the interstitium. In a pilot study of human renal allograft biopsy specimens, three patterns of extracellular
matrix (ECM) composition were identified. Pattern 1 showed no change in ECM composition; pattern 2 showed generalized
accumulation of collagens I and III in the interstitium; and pattern 3 showed new expression of COL4A3 and LM-beta2 in the
proximal TBM. Criteria were established for the clinicopathological diagnosis of CsAT and rejection. These diagnoses were
correlated with the ECM composition in 22 renal allograft biopsy specimens. Control groups were examined in a similar
manner and included native kidney biopsy specimens from patients with other allografts (n = 7), renal biopsy specimens from
patients with glomerular disease (n = 9), and renal allograft biopsy specimens from patients without clinicopathological evidence
of renal disease. These data show that rejection is associated with pattern 3 and CsAT is associated with pattern 2. Thus,
detection of ECM composition may be a useful adjunct to standard microscopy in distinguishing rejection from CsAT in renal
allograft biopsy specimens. These data suggest that interstitial fibrosis associated with rejection and CsAT result from different
pathogenic mechanisms. |
