Improvement of Renal Function in Transplanted Kidneys With a New
`Immunosuppressive Drug, 15s Deoxyspergualin: Treatment of
`Chronic Rejection
`
`Y. lino, E. Ohzono, M. Kawabe, S. Matsunobu, M. Takeuchi, N. Hayama, K. Hara, A. Terashi, S. Suzuki,
`and H. Amemiya
`
`15-DEOXYSPERGUALlN (DSG) is a drug discov(cid:173)
`
`ered by Takeuchi et all in 1981 as an antibiotic,
`extracted from Bacillus laterosporus. Thereafter, this drug
`was shown to have immunosuppressive activity by
`Umezawa et a12 and Dickneit et a1. 3 In animal experiments,
`DSG was useful as an immunosuppressant for kidney,
`liver, heart, and pancreas transplantation. In clinical cases
`of renal transplantations, DSG also was effective for the
`treatmcnt of rejection as rescue therapy. 4
`In this study, we examine the effects of DSG on trans(cid:173)
`plant kidney fUnction in chronic rejection.
`
`MATERIALS AND METHODS
`
`Six renal transplant recipients whose serum creatinine (SCr)
`levels were chronically elevated (mean SCr 3.7 ± 1.6 mg/dL) were
`treated with 5 mg/kg of DSG IV, given daily for 5 days. Biopsy
`findings were compatible with chronic rejection; in some cases.
`cyclosporine (CyA) nephrotoxicity coexisted. The transplanted
`kidneys were all obtained from living donors, and the starting time
`of treatment ranged from 6 months to 5 years after renal trans(cid:173)
`plantations.
`SCr and urine creatinine, urea. and electrolyte concentrations
`were measured before and after treatment. Arterial blood gases
`were also monitored. Maintenance immunosuppression with
`prednisone (5 to 10 mg/d) and eyA (3 to 5 mg/kg/d) was continued.
`During DSG administration, azathioprine (25 to 75 mg/d) was
`discontinued, because DSG is known to cause leukopenia.
`
`RESULTS
`SCr and urea nitrogen levels did not change significantly.
`The fractional N a excretion rate (FEna) changed from 1.7
`± 0.9 to 1.3 ± 0.6, although the serUm Na concentration
`was not altered. Urinary phosphate excretion was dimin(cid:173)
`ished (Up/cr), from 44 ± 12.3 to 34.7 ± 12.7 (P < .05).
`Urinary Ca excretion was decreased after the administra(cid:173)
`tion of DSG. The fractional tubular absorption of phospho(cid:173)
`rus (percent TRP) was significantly increased, from 55.5 ±
`12.2 to 70.0 ± 10.3% (P < .05), although the plasma
`C-PTH and midportion PTH were unaffected (Fig 1).
`Three of the six patients needed granulocyte colony(cid:173)
`stimulating factor (G-CSF) for treatment of leukopenia,
`and recovered with this treatment.
`
`DISCUSSION
`In the present study, we find that although DSG has no
`effect on SCr levels and blood urea nitrogen (BUN) in
`
`%TAP
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`TK
`
`KI
`
`MG
`
`AS
`
`HS
`
`TH
`
`Fig 1. Change in percent TRP after DSG. Black bar, before DSG
`treatment; speckled bar, after DSG treatment.
`
`chronic renal impairment after renal transplantation, this
`drug may improve tubular function, in terms of phosphate
`and sodium absorption. The most prominent change in
`electrolyte transport was phosphate transport, which was
`demonstrated by the increase in %TRP. From these re(cid:173)
`sults, we speculate that DSG may improve renal proximal
`tubular fUnction. where phosphate transport was regulat(cid:173)
`ed.s
`There are three possibilities for an explanation of the
`changes produced by DSG. First, renal blood flow may
`affect tubular electrolyte absorption. This is not the case
`here, since DSG did not produce changes in the glomerular
`filtration rate (GFR). Another possibility is that DSG may
`directly improve renal tubular function. There is no evi(cid:173)
`dence, however, that DSG can affect electrolyte transport,
`membrane enzymes, or carriers. Third, DSG may elicit
`these effects through improvement of chronic rejection by
`better suppression of immune responses. Dickneit ct al3
`showed that prolongations of skin graft survival occur after
`tht: use of DSG in rats. Also, in humans, DSG is the drug
`
`From the Department of Nephrology, Nippon Medical School,
`lidabashi. Tokyo. Japan.
`Address reprint requests to Y. lino, MD. Department of Nephrol(cid:173)
`ogy, Nippon Medical School, lidabashi. Chiyoda-ku, Tokyo 113.
`Japan.
`© 1 ~92 by Appleton & Lange
`0041-1345/92/$3.00/ + 0
`
`Transplantation Proceedings, Vol 24, No 4 (August), 1992: pp 1381-1382
`
`1381
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`NOVARTIS EXHIBIIT 2025
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`1382
`
`IINO, OHZONO, KAWABE I::T AL
`
`of choice for rescue therapy III acute rejection of renal
`transplants. 4
`In summary, the administration of DSG has increased
`tubular sodium and phosphate transport, and i~ is specu(cid:173)
`lated that these changes may be due to a modulation of
`immune responses by DSG, improving changes in the
`kidney interstitium after chronic rejection. DSG may be a
`useful drug, not only in acute rejection, but in chronic
`impairment of the transplanted kidney.
`
`REFERENCES
`1.' Takeuchi T, et al: J Antibiot (Tokyo) 34: 1619, 1981
`2. Urneda Y, Moriguchi M, Kuroda H, et al: J Antibiot (Tokyo)
`38:886, 1985
`3. Dickneit G, et al: In: Ishigami J (ed). Recent Advances in
`Chemotherapy. Tokyo: Tokyo University Press, 1985, p 949
`4. Amemiya H, ct al: Transplantation 49:337, 1990
`5. lino Y, et al:Am J PhysioI236:F387, 1979
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