Peritoneal Sclerosis in a Patient on Long-term Continuous Ambulatory Peritoneal Dialysis (CAPD). : An Autopsy Case.

若年性ネフロン癆による慢性腎不全でCAPD (continuous ambulatory peritoneal dialysis)導入し, 6年6ヵ月後に死亡した20歳男性の1剖検例を報告した。CAPD導入数カ月後, 腹膜炎による除水能低下を起こしたが, 約5ヵ月後に回復した。CAPD導入1年5ヵ月以降重症な腹膜炎罹患により除水能低下状態が遷延したが, 次第に回復した。しかし, 体液貯留傾向のため, 3年2ヵ月後より高張透析液を使用し除水量の増加を得たが, 3年9ヵ月後に不可逆的な除水能低下状態となった。一方, クレアチニンの透析排液/血漿濃度比(D/P)から見た溶質除去能は, その約半年後まで保たれており, 血清クレアチニン値の上昇は軽度であった。剖検にて腹膜の線維性肥厚と高度の内腔狭窄を伴う動静脈硬化を認め, 腹膜硬化症と診断した。本例の腹膜硬化症は, 頻回の腹膜炎と高張透析液の使用が主な原因と考えられた。腹膜機能を長期に維持するためには, 腹膜炎の予防と高張透析液の使用を最小限にすることが重要と考えられた。A 20-year-old man, treated with continuous ambulatory peritoneal dialysis (CAPD) for 6.5 years because of-end-stage renal disease due to juvenile nephronophthysis, died of ultrafiltration failure, and the morphological examination of peritoneum was carried out at autopsy. Nine episodes of peritonitis developed, and ultrafiltration transiently decreased after each episodes. At 2 years after the start of CAPD, severe peritonitis occurred, and then his body weight and blood pressure gradually increased. At 4 years after the beginning of CAPD, when hyperosmotic dialysate was frequently used, ultrafiltration was irreversively deteriorated. On the other hand, creatinine dialysate/plasma ratio remained within normal limits for about several months, and the increase in the level of serum creatinine was very little. The peritoneum obtained at autopsy revealed marked fibrous thickening as well as the conspicuous luminal narrowing of arteries and veins due to intimal thickening. The development of peritoneal sclerosis seemed to be related with the frequency and severity of peritonitis and the use of hyperosmotic dialysate

Individual follow up of bioluminescence (parasite load) and “lesion” area in mice treated with WR279396 without any dressing.

<p>10⁴ luciferase-expressing <i>L. major</i> metacyclic promastigotes were inoculated into the dermis of the right ear of C57BL/6 mice (n = 10; day 0) treated with WR279396 (5 applications (↑) for 10 days) at day 11 post-inoculation. The parasite load (photons/sec/ear) in individual mice (A, B) and the area (mm2; C) of the lesion displayed by the same mice were followed for 3 months. (A, B, C) Green colour assesses the profile in mice that controlled their ear parasite load, i.e. exhibiting a bioluminescence value<1×10⁶ photons/sec/ear at day 33 (green points in panel A and green lines in panels B and C). In contrast, red colour corresponds to mouse ears that display a high bioluminescence value at day 33 (>1×10⁶ photons/sec/ear; red points in panel A and red lines in panels B and C). Note that lesion area values (C) did not assess any clinical failure except in 1 mouse (arrow). Values obtained for control mice are shown in the grey areas indicated in each graph.</p

C57BL/6 mice given an application of WR279396 formulation under an occlusive dressing.

<p>10⁴ luciferase-expressing <i>L. major</i> metacyclic promastigotes were inoculated into the dermis of the right ear of C57BL/6 mice (day 0). (a, b) From day eleven post-<i>L. major</i> inoculation, the topical ointment WR279396 was applied directly to parasite-loaded ears and (c) then covered with an adhesive polyurethane dressing (arrow). (d,e) Two independent leaflets of surgical tape were applied directly on the occlusive dressing. This surgical tape permitted maintenance of the dressing and kept the formulation in contact with the parasite-loaded site for two days.</p

<i> In vivo</i> bioluminescence imaging of <i>Leishmania</i> in the C57BL/6 ear model.

<p>Simultaneous follow up of parasite load in the ear dermis and of lesion onset, features and cure in mice inoculated with luciferase-transgenic <i>Leishmania major</i>. 10⁴ luciferase-expressing NIH 173 metacyclic promastigotes were inoculated into the dermis of the right ear of C57BL/6 mice (day 0) and followed for more than 80 days. The bioluminescent signal is displayed as a pseudo-colour image representing light intensities over the body surface area. Red represents the most intense signal while blue corresponds to the weakest one. A, B: Individual follow up of a representative mouse left without any ointment application. Clinical features (A) were simultaneously monitored with parasite load fluctuations assessed by the bioluminescence of luciferase-expressing parasites (B). (C) Bioluminescence quantification of the parasite load (left panel; photons/sec/ear; grey area = background measurement) and “lesion” area (right panel; mm²) were followed for 7 mice left without any ointment and depicted as medians +/−sd. Note the detection of a bioluminescence signal before any significant clinically detectable features. Of note, the so called “lesion” area measured between day 11 and day 15 was still made up of inflammatory processes free of any leukocyte infiltrates.</p

Determination of the most suitable regimen for WR279396 application under an occlusive dressing.

<p>Eleven days post-inoculation of 10⁴ luciferase-transfected <i>L. major</i> parasites, three groups of 7 mice were constituted: In the control group, mouse ears were left without any ointment (blue plain line), and in the other group WR279396 was applied on the mouse ear under an occlusive dressing with different application frequencies; either 5 applications/10 days (brown plain line) or 5 applications/5 days (brown dotted line). Bioluminescence evaluation of parasite load was performed over the course of 64 days post-inoculation (A). Note that the rebound of the parasite load in the every day-application group can be associated to a more severe lesion as illustrated by a representative mouse at day 36 post-inoculation (B/5 days). White squares delimit the “lesion” area. (C, D) Parasites loads were analysed with ANOVA whose two factors were the treatment (WR279396 10 days or 5 days) and the period of observation. Pair wise comparisons using t-tests were realized for each combination of factors.</p

Boundaries of the one-sided triangular test.

<p>Left to right; top to bottom: pa = 0.18, pa = 0.20, pa = 0.25, example of sequential analyses with modeled data.</p

Differences in sample size for a non-inferiority trial when calculated using rates or allowing for survival analysis.

<p>Sample size expressed as % underestimation when calculated using rates vs. survival analysis; delta set at 5, 7, 10%; efficacy of comparator arm (Ref) set at 80% dark blue; 85% pale blue; 90% pale yellow. The size of the bubble is proportional to the sample size (figure next to the bubble).</p

Sample size calculation for the one-sided triangular test.

<p>pa = 0.18, 0.20 and 0.25; and two-sided test, pa = 0.20.</p

Sample size calculations for comparative superiority trials.

<p>Sample size calculations for comparative superiority trials.</p

Typical CL lesions.

<p>Typical CL lesions.</p