Acute humoral rejection (AHR) is currently perceived as an immunological reaction against donor antigens mediated by complement-binding antibodies. C4d, a split product of complement activation and bound to endothelial cells of the peritubular capillaries, is used as a diagnostic marker for AHR. We report on three patients with biopsyproven acute humoral rejection who were treated initially with plasmapheresis (PS). As two of the patients did not recover renal function, and biopsy showed persistent C4d staining after PS, immunoadsorption (IAS) was additionally performed on them. In all patients, renal function recovered, and follow-up biopsies in two patients showed complete disappearance of C4d, 29 days and 58 days after transplantation and only minimal residual C4d deposits in one patient 48 days after transplantation. We conclude that successful treatment of AHR is followed by complete resolution of serological and histological markers of AHR, displayed by the disappearance of C4d.
Our results suggest that the acceleration of PMN apoptosis in the presence of CU is mediated via an antibody-dependent activation of the classical complement pathway mobilizing both caspase-dependent and -independent pathways.
To the Editors:Ruf et al. report hyponatremia to be an excellent predictor of outcome in patients with advanced cirrhosis and that the presence of hyponatremia significantly increases the efficacy of the Model for End-Stage Liver Disease (MELD) to predict waitlist mortality. 1 Furthermore, they suggest hyponatremia to be incorporated into the MELD formula.However, we believe that with the emergence of aquaretics (i.e., V2-receptor antagonists) for treatment of hyponatremia these suggestions should be viewed with caution. These drugs, which are expected to be approved by the FDA this year, have been shown to reverse hyponatremia efficiently in patients with advanced liver disease. 2,3 While it has yet to be shown that treatment with aquaretics increases survival in this patient population, the prevalence of hyponatremia will certainly decrease with the more widespread use of these drugs. Furthermore, it can be assumed that the management of ascites will also be affected due to the aquaretic effect of these drugs. With the emergence of these new drugs and the anticipated change of the incidence of hyponatremia in this patient population, we believe that the suggestion to incorporate serum sodium into the MELD score might be premature and will need to be reconsidered after the full impact of these drugs have been evaluated. To the Editors:We agree with Dr. Koller that the advent of effective and safe aquaretic drugs may potentially reduce the incidence of dilutional hyponatremia and thus the usefulness of incorporating serum sodium into the Model for End-Stage Liver Disease (MELD) formula to increase its prognostic power. However, for a number of reasons we believe that at the present time this should be regarded more as an optimistic theory than as a fact. First, only a total of 125 patients with cirrhosis and hyponatremia were enrolled in the 4 reported phase II clinical trials using VPA-985, a selective vasopressin V2-receptor antagonist. [1][2][3][4] Second, although the use of VPA-985 for a maximum of only 7 days was associated with increased free-water clearance, normalization of serum sodium in the European multicenter study occurred in 50% of patients treated with 200 mg/day and in only 27% of the 100 mg/day group. 4 An increase of Ն5 mEq/L of serum sodium was observed in 67% and 45%, respectively. However, how clinically significant is a short-term increase in natremia from 120 to 125 mEq/L in a given patient? How efficacious are aquaretics in the long term? How many patients will escape from the aquaretic effects of VPA-985 during continuous administration? Third, safety of aquaretic drugs is still largely unknown, especially when considering long-term therapy. In the North American multicenter trial, 24% of patients with cirrhosis developed adverse effects such as worsening encephalopathy and dehydration with systemic postural hypotension. 3 Of major concern is the synergic interaction between aquaretic and natriuretic agents in patients with endstage cirrhosis and circulatory dysfunction. Finally, Dr...
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We appreciate the attempts by Lowrie and others to explain the suspected gender effect as simply reflecting the difference in body size. In the analysis of our findings we explored functions of body size that might diminish or erase the difference between the genders in their response to the dialysis dose, expressed either as Kt or Kt/V. As detailed in our paper [1], the dependence of the dose effect on gender was not explained by differences in body size expressed as several different parameters, including weight, height, body surface area, water volume, and body mass index ( Table 6). The dose effect was not significantly associated with any of these size parameters. In fact, the nonsignificant weak trends that were detected were further diminished by correction for gender (Table 5). Furthermore, the suggested increased mortality of males treated at the higher dose could not be explained by any consideration of body size.A non-0 intercept for a linear relationship between body size and required solute clearance is a clear mathematic concept that is difficult to understand physiologically. It implies an enormous amount of dialysis (or kidney function) for very small people, and a near infinite amount for even smaller biological organisms. Probably the relationship is nonlinear but with a 0 intercept (e.g., a power function of body mass). This is consistent with the universal scaling law that relates physiologic functions to the 3/4 power of body mass and to the current practice of correcting the creatinine clearance or GFR for body surface area (2/3 power of body mass) [2, 3, 4].The effect of body size as an independent mortality risk factor in hemodialyzed patients reported by Lowrie et al [5] is now commonly accepted, and was also observed in the HEMO Study (Table 4). However, the marked rotation of the line depicting dose versus size in the graph provided by Lowrie et al suggests that the relationship of size with outcome can be altered by changing the dose. Post-hoc analyses of our data [1] do not support such a dependence of the effect of dose on the risk associated with body size in a range of eKt/V from 1.16 to 1.53, but do indicate that women were more responsive to the dose effect than men. The risk associated with female gender, in contrast to small body size, can be viewed as favorable because females appeared to respond to the higher dose, whereas both small patients and males did not.Finally, we must reiterate two important limitations that we noted in our paper. First, the finding of a different dose effect in men and women must be viewed as a suggestion only because the level of significance was not high in the context of multiple subgroup analyses. Second, because the power of the study to detect effects in subgroups is limited, it cannot rule out the possibility of an undetected dependence of the dose effect on body size.
Living donor renal transplantation is the preferred treatment for end-stage renal failure as the risk-benefit ratio for the recipient usually very much favours this approach. However, the benefit for the donor is much harder to define and probably very small if pure medical criteria are considered. Nonetheless 'non-medical' issues (mostly socio-psychological) may outweigh the small medical risk. The medical pre-transplant evaluation of the potential donor must identify absolute contraindications and abnormalities, which would increase the peri-operative risk. Difficulties may arise, if during the process, minor abnormalities are detected that marginally increase the acute or especially the long-term risk or whose implications are not well defined. In this situation two options are available. If the transplant team assumes that donation per se is of no benefit for the donor, transplantation should not be performed. If, however, the supposed 'non-medical' benefit is large enough, this approach will be against the principle of 'doing no harm' because the individual is denied the possibility to help somebody and might suffer from the consequences. In these complicated cases the final decision should be with the potential donor after an intense discussion with everybody involved in the transplantation process. Such an approach, however, necessitates a post-donation follow-up programme to be offered.
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