Fetal rhesus monkey model of obstructive renal dysplasia.

BACKGROUND: Disorders of kidney development represent a major cause of renal failure and end-stage renal disease in the pediatric population. To understand further the prenatal pathogenesis of obstructive renal dysplasia, a fetal monkey model was developed using ultrasound-guided techniques. METHODS: Ureteropelvic obstruction (N = 13) was induced during the early or late second trimester by the injection of purified guluronic alginate spheres. All fetuses were monitored sonographically, and then fetal tissues were removed at varying time points during the second and third trimesters. RESULTS: There was no evidence of oligohydramnios during the course of gestation, and the obstructed kidneys were typically progressively smaller than the contralateral (nonobstructed) kidneys when monitored sonographically over time. Obstructed kidneys displayed most features of renal dysplasia, including numerous cortical cysts of various sizes derived predominantly from collecting ducts and glomeruli. Mesenchymal changes included expansion of both the cortical and medullary interstitium, as well as mesenchymal-myocyte transformation, expressed as pericystic and peritubular fibromuscular collar formation. An important feature of this model was the disruption of normal glomerular development and architecture, associated with significant podocyte apoptosis, evident as early as the prevascularized S-shaped nephron. As in other models, collecting duct cell apoptosis was apparent, particularly in areas of cyst formation and cellular atrophy. CONCLUSIONS: These results demonstrate the importance of this nonhuman primate model for exploring the pathophysiology of congenital obstructive uropathy and highlight the potential role of podocyte injury in determining long-term renal function associated with this condition.

Studies in fetal wound healing: III. Early deposition of fibronectin distinguishes fetal from adult wound healing.

Wound healing in the fetus proceeds through a series of steps that differ in the fetus and the adult. At each phase of this complex process, there is signaling between the tissue cells and the wound microenvironment, signals that are mediated by and through the extracellular matrix. We postulate that these signals occur earlier in fetal wounds, resulting in more rapid repair. To investigate this, we compared the first 24 hours of wound healing in the rabbit fetus and adult, using antibodies against key extracellular matrix macromolecular components: laminin, fibronectin, and type-specific collagens I, III, IV, and V. Fibronectin was the first matrix component to be deposited, and was visualized as early as four hours after fetal wounding and 12 hours after adult wounding. There was no evidence of new laminin or collagen deposition in either the fetal or adult wounds at any time point examined. The early deposition of fibronectin, a matrix adhesion molecule that provides a scaffolding for epithelial migration, may underlie the rapid reepithelialization observed in fetal wounds.

Prognostic features of early renal transplant rejections.

In an analysis of 632 cadaver transplants, the early renal transplant course gave important prognostic information depending on temporal and/or renofunctional characteristics of rejection episodes. Two transplant rejections occurring within the first 2 mo posttransplant were associated with either 37%, 27%, or 6% 1-yr graft survivals depending on whether these episodes were separate, temporally back-to-back, or were without interrejection renofunctional recovery, respectively. This compares to 1-yr graft survivals of 89% or 73% in those patients who had no rejection or one with recovery early posttransplant. Patient survival in groups with multiple early rejections was also associated with a poor prognosis. Ninety to 93% 1-yr patient survival was noted when there was no or one rejection. There was only a 74%-83% 1-yr patient survival with two early treated rejections. Transplant rejection therapy must be individualized or even withheld in order to ensure optimum graft and patient survival.

Pretreatment with donor-specific blood transfusions in related recipients with high MLC.

Pretreatment with deliberate DST has not resulted in hyperacute or irreversible rejection in patients receiving kidneys after negative donor-specific crossmatches, but has afforded immunologically disparate related recipients enhanced opportunity at successful transplantation. Additionally, with a post-transplant course paralleling that of HLA-identical siblings, high-dose immunosuppressive therapy for rejection has been spared in many recipients. Transplantation, however, proved unsuccessful in a patient receiving a kidney from his positive B-warm crossmatch blood donor in a protocol departure. This case experience and subsequent antibody studies have reconfirmed our initially established criterion of not proceeding with transplantation against a persistently positive B-warm donor-specific crossmatch. By pursuing the initially established DST protocol, it appears that a potentially unsuccessful living related transplant can be avoided, while the transplants actually performed have enhanced prospects of success. The nature of the various immunologic responses in this patient population remain to be more clearly defined.

Deliberate donor-specific blood transfusions prior to living related renal transplantation. A new approach.

In order to select MLC incompatible one-haplotype related donor-recipient pairs that would achieve better graft survival and in an effort to alter the recipient immune response, 45 patients received three fresh blood transfuions from their prospective kidney donors. Recipient sensitization was evaluated by cross-match testing weekly sera obtained during and after the blood transfusions against donor T- and B-lymphocytes at 5 C (cold) and 37 C (warm). Thirteen (29%) of the 45 potential related recipients developed a positive warm T-cell cross-match or a persistent warm B-cell cross-match to their blood donor and related transplantation was not performed. Thirty-two (71%) patients had an appropriate negative cross-match to their blood donor. Thirty of these patients subsequently received kidneys from their blood donor. Ninety-seven per cent of the kidneys are functioning from one to 25 months with a single graft failure due to a patient discontinuing immunosuppressive medication. In addition to the excellent graft survival there was an unusually low incidence of rejection episodes in the recipients of kidneys from their blood donor so that the posttransplant course paralleled that of HLA-identical siblings. This approach may have future application with two-haplotype mismatched donor-recipient pairs, both related and unrelated.

Analysis of costs and outcomes of renal transplantation at one center. Its implications.

A cost increase of more than 900% for medical services to dialysis patients and transplant recipients has been projected during the decade 1974 to 1984. To evaluate the role of renal transplantation in the End-Stage Renal Disease Program, we analyzed direct costs and patient outcomes in 466 consecutive transplants at our center. A successful transplant from either a living related or cadaver donor cost less than +7,000 per year for two years of graft function. The cost of transplants rejected during the second year also proved cost-effective when compared with the yearly costs of maintenance-facility hemodialysis. Patient survival was 100% at two years for recipients of a transplant from a living related donor and 84% at two years for recipients of a transplant from a cadaver. Renal transplantation can reduce the rising costs for end-stage renal disease patient care, without reducing life expectancy.

The influence of donor age on graft survival.

Recent papers report differing conclusions concerning use of kidneys from different donor age groups. We analyzed graft survival of 652 consecutive cadaver kidney donor-recipient pairs. Overall cumulative graft survival was 45 per cent at two years post transplantation. Kidneys from donors aged less that fifteen, sixteen to thirty. thirty-one to forty-five, and forty-six to sixty years had a cumulative graft survival of 51, 44, 39, and 40 percent, respectively. The difference is not statistically significant. When both donor and recipient ages are controlled, the pediatric aged kidney may be superior in the pediatric recipient or the older normotensive adult recipient. Use of properly selected cadaver kidneys in patients of all age ranges is encouraged.

Do blood transfusions enhance the possibility of a compatible transplant?

Blood transfusions prior to first cadaver kidney transplants have a significant beneficial effect on graft survival and, in this sense, appear to enhance the possibility of a compatible transplant. This desirable effect, however, occurs concomitantly with an increased degree of sensitization, which in turn reduces the likelihood of identifying a compatible kidney by direct crossmatch testing. This report illustrates that the beneficial effect is achieved with one to five transfusions prior to transplantation, but that more transfusions afford no additional benefits. In addition, the presence of cytotoxic antibodies per se does not have an adverse influence on graft survival. Liberal transfusion policies are therefore indicated in cadaver transplant candidates, but more than five transfusions prior to transplantation should probably be avoided unless clinically necessary.

Macrophage-T cell interactions in the Con A induction of human suppressive T cells.

Macrophage-T interactions are required for the Con A-induced generation of human Ts capable of inhibiting PHA-induced blastogenesis among autologous PBMC. Con A treatment of adherent cell-depleted PBMC, or PBMC recovered after a 7-day incubation in FCS, failed to generate Ts. Addition of adherent cells to either of these populations restored Con A inducible Ts. Discontinuous density gradient fractionation of adherent cells demonstrated that the required accessory cell was a low density macrophage bearing the human equivalent of murine Ia.