Delayed hyperacute rejection in recipients of kidney transplants from HLA identical sibling donors.

Delayed hyperacute rejection, with its characteristic clinical course and histopathologic findings, occurred within one month after transplantation in five recipients of kidney transplants from HLA-A, B and D identical sibling donors. In all cases, unidirectional mixed lymphocyte cultures and immunologic studies to detect cytotoxic antibodies in the recipients against their respective donors, before kidney transplantation and after transplant nephrectomy, were unresponsive or negative. Onset of delayed hyperacute rejection was preceded by bacteremia in two of these patients. Two of these received second kidney transplants, three to six months later, from HLA-A, B and D identical sibling donors again. Although both have had an episode of acute rejection in the early postoperative period, the grafts have maintained excellent function for 21 and 25 months, respectively. Irreversible forms of transplant rejection, such as delayed hyperacute rejection, do occur even in recipients of kidney transplants from HLA-A, B and D identical sibling pairs, indicating that genetic determinants other than HLA-A, B and D loci, and perhaps other nongenetic immune mechanisms, play an important role in the ultimate results of kidney transplantation.

Clinical effects of bilateral nephrectomy.

The effects of removal of all renal tissue on hematopoiesis, osteodystrophy, blood pressure regulation and metabolic functions are reviewed; and, the indications for, and results of, bilateral nephrectomy are discussed. Nephrectomy results in a more severe anemia in dialysis patients which is poorly responsive to androgen therapy. No differences were detected in the severity of osteodystrophy between nephric and anephric patients. However, bilateral nephrectomy can occasionally result in the acute onset of hypocalcemia. Blood pressure regulation must be accomplished in the absence of a functioning renin-angiotensin system. This is largely on the basis of volume, but changes in vascular tone may also be significant. Little is known about the metabolic consequences of nephrectomies. The effect on substances metabolized by the kidney is an area for further investigation. Kidney tissue should be preserved, if at all possible, and nephrectomy performed only for specific indications.

Impact of renal donation. Long-term clinical and biochemical follow-up of living donors in a single center.

Forty-six renal donors who responded to a questionnaire and two additional donors with nephrotic syndrome and renal insufficiency were studied. The mean age was 46 +/- 2.0 years (mean +/- SE). Duration of follow-up was 6 +/- 0.5 years. Serum creatinine levels increased from 1.0 +/- 0.03 mg/dl before donation to 1.2 +/- 0.04 mg/dl at follow-up. The incidence of proteinuria (more than 150 mg over 24 hours) was 39 percent. The serum creatinine level was 1.0 +/- 0.08 mg/dl and 1.2 +/- 0.06 mg/dl in the proteinuric and nonproteinuric groups, respectively. The incidence of hypertension was 31 percent with a serum creatinine level of 1.1 +/- 0.11 mg/dl and 1.2 +/- 0.07 mg/dl in the hypertensive and normotensive groups, respectively. One patient with nephrotic syndrome had proliferative glomerulonephritis. It is concluded that renal donation is associated with a minimal but statistically significant increment in serum creatinine levels. The incidence of mild hypertension and proteinuria is increased, but impact on renal function is minimal as assessed by serum creatinine determination.

Induction of immune alterations and successful renal transplantation with a simplified method of donor-specific blood transfusion.

We developed a new and simplified donor-specific blood transfusion (DSBT) protocol for prospective kidney transplant recipients from one-haplotype-mismatched related donors. Prospective kidney donors gave 450 ml of blood in a quad-pack unit, and the blood was stored in a blood bank. Twenty-five patients were transfused with 100 ml of the respective donor's whole blood at 1, 8, and 15 days after its storage. After DSBT, only three (12%) developed donor-specific lymphocytotoxic antibodies. Following DSBT, donor-specific mixed lymphocyte culture (MLC) was significantly suppressed, without any accelerated (secondary-type) response in early MLC. In addition, sera obtained after DSBT also suppressed donor-specific MLC significantly. Sixteen recipients subsequently received a kidney transplant from the donor, and all had functioning grafts at three months, but one lost the graft thereafter (graft survival rate: 94% at 12 months). This study indicates that (1) 100 ml of stored whole-blood DSBT three times at weekly intervals is a practical, less immunizing, and effective approach to enhance graft survival in recipients of a one-haplotype-mismatched graft; and (2) immune consequences of DSBT include induction of donor-specific cellular and humoral adaptive responses that might be conducive to successful graft outcome.

Enhanced kidney graft survival with retroplacental source gamma-globulin. Results of a 5-year prospective study at a single center.

We examined the possibility that retroplacental source gamma-globulin (RPGG), with its content of anti-HLA antibodies, would improve cadaver kidney graft survival rates. In a 5-year controlled prospective study of 208 transplants, we found that the addition of RPGG to a standard immunosuppressive drug regimen (azathioprine and prednisone) resulted in significant improvement of the cumulative survival rate (CSR) of first and second grafts. At 2 years, the overall CSR of first grafts increased from a control value of 37% +/- 6 to 52% +/- 6 (P = 0.037). Among second graft recipients, the CSR increased from a value of 19% +/- 8 to 50% +/- 10 (P = 0.014). This improvement in graft survival was seen as early as 3 months after surgery and was sustained through 3 years without added recipient morbidity or mortality. When recipient populations were stratified for various factors, those groupings remonstrative of an intact or active humoral immune response capacity were found to have the highest survival rates in the study; 2-year graft CSRs of 70% +/- 6 and 65% +/- 10 were found in recipients with preformed antibody resulting from blood transfusions (P - 0.003) and cytomegalovirus infectivity (P = 0.0006), respectively. These findings indicate that the improved graft survival seen in this study may have resulted from a recipient's immunological response to challenge with RPGG.

Minimal sensitization and excellent renal allograft outcome following donor-specific blood transfusion with a short course of cyclosporine.

UNLABELLED: A new protocol of donor-specific blood transfusion under cyclosporine coverage was developed and examined for immunologic consequences and clinical efficacy in recipients of one- or zero-HLA-haplotype-matched renal allografts. Between 1985 and 1989, 75 recipients were transfused with 100 ml of stored whole blood at 1, 8, and 15 days of its storage from either one-HLA-haplotype-matched related donors (n = 65, 33 from their parents, 30 from siblings, and 2 from offspring) or from zero-HLA-haplotype-matched donors (n = 10, 7 from spouses and 3 from siblings). During DST, all recipients received cyclosporine, 6 mg/kg/day, starting a day before and finishing a week after DST (23 days). Recipients were monitored by donor-specific mixed lymphocyte culture responses before and after DST, and serially for antibodies by fluorescence activated cell sorter analysis and by standard complement-dependent lymphocytotoxicity assay. Following DST with CsA, only 3 of 75 patients (4%) were sensitized against the blood donor. This rate is considerably lower, albeit statistically not significantly, compared with the 10% rate found in 30 recipients who had received DST without CsA in our previous study. Repeat MLC studied one to two months after DST (the day before transplant) were significantly increased compared with pre-DST (stimulation index: mean +/- SEM; 10.3 +/- 1.4 to 15.8 +/- 2.8, P = 0.004, and relative response: 40.9 +/- 5.1% to 49.8 +/- 5.5%, P = 0.003). Since the stimulation index with controls did not change after DST (23.4 +/- 2.9 to 26.2 +/- 3.3), enhanced MLC responses appear to be donor-specific. The changes in MLC responses did not correlate with the number of blood transfusion received prior to DST, the number of rejection episodes, or graft outcome. Fifty-seven recipients underwent a kidney transplant from their one-HLA-haplotype-matched blood donors within two to three months after DST. All 10 recipients of zero-haplotype-matched donors were also successfully transplanted from their respective blood donors. The graft survival rates were at least 90% at two years in both groups. IN CONCLUSION: (1) 100 ml of stored whole-blood DST, three times at weekly intervals with a short course of CsA is minimally sensitizing but effective in enhancing graft survival; (2) this protocol could be used in donor-recipient pairs who do not share a haplotype; and (3) DST with CsA elicits augmentation of donor-specific MLC responses.

Excellent outcome with a calcium channel blocker-supplemented immunosuppressive regimen in cadaveric renal transplantation. A potential strategy to avoid antibody induction protocols.

Many transplant centers routinely utilize monoclonal antibody or polyclonal antibody based induction protocols in recipients of cadaver renal allografts. Given the potential complications associated with antibody-based immunosuppression regimens (e.g., CMV disease), we tested the hypothesis that a combination of a calcium antagonist and a triple drug protocol (cyclosporine + prednisone + azathioprine) would be an effective substitute for antibody-based induction protocols in ensuring excellent patient and graft survival rates. Our postulate was tested in a prospective study of 52 consecutive recipients of cadaver renal allografts (44 first, 5 second, and 3 third grafts) utilizing nifedipine as the first line calcium antagonist. Nifedipine was selected over verapamil or diltiazem due to its lack of interference with the metabolism of CsA. Some of the significant outcomes of our prospective trial were (A) a cumulative patient survival rate of 98.1% for the 52 recipients at 18 months posttransplantation; (B) a cumulative allograft survival rate of 92.1% for the 52 consecutive cadaver renal allografts at 18 months; (C) a cumulative allograft survival rate of 100% at 18 months for the 24 of 52 renal allografts without delayed graft function following transplantation; and (D) a cumulative allograft survival rate of 86% at 18 months for the 28 of 52 renal allografts with delayed graft function. Of the 4 of 52 who lost their grafts, 2 grafts were removed following discontinuation of immunosuppressive therapy while the remaining 2 had primary nonfunction; and (E) the lack of a requirement for monoclonal or polyclonal antibodies for the treatment of acute rejection episodes in this patient population. These gratifying results compare very favorably with (A) recent reports of the effects of long-term diltiazem therapy and of verapamil used in conjunction with an induction protocol that included Minnesota antilymphocyte globulin in recipients of cadaver renal allografts, and (B) the clinical outcome in many institutions with OKT3/ATG/ALG induction protocols. Whereas the mechanisms involved in the excellent clinical outcome found with the calcium antagonist remain undefined, our results strongly argue for a prospective, randomized and controlled study in which a calcium antagonist-supplemented immunosuppressive regimen is compared with antibody-based induction protocols.

Hypertension in kidney transplant recipients. Effect on long-term renal allograft survival.

To examine the effects of hypertension on renal graft function, we studied the clinical course of 144 kidney transplant recipients who had functioning grafts for three to 13 years. The patients were divided into three groups: normotensive (n = 32), controlled hypertensive (n = 49) and uncontrolled hypertensive group (n = 63). In addition to the difference in their blood pressure status, the three groups had significantly different levels of serum creatinine at entry to the study (mean +/- SE in mg/dL: 1.41 +/- 0.02, 8.89 +/- 0.02 and 2.30 +/- 0.03, respectively, P = .0002). Cumulative graft survival (CGS) at ten years for normotensive patients was 81%, whereas it was 58% for controlled hypertensive patients and 50% for uncontrolled hypertensive patients. The difference of CGS between normotensive and hypertensive patients was significant (P = .01), whereas the difference between the two hypertensive groups, controlled v. uncontrolled, was not. If serum creatinine levels at entry to the study were adjusted and the CGS of hypertensive patients was compared to normotensive patients with comparable levels of serum creatinine, the differences in CGS between the two groups were no longer significant. Regression analyses for potential prognostic factors revealed that serum creatinine levels were of more primary importance as a prognostic variable than blood pressure status. We conclude that hypertension is an important risk factor for renal graft survival, but control of hypertension alone does not appear to improve it. Graft survival appears to be influenced more by the severity of graft dysfunction at entry to the study irrespective of blood pressure control.

Renal transplantation between HL-A identical siblings with partial nephrectomy and machine preservation for ossified renal cell carcinoma.

A case of renal transplantation between HL-A identical siblings is reported in which the donor kidney was found to have a calcified mass in the upper pole. Because an immediate pathologic diagnosis could not be made at the time of nephrectomy, the kidney was preserved with pulsatile perfusion for fifty-four hours after excision of the upper pole. At that time the diagnosis was still not available, and transplantation was performed only to have the report of ossified renal cell carcinoma established the following day.

Effect of nifedipine on renal allograft function and survival beyond one year.

We previously reported that a calcium channel blocker supplemented immunosuppression produced excellent patient and graft survival rates in cadaveric kidney transplantation. We report here the long term outcome of patients treated with nifedipine-supplemented triple immunosuppression as compared with those of historical controls who were treated similarly without nifedipine. Study subjects included 111 patients transplanted in 1990-1994, treated with nifedipine and triple immunosuppression and with functioning grafts for more than one year (Nifedipine group). The results of cyclosporine (CyA) dose, blood pressure (BP), serum creatinine (Cr), and actuarial graft survival rate (GSR) up to 5 years posttransplant in these patients were compared with those of 52 patients transplanted in 1985-1990, treated similarly without calcium channel blockers (Control group). Donor sources, gender ratio, age distribution, causes of end stage renal disease, incidence of hypertension prior to transplantation and incidence of rejection in the first year between the groups were comparable. Throughout the study period the Nifedipine group had significantly lower serum Cr (1.5 +/- 0.7 vs. 1.8 +/- 0.7 mg/dl) and higher GSR (93.8% vs. 88% at 5 years) than the Control group. BP was comparable despite higher CyA doses in the Nifedipine group (4.3 +/- 1.1 vs. 3.3 +/- 1.1 mg/kg/day). We conclude that nifedipine is beneficial in improving long-term graft function and survival in kidney transplant recipients by mitigating CyA associated renal injury.

Effects of intravenous methylprednisolone on mixed lymphocyte cultures in normal humans.

Mixed-lymphocyte-culture response and peripheral lymphocyte counts were determined after 100 mg and 1,000 mg of methylprednisolone were administered intravenously to healthy volunteers; The MLC response was significantly suppressed in both groups for at least 12 hr. The degree of suppression of the MLC response did not differ between the two groups. Lymphocytopenia persisted for at least 24 hr. The MLC response, however, returned to its full capacity within 24 hr. In the low-dose group this response showed a marked rebound phenomenon at 24 hr. These findings indicate that methylprednisolone has a profound inhibitory effect on lymphoid cells' response to allogenic stumli in the MLC system.

Optimization of donor specific blood transfusion in kidney transplantation.

1. One hundred milliliters of stored whole blood DST, three times at weekly intervals is a practical, less immunizing and effective approach to enhance graft survival in recipients of a living-related donor kidney. 2. This protocol could also be used in sibling donor/recipient pairs who do not share a haplotype as well as in those who share two haplotypes to enhance graft survival. 3. The use of a short course of Cs (6 mg/kg/d for three weeks) along with DST appears to reduce the sensitization rate even lower. The dose of Cs used in this study produced no clinically significant adverse reactions, whereas Aza (1 mg/kg/d) often produces leukopenia. 4. DST produces significantly suppressed donor specific MLC responses in the early post-DST period; however, it increases the response at a later time. DST modulates immune responses in such a way that secondary responses upon grafting are more readily reversible by immunosuppressive agents.

Kidney transplantation in insulin dependent diabetic patients: improved survival and rehabilitation.

Between 1977 and 1986, 50 insulin-dependent diabetic patients received a kidney transplant, 19 from living related donors and 31 from cadaveric donors. Cumulative patient survival was 81% and graft survival was 64% and 33% for living related and cadaveric donor kidneys, respectively, at five years. These results are comparable to that of nondiabetic patients. While physical performance and visual acuity significantly improved after a successful kidney transplantation, neuropathies and angiopathies might not improve. Physical performance improved even in those patients whose nerve conduction time had deteriorated. These findings suggest that kidney transplantation is an effective means of improving survival and rehabilitation of diabetic patients with end-stage renal disease.