Prednisolone disposition in cushingoid and noncushingoid kidney transplant patients.

Little information is available on the disposition of prednisolone in kidney transplant patients and whether correlations exist between the pharmacokinetics and therapeutic or toxic effects of this drug. The present study was designed to determine the pharmacokinetics of prednisolone in six noncushingoid and six cushingoid transplant recipients. The elimination half-lives were not significantly different in the noncushingoid and cushingoid patients (2.3 vs. 3.3 h). However, other pharmacokinetic parameters were significantly lower in the cushingoid group: plasma clearance (147 vs. 82 ml/min) and volume of distribution (32 vs. 20 liters). In addition, the availability of prednisolone after oral prednisone administration was considerably variable (overall range, 27-108%) and was not significantly different between the two groups. Thus, in kidney transplant patients it appears that the plasma clearance and volume of distribution of prednisolone may distinguish between noncushingoid and cushingoid patients.

Endogenous hydrocortisone, a possible factor contributing to the genesis of cushingoid habitus in patients on prednisone.

To establish if the cushingoid habitus in patients taking prednisone is associated with relatively high total or free prednisolone and low endogenous hydrocortisone concentrations in plasma, 15 stable renal transplant patients and 12 patients treated with prednisone for oral mucocutaneous vesiculo-erosive diseases were investigated. After the patients' usual prednisone doses, the areas under the plasma concentration time curve of total and free prednisolone were not different when the 14 patients without cushingoid appearance were compared to the 13 patients with cushingoid appearance. Patients with cushingoid habitus more frequently exhibited peak hydrocortisone levels within the normal range (6 of 14 vs. 1 of 13) and had higher areas under the plasma concentration time curve of hydrocortisone (median, range), i.e. 2672 ng/ml.min (0-21, 637 ng/ml.min) vs. 308 ng/ml.min (0-12, 495 ng/ml.min) compared to those without cushingoid appearance (P less than 0.05). These results indicate that pharmacokinetic differences of prednisone do not explain the presence or absence of cushingoid habitus and that there is an association between cushingoid habitus and endogenous hydrocortisone levels.

The role of hypertension in hemodialysis-associated atherosclerosis.

Atherosclerosis in 50 nondiabetic patients undergoing hemodialysis was assessed at the time of renal transplantation by intraoperative examination and histologic evaluation of the iliac vasculature. Patients were grouped accordingly: minimal (group 1), moderate (group 2) or severe (group 3) atherosclerosis. Sixty-two per cent of the patients had atherosclerosis, half of them with severe involvement. No sex differences were noted. There was a significant correlation between the patient's age and the degree of atherosclerosis (p less than 0.02). Thirty-five per cent of the patients under 30 years of age had atherosclerosis whereas similarly studied nonuremic control subjects had no atherosclerosis. Metabolic and lipid abnormalities, and duration of hemodialysis did not correlate with degree of atherosclerosis. Hypertension was present in 90 per cent of the patients in groups 2 and 3. When patients between the ages of 25 and 40 years were selected, atherosclerosis was present only in previously hypertensive patients (p less than 0.02). Atherosclerosis may not be accelerated by hemodialysis and may be prevented by more stringent control of hypertension in uremia.

The importance of eosinophil cells in kidney allograft rejection.

The composition of the intragraft cellular infiltrate was studied in 83 renal allograft recipients with the technique of fine-needle aspiration cytology in the first four weeks following kidney transplantation. We found a significantly (P less than 0.05) higher mean tissue eosinophil percentage in patients who had irreversible rejections with transplant loss than in those who had reversible rejections (12.54 +/- 2.31 versus 3.79 +/- 1.14, mean +/- SEM). Patients who had serious, dialysis-requiring rejections also showed a significantly (P less than 0.05) higher mean tissue eosinophil percentage than those who had reversible rejections (21.40 +/- 5.98 versus 3.79 +/- 1.14, mean +/- SEM). The frequency of the HLA B8 antigen was 46.2% in patients who had excessive tissue eosinophilia, whereas its frequency in all the studied patients was 18.3%. Based on our observations, the presence of more than 4% eosinophils in the tissue inflammatory exudate is a specific (91%) and fairly sensitive (78%) indicator of irreversible and severe acute rejections.

Long-term renal function in kidney donors. Sustained compensatory hyperfiltration with no adverse effects.

Twenty patients who underwent uninephrectomy for kidney donation between 1964 and 1968 participated in a long-term study of the function of the solitary kidney. Mean follow up after uninephrectomy was 15.8 +/- .3 years. One patient with a strong family history of essential hypertension developed de novo mild hypertension. The current creatinine clearance of the donors was 80 +/- 4 ml/min. The 1-week, 3-6 months and 14-18 years postuninephrectomy percentages of predonation creatinine clearance were 72 +/- 3%, 76 +/- 3% and 78 +/- 2%, respectively. The 24-hr urine protein excretion in kidney donors was significantly higher than in controls (141 +/- 20 mg vs. 74 +/- 3 mg, respectively, P less than .0005). Except for one donor who may have developed glomerulonephritis, the donors had normal urinary albumin excretion. The cause of the slightly elevated nonalbumin proteinuria is not known. However, this long-term study of kidney donors shows no adverse effects on the blood pressure and renal function after many years of compensatory hyperfiltration.

De novo and recurrent membranous glomerulopathy following kidney transplantation.

Membranous glomerulopathy, de novo or recurrent, in the allograft kidney is a recognized, albeit uncommon, clinical entity. We examined the records of 936 renal allograft recipients in a seven and one-half year period. De novo membranous glomerulopathy developed in six patients. The mean onset of nephrotic-range proteinuria after transplantation was at 18.1 months (with a range of from 4 to 30 months). De novo membranous glomerulopathy did not adversely affect graft survival. Twenty-five patients were transplanted for end-stage renal disease caused by membranous glomerulopathy. The rate of recurrence of membranous glomerulopathy in patients who did not lose their allograft to rejection in the immediate posttransplant period was 7%. Additional prednisone therapy to the standard immunosuppressive protocol did not appear to be beneficial. One patient, who developed a recurrence of the original lesion, received an HLA-identical kidney. Onset of nephrotic-range proteinuria occurred four weeks post-transplant. Recurrent membranous glomerulopathy has been reported in five other patients. In the two recipients of living related allografts nephrotic-range proteinuria developed within two weeks of the transplant. Patients with end-stage renal disease caused by membranous glomerulopathy who receive a living related allograft, especially one that is HLA-identical, may be at a higher risk for morbidity and for early recurrence. We recommend caution in the use of a living related transplant for patients with end-stage renal disease caused by membranous glomerulopathy.

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.

Histopathological concordance of paired renal allograft biopsy cores. Effect on the diagnosis and management of acute rejection.

To assess the effect of sampling error on renal allograft biopsies, we determined the concordance of diagnoses between 2 biopsy samples from the same renal allograft and the frequency with which 1 biopsy sample would underdiagnose or lead to the undertreatment of acute rejection. Two core samples from the same allograft biopsy procedure were labeled as core A and core B and presented to both unblinded and blinded pathologists, and each pathologist independently assigned an acute and a chronic rejection grade. A set of clinical data with pertinent prebiopsy information was combined with either the core A or core B histopathological diagnosis and presented to 3 transplant nephrologists who made treatment recommendations for each combination. Two cores were obtained in 79 allograft biopsies. Core pairs differed by > or = 1 grade of acute rejection in 30% and 50% of cases for unblinded and blinded pathologist readings, respectively. Moderate or severe acute rejection would have been missed with a 1 core in 9.5% of cases, increasing to 25.6% if only biopsy pairs containing at least 1 reading of moderate or severe acute rejection are included. Therapy would have failed to be increased with a single core in 7.5% of cases, increasing to 10.5% if only pairs containing at least one recommendation of an increase in therapy are included. The use of 2 cores of renal allograft tissue provides better diagnostic information and thereby leads to appropriate increases in antirejection therapy without increasing the complication rate of the procedure.

The beneficial effect of pretransplant blood transfusions in cyclosporine-treated cadaver renal allograft recipients.

212 cyclosporine-treated recipients of mismatched first cadaveric renal allografts are evaluated with respect to the effect of pretransplant random blood transfusions. It is determined that transfusions do not effect patient survival or morbidity. Pretransplant random blood transfusions correlate with significantly improved allograft success. There is also a trend, although not statistically significant, for further improvement of allograft survival with increasing numbers of transfusions. The transfusion effect is not related to the time at which the transfusions are given up to 2 years prior to transplantation. Transfused patients have a higher percent reactive antibody (PRA) than untransfused patients, but this does not cause them to wait for a cadaveric allograft significantly longer than the untransfused patients. Rejections are less severe in transfused patients. It is concluded that cyclosporine-treated recipients of first cadaveric renal allografts benefit from pretransplant blood transfusions.

Inability of cyclosporine to completely prevent the recurrence of focal glomerulosclerosis after kidney transplantation.

From January 1984 through July 1986, 15 patients with biopsy-proven focal glomerulosclerosis (FGS) underwent kidney transplantation. Following transplantation, all patients were immunosuppressed with cyclosporine and prednisone. There were 8 men and 7 women with a mean age of 33 years (range, 16-47 years). Five patients (33%) had recurrence of FGS. Two patients had received kidneys from HLA identical siblings, and 3 patients were transplanted with cadaveric kidneys. In 4 out of 5 patients, the recurrence of FGS occurred within 3 months of transplantation. Of the 2 graft losses in this group, one was from recurrence of FGS. Ten patients followed for a mean of 25 months did not develop recurrence of FGS. No graft loss occurred in this group. Three patients with end-stage renal disease of unknown etiology were found to have FGS in the renal allograft and were presumed to have recurrence of FGS. All 3 patients developed the nephrotic syndrome following transplantation, and 1 patient has had progressive renal failure. Cyclosporine did not prevent the recurrence or the clinical manifestations of FGS following kidney transplantation. Additional studies are needed to determine if cyclosporine is effective in certain subgroups of patients with FGS.

A seven-year experience with donor-specific blood transfusions. Results and considerations for maximum efficacy.

Two hundred thirty-nine transplants have been performed following donor-specific blood transfusions (DSTs) since 1978. Graft and patient survival in 1- and 0-haplotype-matched transplants with DST pretreatment is comparable to HLA-identical results through 4 years. Graft survival in 174 consecutive nondiabetic, non-HLA-identical DST recipients shows that the transfusion effect persists for at least 4 years, with graft survival of 88 +/- 3% at that time, compared with 83 +/- 4% in the concurrent HLA-identical group. Graft function, as determined by serum creatinine, was the same in both groups. Graft and patient survival in 20 0-haplotype matched pairs with DST pretreatment is 100% at 2 years. Low-dose Imuran coverage during DST administration (n = 91) was compared with a concurrent group with no Imuran (n = 93). Imuran had its maximum effect in patients undergoing their first transplant and with a pre-DST PRA less than 10% (12% vs. 21% sensitization rate in the no-Imuran group). Imuran did not appear to confer any beneficial effect in primary transplants with high PRAs and in patients undergoing a second or third transplant. The majority of patients formally excluded from transplantation because of a post-DST positive B-warm crossmatch can now be successfully transplanted with the use of flow cytometry analysis to rule out previously undetectable low levels of anti-T-lymphocyte antibodies. Of 62 patients with a positive B-warm crossmatch alone since 1982, 73% had a subsequent negative fluorescence-activated cell sorter (FACS) crossmatch permitting transplantation. Preliminary results of a DST and cyclosporine treatment study are described. In conclusion, a long-term immunologic effect of DST has been confirmed and the indications and considerations for optimum use of the DST protocol have been more clearly defined.

The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors.

Liver allografts from HBcAb(+), IgM(-), HBsAg(-) donors can transmit HBV to uninfected recipients. We currently no longer accept these livers for transplantation while continuing to accept the kidneys. The purpose of this study is to determine the risk of donor-transmitted HBV infections from HBcAb(+), HBIgM(-), HBsAg(-) organ donors and determine if the risk of donor-transmitted HBV infections and their severity is dependent on the organ being transplanted. This study consists of a retrospective review of the posttransplant course of recipients of HBcAb(+), HBIgM(-), HBsAg(-) donors accepted at UCSF from 6/85 to 12/93. Transmitted HBV infection was defined as one in which the recipient changed from HBsAg(-) prior to transplantation to HBsAg(+) posttransplant, with no other source. There were 25 of 1190 donors who were HBcAb(+), HBIgM(-), HBsAg(-); 1/42 kidney, 3/6 liver, and 0/7 heart HBsAg(-) transplant recipients of organs from these donors became HBsAg(+) after transplantation. This difference in infection rate (liver vs. kidney and heart) is statistically significant. The clinical course of the liver recipients was also more severe. All of the patients who became infected were HBsAb(-) and HBcAb(-) prior to transplant. We conclude that (1) HBV can be transmitted from HBcAb(+), HBIgM(-), HBsAg(-) organ donors, (2) the rate of transmission is highest and severity of infection is worst in the liver recipients; and (3) we will continue to transplant kidneys from these donors, preferably into immunized recipients.

Cytokine and T cell receptor gene expression at the site of allograft rejection.

Intragraft cytokine and T cell receptor gene expression was analyzed in rejecting renal allografts by polymerase chain reaction (PCR). Message for IL-1 beta, IL-6, and TNF-alpha was detected in nephrectomy tissue with pathological evidence of acute or chronic rejection. Similarly, mRNA for both IL-6 and TNF-alpha was present in renal biopsies from acute rejecting kidneys. IL-2R, IL-4, and IL-5 mRNA was present in both rejecting and rejected kidney allografts, indicating that these cytokines may play a role in ongoing renal allograft rejection. Conversely, IL-2, IL-7, and IFN-gamma message was detected infrequently. In order to address the diversity of T cells in rejecting kidneys, we have analyzed the clonality of the TcR present within the allograft tissue. Rearranged TcR genes were identified in all allografts examined (n = 16) indicating the presence of T cells bearing the alpha/beta TcR. We have determined that there is a heterogeneous infiltration of T cells in the rejected allograft with TcR representing x = 7.47 +/- 2.4 families rearranged in samples obtained from nephrectomies, whereas x = 5.33 +/- 0.58 families were detected in samples obtained from biopsy tissue. These data indicate that (1) cytokines are produced locally which may contribute to graft cell destruction, (2) the heterogeneity of intragraft T cells during kidney allograft rejection may exist because nonspecific lymphocytes have been recruited to the site by locally produced cytokines or because T cells are responding to multiple epitopes or multiple donor antigens. Detection of intragraft cytokines and TcR may prove useful in elucidating the mechanism of rejection and therefore lead to improved immunosuppression.

Antiphospholipid antibody syndrome in renal transplantation: occurrence of clinical events in 96 consecutive patients with systemic lupus erythematosus.

We report the results of a detailed examination of clinical events associated with the antiphospholipid antibody (aPL) syndrome in 96 consecutive patients with systemic lupus erythematosus (SLE) who underwent renal transplantation between January 1, 1984, and September 1, 1996. Because of the retrospective nature of our study, we developed strict definitions of clinical events considered to be associated with the aPL syndrome. We reviewed all available hospital, clinic, and outside records of the patients with SLE who underwent transplantation at our center during this time period and noted the results of three standard serological tests for aPLs, when available. Mean follow-up of the 96 patients was 62.6 months. Eighty-five of the 96 patients (88.5%) had at least one test for aPLs performed, and 25 patients (29.4%) had at least one abnormal test result. Among these 25 patients, 15 patients (60%) had clinical events associated with aPL syndrome. Ten patients (10.4%) either died of the aPL syndrome or had an aPL-associated clinical event within 3 months of transplantation. Other morbidity from the aPL syndrome in these 15 patients included: thrombotic arteriolar microangiopathy (2 patients), stroke (4 patients), ocular ischemia (7 patients), deep vein thrombosis or pulmonary embolism (6 patients), renal artery or vein thrombosis (4 patients), peripheral ischemia (1 patient), and fetal wastage (3 patients). By comparison, among the 60 patients with normal aPL test results, only 5 patients had clinical events compatible with the aPL syndrome (P < 0.0001 by chi-squared test). aPLs may be associated with significant morbidity and mortality in patients with SLE undergoing renal transplantation. This study is the first attempt to quantify the impact of aPLs on renal transplantation in a large population of patients with SLE. Further investigation of aPLs in SLE patients with end-stage renal disease is required to clarify the risks, benefits, and optimal clinical management of renal transplantation for these patients.

Outcome of renal transplantation in systemic lupus erythematosus.

OBJECTIVES: (1) To provide an overview of the world's experience with renal transplantation in systemic lupus erythematosus (SLE), and to consider the most important studies in detail. (2) To examine four specific questions raised by the review, including (a) the frequency of recurrent lupus glomerulonephritis (GN); (b) the effect of pretransplantation dialysis on transplantation outcome; (c) the method of monitoring lupus activity in transplant patients; and (d) the frequency of early graft loss among lupus patients. METHODS: We performed a MEDLINE search of the world's literature from 1975 to 1997 on the subject of renal transplantation in SLE, using the search terms "lupus," "SLE," "kidney," "renal transplantation," and "outcome." We included in this review 20 original reports that devoted significant attention to the outcome of renal transplantation among patients with lupus. RESULTS: Of the nine studies that compared the transplantation outcomes of lupus patients with those of transplant patients with other causes of end-stage renal disease, the allograft survival rates were superior in the comparison groups in six, and approximately equivalent in three. The 1-year allograft survival rate of lupus patients with cadaveric renal transplants (CRTs) was 67% in the largest multicenter study, significantly lower than the rate for the other 14 diseases examined (77%; P = .009). In most studies, the lupus groups were significantly younger than their comparison groups, but they frequently included larger percentages of black patients. Lupus patients who received living-related renal transplants (LRRTs) generally had superior graft survival rates compared with those who received CRTs. In the largest single-center report, the 5-year graft survival rate in the cyclosporine era was 89% for LRRTs, compared with 41% for CRTs. Recurrence of lupus nephritis in the allograft is relatively rare, approximately 2%; this estimate is probably low. However, recurrent lupus glomerular nephritis (GN) did not invariably result in allograft failure. Short length of pretransplantation dialysis (i.e., less than 6 months) had no adverse effect on transplantation outcome in 10 of 11 studies that examined the relationship. Pretransplantation serological parameters, such as complement and anti-double-stranded DNA antibody levels, appear to be unreliable predictors of the likelihood of recurrence, and also may be inaccurate measures of disease activity in the posttransplantation period. Finally, 9 of the 20 studies reviewed noted an increased risk of early graft loss among lupus transplant patients, possibly because of an increased frequency of acute injection reactions and thrombotic events associated with antiphospholipid antibodies. CONCLUSIONS: Despite the fact that many lupus patients have excellent renal transplantation outcomes, substantial evidence indicates that renal transplant patients with lupus do not fare as well as patients with other causes of end-stage renal disease. Lupus patients may be particularly susceptible to adverse events occurring in the first year after transplantation. Further investigation is needed to improve renal transplantation outcomes for patients with lupus.

Improved patient survival in renal transplantation.

Patient and graft survival in 655 consecutive renal transplants performed at the University of California, San Francisco, was analyzed in two separate groups to assess the results of the low-dose immunosuppressive regimen established in September, 1972. These results show that graft survival is not jeopardized by adopting a policy of low-dose immunosuppressive therapy, but, in fact, that patient survival is improved significantly. This study also shows that cadaver renal transplantation can be performed with a mortality rate comparable to or better than that in patients on chronic hemodialysis.

Peptic ulcer disease in kidney transplant recipients.

The occurrence of peptic ulcer in kidney transplant recipients treated with corticosteroids for immunosuppression is a problem of considerable magnitude and threatens both patient and graft survival. The fact that peptic ulcer usually occurs in the early months after transplantation, and that there are known risk factors including treatment for rejection, sepsis, and hepatitis, demand a high level of clinical suspicion, early and accurate diagnosis, and prompt treatment. Aggressive medical prophylaxis is important, but if it should fail prompt reduction of the dose of corticosteroids is imperative so that continued patient survival is emphasized rather than the continued survival of the transplant. Surgical intervention, when indicated, should also be prompt, and the more definitive operations such as vagotomy with pyloroplasty or gastric resection are preferred because of a lesser occurrence of reoperation among such patients. Prophylactic operations in patients with an antecedent history of peptic ulcer may provide considerable protection against the development of corticosteroid-related ulcers after transplantation.

Is a "low" dose of prednisone better than a "high" dose at the time of renal transplantation?

It has been suggested that a low dose of prednisone initially given post-transplant, besides producing lower patient morbidity, is as effective as high dose regimens in providing positive graft and satisfactory patient outcome. In 1981 and 1982, we prospectively and randomly studied 77 cadaveric kidney recipients who received a high dose (2.0 mg/kg body weight) (H) and 66 who received a low dose of prednisone (0.5 mg/kg body weight) (L) at the time of transplant. Mean time to the first rejection episode was 9.7 +/- 13.8 and 13.3 +/- 12.9 days in the L and H groups, respectively; 10.6% and 15.6% of the patients in the L and H groups, respectively, never had a rejection episode. Among subjects younger than 45 years, graft and patient survival was better for those treated with the high dose (N = 60, 63.9% vs 32.2%, P = 0.032, and 100% vs 88.4%, P = 0.027, respectively) than for those treated with the low dose (N = 46). Patient and graft response to H and L was similar for patients older than 45. Morbidity was similar for both the L and H groups.

Blood transfusions before and on the day of transplantation: effects on cadaver graft survival.

Pre-BTs significantly improve the survival rate for first cadaver transplants, by a mechanism that remains obscure. The maximal influence is seen with smaller numbers of pre-BTs (1-5 units), but is also observed with larger numbers of pre-BTs. The possible beneficial influence of Tx-BTs on graft survival is not proven, and if it exists at all is not nearly as striking as the effect seen with pre-BTs. Tx-BTs neither potentiate nor nullify the benefit of pre-BTs on graft survival. It is therefore recommended that pre-BTs in smaller numbers, such as 1-5 units, be administered to candidates for first cadaver transplants to increase the probability of a successful outcome. Tx-BTs should be utilized when clinically indicated but not with the expectation that they will necessarily improve graft survival.

Donor-specific blood transfusions versus cyclosporine--the DST story.

DST provides excellent graft survival in one- and zero-haplotype-matched donor-recipient pairs as well as a trend towards improving graft survival in HLA-identical matches; serum creatinine levels are good in functioning grafts; Imuran coverage does appear to decrease DST sensitization to the blood donor in nonsensitized patients undergoing a first transplant, which encourages early DST and transplantation in this group; flow cytometry has been extremely helpful in excluding subliminal anti-class 1 antigen activity in patients with positive B warm crossmatches alone; DST, in itself, does not appear to preclude subsequent cadaveric transplantation in patients sensitized to their blood donor; and the family history of the blood donor is known, with essentially no risk to the recipients of hepatitis, AIDS, etc. In regards to the issue of whether DST or Cs is better, both have merits, and one must be aware of the circumstances that relate to the optimum application of each therapy. Only a prospective study of DST- and Cs-treated patients with a long-term follow-up will probably resolve the issue of the optimum regimen for one-haplotype-matched living related donor-recipient pairs. The ultimate strategy may involve the selective use of each regimen for the most appropriate circumstances.