William Amend

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.

Recurrent focal glomerulosclerosis: Natural history and response to therapy

PURPOSE Recurrent focal glomerulosclerosis (FGS) has been well documented since it was first reported in 1972. However, the course of the disease after transplantation and the optimal treatment regimen have not been well defined since the introduction of newer treatment modalities. PATIENTS AND METHODS We reviewed all the charts of patients with biospy-proven FGS who received renal transplants at our institution from January 1980 through December 1990. Case histories consistent with diagnoses other than primary FGS (such as reflux nephropathy or intravenous drug use) were eliminated from the study. During this time period, 78 allografts were received by 71 patients with FGS. Independent variables that were analyzed included sex, race, time in months between the diagnosis of FGS and end-stage disease (dialysis or transplantation), age at time of transplantation, type of dialysis, source of allograft (cadaveric or living related), haplotype matching, donor-specific transfusions, age and sex of the donor, post-transplantation acute tubular necrosis, rejection episodes, immunosuppression regimen, use of plasmapheresis and angiotensin converting enzyme (ACE) inhibitors, and outcome. RESULTS FGS recurred in 25 allografts (32%) of 21 patients. Biopsy-proven diagnosis of recurrence was made a mean of 7.5 months (range: 0.5 to 44 months) after transplantation. Patients who had rapid progression to end-stage disease tended to experience more frequent recurrences. Of seven patients who received a second transplant, five patients lost the first graft to recurrent FGS, and four of those patients (80%) had a recurrence in the second allograft. Recurrent disease developed in 34% of patients concurrently treated with cyclosporine and in 28% of those treated with prednisone and azathioprine alone (NS). Patients with recurrent FGS who were treated with ACE inhibitors benefited from a significant reduction of proteinuria. Six patients underwent plasmapheresis after diagnosis of the recurrence. Three of five patients in whom the diagnosis was made early in the course of the disease and in whom plasmapheresis was initiated immediately had reversal of epithelial foot process effacement and remission of proteinuria. End-stage disease eventually developed in 14 allografts (56%) an average of 23.7 months (range: 1 to 65 months) after diagnosis of recurrent disease. The cause of failure was chronic rejection in four allografts and recurrent disease in the remaining 10 allografts. CONCLUSIONS FGS recurs in approximately 30% of allografts and causes graft loss in half of these. Patients who have lost a first allograft to recurrent FGS are at high risk for developing recurrent disease in a second allograft. Prolonged allograft survival is possible in patients with recurrent FGS and may best be obtained with a combination of treatment modalities including cyclosporine (perhaps in higher dosages than are routinely used in clinical renal transplantation), ACE inhibitors, and early use of plasmapheresis. The efficacy of these modalities supports the notion that recurrent FGS is caused by a circulating humoral mediator.

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 transfusions 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.

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 patients 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.

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.

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-1β, IL-6, and TNF-α was detected in nephrectomy tissue with pathological evidence of acute or chronic rejection. Similarly, mRNA for both IL-6 and TNF-α 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-γ 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 α/β 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.

Cardiac consequences of renal transplantation: Changes in left ventricular morphology and function

To characterize changes in left ventricular morphology and function associated with renal transplantation, noninvasive cardiac evaluations were performed in 41 adults at the time of surgery and at follow-up. At the time of transplantation, 36 patients had undergone hemodialysis through a fistula for 2.3 +/- 2.5 years (mean +/- SD); their hematocrit level was 26 +/- 6% and systolic blood pressure was 151 +/- 19 mm Hg. Perioperatively, left ventricular hypertrophy was present in 93% of patients by echocardiography, but in only 37% by electrocardiography. Abnormal left ventricular diastolic function was present in 67% of patients and indicated a high risk for perioperative pulmonary edema. At follow-up (1.5 +/- 1.4 years), mean hematocrit level increased to 39 +/- 7%, systolic blood pressure decreased to 132 +/- 14 mm Hg and spontaneous closure of the fistula occurred in 13 patients. Left ventricular mass by echocardiography decreased from 237 +/- 66 to 182 +/- 47 g (p less than 0.001), a decrease of 23%. Left ventricular volumes and cardiac index also decreased significantly, reflecting the rapid resolution of a pretransplant high output state. Despite proportionate regression of left ventricular hypertrophy within months of transplantation, diastolic function did not improve. The significant regression of left ventricular hypertrophy that occurs after renal transplantation may help explain the improved cardiovascular survival of patients with a renal transplant over that of patients on long-term dialysis.

Urological complications of renal transplantation can be prevented or controlled.

Our incidence of urological complications in 860 consecutive renal transplants in 3.4 per cent. A further reduction in incidence is demonstrated in the most recent 250 transplants of this series. Urological complications have been kept to a minimum by strict adherence to certain principles in donor nephrectomy, management of multiple and small arteries, and the technique of graft implantation. When urological complications were suspected early and judicious use of 131I hippurate scintiphotographic techniques has proved to be the most helpful method to evaluate patients. If a urological complication did occur prompt recognition and treatment were responsible for a high rate of graft salvage, low incidence of sepsis and absence of patient mortality.

Results and Significance of Angiography in Potential Kidney Donors

Multiple renal arteries originating from the aortoiliac vessels were identified angiographically in 44% of 444 prospective renal donors. Bilateral multiple renal arteries were identified in 12%. With good immunological donor-recipient matching, 17 kidneys with multiple renal arteries were transplanted with excellent results; therefore, presence of multiple renal arteries should not be considered a contraindication to kidney transplantation. A high proportion (17%) of the prospective donors, acceptable by all other means of evaluation, had abnormmal angiographic findings that led to reconsideration of their acceptance. In addition to multiple renal arteries, neither renovascular atherosclerosis nor fibromuscular dysplasia proved to be an absolute contraindication to transplantation.

Frequency of recurrent lupus nephritis among ninety-seven renal transplant patients during the cyclosporine era

OBJECTIVE To determine the frequency of recurrent lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE) who underwent renal transplantation. METHODS We reviewed the posttransplant clinical course and renal biopsy results in 97 consecutive SLE patients who underwent a total of 106 renal transplantation procedures at our center from January 1984 to September 1996. RESULTS There were 81 female and 16 male patients, with a mean age of 35 years. Mean duration of dialysis prior to transplantation was 33.5 months; 9 patients were never dialyzed. In all patients, the disease was clinically and serologically quiescent at the time of transplantation. The mean posttransplantation followup period was 62.6 months. Patients underwent a total of 143 posttransplant biopsies. Nine patients had pathologic evidence of recurrent LN. Six of the patients with recurrence had cadaveric grafts, 2 had living-related grafts, and 1 had a living-unrelated graft. Recurrence occurred an average of 3.1 years after transplantation; the longest interval was 9.3 years and the shortest, 5 days. Histopathologic diagnoses on recurrence included diffuse proliferative glomerulonephritis, focal proliferative glomerulonephritis, membranous glomerulonephritis, and mesangial glomerulonephritis. In 4 patients, recurrent LN contributed to graft loss. Three of the patients with recurrence had serologic evidence of active lupus, but only 1 had symptoms of active lupus (arthritis). Three patients who lost their grafts secondary to recurrent LN underwent second renal transplantation procedures and had functioning grafts at 7, 30, and 35 months, respectively. CONCLUSION In the largest single medical center series of renal transplant patients with SLE, recurrent LN was more common than reported in the literature, but was not always associated with allograft loss. Recurrent LN was often present in the absence of clinical and serologic evidence of active SLE.