Allan M. Roza

Recurrent and de novo glomerular disease after renal transplantation : A report from renal allograft disease registry (RADR)

INTRODUCTION Short-term and long-term results of renal transplantation have improved over the past 15 years. However, there has been no change in the prevalence of recurrent and de novo diseases. A retrospective study was initiated through the Renal Allograft Disease Registry, to evaluate the prevalence and impact of recurrent and de novo diseases after transplantation. MATERIALS AND METHODS From October 1987 to December 1996, a total of 4913 renal transplants were performed on adults at the Medical College of Wisconsin, University of Cincinnati, University of California at San Francisco, University of Louisville, University of Washington, Seattle, and Washington University School of Medicine. The patients were followed for a minimum of 1 year. A total of 167 (3.4%) cases of recurrent and de novo disease were diagnosed by renal biopsy. These patients were compared with other patients who did not have recurrent and de novo disease (n=4746). There were more men (67.7% vs. 59.8%, P<0.035) and a higher number of re-transplants (17% vs. 11.5%, P<0.005) in the recurrent and de novo disease group. There was no difference in the rate of recurrent and de novo disease according to the transplant type (living related donor vs. cadaver, P=NS). Other demographic findings were not significantly different. Common forms of glomerulonephritis seen were focal segmental glomerulosclerosis (FSGS), 57; immunoglobulin A nephritis, 22; membranoproliferative glomerulonephritis (GN), 18; and membranous nephropathy, 16. Other diagnoses include: diabetic nephropathy, 19; immune complex GN, 12; crescentic GN (vasculitis), 6; hemolytic uremic syndrome-thrombotic thrombocytopenic purpura (HUS/TTP), 8; systemic lupus erythematosus, 3; Anti-glomerular basement membrane disease, 2; oxalosis, 2; and miscellaneous, 2. The diagnosis of recurrent and de novo disease was made after a mean period of 678 days after the transplant. During the follow-up period, there were significantly more graft failures in the recurrent disease group, 55% vs. 25%, P<0.001. The actuarial 1-, 2-, 3-, 4, and 5-year kidney survival rates for patients with recurrent and de novo disease was 86.5%, 78.5%, 65%, 47.7%, and 39.8%. The corresponding survival rates for patients without recurrent and de novo disease were 85.2%, 81.2%, 76.5%, 72%, and 67.6%, respectively (Log-rank test, P<0.0001). The median kidney survival rate for patients with and without recurrent and de novo disease was 1360 vs. 3382 days (P<0.0001). Multivariate analysis using the Cox proportional hazard model for graft failure was performed to identify various risk factors. Cadaveric transplants, prolonged cold ischemia time, elevated panel reactive antibody, and recurrent disease were identified as risk factors for allograft failure. The relative risk (95% confidence interval) for graft failure because of recurrent and de novo disease was 1.9 (1.57-2.40), P<0.0001. The relative risk for graft failure because of posttransplant FSGS was 2.25 (1.6-3.1), P<0.0001, for membranoprolifera. tive glomerulonephritis was 2.37 (1.3-4.2), P<0.003, and for HUS/TTP was 5.36 (2.2-12.9), P<0.0002. There was higher graft failure (64.9%) and shorter half-life (1244 days) in patients with recurrent FSGS. CONCLUSION In conclusion, recurrent and de novo disease are associated with poorer long-term survival, and the relative risk of allograft loss is double. Significant impact on graft survival was seen with recurrent and de novo FSGS, membranoproliferative glomerulonephritis, and HUS/TTP.

Transplant tumor registry: donor related malignancies.

Background. Transmission of donor malignancies has been intermittently reported since the early days of clinical transplantation. The incidence of United States donor related malignancies has not previously been documented. Methods. All donor related malignancies reported to the Organ Procurement and Transplantation Network/United Network for Organ Sharing from 4/1/94–7/1/01 in a cohort of 34,933 cadaveric donors and 108,062 recipients were investigated by contacting the transplant centers to verify that the reported tumors were of donor origin. Time and mode of discovery, as well as graft and patient outcome, were determined. The status of other recipients from the donor was investigated. Results. A total of 21 donor related malignancies from 14 cadaveric and 3 living donors were reported. Fifteen tumors were donor transmitted and 6 were donor derived. Transmitted tumors are malignancies that existed in the donor at the time of transplantation. Derived tumors are de novo tumors that develop in transplanted donor hematogenous or lymphoid cells after transplantation. The cadaveric donor related tumor rate is 0.04% (14 of 34,993). The donor related tumor rate among transplanted cadaveric organs is 0.017% (18 of 108,062). Among patients developing donor related malignancies, the overall mortality rate was 38%, with that of transmitted tumors being 46% and derived tumors being 33%. The cadaveric donor related tumor mortality rate is 0.007% (8 of 108,062). Conclusions. The United States incidence of donor related tumors is extremely small. The donor related tumor death rate is also extremely small, particularly when compared with waiting-list mortality.

Multicenter Randomized Prospective Trial of Steroid Withdrawal in Renal Transplant Recipients Receiving Basiliximab, Cyclosporine Microemulsion and Mycophenolate Mofetil

Corticosteroids withdrawal from immunosuppressive regimens has thus far been associated with increased risk of acute rejection episodes. In this study, basiliximab, a chimeric monoclonal interleukin‐2 receptor antagonist, added to a maintenance regimen consisting of cyclosporine microemulsion and mycophenolate mofetil was studied for its effectiveness in allowing early corticosteroid withdrawal in de novo renal allograft recipients.

Factors influencing weight gain after renal transplantation.

Weight gain following renal transplantation occurs frequently but has not been investigated quantitatively. A retrospective chart review of 115 adult renal transplant recipients was used to describe patterns of weight gain during the first 5 years after transplantation. Only 23 subjects (21%) were overweight before their transplant. Sixty-six subjects (57%) experienced a weight gain of greater than or equal to 10%, and 49 subjects (43%) were overweight according to Metropolitan relative weight criteria at 1 year after transplantation. There was an inverse correlation between advancing age and weight gain, with the youngest patients (18–29 years) having a 13.3% weight gain and the oldest patients (age greater than 50 years) having the lowest gain of 8.3% at 1 year (P =0.047). Black recipients experienced a greater weight gain than whites during the first posttransplant year (14.6% vs. 9.0%; P =0.043), and maintained or increased this difference over the 5-year period. Men and women experienced comparable weight gain during the first year (9.5% vs. 12.1%), but women continued to gain weight throughout the 5-year study (21.0% total weight gain). The men remained stable after the first year (10.8% total weight gain). Recipients who experienced at least a 10% weight gain also increased their serum cholesterol (mean 261 vs. 219) and triglyceride (mean 277 vs. 159) levels significantly, whereas those without weight gain did not. Weight gain did not correlate with cumulative steroid dose, donor source (living-related versus cadaver), rejection history, pre-existing obesity, the number of months on dialysis before transplantation, or posttransplant renal function. Posttransplant weight gain is related mainly to demographic factors, not to treatment factors associated with the transplant. The average weight gain during the first year after renal transplantation is approximately 10%. This increased weight, coupled with changes in lipid metabolism, may be significant in terms of altering risk from cardiovascular morbidity.

Highly variable gastric emptying in patients with insulin dependent diabetes mellitus.

Some diabetic patients--particularly those with nausea and vomiting--frequently have evidence of delayed gastric emptying while other diabetic patients may in fact exhibit accelerated gastric emptying. Whether the presence or absence of symptoms of upper gastrointestinal dysfunction correlated with objective measures of gastric emptying in insulin dependent diabetic subjects was investigated. Twenty one insulin dependent diabetic patients underwent a solid phase gastric emptying scintiscan using in vivo labelled chicken liver. Thirteen patients had symptoms suggestive of gastrointestinal dysfunction (nausea, vomiting, early satiety, or constipation), while eight patients had no gastrointestinal symptoms. Eleven patients had orthostatic hypotension. All patients had been diabetic since childhood or adolescence. As a group, the diabetic patients showed a half time (T50) of gastric emptying (mean (SD) 150.0 min (163.7) that was not significantly different from that of 12 healthy control subjects (148.1 min (62.4)). Those diabetic patients without gastrointestinal symptoms and without orthostatic hypotension, however, showed a gastric emptying half time (70.1 min (41.6)) that was significantly faster than that of the control subjects. Conversely, those diabetic patients with nausea, vomiting, and early satiety (or early satiety alone) showed T50 values that were significantly greater than those of the diabetic patients without these symptoms. No correlation was found between the T50 value and the duration of diabetes, the fasting blood glucose at the time of study, or the respiratory variation in heart rate (E:I ratio). These observations indicate that highly variable rates of gastric emptying occur in insulin dependent diabetic patients, and that accelerated gastric emptying may occur in diabetic patients who have no symptoms of gastrointestinal dysfunction.

Peroxidative stress in diabetic blood vessels. Reversal by pancreatic islet transplantation.

Diabetic complications are believed to arise, in part, through an increase in oxidative stress. We characterized antioxidant status in vascular tissue in untreated diabetic rats and in diabetic rats rendered euglycemic by pancreatic islet transplantation. Three key endogenous antioxidant enzymes (e.g., superoxide dismutase, catalase, and glutathione peroxidase) were measured. Sprague-Dawley rats with streptozotocin-induced diabetes were killed after 8 weeks of untreated hyperglycemia and compared with age-matched controls. Eight weeks of untreated diabetes resulted in a significant increase of tissue catalase in aorta, iliac artery, and femoral artery as compared with controls. No significant changes in either superoxide dismutase or glutathione peroxidase were observed in aorta, iliac artery, or femoral artery of diabetic animals. This increase in catalase in diabetic vascular tissue suggests increased oxidative stress due to chronic exposure to H2O2 in vivo. To assess the impact of islet transplantation on oxidative stress in vascular tissue, inbred Lewis strain rats were rendered diabetic with streptozotocin. After 8 weeks of untreated diabetes, rats received an intraportal islet isograft and were monitored for 4 subsequent weeks of euglycemia. Islet transplantation improved weight gain and normalized blood glucose and total glycosylated hemoglobin. While catalase was significantly increased in aorta and iliac artery at 8 and 12 weeks of diabetes, vascular catalase was restored to normal by islet transplantation. These data suggest that islet transplantation is an effective treatment strategy to minimize increased oxidative stress in diabetic vasculature.

Early Mortality Rates in Older Kidney Recipients With Comorbid Risk Factors

Background. There are over 60,000 candidates on the deceased donor kidney wait-list and the percentage of candidates over age 50 years continues to grow each year. National data have not previously been used to evaluate the association of comorbidities with mortality in older patients. Methods. A multivariate analysis of 30,262 deceased donor primary kidney recipients aged 18–59 years and 8,895 aged ≥60 years evaluated the association of six recipient comorbidities on 90- and 365-day patient mortality rates. The additional effects of expanded criteria donors (ECD) and development of delayed graft function (DGF) were also evaluated. Results. The 365-day mortality rate for recipients aged ≥60 years (10.5%) was more than twice that of recipients aged 18–59 years (4.4%) and comorbidities significantly increased mortality rates even higher (10.6–21.4%). The 365-day mortality rate for recipients aged ≥60 years who received an ECD kidney was 14.4% and who developed DGF was 15.9% while recipients with comorbidities but no DGF and no ECD ranged from 16.0 to 42.3%. The 365-day transplant mortality rate of recipients aged ≥60 years with comorbidities is higher than the 365-day wait-list mortality for patients with the same comorbidities, suggesting a lack of survival benefit from transplantation. Conclusions. Mortality rates for patients aged ≥60 years with comorbidities are higher than for those without comorbidities, significantly higher than for younger patients, and higher than for wait-listed patients. Thus, utility may be poorly served by allocating kidneys to older patients with comorbidities, and perhaps discussion of exclusionary listing criteria is warranted.

Renal transplantation for end-stage renal disease following bone marrow transplantation: a report of six cases, with and without immunosuppression.

Background. Over 12 000 bone marrow transplantations (BMT) are performed in the USA each year. This procedure is associated with significant morbidity including acute and chronic renal failure (CRF). CRF after BMT is usually secondary to radiation nephropathy and/or cyclosporine (CsA) toxicity. Survival on dialysis therapy for patients with radiation nephropathy is poor and renal transplantation may be a preferable form of renal‐replacement therapy.Methods. We report our experience with renal transplantation in 6 patients with end‐stage renal disease (ESRD) following BMT: 4 as a result of radiation nephropathy; one secondary to hemolytic–uremic syndrome; and 1 as a result of antitubular basement membrane nephritis. Ages at the time of BMT ranged from 26 to 40 yr. ESRD developed after a mean period of 94 months (range 42–140 months) after BMT. The kidney source was from a living donor in 5 patients, and a cadaveric donor (CAD) in 1 patient. In 3 recipients, the bone marrow and kidney were from the same donor. They are managed without any immunosuppressive therapy. The other 3 were initiated on triple therapy (prednisone, mycophenolate mofetil/azathioprine and cyclosporine/tacrolimus).Results. These patients have been followed for up to 31 months (range 3–30 months) after kidney transplant, and 5 out of 6 are alive with functioning bone marrow and renal transplants. Their plasma creatinines range from 70 to 160 μmol/L (mean 97 μmol/L). One patient died following metastatic squamous cell cancer of the genital tract.Conclusions. 1) Renal transplant is a feasible alternative for patients with ESRD following BMT; 2) if bone marrow and kidney are from the same donor, the recipient requires little or no maintenance immunosuppression; 3) short‐term results show good survival, but long‐term follow‐up is needed; 4) infections and malignancy post‐renal transplantation were seen in recipients who needed immunosuppression; and 5) reduction in immunosuppression may be needed in such post‐BMT patients who undergo kidney transplants.

Reversal by L-arginine of a dysfunctional arginine/nitric oxide pathway in the endothelium of the genetic diabetic BB rat

Summary We examined the effects of acute supplementation with arginine in vitro on endothelium-dependent relaxation in aortic rings taken from female genetic, diabetes-prone BB rats. Sensitivity to norepinephrine-induced contraction was unaltered in rings of diabetic BB rats compared to rings from non-diabetic littermates. In precontracted rings, acetylcholine produced a concentration-dependent relaxation which was impaired by diabetes. This relaxation was blocked by l-nitroarginine in both control and diabetic rings. Addition of 3 mmol/l l-arginine (but not d-arginine) enhanced relaxation in diabetic rings similar to that seen in control rings without arginine. l-arginine had no effect on acetylcholine-induced relaxation in control rings. In contrast, relaxation-induced by nitroglycerin in diabetic rings without endothelium was not altered by l-arginine treatment. Thus, a defect in the utilization of arginine by nitric oxide synthase exists in the endothelium of the diabetic BB rat. [Diabetologia (1997) 40: 910–915]

Transferrin--a poor measure of nutritional status.

The present study evaluated the sensitivity and specificity of the serum transferrin concentration as a measure of the nutritional state. Serum transferrin was derived from total iron-binding capacity measurements in 74 patients on 114 occasions and correlated with body composition as measured by multiple isotope dilution. Highly significant correlations (p less than 0.001) existed between serum transferrin and both the body cell mass and the nutritional state as measured by the Nae/Ke ratio. However, the 95% confidence limits about both regressions were wide. The false-positive rate was 60% while the false-negative rate was 31%. Body composition and transferrin were measured before and after 2 wk of total parenteral nutrition in 34 malnourished patients. Eighteen patients restored body cell mass toward normal after 2 wk of total parenteral nutrition while in 16 patients the body cell mass continued to decrease in size, despite 2 wk of total parenteral nutrition. The changes in serum transferrin were not significant over this period of time in either group, despite significant changes in the nutritional state in both groups. The presence of a statistically significant relationship between the serum transferrin concentration and the nutritional state indicates that the serum transferrin concentration accurately reflects a populations nutritional status, and is therefore useful in epidemiologic surveys. However, because of the large variance of the data, as demonstrated by the wide 95% confidence limits, and because of the poor sensitivity and specificity, in an individual patient it is of little value as a measure of the nutritional status.