Eric P. Cohen

Risk factors for renal allograft survival from older cadaver donors

BACKGROUND The shortage of cadaver donors for kidney transplantation has prompted many centers to use kidneys from older donors. The use of older donor kidneys has been associated with lower graft survival. METHODS United Network for Organ Sharing data of all adult cadaveric renal transplant recipients receiving kidneys from adult donors between 1988 and 1994 (transplants, n=35,621) were analyzed to further study this issue. All patients were followed for a minimum of 1 year after transplantation. The recipients were classified according to donor age: group 1, 19-50 years; group 2, 51-60 years; and group 3, >60 years. RESULTS The actuarial kidney survival estimates for group 1: (n=27,999) at 1, 3, and 5 years were 82.7%, 72.2%, and 61.4%. The corresponding values for group 2 (n=5,367) and group 3 (n=2,255) were 77.3%, 63.3%, and 51.3%; and 71.7%, 55.3%, and 42.7%, respectively (P<0.0001). Logistic regression analysis for 1-year graft survival was performed, and odds ratios (ORs) were computed for various risk factors. Increased odds of graft failure were seen with increasing donor age, previous transplantation, and elevated panel-reactive antibody. In the older donor group, lower ORs were observed if the recipients were Hispanic or Asian. In addition, kidneys from African-American or Asian donors had a poorer graft outcome. A similar analysis for 3-year graft survival for those grafts functioning at 1 year revealed poorer survival with older African-American donors (OR=1.78, P<0.02), whereas improved survival rates were seen when older kidneys were used for older (OR=0.635, P<0.01) and female (OR=0.733, P < 0.01) recipients. Statistically significant factors such as HLA mismatch, cold ischemia time, and African-American or diabetic recipients differ in their impact on graft survival across the donor age groups. CONCLUSION In conclusion, kidneys from older donors are associated with poorer graft survival rates with African-American and Asian donors and African-American recipients, and no detrimental effects when used for older, Hispanic, Asian, or female recipients.

Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis

Division of Nephrology, and Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226 Background. Polyoma virus infection is characterized by lymphocytic interstitial infiltrate in the kidney, and it mimics acute rejection. The purpose of this study is to estimate renal allograft outcome with this infection and characterize the lymphocytic infiltrates in polyoma virus-infected renal allografts. Methods. Patients who had polyoma virus inclusions in renal allograft biopsies were identified. Other viral inclusions were excluded by immunohistochemistry. The lymphocytic infiltrates of six cases of polyoma virus infection were compared with six cases of definite acute rejection by immunostaining for T and B cells. Results. There were 10 cases of polyoma virus infections in renal transplant recipients. Immunosuppressants consisted of mycophenolate mofetil with tacrolimus in eight cases and mycophenolate mofetil with cyclosporine in two. The median time of diagnosis of polyoma virus infection after transplantation was 9.5 months, and the time to graft failure after the diagnosis was 4 months. Reduced allograft survival was seen in patients who had polyoma virus infection. Immunostaining for T and B cells revealed marked increase in the B cells (CD20) in renal allografts with polyoma virus infection of 21% (range, 5‐ 40%) compared with 6% (range, 0 ‐10%) in those with acute rejection (P50.039). Reduced cytotoxic T cells (TIA-1: median, 7%; range, 2‐15%) were seen in polyoma virus-infected allografts compared with 24% (range, 15‐30%) in those patients who had acute rejection (P50.0159). Conclusion. Irreversible graft failure is more prevalent with polyoma virus infection. Enhanced immunosuppressants with mycophenolate mofetil with tacrolimus may play a role in the development of this infection. An increase in CD20 and a decrease in cytotoxic T cells in allografts is characteristic of polyoma virus infection.Background. Polyoma virus infection is characterized by lymphocytic interstitial infiltrate in the kidney, and it mimics acute rejection. The purpose of this study is to estimate renal allograft outcome with this infection and characterize the lymphocytic infiltrates in polyoma virus-infected renal allografts. Methods. Patients who had polyoma virus inclusions in renal allograft biopsies were identified. Other viral inclusions were excluded by immunohistochemistry. The lymphocytic infiltrates of six cases of polyoma virus infection were compared with six cases of definite acute rejection by immunostaining for T and B cells. Results. There were 10 cases of polyoma virus infections in renal transplant recipients. Immunosuppressants consisted of mycophenolate mofetil with tacrolimus in eight cases and mycophenolate mofetil with cyclosporine in two. The median time of diagnosis of polyoma virus infection after transplantation was 9.5 months, and the time to graft failure after the diagnosis was 4 months. Reduced allograft survival was seen in patients who had polyoma virus infection. Immunostaining for T and B cells revealed marked increase in the B cells (CD20) in renal allografts with polyoma virus infection of 21% (range, 5–40%) compared with 6% (range, 0–10%) in those with acute rejection (P =0.039). Reduced cytotoxic T cells (TIA-1: median, 7%; range, 2–15%) were seen in polyoma virus-infected allografts compared with 24% (range, 15–30%) in those patients who had acute rejection (P =0.0159). Conclusion. Irreversible graft failure is more prevalent with polyoma virus infection. Enhanced immunosuppressants with mycophenolate mofetil with tacrolimus may play a role in the development of this infection. An increase in CD20 and a decrease in cytotoxic T cells in allografts is characteristic of polyoma virus infection.

Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation

The purpose of this study was to evaluate the effect of partial renal shielding used in conjunction with total body irradiation (TBI) on the incidence of bone marrow transplantation nephropathy (BMT Np) seen as a late sequelae after transplantation. Of 402 patients who have undergone bone marrow transplantation (BMT) at the Medical College of Wisconsin (MCW) 157 were greater than 18 years of age, received 14 Gy TBI and survived at least 100 days post-transplant. The incidence of BMT nephropathy was evaluated in these patients by dose to the kidneys. In the 72 patients who received 14 Gy TBI with no renal shielding, the actuarial risk of developing BMT Np at 2½ years (30 months) post-BMT was 29 ± 7%. Sixty-eight patients received 14 Gy TBI with partial renal shielding of 15% (renal dose = 11.9 Gy), the actuarial risk of developing BMT Np was 14 ± 5% at 2½ years. Seventeen patients received 14 Gy TBI with renal shielding of 30% (renal dose = 9.8 Gy); none of this group have developed BMT Np despite a median follow-up of over 2½ years (985 days). The trend of decreasing BMT Np with increasing shielding is statistically significant (P = 0.012). Prognostic factors such as age, type of transplant and good-risk vs poor-risk disease status were evaluated and were similar in each cohort of patients described above. We conclude that given the statistically significant benefit seen here in the reduced incidence of BMT Np by the use of selective renal shielding, this should be seriously considered for all patients who receive TBI, but especially for patients whose renal doses exceed 10 Gy.

Late renal dysfunction in adult survivors of bone marrow transplantation.

Until recently long‐term renal toxicity has not been considered a major late complication of bone marrow transplantation (BMT). Late renal dysfunction has been described in a pediatric population status post‐BMT which was attributable to the radiation in the preparatory regimen. A thorough review of adults with this type of late renal dysfunction has not previously been described. Fourteen of 103 evaluable adult patients undergoing allogeneic (96) or autologous (7) bone marrow transplantation, predominantly for leukemia and lymphomas, at the Medical College of Wisconsin (Milwaukee, WI) have had a syndrome of renal insufficiency characterized by increased serum creatinine, decreased glomerular filtration rate, anemia, and hypertension. This syndrome developed at a median of 9 months (range, 4.5 to 26 months) posttransplantation in the absence of specific identifiable causes. The cumulative probability of having this renal dysfunction is 20% at 1 year. Renal biopsies performed on seven of these cases showed the endothelium widely separated from the basement membrane, extreme thickening of the glomerular basement membrane, and microthrombi. Previous chemotherapy, antibiotics, and antifungals as well as cyclosporin may add to and possibly potentiate a primary chemoradiation marrow transplant renal injury, but this clinical syndrome is most analogous to clinical and experimental models of radiation nephritis. This late marrow transplant‐associated nephritis should be recognized as a potentially limiting factor in the use of some intensive chemoradiation conditioning regimens used for BMT. Some selective attenuation of the radiation to the kidneys may decrease the incidence of this renal dysfunction.

Bone Marrow Transplant Nephropathy: Radiation Nephritis Revisited

Late-onset renal failure occurs in up to 20% of survivors of bone marrow transplantation. Total body irradiation is a major factor in this syndrome, so-called bone marrow transplant nephropathy (BMT NP), which is defined by disproportionate anemia, hypertension, and azotemia. Previous or concurrent chemotherapy may potentiate the effect of radiation on the kidney. Kidney function may decline acutely or more gradually, with eventual long-term stabilization. Patient survival is associated with control of the blood pressure. BMT NP is a recognized complication of bone marrow transplantation, which will require ongoing attention.

Humanized anti-CD20 monoclonal antibody (Rituximab) treatment for post-transplant lymphoproliferative disorder.

Abstract: Introduction: Post‐transplant lymphoproliferative disorders (PTLD) is a consequence of Epstein–Barr virus (EBV) infection and is a B‐cell hyperplasia with CD‐20 positive lymphocytes. The treatment of PTLD includes reduction/withdrawal of immunosuppression and chemotherapy. This study reports our center experience with humanized monoclonal antibody against CD‐20 (Rituximab) for the treatment of PTLD.

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.

Prevalence of chronic kidney disease in Kinshasa: results of a pilot study from the Democratic Republic of Congo

BACKGROUND The burden of chronic kidney disease (CKD) in sub-Saharan Africa is unknown. The aim of this study was to investigate the prevalence and the risk factors associated with CKD in Kinshasa, the capital of the Democratic Republic of Congo (DRC). METHODS In a cross-sectional study, 503 adult residents in 10 of the 35 health zones of Kinshasa were studied in a randomly selected sample. Glomerular filtration rate was estimated using the simplified Modification of Diet in Renal Disease Study equation (eGFR) and compared with the Cockcroft-Gault equation for creatinine clearance. The associations between health characteristics, indicators of kidney damage (proteinuria) and kidney function (<60 ml/min/1.73 m(2)) were examined. RESULTS The prevalence of all stages of CKD according to K/DOQI guidelines was 12.4% [95% confidence interval (CI), 11.0-15.1%]. By stage, 2% had stage 1 (proteinuria with normal eGFR), 2.4% had stage 2 (proteinuria with an eGFR of 60-89 ml/min/1.73 m(2)), 7.8% had stage 3 (eGFR, 30-59 ml/min/1.73 m(2)) and 0.2% had stage 5 (eGFR < 15 ml/min/1.73 m(2)). Hypertension and age were independently associated with CKD stage 3. The prevalences of major non-communicable diseases considered in this study were 27.6% (95% CI, 25.7-31.3%) for hypertension, 11.7% (95% CI, 10.3-14.4%) for diabetes mellitus and 14.9% (95% CI, 13.3-17.9%) for obesity. Hypertension was also independently associated with proteinuria. CONCLUSION More than 10% of the Kinshasa population exhibits signs of CKD, which is affecting adults in their productive years. Risk factors for CKD, including hypertension, diabetes and obesity, are increasing. These alarming data must guide current and future healthcare policies to meet the challenge raised by CKD in this city and hopefully in the whole country.

Evolution of Endpoints for Renal Transplant Outcome

Progressive improvement in short‐term kidney transplant survival and reduction in acute rejection rates have restricted our ability to assess newer therapy. Past and present conventional endpoints, such as short‐term graft survival and acute rejection rates, are no longer practical. This has prompted investigators to search for alternative endpoints. Long‐term graft survival is an ideal endpoint. However, this requires a large cohort of patients with longer follow‐up. A simpler approach would be to identify short‐term markers, which can predict long‐term survival. Short‐term potential markers that can predict long‐term survival are: clinical (renal function), histological (renal pathological markers) and immunological (anti‐donor antibody, blood and urine cytokines). Post‐transplant renal function estimated by serum creatinine, cystatin C and creatinine clearance within 1 year, and histological indices, as the Banff chronicity score, have the potential to predict long‐term graft survival. Serum creatinine is limited as a marker by its variability based on recipient age, body weight, race and sex. Histological indices are limited, due to the invasive nature of evaluation. Post‐transplant renal function and histological indices can be used potentially as a composite endpoint, in combination with conventional endpoints, such as graft loss, death and acute rejection. A practical approach for assessing newer therapies in future studies is to use composite endpoints, which combine conventional endpoints (graft loss, death, acute rejection) with newer endpoints (renal function, histological indices).

Clinical course of late-onset bone marrow transplant nephropathy

Late-onset renal insufficiency is an increasingly recognized complication of bone marrow transplantation (BMT) which occurs between 6 and 12 months after BMT. This syndrome, which has occurred in 25% of our 2-year survivors, is characterized by azotemia, hypertension, and disproportionate anemia. A minority of our subjects have had a presentation similar to hemolytic-uremic syndrome, with rapid decline in kidney function. The others have had slower declines in kidney function, without apparent ongoing hemolysis. Stabilization of function has occurred in about one third of cases. Light microscopy has shown mesangial and endothelial cell dropout with widening of glomerular capillary loops. Electron microscopy has shown a striking subendothelial expansion of the glomerular basement membrane. This syndrome is similar to acute radiation nephritis. Stabilization of kidney function has occurred in some cases, perhaps reflecting control of the blood pressure. Studies of the prevention of this condition are needed because of the frequency of its occurrence and the growing number of BMT worldwide.