Jorge A. Velosa

Complete avoidance of calcineurin inhibitors in renal transplantation : A randomized trial comparing sirolimus and tacrolimus

Calcineurin inhibitors have decreased acute rejection and improved early renal allograft survival, but their use has been implicated in the development of chronic nephrotoxicity. We performed a prospective, randomized trial in kidney transplantation comparing sirolimus‐MMF‐prednisone to tacrolimus‐MMF‐prednisone. Eighty‐one patients in the sirolimus group and 84 patients in the tacrolimus group were enrolled (mean follow‐up = 33 months; range 13–47 months). At 1 year, patient survival was similar in the groups (98% with sirolimus, 96% with tacrolimus; p = 0.42) as was graft survival (94% sirolimus vs. 92% tacrolimus, p = 0.95). The incidence of clinical acute rejection was 10% in the tacrolimus group and 13% in the sirolimus group (p = 0.58). There was no difference in mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 year (61 ± 19 mL/min vs. 63 ± 18 mL/min, p = 0.57) or 2 years (61 ± 17 mL/min vs. 61 ± 19 mL/min, p = 0.84). At 1 year, chronicity using the Banff schema showed no difference in interstitial, tubular or glomerular changes, but fewer chronic vascular changes in the sirolimus group. This study shows that a CNI‐free regimen using sirolimus‐MMF‐prednisone produces similar acute rejection rates, graft survival and renal function 1–2 years after transplantation compared to tacrolimus‐MMF‐prednisone.

Overcoming a Positive Crossmatch in Living‐Donor Kidney Transplantation

Many patients who have an otherwise acceptable living‐kidney donor do not undergo transplantation because of the presence of antibodies against the donor cells resulting in a positive crossmatch. In the current study, 14 patients with a positive cytotoxic crossmatch (titer ≤ 1 : 16) against their living donor underwent a regimen including pretransplant plasmapheresis, intravenous immunoglobulin, rituximab and splenectomy. Eleven of 14 grafts (79%) are functioning well 30–600 days after transplantation. Two grafts were lost to accelerated vasculopathy and one was lost to death with good function. No hyperacute or cellular rejections occurred. Antibody‐mediated rejection occurred in six patients [two clinical (14%) and four subclinical (29%)] and was reversible with plasmapheresis and steroids. Our results suggest that selected crossmatch‐positive patients can be transplanted successfully with living‐donor kidney allografts, using a protocol of pretransplant plasmapheresis, intravenous immunoglobulin, rituximab and splenectomy. Longer follow‐up will be needed, but the absence of anti‐donor antibody and good early outcomes are encouraging.

ABO-incompatible kidney transplantation using both A2 and non-A2 living donors

Background. Given the scarcity of cadaveric organs, efforts are intensifying to increase the availability of living donors. The current study assessed the feasibility of using ABO-incompatible living-donor kidneys to expand the donor pool. Methods. The authors performed 18 ABO-incompatible living-donor kidney transplants between May 1999 and April 2001. Ten patients received living-donor kidneys from A2 and eight patients received kidneys from non-A2 blood group donors. Immunosuppression consisted of Thymoglobulin antibody induction, tacrolimus, mycophenolate mofetil, and prednisone. Eight non-A2 and two A2 kidney recipients also received a pretransplant conditioning regimen of four plasmapheresis treatments followed by intravenous immunoglobulin and splenectomy at the time of transplantation. Antidonor blood group antibody titer was measured at baseline, pretransplant, at 1- to 3-month and 1-year follow-up, and at the time of diagnosis of antibody-mediated rejection. Results. No hyperacute rejection episodes occurred. One-year graft and patient survival rates in the 18 ABO-incompatible recipients were only slightly lower than those of 81 patients who received ABO-compatible kidney transplants during the same period (89% vs. 96% and 94% vs. 99%, respectively). Glomerular filtration rate and serum creatinine levels did not differ between the groups. Antibody-mediated rejection occurred in 28% of ABO-incompatible recipients, and was reversible with plasmapheresis, intravenous immunoglobulin, and increasing immunosuppression in all patients except one. Conclusions. ABO-incompatible living donor kidney transplants can achieve an acceptable 1-year graft survival rate using an immunosuppressive regimen consisting of Thymoglobulin induction, tacrolimus, mycophenolate mofetil, and prednisone combined with pretransplant plasmapheresis, intravenous immunoglobulin, and splenectomy.

The progression of vesicoureteral reflux nephropathy

The relations among renal function, proteinuria, and glomerular lesions were studied in 54 patients with reflux nephropathy. The clinical course to end-stage renal disease was not appreciably altered by late surgical correction of the reflux, occurrence of urinary tract infection, or hypertension. All patients with progressive renal disease had significant proteinuria. Mesangial glomerular lesions can occur in the absence of proteinuria detectable by routine analysis, whereas lesions similar to those seen in idiopathic focal sclerosing glomerulopathy were present in the renal biopsies from proteinuric patients. Deposition of immunoproteins was limited to glomeruli undergoing sclerosis. Similarly, electron-dense deposits were confined to areas of mesangial alterations. Our results suggest that mesangial alterations occur early in the course of reflux nephropathy and may lead to the development of focal sclerosis. At later stages, counterproductive mechanisms of adaptation to the loss of viable nephrons might result in an acceleration of the clinical course to renal failure.

Kidney Allograft Fibrosis and Atrophy Early After Living Donor Transplantation

Kidney allograft failure is most often caused by chronic allograft nephropathy, a process of interstitial fibrosis (GIF) and tubular atrophy (TA). We assessed the pathology of living donor (LD) grafts compared to deceased donor (DD). Included are 321 recipients (245 LD; 76 DD) with protocol biopsies the first 2 years of transplant. In LD, GIF was present in 7%, 31%, 61% and 71% of grafts at 0, 4, 12 and 24 months. TA progressed in parallel to GIF. Compared to LD, more DD grafts had GIF at time 0 (29%, p = 0.002); thereafter the incidence of GIF was similar. In LD, GIF was associated with lower glomerular filtration rate (GFR)1  year (no GIF, 62 ± 16; GIF, 49 ± 15 mL/min/m2 iothalamate clearance, p = 0.001) and reduced graft survival (HR = 2.2, p = 0.009). GIF in LD related to acute rejection (HR = 2.6, p = 0.01), polyoma nephropathy (OR = 4.4, p = 0.02) and lower levels of GFR 3 weeks post‐transplant (HR = 0.961; p = 0.03, multivariate). However, GIF also developed in 53% of recipients lacking these covariates. Thus, GIF/TA develops in the majority of LD grafts, it is often mild but is associated with reduced function and survival. GIF frequently develops in the absence of risk factors. Lower GFR post‐transplant identify patients at highest risk of GIF.

Long-term follow-up and response to chemotherapy in patients with light-chain deposition disease

Nineteen patients with light-chain deposition disease (LCDD) were studied retrospectively. This report presents data on long-term patient and renal survival and the response to intermittent administration of melphalan and prednisone. Immunoelectrophoresis or immunofixation demonstrated a monoclonal protein in the serum of 78% and in the urine of 84% of the patients; 16% had no demonstrable monoclonal protein in serum or urine. The median age at presentation was 51 years (range, 37 to 77 years). Twelve (63%) of the patients had a monoclonal protein of undetermined significance without evidence of myeloma. The typical glomerular lesion was a diffuse mesangial nodular lesion that was positive for periodic acid-Schiff (PAS) stain with acute and chronic tubulointerstitial changes. Fifteen patients had kappa light-chain deposition and four had lambda light-chain deposition. Five-year actuarial patient survival and survival free of end-stage renal disease were 70% and 37%, respectively. Seventeen patients received melphalan and prednisone, and one patient received chlorambucil and prednisone. All of the patients had some impairment of renal function at presentation, and 58% had a serum creatinine concentration greater than 354 mumol/L (4.0 mg/dL). There was either stabilization or improvement in renal function after chemotherapy in five of eight patients who had a serum creatinine concentration less than 354 mumol/L (4.0 mg/dL) at the initiation of therapy. Of the 11 patients with a high serum creatinine concentration (greater than 354 mumol/dL [4.0 mg/dL]), 82% progressed to end-stage renal disease despite therapy. Follow-up urine protein studies demonstrated at least a 50% decrease in urine protein excretion in five of 15 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The Risks of Unilateral Nephrectomy: Status of Kidney Donors 10 to 20 Years Postoperatively

We received requested follow-up information from 105 (73%) of our 144 kidney donors who had undergone unilateral nephrectomy 10 to 20 years previously. Five donors had died of unrelated causes 6 or more years postoperatively. Studies in the remaining 100 donors showed that the current mean serum creatinine concentration was 1.2 mg/dl and the mean 24-hour urinary protein value was 89 mg. Hypertension (defined as 160 mm Hg or more systolic, 95 mm Hg or more diastolic, or both) was present in 19% of the donors. In a subgroup of 66 donors who had had serial serum creatinine determinations, the renal function, as estimated on the basis of these serum creatinine values, had not deteriorated with time. Thus, we consider unilateral nephrectomy in this group of patients relatively safe. Subsequent evaluation will be necessary to ascertain whether these findings prevail.

Effects of Pancreas Transplantation on Postprandial Glucose Metabolism

BACKGROUND Because a pancreas allograft is placed in the pelvis, pancreas transplantation abolishes the normal gradient between portal-vein and peripheral-vein insulin concentrations and causes systemic hyperinsulinemia. Whether pancreas transplantation restores carbohydrate metabolism to normal is not known. METHODS We studied seven patients with insulin-dependent diabetes mellitus after pancreas-kidney transplantation, seven nondiabetic patients after kidney transplantation (to control for immunosuppression), and eight normal subjects. Measurements were made after an overnight fast and after ingestion of a mixed meal. RESULTS Although plasma glucose concentrations did not differ in the two transplant groups, plasma insulin concentrations were significantly higher in the diabetic pancreas-kidney recipients than in the nondiabetic kidney recipients, both before the meal (mean +/- SE, 102 +/- 15 vs. 53 +/- 6 pmol per liter; P less than 0.05) and afterward (123 +/- 22 vs. 61 +/- 6 nmol per liter per six hours; P less than 0.05). Plasma C-peptide concentrations were the same in both groups, indicating that hyperinsulinemia was due to decreased insulin clearance rather than increased insulin secretion. Despite drainage of the venous effluent from the transplanted pancreas into the systemic circulation, the values for splanchnic clearance of ingested glucose, suppression of hepatic glucose release, incorporation of carbon dioxide into glucose, stimulation of glucose oxidation, glucose uptake, and forearm glucose clearance were all similar in the transplant groups and differed minimally from the values in the normal group. The similar rates of glucose uptake in the presence of higher systemic insulin concentrations indicated that the extrahepatic tissues of the diabetic pancreas-kidney recipients were insulin-resistant. CONCLUSIONS Despite systemic delivery of insulin, pancreas-kidney transplantation in patients with diabetes results in carbohydrate metabolism similar to that in nondiabetic subjects receiving the same immunosuppressive agents after kidney transplantation.

Subclinical Rejection in Tacrolimus-treated Renal Transplant Recipients

Background. Subclinical rejection, defined as histologic acute rejection in the absence of graft dysfunction, has been suggested as a cause of chronic allograft rejection. In cyclosporine-treated patients, the incidence of subclinical rejection 3 months after transplant is reported to be approximately 30%. The intent of our study was to determine the incidence of subclinical rejection in tacrolimus-treated renal allograft recipients. Methods. We prospectively studied the incidence of subclinical rejection on surveillance biopsies performed 3 months after transplantation in 114 patients transplanted between September 1, 1998 and November 30, 2000. All patients received tacrolimus, mycophenolate mofetil, and prednisone, and 56% received antibody induction. Results. Subclinical rejection was detected in 2.6% of patients (3/114, 95% confidence interval 0.5–7.5%). Borderline changes were detected in 11% (12/114). Subclinical rejections were treated with bolus methylprednisolone. Conclusions. The incidence of subclinical rejection early after kidney transplantation is extremely low in tacrolimus-treated patients in whom early rejections are aggressively treated, suggesting that surveillance biopsies may not be necessary with this regimen.

Correlation of Quantitative Digital Image Analysis with the Glomerular Filtration Rate in Chronic Allograft Nephropathy

Chronic allograft nephropathy (CAN) is characterized by progressive renal functional loss and histologic abnormalities of one or more tissue compartments. In this study, correlations between histologic abnormalities and graft function [glomerular filtration rate (GFR, measured by iothalamate clearance), serum creatinine (SCr) and urinary protein (UPr)] were investigated using biopsies from 49 patients with newly diagnosed CAN. Extent of tubulointerstitial fibrosis (%TIF), as assessed by a semi‐quantitative score, correlated significantly with GFR, SCr and UPr. The close correlation between %TIF and GFR suggested that quantitative measurement of %TIF may predict functional consequences of CAN. Calculation of %TIF by computerized digital analysis was performed using four strategies: (a) quantitation of blue material in Massons trichrome (MT)‐stained sections, (b) quantitation of red material in Sirius Red‐stained sections (SR‐nonpolarized), (c) quantitation of birefringent material in Sirius Red stained‐sections examined under polarized light (SR‐polarized) and (d) quantification of brown material in sections stained by immunoperoxidase for alpha‐smooth muscle actin. Only the SR‐nonpolarized score correlated significantly with GFR at the time of biopsy‐diagnosis of CAN. We conclude that digital analysis strategies demonstrate variable accuracy in quantifying %TIF. Validation of the SR‐nonpolarized strategy against histologic scoring and GFR supports the application of this technique to longitudinal studies of CAN.