Thrombophilic Genetic Anomalies and Their Association With Dialysis Initiation Age in a Cohort of Lebanese Hemodialysis Patients.

OBJECTIVES: The relationship between chronic kidney disease and cardiovascular disease is complex and bidirectional. This relationship may be partially linked to thrombophilic genetic anomalies that may predispose to the progression of both diseases. MATERIALS AND METHODS: We analyzed blood samples from 102 Lebanese patients with end-stage renal disease and undergoing hemodialysis and 20 randomly selected healthy volunteers for frequencies of 12 cardiovascular disease gene mutations and traditional risk factors. The frequencies of these mutations were calculated and compared in both groups. We stratified patients by quartiles according to their mean score of genetic mutations and traditional risk factors, as well as their mean age at dialysis initiation. Correlation analyses were performed on the various patient groups. RESULTS: We observed a high frequency of mutations in patients on dialysis. Homozygous mutations (> 10% of patients) were observed in the PAI-1 (11%), MTHFR A1298C sequence variant (12.7%), and ACE genes (12%); in addition, the FXIII V34L and PAI-1 4G/5G genotypes were significantly associated with early dialysis initiation (P < .001 and P = .004, respectively). We observed a strong linear relationship between the different scores and age at dialysis initiation, with older patients exhibiting the highest genetic, traditional, and total scores versus those shown in the youngest patients (R2 = 0.72 and P < .001; R2 = 0.98 and P < .001; and R2 =0.96 and P < .001, respectively). CONCLUSIONS: Our results revealed a polygenic thrombophilic profile in our population of Lebanese patients with end-stage renal disease. This profile showed a strong association between early dialysis initiation and specific homozygous cardiovascular disease gene mutations. The cumulative load of these genetic and traditional risk factors may be partly responsible for the increased risk of cardiovascular disease and risk of progression to end-stage renal disease in patients with chronic kidney disease.

Bortezomib as a Novel Approach to Early Recurrent Membranous Glomerulonephritis After Kidney Transplant Refractory to Combined Conventional Rituximab Therapy.

We report a case of early recurrent membranous glomerulonephritis after kidney transplant from a deceased donor. The patient received induction therapy and was discharged with a serum creatinine level of 0.78 mg/dL on triple maintenance immunosuppressive therapy, which included tacrolimus, mycophenolate mofetil, and prednisone. At 7 months after transplant, a graft biopsy for new-onset isolated proteinuria (2.7 g/day) revealed stage 2 recurrent membranous glomerulonephritis. In the face of persistent proteinuria despite combined conservative rituximab therapy over several months and the total eradication of CD20-positive cells, bortezomib was introduced. This resulted in a substantial decline in proteinuria within 2 months and its subsequent disappearance several months later. This was paralleled by a considerable drop in plasma CD34-positive and CD138-positive cell counts. These preliminary observations indicate that recurrent posttransplant membranous glomerulonephritis is associated in part with a B-cell- mediated immunologic process that may involve both CD20-positive and plasma cells. Rituximab-resistant or partially responsive recurrent posttransplant membranous glomerulonephritis may benefit from a proteasome inhibitor-based therapy.

Approach to kidney transplant in sensitized potential transplant recipients.

More than one-third of patients on waiting lists for kidney transplant are sensitized. Most have previously formed donor-specific and non-donor-specific serum antibodies and/or positive crossmatch by complement-dependent cytotoxity and/or flow cytometry. Two categories of alloantibodies include antibodies against major histocompatibility complex human leukocyte antigen class 1 and class 2 and antibodies against minor histocompatibility complex. A current positive crossmatch is an absolute contraindication for transplant. Positive historical panel reactive antibody and/or donor-specific antibodies (human leukocyte antigen and minor histocompatibility complex), even in the absence of a historical positive crossmatch, are associated with an increased risk for allosensitization, antibodymediated rejection, and accelerated graft failure. Desensitization protocols are numerous, complex, and expensive. It is recommended to perform a systematic determination of historical and current panel reactive antibody, donor-specific antibodies (human leukocyte antigen and minor histocompatibility complex), and crossmatch by the most sensitive assays. The risk of sensitization may be estimated from the combined results of the crossmatch with the donor and those of the recipient's panel reactive antibody and donor-specific antibodies at baseline. The adoption of a scoring system for risk stratification may facilitate the task of organ allocation for sensitized patients. Recipients with an estimated sensitization risk ≥ high may be referred preferably to the national waiting priority list and informed about the financial and the medical risks that may incur with future transplant. Sensitized patients at high risk for antibody-mediated rejection may benefit from a structured monitoring process involving systematic and regular immunologic, histologic, and functional assessments of the graft after transplant. We recommend the adoption and regular updating of these approaches to ensure safe and appropriate therapeutic standards in these sensitized patients, in accordance with best clinical practice.