George C. Francos

Accelerated atherosclerosis in chronic-dialysis patients--another look.

Actuarial statistics of 53 dialysis patients treated between 1965 and 1976 are reviewed. It is suggested that dialysis did not accelerate atherosclerosis over the observed time period. It appears as though a fundamental change in the dialysis population has occurred and there are too few long-term dialysis patients available to establish whether dialysis does accelerate atherosclerosis.

A comparison of the effects of cyclosporine versus antilymphocyte globulin on delayed graft function in cadaver renal transplant recipients

There has been concern that cyclosporines nephrotoxicity increases the incidence of delayed graft function (DGF), prolongs periods of oliguria, and reduces graft survival. In order to further study whether CsA should be used in DGF, we conducted a randomized prospective trial of the effect of CsA versus antilymphocyte globulin on the effects of DGF. Between 12/22/85 and 3/11/88, all patients with DGF after an initial 12-24 hr of CsA were randomized to either daily Minnesota ALG and prednisone or lower-dose CsA (10 mg/kg/day) and prednisone. Resolution of DGF was defined as a lack of dialysis dependency and a 25% fall in the serum creatinine (CR). If DGF was not resolved by 2 weeks, transplant renal biopsies were performed to assess the presence of occult rejection. CsA (10 mg/kg/day) was initiated in the ALG group only after resolution of the DGF. Of the 45 patients who recovered graft function, 19 received ALG and 26 received CsA. CsA significantly prolonged the duration of DGF (ALG 9.74 days, CsA 13.69 days, P = 0.035) but did not result in a prolongation of hospitalization. No difference in CR was found between the two groups at 1 month, 3 months, 6 months, or 12 months. Mean CR at 12 months was 1.98 mg/dl for ALG versus 1.96 mg/dl for CsA. Overall graft survival did not differ in the CsA and ALG groups (P = 0.33). CsA does slightly increase the duration of DGF as compared with ALG but has no effect on one-year serum CR or one-year graft survival. Since there appeared to be no harmful long-term effects of the slight lengthening of DGF, a lower-dose of CsA protocol with biopsy surveillance for occult rejection can be used in patients with DGF.

Acute Humoral Rejection in a Zero Mismatch Deceased Donor Renal Transplant Due to an Antibody to an HLA-DP α

We present a case of a highly sensitized 54-year-old African American male with three prior failed transplants who received a zero mismatch deceased donor kidney and had antibody-mediated rejection directed against a human leukocyte antigen (HLA)-DP donor-specific antigen. The donor was a 21-year-old man with normal renal function. The recipient’s calculated panel reactive antibody was 99%. The standard anti-human globulin-enhanced T-cell and National Institute of Health (NIH) B-cell cytotoxicity crossmatches were negative. Flow cytometric Band T-cell crossmatches were weakly positive by a few channels over the established cutoffs. Intraoperatively, 1 mg/kg antithymocyte globulin, 250 mg methylprednisolone, and 1 g/kg intravenous immunoglobulin (IVIG) were given. Postoperatively, an additional four daily doses of 1 mg/kg antithymocyte globulin, a tapering dose of steroids, and two doses of 500 mg/kg of IVIG were given. The recipient did not have delayed graft function but presented 2 weeks later with increased creatinine and oliguria. Biopsy revealed both borderline acute cellular and acute antibody-mediatedrejection with diffuse C4d positivity in the peritubular capillaries on immunofluorescence. High-resolution HLA typing of the donor was pursued, and a mismatch at the DPA1 locus was identified. Singleantigen bead screening of pretransplant and posttransplant sera revealed a strong complement-fixing antidonor antibody (Luminex C1q antibody fixing assay, reference laboratory: Stanford University Blood Center Histocompatibility Laboratory) against DPA1*0103 with a titer by doubling dilution of 1/1024. The patient received high-dose steroids, multiple rounds of alternate day plasmapheresis, each followed by 100 mg/kg IVIG and 1 g rituximab. His antibody titers decreased to 1/64 and his creatinine nadired at 1.4 mg/ dL. Six months later, he had another 1a cellular and chronic antibody-mediated rejection with a creatinine of 2.1 mg/dL. The United Network for Organ Sharing allocates zero-mismatched kidneys based on six antigens derived from the paired loci A, B, and DR encoded by the major histocompatibility complex located on chromosome 6. The rationale for this policy is improved graft survival in the setting of a more favorable immunologic environment. High-resolution HLA typing is not routinely performed for renal transplantation, and thus, DP status is usually unknown. DPA1 and DPB1 are similarlypolymorphicasA,B,andDR,andasof January 2010, they have 28 and 138 known alleles, respectively (1). DP antigens were discovered in 1980 in restimulation experiments of previously primed T cells. They belong to HLA class II major histocompatibility complex and are composed of polymorphic and chains of similar molecular weight (32 kDa). They are characterized by weak primary allogeneic proliferative response but strong secondary cellmediated cytotoxicity (2). HLA DP mismatches do not influence first kidney transplants but significantly impact outcomes for retransplants (3–5). It has been shown that donor-recipient pairs matched at A, B, and DR have a greater than 80% probability of being mismatched at DP loci (6, 8). We pursued DP typing for the donor, and our pair was matched at A, B, Cw, DR, and DQ alleles as determined by high-resolution (allele level) DNA sequence-specific priming typing (Table 1). The pretransplant sera of recipient contained a strong antidonor antibody against the donor’s DPA1*0103 allele, with a mean fluorescence intensity in the range of 8000 to 14,000. An additional mismatch at DPB1*0601 was revealed and studied, but the antibodies against this allele were found to have mean fluorescence intensity less than 1000. Clinically significant antidonor antibodies to DPB1 have been associated with rejection in both variably matched and zero-mismatched renal allografts (7–9). In addition, antibodies to DPB1 have also been implicated in chronic humoral rejection in retransplants and have been found to share epitope with other HLA molecules (10). Further epitope classification of DPB1 has been pursued, which has helped in the identification of antibodies directed against them (11). It is known that failed renal allografts can elicit an antibody response to DP (12). However, rejection related to antibodies to DPA1 has not been described previously, and our case is unique as it is the first one to report antibody-mediated rejection because of a high-strength antibody to DPA1. It is logical to think that incorporating appropriate donor and recipient HLA-Cw and DP antigens/alleles and antibody information using luminex solid phase assays into UNet would improve concordance between the virtual crossmatching being used for kidney allocation and the actual flow crossmatches. For zero-mismatched grafts, Cw concordance is likely, whereas DP is not. We think that the data forming the basis for virtual crossmatch TABLE 1. Our donor and recipients’ typing by high-resolution DNA sequence-specific priming method

Tacrolimus as secondary intervention vs. cyclosporine continuation in patients at risk for chronic renal allograft failure

Abstract:  Background:  Chronic renal allograft failure (CRAF) is the leading cause of graft loss post‐renal transplantation. This study evaluated the efficacy and safety of tacrolimus as secondary intervention in cyclosporine‐treated kidney transplantation patients with impaired allograft function as indicated by elevated serum creatinine (SCr) levels.

Dialysis-Induced Hypoxemia: Membrane Dependent and Membrane Independent Causes

Hypoxemia during hemodialysis may result from several differing processes. We initially studied patients undergoing standard acetate hemodialysis. At 15 minutes of dialysis, leukopenia (primarily neutropenia), a decline of platelet count, and hypoxemia occurred, but without a significant change in mean minute ventilation. Complement activation (V/A ratios of C5a greater than 1.0) persisted throughout dialysis. Leukocyte count returned to baseline by one hour. To separate the effects of solute and/or gas fluxes from those of blood-membrane interaction we studied changes in Po2, WBC, C5a, TxB2, and PGI2 during a period of blood membrane interaction without dialysis, and during subsequent acetate dialysis. Patients were studied with both polyacrylonitrile (PAN) and cuprophan membranes containing different priming solutions during membrane contact alone. Despite leukopenia and complement activation, hypoxemia failed to occur during membrane contact alone. At 15 minutes of subsequent acetate dialysis, significant hypoxemia occurred with both membranes. However, the degree of hypoxemia was twice as great with a cuprophan membrane primed with acetate (18.6 +/- 3.3 mm Hg) compared with air or bicarbonate (9.1 +/- 1.4 and 7.0 +/- 2.0 mm Hg, respectively), or compared with PAN (8 +/- 2.8 mm Hg). Changes in thromboxane B2, PGI2, and C5a did not correlate with changes in Po2. We conclude that there are two major components to dialysis related hypoxemia. One is membrane independent, and may relate to the metabolic effects of acetate or to dialyzer CO2 loss. The remaining portion is membrane dependent, occurring with cuprophan, but not with PAN, and is conditioned by an acetate dependent interaction between blood and membrane.

Effect of cyclosporine and delayed graft function on posttransplantation erythropoiesis.

The effect of delayed graft function and immunosuppressive drugs on posttransplant erythropoiesis was studied prospectively in 18 living-related (LR) and 84 cadaver-donor (CD) recipients. Eight of 18 LR and 20 of 84 CD recipients received antilymphoblast globulin (ALG) in addition to azathioprine and prednisone. Sixty-four CD recipients received cyclosporine (CsA) with prednisone. In the absence of rejection reticulocytosis began 6.7\pm 0.2 days following graft implantation in azathioprine-only-treated LR recipients. This was lengthened by ALG to 9.4\pm 0.3 and 9.9\pm 0.7 days in LR and CD recipients, respectively, whose grafts functioned immediately. Delayed graft function prolonged onset of reticulocytosis to 15.9\pm 0.9 days in ALG-treated but not in CsA-treated recipients (5.8\pm0.4 days). The shortest latency was noted in CsA-treated recipients (4.9\pm0.5 days) with immediately functioning grafts. The earlier onset of reticulocytosis of CsA-treated recipients was followed by statistically significant blunting of peak reticulocytosis, which correlated with a slower rate of correction of anemia (ΔHct = 0.19/day) compared with non-CsA-treated recipients (Hct = 0.34/day). Early rejection was associated with abrogation of reticulocytosis and correction of anemia without regard to immunosuppressive regimen) until rejection was reversed. Erythropoietin (EPO) was measured sequentially in 5 patients with immediate function. In 4 of 5 cases changes in EPO preceded those in reticulocytosis. EPO rose from a mean of 13 mU/ml pretransplant to a peak of 50 within 3 weeks and decreased to 18 mU/ml within 6 weeks of graft implantation. At six months posttransplant, normalized reticulocyte counts were only 55% higher (1.75 vs. 1.13%) but hematocrit had increased from 26\pm 1% to 42\pm 1%. Hematocrit varied inversely with serum creatinine, which was highest in CsA-treated patients with initial delayed graft function. We conclude that correction of anemia posttransplantation is driven by EPO but other factors may also be important, that neither ATN nor ALG-therapy have clinically important effects on erythropoiesis, and that CsA reduced “effective” erythropoiesis and influences correction of anemia—particularly if delayed graft function complicates the initial course posttransplantation.

Ranitidine-Induced Acute Interstitial Nephritis With Epithelial Cell Foot Process Fusion

Although acute interstitial nephritis has been well described with the histamine H2-receptor antagonist cimetidine, we found only one previous case report of ranitidine-induced interstitial nephritis in the literature. We describe an additional patient who developed acute interstitial nephritis after taking ranitidine. Electron microscopy showed focal fusion of the epithelial cell foot processes that was not described in the previous report of ranitidine-induced interstitial nephritis.

Successful living donor renal transplantation despite ABO incompatibility and a positive crossmatch.

Abstract:  Potential live kidney donors have been rejected when the prospective recipients are blood type or crossmatch incompatible. By utilizing plasmapheresis combined with intravenous immune globulin (PP/IVIg) prior to surgery, donor‐specific antibodies against blood group or human leukocyte antigens (HLA) have been removed, thereby allowing successful renal transplantation. A 26‐yr‐old male with a panel reactive antibody level of 100% and repeated positive crossmatches against deceased donor kidney offers, including zero HLA mismatched donors, successfully underwent ABO‐incompatible kidney transplantation from his HLA‐identical but nevertheless crossmatch‐incompatible sister. The initial anti‐A blood group isoagglutinin titers were 128, 256, and 1024 at room temperature, 37°C, and 37°C anti‐IgG enhanced, respectively. With an individualized PP/IVIg regimen based on donor‐specific antibody titer, however, the relevant antibodies were adequately reduced and hyperacute rejection avoided. Subsequent antibody‐mediated rejection, likely directed against a minor histocompatibility antigen, was diagnosed on postoperative day 7 and successfully treated. Neither ABO, or crossmatch incompatibility, or both in combination prohibit kidney transplantation.

Rifampicin-induced renal failure

Renal failure is a rare complication associated with the use of rifampicin for the treatment of tuberculosis, usually occurring well into the course of therapy. The following is a report of 2 cases of rifampicin-induced renal insufficiency. In the first case oligo-anuric renal failure occurred on the thirteenth day of treatment, after the patient had taken only 9 doses of medication. The second case occurred in a patient who developed renal failure while on daily therapy in the hospital. A literature review revealed 83 other reported cases of rifampicin-induced renal insufficiency. Intermittent or interrupted therapy appears to be a significant risk factor for the development of this complication.

Peritransplant kidney biopsies: comparison of pathologic interpretations and practice patterns of organ procurement organizations.

Singh P, Farber JL, Doria C, Francos GC, Gulati R, Ramirez CB, Maley WR, Frank AM. Peritransplant kidney biopsies: comparison of pathologic interpretations and practice patterns of organ procurement organizations. 
Clin Transplant 2012 DOI: 10.1111/j.1399‐0012.2011.01584.x. 
© 2012 John Wiley & Sons A/S.