Reginald Y. Gohh

Preemptive Plasmapheresis and Recurrence of FSGS in High‐Risk Renal Transplant Recipients

Recurrent focal segmental glomerulosclerosis (FSGS) following transplantation is ascribed to the presence of a circulating FSGS permeability factor (FSPF). Plasmapheresis (PP) can induce remission of proteinuria in recurrent FSGS. This study addressed the efficacy of pre‐transplant PP in decreasing the incidence of recurrence in high‐risk patients. Ten patients at high‐risk for FSGS recurrence because of rapid progression to renal failure (n = 4) or prior transplant recurrence of FSGS (n = 6) underwent a course of 8 PP treatments in the peri‐operative period. Recurrences were identified by proteinuria >3 g/day and confirmed by biopsy. Seven patients, including all 4 with first grafts and 3 of 6 with prior recurrence, were free of recurrence at follow‐up (238–1258 days). Final serum creatinine in 8 patients with functioning kidneys averaged 1.53 mg/dL. FSGS recurred within 3 months in 3 patients, each of whom had lost prior transplants to recurrent FSGS. Two of these progressed to end‐stage renal disease (ESRD) and the third has significant renal dysfunction. Based on inclusion criteria, recurrence rates of 60% were expected if no treatment was given. Therefore, PP may decrease the incidence of recurrent FSGS in high‐risk patients. Definitive conclusions regarding optimal management can only be drawn from larger, randomized, controlled studies.

Treatment of Hyperhomocysteinemia in Renal Transplant Recipients: A Randomized, Placebo-Controlled Trial

A meta-analysis of 27 studies published between 1976 and 1995 [1] concluded that mild to moderate hyperhomocysteinemia, occurring either during fasting or after methionine loading, was a clinically significant risk factor for coronary heart, cerebrovascular, and peripheral vascular disease in general populations of men and women. Stable renal transplant recipients have disproportionately high rates of arteriosclerotic outcomes [2]. We recently provided controlled evidence that clinically stable renal transplant recipients have an excess prevalence of both fasting and post-methionine-loading hyperhomocysteinemia [3], which may contribute to their increased risk for arteriosclerotic vascular disease. Additional data indicated that in these patients, plasma folate and vitamin B12 levels were inversely related to fasting plasma total homocysteine levels, whereas plasma vitamin B6 (as pyridoxal 5-phosphate) levels were inversely associated with the post-methionine-loading increase in plasma total homocysteine levels [3]. Randomized, placebo-controlled studies have established that elevated fasting total homocysteine levels can be decreased by treatment with folic acid, alone or in combination with vitamin B12 [4, 5]. In contrast, no published randomized, placebo-controlled trials have assessed the impact of vitamin B6 treatment on post-methionine-loading increases in plasma total homocysteine levels above those seen during fasting. Accordingly, we conducted a block-randomized, placebo-controlled, 2 2 factorial study to evaluate the potential independent effect of vitamin B6 treatment on post-methionine-loading increases in plasma homocysteine levels among clinically stable renal transplant recipients. We also sought to provide placebo-controlled confirmation of an earlier uncontrolled study [6] showing that combined folic acid and vitamin B (12) treatment reduced fasting homocysteine levels in this patient population. Methods The institutional review board at Rhode Island Hospital, Providence, Rhode Island, approved the study protocol, and all study participants provided written informed consent. Study participants were 29 clinically stable renal transplant recipients (that is, they had had transplantation 6 months previously, had no clinical evidence of renal graft rejection, and had normal liver aminotransferase values) who were selected from among 35 consecutive renal transplant recipients involved in ongoing investigations [3] of homocysteine metabolism. Six of the 35 patients did not participate in our current study because of deteriorating renal function (n = 2), only part-time residence in Rhode Island (n = 2), and lack of interest (n = 2). Study participants either did not use vitamin supplements or had abstained from taking any supplements containing folic acid, vitamin B12, or vitamin B6 for at least 6 weeks before the start of the study. On the basis of their initial pretreatment levels of fasting total homocysteine (>20 mol/L) and post-methionine-loading increases in total homocysteine levels (>30 mol/L), participants were randomly assigned in blocks to one of four regimens: placebo (n = 8); vitamin B6, 50 mg/d (n = 7); folic acid, 5 mg/d, and vitamin B12, 0.4 mg/d (n = 7); or vitamin B6, 50 mg/d, folic acid, 5 mg/d, and vitamin B12, 0.4 mg/d (n = 7). Treatment assignments were made by a pharmacist who was blinded to all other aspects of the study. Laboratory analyses, data entry, and data analyses were performed by code so that treatment assignments remained concealed. Compliance with treatment was assessed by pill counts and determination of the change in plasma vitamin status. Fasting and 2-hour post-methionine-loading blood samples were collected twice before treatment and twice during the sixth week of treatment, as described elsewhere [3]. Plasma total homocysteine levels were determined by high-performance liquid chromatography with fluorescence detection [7], plasma folate levels were measured by microbiological (Lactobacillus casei) assay [8], plasma pyridoxal 5-phosphate levels were measured by radioenzymatic (tyrosine decarboxylase) assay [9], and plasma vitamin B12 levels were ascertained by radioassay. Serum creatinine, albumin, and liver aminotransferase levels were measured by using standard automated clinical chemistry laboratory techniques. To eliminate interassay variability, all analytes were batch assayed from aliquots (which had been cryopreserved at 70C)obtained during each of the four study visits. Two independent treatment effects were assumed a priori: 1) that vitamin B6 treatment would reduce the post-methionine-loading increase in plasma total homocysteine levels and 2) that folic acid plus vitamin B (12) treatment would decrease fasting plasma total homocysteine levels. We also assumed that these treatments would not interact. Variance estimates were derived by using natural log-transformed data from a single pretreatment determination of fasting and post-methionine-loading homocysteine levels. On the basis of these data, with 14 patients in each main treatment group, our study had 80% power at a two-tailed level of 0.05 to demonstrate a 35% reduction in the post-methionine-loading increase in plasma total homocysteine levels with vitamin B6 treatment and 90% power at a two-tailed level of 0.05 to show a 35% reduction in fasting plasma total homocysteine levels with folic acid plus vitamin B (12) treatment. All laboratory analyte values reported are based on averages of two pretreatment and post-treatment values, and all skewed variables were appropriately transformed. Baseline continuous variables were compared by using unpaired t-tests, and categorical variables were compared by using Fisher exact tests. Treatment effects for percentage changes in fasting total homocysteine levels and post-methionine-loading increases in total homocysteine levels were presented as ([average pretreatment level average post-treatment level] average pretreatment level) 100 and were compared by using unpaired t-tests. General linear modeling with analysis of covariance was performed to assess the independent effect of combined folic acid and vitamin B12 treatment or vitamin B6 treatment on fasting total homocysteine levels and the post-methionine-loading increase in total homocysteine levels; adjustments were made for age; sex; and pretreatment fasting total homocysteine levels, post-methionine-loading increases in total homocysteine levels, pyridoxal 5-phosphate levels, folate levels, vitamin B12 levels, and creatinine levels. Reported P values were based on two-tailed calculations. All statistical analyses were performed by using SYSTAT software (version 6.0.1, SPS, Chicago, Illinois). The funding source had no role in the gathering, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results As shown in Table 1, block randomization was successful with respect to both main-effect treatment assignments. The one exception was age in the vitamin B6 treatment group. All patients completed the entire study protocol. Average compliance by pill count was 97.2%, a finding confirmed by marked increases ( 680%; P < 0.001) in the geometric-mean levels of both folate and pyridoxal 5-phosphate. Independence of the hypothesized main a priori treatment effects is evident in the individual group (7 patients per group) percentage changes in fasting and post-methionine-loading increase in plasma total homocysteine levels (Table 2). Any vitamin B6 treatment (14 patients) resulted in a 22.1% reduction in the post-methionine-loading increase in plasma total homocysteine levels (P = 0.049), whereas any combined folic acid and vitamin B12 treatment (14 patients) caused a 26.2% reduction in fasting plasma total homocysteine levels (P = 0.004). Analysis of covariance revealed that both of these main treatment effects persisted (P = 0.042 for vitamin B6 treatment; P = 0.027 for folic acid plus vitamin B12 treatment) after adjustment for age; sex; and pretreatment levels of post-methionine-loading or fasting plasma total homocysteine, plasma B vitamins, and serum creatinine. Finally, when we used 90th-percentile cut points previously reported [3] from matched controls without renal disease for fasting plasma total homocysteine levels and the post-methionine-loading increase in plasma total homocysteine levels, 6 of 9 patients in the active-folic acid plus vitamin B12 group compared with 1 of 5 patients in the placebo-folic acid plus vitamin B12 group had baseline fasting total homocysteine levels reduced to less than 14 mol/L; 3 of 3 patients in the active-vitamin B6 group compared with 0 of 4 patients in the placebo-vitamin B6 group had their baseline post-methionine-loading increase in total homocysteine levels reduced to less than 26 mol/L. Table 1. Baseline Characteristics by Treatment Group Table 2. Results of Analyses of Individual Groups and Main A Priori Effects Discussion These data are the first placebo-controlled evidence in any patient population that vitamin B6 treatment independently reduces the post-methionine-loading increase in plasma total homocysteine levels. Our findings are consistent with those of three open-label, uncontrolled investigations [10-12] that examined the effect of vitamin B6 treatment on post-methionine-loading homocysteine levels in persons without renal disease. We also provide placebo-controlled confirmation of an earlier uncontrolled study [6] showing that combined folic acid and vitamin B12 treatment decreases fasting total homocysteine levels in renal transplant recipients. We evaluated only 29 patients, however, and the uncertainty associated with this modest sample size remains an important limitation. Investigation of more renal transplant recipients undergoing longer treatment is required to confirm the external validity of our findings. Selhub and Miller [13] hypothesized that two forms of hyperhomocysteinemia result from d

Enhanced Reduction of Fasting Total Homocysteine Levels With Supraphysiological Versus Standard Multivitamin Dose Folic Acid Supplementation in Renal Transplant Recipients

The mild fasting hyperhomocysteinemia commonly observed in chronic (ie, >/=6 months posttransplantation) renal transplant recipients (RTRs) can be effectively treated with combined B-vitamin supplementation featuring supraphysiological doses of folic acid. There are no controlled data evaluating the comparative efficacy of supraphysiological versus standard multivitamin dose folic acid supplementation in reducing fasting total homocysteine (tHcy) levels among RTRs. We block-randomized 60 chronic, stable RTRs on the basis of their screening fasting tHcy level to 3 groups of 20 subjects treated for 12 weeks with folic acid at either 2.4 (group 1), 0.4 (ie, standard multivitamin dose) (group 2), or 0.0 (group 3) mg/d. All 60 study participants also received 50 mg/d vitamin B(6) and 0.4 mg/d vitamin B(12). The mean percent reductions (+/-SEM) in fasting tHcy were as follows: group 1, 32.3+/-2.4%; group 2, 23.4+/-2.3%; and group 3, 19.1+/-2.3%. ANCOVA accounting for the pretreatment matching and adjusted for pretreatment levels of fasting tHcy, folate, and albumin; change in creatinine during the study; and cyclosporine A use revealed significant overall group differences (P=0.005) and significant differences between groups 1 and 2 (P=0. 038) and groups 1 and 3 (P=0.001), but not between groups 2 and 3 (P=0.153). Moreover, a chi(2) analysis of participants with pretreatment tHcy levels >/=15 micromol/L (n=29) indicated that a significantly greater proportion of those in group 1 achieved posttreatment levels <12 micromol/L: group 1, 5 of 10 (50%); group 2, 1 of 11 (9%); and group 3, 0 of 8 (0%) (P=0.016; test of trend P=0. 007). We conclude that a supraphysiological dose of folic acid is superior to standard multivitamin dosing for the reduction of fasting tHcy levels in chronic RTRs.

Management of Thrombophilia in Renal Transplant Patients

Renal allograft recipients with thrombophilia (a hypercoagulable state) are at higher risk for early allograft loss. Following an episode of allograft renal vein thrombosis in a patient subsequently diagnosed with protein C deficiency, we adopted universal screening for hypercoagulable risk factors. Patients with a history of a thromboembolic event underwent laboratory screening for thrombophilia. Eight patients with a defined hypercoagulable disorder or a strong clinical history of thrombosis even in the absence of hematologic abnormalities were treated with anticoagulation following renal transplantation. We reviewed the outcomes of these eight patients and all renal transplant recipients at our center who developed thrombotic complications after renal transplantation.

Donor-transmitted parvovirus infection in a kidney transplant recipient presenting as pancytopenia and allograft dysfunction

Abstract: Parvovirus B19 is a nonenveloped single‐stranded DNA virus that commonly causes a benign childhood infection typically manifesting as a ‘slapped‐cheek’ rash. In immunodeficient hosts, this infection can cause persistent anemia and occasionally pancytopenia. Recently, direct renal involvement has been reported in renal transplant recipients leading to various forms of glomerulopathy and allograft dysfunction. Most cases are primary infections and are donor transmitted through the transplanted organ. Clinical and virological response to intravenous immunoglobulin (Ig) is usually excellent.

Good samaritan kidney donation

Because close genetic matching between the donor and recipient is no longer required to achieve a highly successful outcome, there is currently widespread acceptance of a kidney transplant from a live donor who is genetically unrelated, but emotionally connected to the recipient. This concept has recently been taken a step further to include kidney donation from strangers—individuals who are not genetically or emotionally tied to the recipient. The volunteer stranger donor may express a desire to donate to any person on the transplant waiting list, termed nondirected live-kidney donation. Alternatively, the volunteer may become aware of a specific individual with end-stage renal disease (ESRD), but have no connection or previous relationship with the patient, termed directed stranger donation. The term “good samaritan” may be applied to either case, because the volunteer helps a stranger in a profoundly charitable way. Herein, we describe the development and growth of a Good Samaritan Kidney Donor program at a single institution. A general acceptance of good samaritan donation at our center, favorable publicity, and a geographically defined population base all contributed to the success of this program.

Treatment of mild hyperhomocysteinemia in renal transplant recipients versus hemodialysis patients.

BACKGROUND Mild hyperhomocysteinemia is common among maintenance hemodialysis (HD) patients and renal transplant recipients (RTR) and may contribute to the excess incidence of arteriosclerotic outcomes experienced by both patient groups. Relative to their RTR counterparts, the hyperhomocysteinemia of HD patients seems to be considerably more refractory to treatment with high-dose folic acid (FA)-based B-vitamin supplementation regimens, although controlled comparison data are lacking. METHODS We compared the relative responsiveness of (n=10) RTR and (n=39) HD patients with equivalent baseline total homocysteine (tHcy) levels (i.e., RTR range=14.2-23.6 micromol/L; HD range=14.4-24.9 micromol/L) to 12 weeks of tHcy-lowering treatment. The RTR received 2.4 mg/day of FA, 50.0 mg/day of vitamin B6, and 0.4 mg/day of vitamin B12, while the HD patients received 15 mg/day of FA or an equimolar amount (17 mg/day) of the reduced folate, L-5-methyltetrahydrofolate, in addition to 50.0 mg/day of vitamin B6, and 1.0 mg/day of vitamin B12. RESULTS The mean percent (%) reductions (+/-95% confidence interval) in tHcy were: RTR=28.1% (16.2-40.0%); HD=12.1% (6.6-17.7%), P=0.027 for comparison of between-groups differences by analysis of covariance adjusted for baseline tHcy levels. Moreover, (50.0%) of 10 of the RTR versus only (5.1%) of 39 of the HD patients had final on-treatment tHcy levels <12 micromol/L; P=0.002 for comparison of between-groups differences by Fishers exact test. CONCLUSION Relative to RTR with comparable baseline tHcy levels, the mild hyperhomocysteinemia of maintenance HD patients is much more refractory to tHcy-lowering B-vitamin treatment regimens featuring supraphysiological amounts of FA or the reduced folate, L-5-methyltetrahydrofolate. Accordingly, RTR are a preferable target population for controlled clinical trials testing the hypothesis that tHcy-lowering B-vitamin intervention may reduce arteriosclerotic cardiovascular disease event rates in patients with chronic renal disease.

Excess risk of renal allograft loss and early mortality among elderly recipients is associated with poor exercise capacity.

BACKGROUND Successful renal transplantation in the elderly offers substantial benefits in quality and life expectancy. However, in this group of patients there is an early increased risk of death compared with those remaining on dialysis. MATERIALS AND METHODS Graft and patient outcomes in 64 older transplant recipients were compared with 338 patients aged 18 - 59 years. We identified potential risk factors that may predict clinical outcomes in older transplant recipients. A log-rank test and Cox regression analyses were performed to assess the impact of various patient characteristics on graft and patient survival. RESULTS Among older patients, graft survival was 76.6% and 67% at 1 and 3 years, respectively. When graft survival was censored for death with functioning graft, the 1- and 3-year graft survival was 83% and 82%, respectively. Patient survival was 78% and 71% at 1 and 3 years, respectively. These survival rates were significantly lower than those of younger recipients. Pretransplant inactivity, delayed graft function, smoking history and longer waiting time predicted poor graft and patient survival. A history of chronic obstructive pulmonary disease, and peripheral vascular disease also predicted a higher mortality among older recipients. CONCLUSION Older kidney transplant recipients are at high risk for allograft failure and early death. Poor functional capacity predicts a poor outcome for older patients undergoing renal transplantation. Therefore, careful patient selection is paramount, and every effort should be made to initiate timely interventions aimed at increasing physical activity in those with low fitness level.

Pregnancy after renal transplantation: a review of registry and single-center practices and outcomes

Registries from North America, Australia and Europe are rich sources of clinical data on pregnancy after kidney transplantation. Single-center reports of pregnancy outcomes are limited by small sample sizes but not by the potential reporting bias that can impact registry data. Despite the differences in data pools, the obstetric and graft outcomes reported by single centers and registries have been similar. The majority of pregnancies are successful in renal transplant patients, but the risk of complications like pre-eclampsia, low birth weight and premature birth is high. Pregnancy has no significant impact on graft function or survival when baseline function is normal.

Glycogen Synthase Kinase 3β: A Novel Marker and Modulator of Inflammatory Injury in Chronic Renal Allograft Disease

One key cell‐signaling event central to inflammation in kidney diseases, including chronic renal allograft dysfunction or disease (CRAD), is the activation of NF‐κB, which controls transcription of numerous proinflammatory mediators. Glycogen synthase kinase (GSK) 3β is an indispensable element of NF‐κB activation, however, the exact role of GSK3β in the pathogenesis of inflammatory kidney diseases like CRAD is uncertain and was examined. Immunohistochemistry staining of GSK3β was weak in normal kidneys, but was markedly induced in inflamed allograft kidneys, with prominent cytoplasmic staining of tubular cells in areas of inflammation. Net GSK3β activity is regulated by inhibitory phosphorylation of its serine 9 residue, and this occurred in CRAD. Thus, the magnitude of GSK3β inactivation was inversely correlated with the degree of injury as assessed by Banff criteria. In vitro in cultured human tubular epithelial cells, GSK3β overexpression augmented, while GSK3β silencing diminished proinflammatory cellular responses to TNF‐α stimulation, including NF‐κB activation and expression of chemokines MCP‐1 and RANTES. These inflammatory responses were obliterated by GSK3β inhibitors. Collectively, GSK3β plays an important role in mediating proinflammatory NF‐κB activation and renal inflammation. Suppression of GSK3β activity might represent a novel therapeutic strategy to treat CRAD.