Non-life-threatening leukopenia in a renal transplant recipient with acute overdose of mycophenolate mofetil.

Mycophenolate mofetil (MMF) is increasingly used as an immunosuppressant for organ transplantation and for treatment of autoimmune diseases. As yet, the experience with acute overdose of MMF in humans is limited. Herein we have reported a 40-year-old female kidney recipient with moderate leukopenia and lack of gastrointestinal toxicity following ingestion of 25 g MMF, which was confirmed by serum drug levels. We treated the patient with charcoal decontamination and oral cholestyramine. She recovered completely without sequelae.

Impact of variability of sirolimus trough level on chronic allograft nephropathy.

The efficacy of sirolimus is strictly dose-dependent; an inappropriate exposure may cause either rejection episodes or drug toxicity. The variability of sirolimus trough levels (C0) may also have an impact on renal allograft function. We prospectively evaluated the impact of the dose-normalized C0 of sirolimus and the intrapatient coefficient of variation (% CV) on renal allograft function at 6 months after the administration of sirolimus to kidney transplant recipients with chronic allograft nephropathy (CAN). We enrolled 51 recipients with CAN who were treated with sirolimus. The dose-normalized C0 of sirolimus was 3.8 +/- 1.9 ng/mL/mg. The intra- and interpatient variabilities of sirolimus C0 were 26.1% and 51.9%, respectively. Based on receiver operating characteristic analysis, patients were divided into 2 groups: group I, sirolimus % CV <22.9% (n = 36) versus group II, sirolimus % CV >22.9% (n = 15). Patients in group II experienced significantly greater risk for progressive deterioration of allograft function (group I vs group II: 11.1% vs 73.3%; P < .05). Multiple logistic regression analysis revealed that higher baseline serum creatinine, but not age, gender, or concomitant immunosuppressants, positively correlated with the sirolimus % CV. In conclusion, both higher baseline serum creatinine and higher intraindividual variability of sirolimus C0 impact the outcome of renal allograft function in CAN. Thus, we suggest that close monitoring of sirolimus C0 is necessary for recipients treated with sirolimus, especially for patients with CAN.

Early diagnosis of polyomavirus type BK infection in tailoring immunosuppression for kidney transplant patients: screening with urine qualitative polymerase chain reaction assay.

Polyomavirus type BK (BKV) nephropathy is increasingly a significant cause of graft dysfunction and even failure. Early diagnosis followed by reduction of immunosuppression has been associated with an improved prognosis. We screened 250 patients with the urine qualitative polymerase chain reaction (PCR) for BKV DNA. We followed with blood BKV PCR if the urine screen was positive and then reduced immunosuppression in viremic patients. One hundred ninety-nine patients (80%) had no viuria; 43 (17%) viuria; and 8 (3%) both viuria and viremia. Graft biopsy performed in three patients (1%) with viremia and impaired graft function all revealed BKV nephropathy. After 6 months of follow-up, seven out of eight viremic patients (88%) had negative repeat blood PCR and stabilized graft function. An early diagnosis of BKV infection with reduction of immunosuppression may reverse viremia and retard progression of BKV nephropathy. BKV screening by PCR assays should be considered in kidney transplant recipients, especially those with impaired graft function.

A Salmonella infection complicated with suppurative thyroiditis and ruptured aortic mycotic aneurysm in a renal transplant recipient.

We report a renal transplant recipient who presented with fever and chills for 2 days. The blood and stool cultures revealed the growth of Salmonella enteriditis. A whole-body gallium scan played an important role in the subsequent diagnosis of suppurative thyroiditis. To our knowledge, this is the first report of acute S. enteriditis thyroiditis in a renal transplant recipient. Despite vigorous antibiotic use and a partial thyroidectomy, he experienced recurrent S. enteriditis infection, resulting in a ruptured thoracic mycotic aneurysm 1 month later. Finally the patient was successfully cured with aneurysm resection, in situ reconstruction of the thoracic aorta, and prolonged antibiotics.

Effect of pentoxifylline on graft function of renal transplant recipients complicated with chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN) is characterized by a progressive deterioration of renal function with various degrees ofproteinuria. Currently, there is no effective treatment despite the introduction of new generations of immunosuppressants. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that possesses antiproteinuric effect and has been proved to be effective in treating several glomerular diseases. The purpose of the current study was to examine the effect of PTX on renal transplant patients with established CAN. MATERIALS AND METHODS: Renal transplant recipients with biopsyproven CAN were recruited for the study. All the patients had been on angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for more than 1 year and were on a triple immunosuppressive regimen including corticosteroid, calcineurine inhibitor and mycophenolate mofetil. PTX in a dose of 1,200 mg/day was administered for at least 6 months. The following parameters were assessed at baseline, the 3rd and the 6th month post treatment: systolic and diastolic blood pressure, number of anti-hypertension drugs, serum creatinine (sCr),estimated glomerular filtration rate (eGFR), 24-hour urinary protein excretion (U/P), urinary N-acetylglucosaminidase (NAG) and intracytoplasmic Thl/Th2 cytokines production of peripheral blood CD4+ cells. RESULTS: A total of 17 (11 male and 6 female) patients were enrolled in the study. The mean duration of follow-up post transplant was 10.6+/- 4.4 years. The baseline data of sCr, eGFR and U/P were 1.83+/-0.46 mg/dl, 38+/-8 ml/min and 2.65+/-2.15 g/day, respectively. Corresponding values at the 3rd and 6th month post treatment were 1.90+/-0.43 mg/dl (p = NS), 33+/-7 ml/min (p=NS), 2.13 +/-1.13 g/day (p < 0.05) and 2.03+/-0.64 mg/dl (p < 0.05), 32+/-10 ml/min (p < 0.05), 2.74 +/-0.93 g/day (p = NS), respectively. When individual data were analyzed, five cases (29.4%) showed a U/P significant reduction of more than 50% of baseline value, while in 10 cases (58.8%) the graft function remained either stable (9 cases) or improved (1 case) at the end of treatment. Urinary NAG was elevated at the 3rd month, but stabilized thereafter. The Thl/Th2 intracytoplasmic cytokine pattern of peripheral blood CD4+ cells showed a significant decrease of cells bearing TNF-alpha (15.0+/-14.4% vs 14.2+/-17.0%, p < 0.05) and cells bearing IL-10 (1.60 +/-1.23% vs 0.90+/-0.66%, p < 0.05) at the 3rd month. CONCLUSION: In this pilot study, PTX seemed to be temporarily effective in reducing proteinuria. The graft function was stabilized in more than half of patients at the end of follow-up.

Predictors of renal function improvement following tacrolimus conversion in cyclosporine-treated kidney transplant recipients.

The objective of this study was to evaluate the relationship between variability of cyclosporine (CsA) absorption and tacrolimus (TAC) conversion seeking factors that predict improvement in allograft function after TAC conversion. We performed a retrospective study of 44 adult kidney transplant recipients undergoing conversion from CsA to TAC-based immunosuppression. Before TAC conversion, patients had complete, consecutive, 6 monthly C2 levels and a follow-up duration beyond 6 months after TAC conversion. The patients were divided into 2 groups: one (n=23) with low variability of CsA absorption and one (n=21) with high variability of CsA absorption. At TAC conversion, the estimated glomerular filtration rate (eGFR) was similar in both patient groups. Six months after TAC conversion, eGFR improved in both groups. Stepwise regression analysis revealed the DeltaSCr6 (change in serum creatinine level at 6 months) to be independently associated with the preconversion serum creatinine (SCr; P<.0001) and the percent coefficient of variation (%CV) of SCr (P=.0034). DeltaSCr6 was inversely associated with posttransplantation years (P=.0033), and 6-month TAC blood levels (P=.0053). The DeltaSCr6 was not associated with variability of oral CsA absorption. The cutoff value of baseline SCr at TAC conversion differentiated an increase in or reduction of SCr to be about 1.0 mg/dL. Our study of CsA-treated kidney transplant recipients who underwent TAC conversion showed that a preconversion SCr>1.0 mg/dL, a high variability of SCr, and early TAC conversion predicted greater short-term benefit on graft function.

Lack of hepatotoxicity upon sirolimus addition to a calcineurin inhibitor-based regimen in hepatitis virus-positive renal transplant recipients.

BACKGROUND: We retrospectively analyzed the impact of sirolimus addition (SRL) with a 25% dosing reduction in calcineurin inhibitors on liver function among patients with or without hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. METHODS: Forty-eight renal transplant recipients (HBsAg-positive, n = 5; anti-HCV-positive, n = 7) with allograft dysfunction (serum creatinine: mean 2.7, median 2.0 mg/dL) and normal liver function were enrolled. The duration of the SRL add-on therapy was 8.0 +/- 3.6 months. SRL trough levels were maintained within 6.5 +/- 3.7 ng/mL. The trough levels of tacrolimus and the 2-hour cyclosporine postdose levels were tapered to 4.6 +/- 1.9 ng/mL (24.6% reduction) and 650 +/- 170 ng/mL (24.3% reduction), respectively. SRL-related hepatitis was defined as a rise in liver transferase or alkaline phosphatase or bilirubin over twice the upper limit of normal. Thirty-six HBsAg-negative and anti-HCV-negative patients served as the controls. RESULTS: Hepatotoxicity developed in 6 (12.5%) of the 48 patients and in 3 (8.3%) of 36 control subjects. One (20.0%) of five HBsAg-positive patients (P = .959) and two (28.6%) of seven anti-HCV-positive patients (P = .496) developed hepatotoxicity, respectively. Three (25.0%) of the 12 HBsAg-positive or anti-HCV-positive patients developed hepatotoxicity (P = .420). CONCLUSIONS: Patients with seropositivity of HBsAg or anti-HCV had an insignificantly higher percentage of hepatitis. Use of SRL in the HBV/HCV patients is not contraindicated, but needs monitoring for HBV/HCV activation.

Early experience with enteric-coated mycophenolate sodium in de novo kidney transplant recipients.

INTRODUCTION: We sought to evaluate the efficacy of enteric-coated mycophenolate sodium (EC-MPS) and the gastrointestinal (GI) adverse events in de novo kidney transplant recipients. METHODS: This noncontrolled, retrospective review includes 22 de novo kidney transplant recipients. All patients received a standard course of basiliximab and were maintained on triple-drug therapy with EC-MPS, cyclosporine microemulsion (CsA), and prednisolone. The follow-up lasted 7.9 +/- 1.2 months. The incidence of GI adverse effects were compared with those of historical mycophenolate mofetil (MMF) studies. RESULTS: The serum creatinine was maintained within 1.4 +/- 0.7 mg/dL. The 2-hour CsA postdose level was 1080 +/- 327 ng/mL initially and gradually tapered to 851 +/- 435 ng/mL. The daily EC-MPS dose was 1404 +/- 180 mg initially and gradually tapered to 1098 +/- 288 mg. The GI adverse effects at the daily dose of EC-MPS 1422 +/- 126 mg included dyspepsia 27%, acid regurgitation 18.2%, epigastralgia 9%, nausea 9%, vomiting 4.5%, and poor appetite 4.5%. In comparison those from historical MMF 2 g/d studies included dyspepsia 3.1% to 40%, epigastralgia 10%, nausea 3.7% to 34%, and vomiting 0.6% to 10.7%. CONCLUSION: Immunosuppression with CsA, EC-MPS, and steroids maintains stable graft functions. Minimal dose reduction of EC-MPS decreases GI adverse events but without significance. EC-MPC and MMF have respective GI side effects; they can be used alternatively in patients with individual GI intolerance.

Neurotrophic factors decrease the release of creatine kinase and prostaglandin E2 from metabolically stressed muscle.

We have used an in vitro model of oxidative stress by exposing rat muscle to 2:4 dinitrophenol. This causes an efflux of creatine kinase (CK) and prostaglandin E2 (PGE2) commonly used as indicators of muscle cell damage. We then investigated compounds with a putative cell protective effect in the system. Ciliary neurotrophic factor, brain derived neurotrophic factor and insulin like growth factor 1 all prevent the release of PGE2 and CK. To the extent that these indicators may reflect cell damage, the results might support the investigation of the therapeutic potential of these compounds in muscle disease.

Prevalence of subclinical cryoglobulinemia in maintenance hemodialysis patients and kidney transplant recipients.

We studied the prevalence and the clinical spectrum of cryoglobulinemia (Cryo) among 101 maintenance hemodialysis (HD) patients and 148 kidney transplant (KT) recipients, with or without chronic hepatitis C virus (HCV) infection. Cryo was present in 32% (16 of 50) of the HCV-positive HD patients, 5.9% (3 of 51) of the HCV-negative HD patients, 37.8% (28 of 74) of the HCV-positive KT recipients, and 27% (20 of 74) of the HCV-negative KT recipients. Cryoprecipitate in 56.3% (9 of 16) of the HCV-positive Cryo HD patients and 53.8% (14 of 26) of the HCV-positive Cryo KT recipients contained HCV-RNA. Interestingly, the cryocrit values among HD and KT patients were much lower than these in other reports on nonrenal failure cases. Also, the cryoglobulinemic syndrome (with purpura, arthralgia, etc.) in HD and KT patients with Cryo were not common (Tables 1 and 2). There was not correlation between Cryo and age,sex, and liver function. Only longer duration of end-stage renal disease was noted in these patients. In addition, we suggested that KT patients are more susceptible to having Cryo. Further studies are necessary to better define whether any other subclinical viral or nonviral chronic infection may induce Cryo in HCV-negative KT recipients.

Lamivudine is effective for the treatment of reactivation of hepatitis B virus and fulminant hepatic failure in renal transplant recipients.

Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication. The aim of this study is to elucidate the effectiveness of lamivudine for the treatment of HBV reactivation with or without fulminant hepatic failure in renal transplant recipients. Forty-two renal transplant recipients (30 men, 12 women) were enrolled onto this study. Eight patients presented with HBV reactivation without fulminant hepatic failure and were administered lamivudine (group I), 5 patients presented with HBV and hepatic failure and were administered lamivudine (group II), 5 patients presented with HBV and hepatic failure but were not administered lamivudine (group III), and 24 patients were asymptomatic HBV carriers who were not administered lamivudine (group IV). Lamivudine was administered at a dose of 100 or 150 mg once daily. A greater prevalence of recent use of a combination of antilymphocyte immunoglobulin (ALG) and methylprednisolone (MP) occurred in patients with hepatic failure (groups II and III) than those without hepatic failure (30% versus 6.3%; P = 0.043). However, there was no significant difference in the incidence of MP use alone (20% versus 25%; P = 0.746). Mortality rates for groups I, II, and III were significantly different (12.5%, 40%, 100%; P = 0.008). One patient in group I died of sepsis without evidence of HBV DNA, even in the terminal event. In group II, 3 of 5 patients (60%) were rescued by lamivudine therapy. In group III, without lamivudine treatment, there was a 100% mortality rate despite intensive plasmapheresis. HBV DNA was not detectable after lamivudine treatment in 7 of 8 patients in group I and 3 of 5 patients in group II. Creatinine levels did not change significantly during lamivudine treatment. Hepatitis B surface antigen and hepatitis B e antigen seroconversion rates after lamivudine treatment were 7.7% and 37.5%, respectively. We conclude that ALG is a potent trigger of HBV-related fulminant hepatic failure in renal transplant recipients, whereas lamivudine is an effective and lifesaving treatment. Prompt use of lamivudine is recommended in renal transplant recipients with evidence of HBV reactivation to prevent catastrophic fulminant hepatic failure.

Placental proteins (human chorionic gonadotropin, human placental lactogen, pregnancy-specific beta 1-glycoprotein, and placental protein 5) in seminal plasma of normal men and patients with infertility.

Placental proteins, including human chorionic gonadotropin (hCG), human placental lactogen (hPL), pregnancy-specific beta 1-glycoprotein (SP1), and placental protein 5 (PP5) have been detected in human seminal plasma of 20 normal men and 42 patients with infertility. Levels of hPL, SP1, and PP5 were similar in these groups. There were significantly higher levels of hCG in subjects with normal sperm counts than in those with oligospermia or azoospermia. The levels of PP5 in seminal plasma showed an association with sperm motility, suggesting that PP5 may have a significant biologic function in the maintenance of sperm motility.

Home treatment of uremia with gastrointestinal dialysis.

Twenty patients with end-stage renal disease and a creatinine clearance of less than 5 ml/min were tre ated with oral gastrointestinal (GI) dialysis. The dialyzate contained an electrolyte solution with 180-220mmoles/l of mannitol. In fasting state in the morning the self-prepared 7 liters of dialyzate was drunk at a rate of one glass every 5 minutes for about 3 hours. Intermittent diarrhea with passage of watery fluid occurred during the whole period. After each treatment the average drop in BUN in individual patients was 11--22%, but no significant decrease in serum creatinine. With twice to thrice weekly GI dialysis uremic symptoms such as anorexia, nauseal and vomiting were usually improved with slight prolongation of life. However, treatment is usually difficult when the patient becomes oliguric or anuric, so its value in long-term management of chronic uremia is limited. Most of our patients either died or shifted to hemodialysis within a few months of institution of the therapy.

Long-term outcome of adult patients with minimal urinary abnormalities and normal renal function.

AIM: To define the long-term outcome of patients with minimal urinary abnormalities (defined by the presence of microscopic hematuria with no or less than 1 gm/day proteinuria), and normal renal function (defined by a serum creatinine < 1.3 mg/dl), we retrospectively studied patients who fulfilled the above criteria and had a kidney biopsy done before the year of 1992 (i.e. at least followed up for 5 years), with a definite pathological diagnosis. METHODS: A total of 41 cases among 719 cases of primary glomerulonephritis (5.7%) were enrolled into the study. There were 19 males and 22 females with a mean age of 35.4+/-14.7 years at biopsy. The duration of renal disease was 116.0+/-60.5 months and the duration of follow-up post biopsy was 100.2+/-38.1 months. The pathological diagnosis was: IgA nephropathy (21 cases), focal glomerulosclerosis (9 cases), mesangial proliferative glomerulonephritis (8 cases), membranous glomerulonephritis (2 cases) and acute glomerulonephritis (1 case). RESULTS: At the end of follow-up, 8 cases (19.5%) had a certain degree of renal insufficiency including 2 (4.9%) in end-stage renal disease. The other cases were either in complete remission (6 cases) or stable condition (27 cases) with persistent microscopic hematuria and normal renal function. The long-term outcome was not correlated with any of the following parameters: age, sex, disease duration, serum creatinine at presentation, daily protein loss at presentation, degree of glomerular change and degree of interstitial inflammatory cell infiltration. However, a poor long-term outcome was correlated with tubular atrophy (p < 0.05) and interstitial fibrosis (p < 0.05). CONCLUSION: We conclude that a minimal urinary abnormality with normal renal function at presentation does not necessarily imply a favorable long-term outcome in certain patients. Tubular atrophy and interstitial fibrosis but not glomerular change correlates with a worse prognosis. This further emphasizes the importance of renal biopsy in such cases.

Glomerulonephritis in ankylosing spondylitis.

There have been a few reports suggesting the association between glomerulonephritis (GN) and ankylosing spondylitis (AS). The reported glomerulonephritides include IgA nephropathy, mesangial proliferative GN and membranous nephropathy. From January 1983, through December 1984, we observed 5 cases of GN among 116 cases of definite AS. Three of them were IgA nephropathy. The other two were mesangial proliferative GN, with IgM deposit in one case and isolated C3 deposit in another. Microscopic hematuria was observed in all of them. The renal function and 24-hour urine protein excretion were all within normal limits. Serum IgA level increased in all but the case of mesangial proliferative GN with IgM deposit. All except one had the antigen of HLA-B27. Serum IgA level was determined in 78 cases (86 estimations) of AS. The mean value was 399.6 +/- 15.0 mg/dl (mean +/- SE) (normal range: 100-350 mg/dl). Fifty-four of them (63%) had a value higher than 350 mg/dl. The interrelationship of AS and IgA nephropathy was discussed.

Serum immunoglobulin E in primary IgA nephropathy.

The biosynthesis of human immunoglobulin E (IgE) is regulated by a complex network involving T and B lymphocytes. Diseases associated with high serum IgE (sIgE) levels are usually characterized by T cell disorders. Total sIgE level has been found to be of clinical relevance in minimal change nephrotic syndrome. However, the clinical significance has rarely been studied in primary IgA nephropathy (IgA N). We retrospectively studied 99 cases of primary IgA N. There were 59 males and 40 females with a mean age of 30.0 +/- 12.1 years. The mean follow-up duration was 45.9 +/- 31.1 months. Pathological grading was done according to the criteria of Meadow et al. Median sIgE for the entire group was 122.0 IU/ml (range: 2.8-5805 IU/ml) which was significantly higher than the healthy control group (median: 43,7 IU/ml, range: 5.0-1003 IU/ml, p < 0.001). However, when the IgA N cases were stratified into grades, only grade I (median: 514 IU/ml, range: 72.1-5805.0 IU/ml) and grade II (median: 229 IU/ml, range: 5.0-5464 IU/ml) patients had significantly higher sIgE than the control group (p < 0.0005 and p < 0.001 respectively). Patients with nephrotic ranged proteinuria (32 cases) were further classified into "stable" and "progressive" groups. The "stable" group had a significantly higher sIgE level (median: 922.0 IU/ml, range: 2.8-5805 IU/ml), compared to that of the "progressive" group (median: 55.3 IU/ml, range: 5.0-1600 IU/ml, p < 0.02). The effect of aggressive treatment (including corticosteroid and/or cyclophosphamide, cyclosporine) was also assessed.(ABSTRACT TRUNCATED AT 250 WORDS)

Sirolimus addition is beneficial for renal allograft dysfunction due to simultaneous acute rejection episode and calcineurin inhibitor nephrotoxicity.

We report a diabetic renal transplant recipient who experienced an episode of acute allograft rejection in the 6th month posttransplant when there was an attempt at steroid withdrawal. The acute rejection was steroid resistant. Furthermore calcineurin inhibitor nephrotoxicity was exacerbated by rescue therapy with tacrolimus conversion. The allograft dysfunction ultimately stabilized upon institution of sirolimus and minimization of tacrolimus.

Statistical and parametric analysis of beta-2-microglobulin removal from uremic patients in high flux hemodialysis.

Beta-2-microglobulin (beta 2M) associated amyloidosis has been seen in patients with chronic renal failure after long-term hemodialysis. However, the exact mechanism of beta 2M formation and accumulation is not clinically understood. In this investigation, the formation and removal kinetics of beta 2M were studied by compartmental modeling of a patient dialyzer system. Statistical and parametric analyses of model equations, coupled with clinical data from selected patients, enabled us to predict the behavior and influence of membrane materials upon the clearance characteristics of beta 2M during and between hemodialysis treatments.

Infantile hypertrophic pyloric stenosis after surgery for esophageal atresia with tracheoesophageal fistula.

Infants with esophageal atresia and tracheoesophageal fistula may have other associated anomalies. The development of infantile hypertrophic pyloric stenosis in the postoperative course of esophageal atresia with tracheoesophageal fistula is rarely reported. Because its symptoms may mimick postoperative complications such as gastroesophageal reflux or anastomotic stricture, the diagnosis may be delayed. We report an infant who had surgery for esophageal atresia with tracheoesophageal fistula at birth. The infant presented with nonbilious projectile vomiting at 4 weeks of age. Plain abdominal x-ray, barium upper gastrointestinal series and abdominal ultrasonography all supported the diagnosis of hypertrophic pyloric stenosis. The diagnosis was confirmed during surgery. After pyloromyotomy, the patient's condition improved.

Lymphocyte proliferation in uremic patients: correlation with zinc status.

The pivotal role of zinc in the immune response has been well demonstrated in animals with normal renal function; however, there are fewer studies in uremic patients. Twenty uremic patients on regular hemodialysis (HD), and 20 patients on continuous ambulatory peritoneal dialysis (CAPD) were studied for their lymphoproliferative response to concanavalin A, phytohemagglutinin and pokeweed mitogen. CAPD patients had significantly lower levels of plasma zinc (65.8 micrograms/dL vs 75.1 micrograms/dL, p < 0.05) and serum albumin (3.5 g/dL vs 4.4 g/dL, p < 0.05) than HD patients. However, the stimulation indices were similar between these two groups no matter what mitogens were used, although they were significantly lower than those for the normal control group. Regression analysis revealed that there was no correlation between zinc status and the stimulation indices. However, there was a significant correlation between serum zinc and the absolute counts in HD patients. These findings suggest that zinc does not play a consistent role in the impaired lymphoproliferative response among uremic patients receiving different modes of dialysis therapy.