Pharmacokinetic Analysis of Mycophenolate Mofetil and Enteric-Coated Mycophenolate Sodium in Calcineurin Inhibitor-Free Renal Transplant Recipients.

BACKGROUND: Considerable interest exists in identifying calcineurin inhibitor (CNI)-free and thus, less-toxic immunosuppressive regimens, with mycophenolic acid (MPA)-based treatments being a suitable approach. Because pharmacokinetic analyses of MPA treatments in stable CNI-free renal transplant recipients are lacking, the authors aimed at comparing the steady-state pharmacokinetic characteristics of MPA in patients on stable treatment with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) plus prednisone (≤5 mg/d). METHODS: In the prospective, nonrandomized, open-label study, patients with stable transplant function since ≥6 months received their routine single dose of either MMF (n = 12) or EC-MPS (n = 11). The MPA plasma concentration was recorded over 12 hours. Parameters assessed were predose MPA concentration (C0), postdose minimum and maximum concentration (Cmin and Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC) for the 12-hours of exposure (AUC0-12). RESULTS: Baseline characteristics were comparable between both the groups. Consistent with enteric coating, the mean Tmax was significantly longer after the intake of EC-MPS compared with MMF (2.2 versus 0.8 hours; P = 0.0002). The exposure measures Cmin, Cmax, and AUC0-12 were not significantly different despite the higher mean MPA equivalent dose in patients receiving MMF compared with those receiving EC-MPS (85% versus 64% of the recommended single dose, respectively). Exposures as reflected by the median AUC0-12 values were 50.7 and 58.7 mg·h·L with MMF and EC-MPS, respectively (P = 0.340). All patients achieved a target AUC of >30 mg·h·L, and 61% had an AUC of >50 mg·h·L. CONCLUSIONS: The study provides first results on the steady-state pharmacokinetics of the 2 MPA drugs in CNI-free immunosuppressant regimens. Pharmacokinetic parameters measured in this study under real-life conditions were comparable in patients receiving MMF or EC-MPS.

Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients.

Regulatory macrophages (M regs) were administered to two living-donor renal transplant recipients. Both patients were minimized to low-dose tacrolimus monotherapy within 24 wk of transplantation and subsequently maintained excellent graft function. After central venous administration, most M regs remained viable and were seen to traffic from the pulmonary vasculature via the blood to liver, spleen, and bone marrow. By 1 y posttransplantation, both patients displayed patterns of peripheral blood gene expression converging upon the IOT-RISET signature. Furthermore, both patients maintained levels of peripheral blood FOXP3 and TOAG-1 mRNA expression within the range consistent with nonrejection. It is concluded that M regs warrant further study as a potential immune-conditioning therapy for use in solid-organ transplantation. The results of this work are being used to inform the design of The ONE Study, a multinational clinical trial of immunomodulatory cell therapy in renal transplantation.

Platelet activation markers after conversion from azathioprine to sirolimus based immunosuppression in renal transplant recipients.

OBJECTIVE: Under immunosupression with sirolimus (rapamycin) procoagulant effects and platelet activation have been controversially discussed. METHODS: We evaluated patients of a prospectly designed substudy as part of a randomized trial investigating the effect of a switch from non-mTOR-based immunosuppression to sirolimus in renal transplant recipients. Our substudy consisted of 7 patients who switched therapy from azathioprine to sirolimus (conversion group) and 8 patients who remained on azathioprine (controls) before (V1) and after (V2) 3 months of treatment. In all patients we assessed flowcytometric markers of platelet activation (PAC-1), platelet degranulation (CD62P), formation of platelet leukocyte-aggregates (PLA), monocyte activation (CD11b), endogenous thrombin potential (ETP) and platelet aggregation. RESULTS: Both groups were similar in terms of baseline demographics and had stable transplant function for at least 6 months. CD62P increased significantly in the control group (p < 0.03). PLA were significantly reduced in the sirolimus conversion group at V2 (p < 0.02), whereas no effect was seen in the controls. Expression of PAC-1, CD11b, ETP-peak, ETP-time to peak, ETP-AUC and platelet aggregation showed no significant changes in both groups compared to V2. CONCLUSION: From clinical data, performing in depth platelet function testing, we found no evidence for increased platelet activation parameters in RTR who switched therapy from azathioprine to sirolimus.

De novo renal cell carcinoma of native and graft kidneys in renal transplant recipients.

OBJECTIVE: • To access the epidemiological, clinical and survival features of renal transplant patients with de novo renal cell carcinoma of native and graft kidneys. PATIENTS AND METHODS: • We performed a retrospective examination of the data of 2001 consecutive renal transplant recipients at our centre between November 1979 and January 2010. RESULTS: • In the patient cohort examined, 30 renal cell carcinomas were observed in 26 individuals (incidence 1.5%) with 25 tumours in the native and five in allograft kidneys. Mean tumour size in surgical specimens was 44 ± 36 mm. The rate of papillary cancer was 37.5%. • After a mean follow-up of 58.6 ± 62.3 months, 15.4% of the patients died from cancer and 57.7% were in complete remission. • Overall and tumour-specific survival rates at 1, 5 and 10 years were 86.1%, 75.1% and 43.8%, and 90.4%, 83.5% and 66.8%, respectively. CONCLUSIONS: • Due to increasingly improved survival after renal transplantation, de novo malignancies might soon become the main cause of intermediate- or long-term mortality. • Current data support an increased risk of renal cell carcinoma in renal transplant recipients in a particularly aggressive way, but low tendency for metachronous contralateral evolution. • With continuous radiological follow-ups, acceptable oncological outcome can be achieved. Graft tumours may have a favourable prognosis.

Development of urological cancers in renal transplant recipients: 30-year experience at the Frankfurt Transplant Center.

Fatal post-transplant malignancies with a high proportion of genitourinary neoplasms represent a serious long-term challenge. With continuous improvement of the allograft and patient survival, cancer development after renal transplantation may soon turn to the leading morbidity cause. In a retrospective single-center study of 1990 renal transplant recipients between November 1979 and November 2009, records of patients with urological neoplasms including epidemiological, clinical and survival parameters were accessed. Sixty-six de novo urological malignancies in 58 recipients were recorded in the study period, being most common after skin cancers (15.6% of enregistered tumors). From these, 29 were renal cell cancers, including five neoplasms of transplanted kidney, 24 transitional cell carcinomas, 11 prostate carcinomas, and two germ cell carcinomas with incidence rates of 1.5%, 1.2%, 0.9% and 0.2%, respectively. The patient follow up was virtually complete. Tumor-related death was found in 44% of cases. By multivariate analysis, no influence of either duration of dialysis, mode or duration of immunosuppression, gender or age at transplantation on overall patient survival could be demonstrated. This study, documenting a 30-year single center experience, emphasizes the increased risk for urological neoplasms occuring after renal transplantation. Screening strategies for urological cancers should be optimized.

Reactivation of hepatitis B two years after rituximab therapy in a renal transplant patient with recurrent focal segmental glomerulosclerosis: a note of caution.

We report on the reactivation of hepatitis B in a renal transplant patient who had been treated with rituximab for recurrent focal segmental glomerulosclerosis two and a half yr previously. He lost his anti-hepatitis B surface antigens and anti-hepatitis B core antigen antibodies and developed hepatitis B virus (HBV)-DNA positive hepatitis. Hepatitis C, which had been successfully treated by alpha interferon 10 yr before, remained quiescent. We suggest regular controls of HBV-DNA, anti-HBV antibodies and transaminases for prolonged periods in patients with status post-hepatitis B treated with rituximab. Prophylactic therapy with lamivudine and/or hepatitis B hyperimmune globulin may be considered in patients with a decrease in anti-HBV antibodies.

Renal transplantation in the elderly: surgical complications and outcome with special emphasis on the Eurotransplant Senior Programme.

BACKGROUND: The purpose of this retrospective study was to evaluate the results of the Eurotransplant Senior Programme (ESP) within our centre compared to elderly recipients >or=60 years from the regular Eurotransplant Kidney Allocation System (ETKAS), specifically focusing on surgical aspects. METHODS: Data from 73 ESP patients (average donor/recipient age: 71.1/67.1) were compared with those from 51 patients (49.7/63.6) treated within the framework of the ETKAS program between the years 1999 and 2006. The mean follow-up was 39.5 months. RESULTS: Cold ischaemic time (ESP versus ETKAS: 10.3 versus 15.0 h), duration of renal replacement therapy (42.2 versus 76.8 months), donor glomerular filtration rate (81.7 versus 109.9 ml/min/1.73 m(2)) and HLA mismatches (4.1 versus 2.4) were significantly different between the two groups (all P < 0.001). Primary graft function was seen in 74% ESP versus 69% of ETKAS patients (P > 0.05). The rate of surgical complications in the ESP versus ETKAS group was 47% versus 28% (P = 0.031) and the revision rate, 33% versus 24% (P = 0.259). Three-year patient and censored graft survival was 84% versus 92% and 85% versus 88% in the ESP and ETKAS group, respectively (all P > 0.05). Ninety-five percent of all deceased patients died with a functioning graft. CONCLUSIONS: The donor and recipient pool has been markedly expanded through ESP with similar patient and graft survival compared to elderly recipients grafted according to ETKAS criteria. However, patients and their physicians should be aware of the high surgical complication rate in elderly recipients, particularly when receiving elderly donor kidneys. This might seriously influence postoperative patient management but ultimately does not compromise the transplant outcome.

Effect of procurement-related organ lesions on renal transplant outcome.

BACKGROUND: The purpose of our study was to examine the nature and incidence of renal injuries during organ procurement, to identify risk factors and to analyse the effects of organ lesions on the following transplantation. METHODS: All cadaveric kidney transplantations performed at our centre from 1996 to 2006 with an organ donated within the Eurotransplant (ET) region were retrospectively analysed. RESULTS: Five hundred and sixty-three renal grafts procured in 62 centres throughout the ET region were transplanted in the analysed period. One hundred and twenty (21.3%) kidneys were inadequately procured with 143 errors in total. The frequency of procurement errors did not differ significantly between kidneys procured by urologists and general surgeons (19.2% vs. 24.6%) nor when kidneys were procured alone or together with pancreas and/or liver (19.3% vs. 22.0%). Inadequate procurement lead to a discard rate of 0.2% and ultimately resulted in a surgical complication rate of 3.4%. Primary graft function (75.8% vs. 78.6%), three-yr graft survival (76.6% vs. 82.4%) and cumulated long-term graft survival were not significantly influenced by procurement errors. CONCLUSION: Additional measures to improve procurement quality are necessary. Nevertheless, adequate repair of organ lesions is possible and most organs can be successfully transplanted with very good short- and long-term results.

Anti-inflammatory effects of clopidogrel intake in renal transplant patients: effects on platelet-leukocyte interactions, platelet CD40 ligand expression, and proinflammatory biomarkers.

BACKGROUND: Increased platelet activation has been described during treatment with various immunosuppressive agents and may contribute to the high cardiovascular mortality rate in renal transplant patients. Platelets are thought to propagate the inflammatory process of atherosclerosis by interaction with leukocytes. METHODS: We tested an experimental therapy with clopidogrel in renal transplant patients treated with either tacrolimus (n = 20) or cyclosporine (INN, ciclosporin) (n = 19). All patients took low-dose steroids and had stable transplant function. Untreated healthy volunteers (n = 11) were included as the reference group. Degranulation (CD62P), glycoprotein IIb/IIIa receptor activation (PAC1), formation of platelet-leukocyte aggregates (monocyte-platelet-leukocyte aggregate, CD11b, mean fluorescence intensity), and platelet CD40 ligand (CD40L) expression (percent positive) were assessed by flow cytometry before therapy (visit 1) and after 4 weeks of clopidogrel (75 mg/d) intake (visit 2). To assess systemic anti-inflammatory effects, we measured levels of high-sensitivity C-reactive protein, soluble CD40L (sCD40L), monocyte chemoattractant protein 1, and matrix metalloproteinase 9 (MMP-9) by enzyme-linked immunosorbent assay. RESULTS: At visit 1, cyclosporine-treated patients had significantly enhanced CD62P and PAC1 expression and platelet-leukocyte aggregate formation, as well as elevated sCD40L concentrations, compared with tacrolimus-treated patients (all P < .03). Clopidogrel intake led to a significant decrease in platelet-leukocyte aggregate formation in tacrolimus-treated patients (median, 237 [interquartile range, 177-510] to 194 [interquartile range, 159-275] mean fluorescence intensity; P < .035) and cyclosporine-treated patients (median, 450 [interquartile range, 362-782] to 254 [interquartile range, 211-458] mean fluorescence intensity; P < .035). CD40L expression was reduced in tacrolimus-treated patients (median, 34 [interquartile range, 28-41] to 21 [interquartile range, 12-26] mean fluorescence intensity; P < .002) and cyclosporine-treated patients (median, 33 [interquartile range, 30-37] to 26 [interquartile range, 19-26] mean fluorescence intensity; P < .02). In addition, CD62P, PAC1, and CD11b were significantly reduced in both groups at visit 2 (P < .02). MMP-9 decreased from 88 ng/mL (range, 49-135 ng/mL) to 57 ng/mL (range, 38-73 ng/mL) (P < .05) in tacrolimus-treated patients and from 79 ng/mL (range, 54-148 ng/mL) to 66 ng/mL (range, 41-97 ng/mL) (P < .01) in cyclosporine-treated patients. The sCD40L concentration decreased significantly only in cyclosporine-treated patients (P < .004). In contrast, high-sensitivity C-reactive protein and monocyte chemoattractant protein 1 were not affected. CONCLUSION: The P2Y(12) receptor antagonist clopidogrel inhibits the expression of platelet activation markers and the interaction of platelets and leukocytes. Because the synthesis of vascular disease markers and inflammatory products such as sCD40L and MMP-9 has been inhibited, anti-inflammatory properties of clopidogrel are likely to be a result of decreasing platelet activation.

Immunosuppressive therapy regimen and platelet activation in renal transplant patients.

BACKGROUND: Increased platelet activation caused by an immunosuppressive therapy regimen may contribute to the high incidence of death from cardiovascular disease in renal transplant patients. Cyclosporine (INN, ciclosporin) and azathioprine are reported to activate platelets, but data are rare and controversial for tacrolimus and mycophenolate mofetil. METHODS: This cross-sectional study assessed markers of platelet degranulation (P-selectin; CD62), the activated glycoprotein IIb/IIIa receptor (PAC1, indicating the fibrinogen binding site), platelet aggregation, and secretion of platelet-derived growth factor (PDGF(AB)) in renal transplant patients treated with 4 different therapy regimens. Immunosuppression was based on low-dose steroids (5 mg/d prednisone) in combination with a single agent: (1) cyclosporine (n = 16), (2) azathioprine (n = 18), (3) tacrolimus (n = 17), or (4) mycophenolate mofetil (n = 13). Effects were compared with those in an age-matched control group of patients with hypertension (n = 11). RESULTS: In all renal transplant patient groups, unactivated platelets exhibited an increased expression of CD62. When stimulated with 2-micromol/L thrombin receptor-activating peptide, CD62 expression in platelets from patients treated with azathioprine (63% +/- 17%; P <.05), cyclosporine (51% +/- 23%; P <.05), and tacrolimus (50% +/- 22%; P <.05) was elevated compared with control subjects (33% +/- 19%). PAC1 expression was significantly increased in the patient groups that received azathioprine and cyclosporine. PDGF(AB) secretion was elevated in patients treated with azathioprine only (51 +/- 24 ng/10(9) platelets [versus 35 +/- 17 ng/10(9) platelets for control subjects]; P <.05). Platelet aggregation in response to collagen (0.5 microg/mL) was decreased in patients treated with tacrolimus (49% +/- 29%; P <.05) and mycophenolate mofetil (55% +/- 32%; P <.05) compared with control subjects (73% +/- 25%). CONCLUSION: This is the first study to compare the effects on platelet function of different immunosuppressive regimens that are based on monotherapy. All renal transplant patients showed preactivated platelets compared with those of patients with hypertension. However, the "newer" immunosuppressive agents tacrolimus and mycophenolate mofetil seemed to have fewer unfavorable effects on platelet CD62 expression and PAC1 expression and aggregation. Whether this finding is accompanied by fewer cardiovascular events remains to be elucidated.

Anti-inflammatory drugs modulate C1q secretion in human peritoneal macrophages in vitro.

The complement system plays an important role in the humoral immune response. Activation of the classical complement pathway is mediated by its subcomponent, C1q, which is involved in the pathogenesis of several autoimmune disorders. Among the main C1q-synthesising tissues, macrophages have been attributed as the main source. We investigated the effects of anti-inflammatory drugs (methylprednisolone and acetylsalicylic acid (ASA)) on C1q secretion in human peritoneal macrophages in vitro. The macrophages were isolated from peritoneal lavage fluid of patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis, and were maintained in culture for up to 6 days. ASA decreased while methylprednisolone increased C1q secretion from human peritoneal macrophages in vitro, which correlated well with the percentage of CD14 positive cells after treatment. We conclude that different response of the macrophages to treatment with methylprednisolone and ASA may point out to the importance of macrophage activation after treatment, as well as an increased abundance of membrane C1q accompanied by increased phagocytosis.

Living kidney donors' long-term psychological status and health behavior after nephrectomy - a retrospective study.

BACKGROUND: The aim of the study was a comprehensive psychological evaluation of living kidney donors. Existing studies indicate a high donor satisfaction with the decision to donate and good donor quality of life in short-term, as well as in long-term follow-up periods. In many studies, questionnaires with only a few items have been used to assess psychological health or well-being; however, most studies exclusively measured quality of life. Therefore, our retrospective single center study applied a broad assessment of psychological variables. We evaluated whether standardized, differentiated and specific psychological research instruments confirmed the positive, long-term condition of kidney donors as reported in the scientific literature, albeit based on a limited set of variables. METHODS: From 1973 to 2001, 152 nephrectomies were performed in Frankfurt. In the context of a detailed medical follow-up examination, a psychological study was implemented using a semi-structured interview and a set of four standardized, well-established questionnaires. Overall, data from 145 donors was included in the medical follow-up and 112 donors participated in the psychological investigation. RESULTS: The mean age of donors was 55.9 (+/- 10.7) yrs at follow-up, and the time-since-donation was 11.2 (+/- 7.5) yrs. Donors scored better on a wide range of the psychological scales such as psychological symptoms, health behavior and health consciousness that was to be expected in comparison with data from representative German population samples. Nearly all donors (97%) would choose to donate again, and 91% remain entirely satisfied with their decision. CONCLUSION: The study demonstrates that existing results, reporting positive long-term psychological donor well-being, could be confirmed by a set of comprehensive, standardized and multi-methodological psychological instruments.

Rejection quantity in kidney transplant recipients is associated with increasing intracellular interleukin-2 in CD8+ T-cells.

BACKGROUND: CD8+ T-cells and interleukin-2 play an important role during organ rejection in kidney transplant recipients. Numerous studies showed increased interleukin-2 levels during acute rejection. The aim of our study is to show an association between intracellular interleukin-2 in CD8+ T-cells and the incidence of those who underwent organ rejection in kidney transplant recipients. METHODS: 407 transplant recipients were included into this study. The rejection incidence was investigated from the patient records. White blood cells from recipients were separated using a ficoll gradient. The cells were double-gated (CD3+ and CD8+) for the analysis of cellular percentage for intracellular interleukin-2 with a flow cytometer. RESULTS: The percentage of CD8+ cells with detectable intracellular interleukin-2 was significantly higher in renal transplant recipients with a documented rejection compared to recipients without any history of rejection (9.06±0.50, N=133 vs. 4.28±0.24, N=274, p<0.0001, t-test). Further, there was a significant increase in patients with one (8.02±0.54, N=80, p<0.0001, t-test), two (10.40±1.17, N=33, p<0.0001, t-test) or three (11.82±1.58, N=18, p<0.0001, t-test) rejection events. CONCLUSIONS: Past studies showed, that during acute organ rejection intracellular interleukin-2 is increased in cytotoxic T-cells, supposed to be a marker for this event. We were able to show, that intracellular interleukin-2 in CD8+ T-cells is also increased after organ rejection. Furthermore it seems to depend on the quantity of rejection events. Further studies in recipients with increased intracellular interleukin-2 in cytotoxic CD8+ T-cells and documented history of organ rejection are needed to identify this as a possible risk factor for further rejection events.

Transcatheter aortic valve implantation improves outcome compared to open-heart surgery in kidney transplant recipients requiring aortic valve replacement.

BACKGROUND: Cardiovascular disease is the most frequent cause of mortality for kidney transplant recipients. Open heart surgery has particularly high mortality and morbidity. As an alternative to traditional aortic valve replacement (AVR) for patients with high-grade aortic stenosis, transcatheter aortic valve implantation (TAVI) was developed as an innovative therapy for patients considered at high surgical risk. METHODS: We considered all kidney transplant recipients as high-risk patients, which are candidates for TAVI. In 2010 and 2011, eight kidney transplant recipients with severe aortic stenosis underwent TAVI (6 transfemoral; 2 transapical; group I). The outcome of these patients was compared retrospectively to 18 kidney transplant recipients with aortic stenosis, who underwent conventional AVR (group II). RESULTS: Both groups had similar baseline characteristics, including estimated perioperative risk (EuroSCORE group I vs. group II: 9.5±5.9 vs. 10.4±10.5; p=0.829). All TAVI procedures were performed successfully with excellent functional results. In the TAVI group (group I), all patients were alive at the 12-month follow-up with one cardiovascular event (stroke). In contrast, the surgical group experienced a 30-day-mortality of 11.1% (n=2) and a 1-year-mortality of 16.7% (n=3). CONCLUSIONS: Based on our center's experience, TAVI appears to be an effective and safe alternative to conventional surgery for AVR in patients with prior renal transplantation. Renal transplantation is not currently identified as a risk factor in our traditional scoring system, and may need to be considered independently when weighing alternatives for AVR.

Transitional cell carcinoma of the native urinary tract after kidney transplantation: recommendations following a long-term retrospective analysis.

INTRODUCTION: The aim of the current study was to explore the clinico-oncological characteristics, and the therapeutic and survival parameters, of renal transplant recipients who developed de novo transitional cell carcinoma (TCC) over a 30-year period at the authors' center. METHODS: Retrospective analysis of records from all registered patients who underwent kidney transplantation at the center between November 1979 and January 2010 who developed de novo TCC of the urinary tract. RESULTS: From all 2001 patients analyzed during the study period, 21 recipients developed 19 TCCs of the bladder and 6 TCCs of the upper urinary tract. Among bladder TCCs, 13 (68.4%) cases were confined to mucosa (pTa or carcinoma in situ, n = 7) or submucosa (pT1, n = 6) and 6 others (31.6%) infiltrated the detrusor muscle (≥p T2); the grading distribution was 5 cases of G1, 6 of G2 and 8 of G3. All recurrent cases (n = 8) revealed local or systemic progression. The overall and tumor-specific patient survival rates were 80.2%, 54.0% and 30.0% and 84.9%, 67.4% and 58.9% for 1, 5 and 10 years, respectively. CONCLUSIONS: In the light of the observed increased aggressiveness of TCC in renal transplant recipients, more frequent examinations and possibly more invasive follow-up protocols should be considered for patients with 1 or more risk factors for development of TCC. Urine cytology (including ureteral wash cytology) may be used as a reliable diagnostic tool in these patients. Prophylactic contralateral nephroureterectomy might be an option in patients at high risk.

Cholesterol-crystal embolism presenting with delayed graft function and impaired long-term function in renal transplant recipients: two case reports.

INTRODUCTION: Impaired renal function and/or pre-existing atherosclerosis in the deceased donor increase the risk of delayed graft function and impaired long-term renal function in kidney transplant recipients. CASE PRESENTATION: We report delayed graft function occurring simultaneously in two kidney transplant recipients, aged 57-years-old and 39-years-old, who received renal allografts from the same deceased donor. The 62-year-old donor died of cardiac arrest during an asthmatic state. Renal-allograft biopsies performed in both kidney recipients because of delayed graft function revealed cholesterol-crystal embolism. An empiric statin therapy in addition to low-dose acetylsalicylic acid was initiated. After 10 and 6 hemodialysis sessions every 48 hours, respectively, both renal allografts started to function. Glomerular filtration rates at discharge were 26 ml/min/1.73m(2) and 23.9 ml/min/1.73m(2), and remained stable in follow-up examinations. Possible donor and surgical procedure-dependent causes for cholesterol-crystal embolism are discussed. CONCLUSION: Cholesterol-crystal embolism should be considered as a cause for delayed graft function and long-term impaired renal allograft function, especially in the older donor population.

Abrogation of nephrotic proteinuria by rituximab treatment in a renal transplant patient with relapsed focal segmental glomerulosclerosis.

Relapse of focal segmental glomerulosclerosis (FSGS) after renal transplantation is 20-40%. Recurrence after a first relapse is 80%. The only current treatment is plasmapheresis and/or cyclophosphamide. We report successful treatment of a second relapse in a 48-year-old patient. At age 33, FSGS was diagnosed. The patient began hemodialysis 1 year later. In her first renal transplant, she developed recurrent FSGS and reached terminal transplant failure 3 years later. Eight years later, a second transplant was performed. Immunosuppressive regimen: steroids, mycophenolate mofetil (MMF), tacrolimus (TAC), and rabbit anti-thymocyte globulin. Proteinuria of 2-6 g/day was detected and a biopsy showed recurrent FSGS. Plasmapheresis was started without success. Another biopsy still showed FSGS. The patient received two doses of rituximab (375 mg/m2 each) i.v. Three weeks later, proteinuria was 350 mg/day (serum-creatinine 1.6 mg/dl). Twelve months later, proteinuria was at 90 mg/day. Rituximab might be an option for recurrent FSGS after renal transplantation.

Long-term consequences of live kidney donation follow-up in 93% of living kidney donors in a single transplant center.

Live kidney donation is increasing rapidly. Increases of blood pressure and proteinuria but no accelerated loss of renal function in kidney donors have been described. The credibility of this research is hampered by retrieval rates of only 50-70% of donors. We studied renal function, blood pressure, proteinuria, parathyroid hormone, 1,25(OH)2 cholecalciferol and calcium and phosphate excretion in a live kidney donor cohort with a 93% retrieval rate. A comprehensive physical and laboratory examination including 24-h urine collection was conducted. None of the 152 donors had renal failure. Mean time after uninephrectomy was 11 +/- 7 (range: 1-28) years. GFR had declined by 25%. Blood pressure had increased from 125 +/- 15/79 +/- 11 to 134 +/- 19/81 +/- 9 mmHg (p < 0.01) but remained significantly below normal. Fifty six percent of donors developed proteinuria (>150 mg/day), but only 10% had albuminuria. Nineteen percent had increased PTH, 30% had a decreased tubular reabsorption rate of phosphate. Regarding risk factors for a higher loss of GFR, greater increases in blood pressure or proteinuria no consistent picture emerged. Because of the high incidence of proteinuria and possible changes in bone metabolism inclusion of kidney donors in registries appears worthwhile.

Prediction of acute renal allograft rejection by urinary monokine induced by IFN-gamma (MIG).

Early diagnosis of acute allograft rejection (AR) is still decisive for long-term renal allograft survival. The aim of this study was to define the role of the chemokine monokine induced by IFN-gamma (MIG) (CXCL9) and IFN-gamma-inducible protein 10 (IP-10) (CXCL10) as early markers of AR in renal transplantation (NTX). In a prospective study, 69 de novo renal transplant recipients were monitored and urine samples were collected after NTX for a median of 29 d. In pH-adjusted urine, MIG and IP-10 were determined by modified ELISA. AR was clinically diagnosed in 15 of 69 recipients and confirmed by biopsy in 14 of 15 AR patients (Banff classification). Corresponding to CXCR3-positive infiltrates in renal tissue, urinary MIG was elevated in 14 of 15 AR patients with a median of 2809 pg/ml (quartile 25% and 75% = 870 and 13,000; n = 15), being significantly (P < 0.0001) different from both nonrejecting allograft patients (NO-AR) (median, 25%, and 75%: 96, 1.0, and 161, n = 54) and healthy controls (median, 25%, and 75%: 144, 19, and 208, n = 13). Urinary MIG predicted AR with a sensitivity of 93% and a specificity of 89%. In AR and NO-AR groups, MIG values correlated well with IP-10 (P < 0.001). MIG values indicated both imminent rejection and response to successful antirejection therapy. MIG was not related to intercurrent infections or other causes for impairment of renal function. In a multivariate analysis, MIG correlated best (P < 0.001) with AR from all AR-associated parameters. In conclusion, urinary MIG serves as a very sensitive and specific predictor for AR, mirrors response to antirejection therapy, and thus may contribute to improved long-term renal allograft survival.