Post-streptococcal glomerulonephritis: not an extinct disease!

We present the case of a 29-year-old type 1 diabetic patient with the diagnosis of acute post-streptococcal glomerulonephritis. The incidence of this textbook example of acute glomerulonephritis has dropped dramatically in the developed world during the past decades due to the more widespread use of antibiotics. However, the present case illustrates that it is not an extinct disease and that clinicians should be aware of this entity. Particular attention is needed for the fact that the clinical context in which the disease occurs may be different from the classical "post-angina" presentation.

Long-term exposure to belatacept in recipients of extended criteria donor kidneys.

Patients in the BENEFIT-EXT study received extended criteria donor kidneys and a more intensive (MI) or less intensive (LI) belatacept immunosuppression regimen, or cyclosporine A (CsA). Patients who remained on assigned therapy through year 3 were eligible to enter a long-term extension (LTE) study. Three hundred four patients entered the LTE (n = 104 MI; n = 113 LI; n = 87 CsA), and 260 continued treatment through year 5 (n = 91 MI; n = 100 LI; n = 69 CsA). Twenty patients died during the LTE (n = 5 MI; n = 9 LI; n = 6 CsA), and eight experienced graft loss (n = 2 MI; n = 1 LI; n = 5 CsA). Three patients experienced an acute rejection episode (n = 2 MI; n = 1 LI). The incidence rate of serious adverse events, viral infections and fungal infections was similar across groups during the LTE. There were four cases of posttransplant lymphoproliferative disorder (PTLD) from the beginning of the LTE to year 5 (n = 3 LI; n = 1 CsA); two of three PTLD cases in the LI group were in patients who were seronegative for Epstein-Barr virus (EBV(-)) at transplantation. Mean ± SD calculated GFR at year 5 was 55.9 ± 17.5 (MI), 59.0 ± 29.1 (LI) and 44.6 ± 16.4 (CsA) mL/min/1.73 m(2) . Continued treatment with belatacept was associated with a consistent safety profile and sustained improvement in renal function versus CsA over time.

Combined kidney and intestinal transplantation in patients with enteric hyperoxaluria secondary to short bowel syndrome.

Kidney transplantation is the treatment of choice for end-stage renal disease whereas indications for intestinal transplantation are currently restricted to patients with irreversible small bowel failure and severe complications of total parenteral nutrition (mostly shortage and infection of venous accesses, major electrolyte disturbances and liver failure). Enteric hyperoxaluria is secondary to certain intestinal diseases like intestinal resections, chronic inflammatory bowel disease and other malabsorption syndromes and can lead to end-stage renal disease requiring kidney transplantation. We report two patients suffering from renal failure due to enteric hyperoxaluria (secondary to extensive intestinal resection) in whom we elected to replace not only the kidney but also the intestine to prevent recurrence of hyperoxaluria in the transplanted kidney.

Chronic histological damage in early indication biopsies is an independent risk factor for late renal allograft failure.

The impact of early histological lesions of renal allografts on long-term graft survival remains unclear. We included all renal allograft recipients transplanted at a single center from 1991 to 2001 (N = 1197). All indication biopsies performed within the first year after transplantation were rescored according to the current Banff classification. Mean follow-up time was 14.8 ± 2.80 years. In multivariate Cox proportional hazards analysis, arteriolar hyalinosis and transplant glomerulopathy were independently associated with death-censored graft survival, adjusted for baseline demographic covariates. Arteriolar hyalinosis correlated with interstitial fibrosis, tubular atrophy, mesangial matrix increase, vascular intimal thickening and glomerulosclerosis. Clustering of the patients according to these chronic lesions, reflecting the global burden of chronic injury, associated better with long-term graft survival than each of the chronic lesions separately. Early chronic histological damage was an independent risk factor for late graft loss, irrespective whether a specific, progressive disease was diagnosed or not, while T cell-mediated rejection did not. We conclude that individual chronic lesions like arteriolar hyalinosis, tubular atrophy, interstitial fibrosis, glomerulosclerosis, mesangial matrix increase and vascular intimal thickening cannot be seen as individual entities. The global burden of early chronic histological damage within the first year after transplantation importantly affects the fate of the allografts.

In vivo CYP3A4 activity, CYP3A5 genotype, and hematocrit predict tacrolimus dose requirements and clearance in renal transplant patients.

Tacrolimus is metabolized by CYP3A4 and CYP3A5 and is characterized by a narrow therapeutic index and highly variable pharmacokinetics. This cross-sectional study in 59 renal transplant patients investigated the relationship among in vivo CYP3A4 activity (assessed using midazolam as a drug probe), CYP3A5 genotype on the one hand, and tacrolimus pharmacokinetics on the other hand, taking into account other potential determinants of tacrolimus disposition. In vivo CYP3A4 activity and CYP3A5 genotype explain 56-59% of variability in tacrolimus dose requirements and clearance, contributing ~25 and 30%, respectively. Hematocrit explains an additional 4-14%. These data indicate that CYP3A4- and CYP3A5-mediated tacrolimus metabolisms are major determinants of tacrolimus disposition in vivo and explain a substantial part of the clinically observed high interindividual variability in tacrolimus pharmacokinetics. Furthermore, these data provide a potential basis for a comprehensive approach to predicting tacrolimus dose requirement in individual patients and hence provide a strategy to tailor immunosuppressive therapy in transplant recipients.

Evidence in favor of a severely impaired net intestinal calcium absorption in patients with (early-stage) chronic kidney disease.

INTRODUCTION: Calcium and phosphorus are essential to many vital physiological processes. Little is known about the net and fractional intestinal absorption of calcium and phosphorus in patients with chronic kidney disease (CKD) and their clinical and hormonal determinants. METHODS: Blood and 24-hour urine samples were collected in 20 healthy volunteers (HV) and 72 stable CKD stage 1-4 patients and analyzed for parameters of mineral metabolism including calcidiol, calcitriol, and parathyroid hormone (PTH). Dietary intake was assessed by dietary history. RESULTS: The 24-hour urinary calcium excretion, as opposed to the phosphorus excretion, showed a stepwise decrease across CKD stages (median of 219, 84, 40, and 22 mg/day in HV and patients with CKD stages 1-2, 3 and 4, respectively). Younger age, high serum calcitriol, and high estimated GFR were associated with a high 24-hour urinary calcium excretion. High serum calcitriol levels and dietary phosphorus intake were associated with a high 24-hour urinary phosphorus excretion. The fractional intestinal calcium absorption, as estimated by the urinary-to-ingested calcium ratio, decreased across CKD stages. CONCLUSIONS: The 24-hour urinary excretion of calcium, as opposed to phosphorus, is markedly decreased in CKD, even in early-stage disease. This is partly explained by low calcitriol levels and older age. Assuming a neutral calcium balance at the time of urine collection, we infer that net intestinal calcium absorption may be severely impaired in CKD.

Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys.

Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients.

In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 ± 73 vs. 354 ± 102 ml/min, P = 0.022) and 31% (479 ± 190 vs. 688 ± 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients.

A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study).

Belatacept, a costimulation blocker, may preserve renal function and improve long-term outcomes versus calcineurin inhibitors in kidney transplantation. This Phase III study (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) assessed a more intensive (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adults receiving a kidney transplant from living or standard criteria deceased donors. The co-primary endpoints at 12 months were patient/graft survival, a composite renal impairment endpoint (percent with a measured glomerular filtration rate (mGFR) <60 mL/min/1.73 m(2) at Month 12 or a decrease in mGFR > or =10 mL/min/1.73 m(2) Month 3-Month 12) and the incidence of acute rejection. At Month 12, both belatacept regimens had similar patient/graft survival versus cyclosporine (MI: 95%, LI: 97% and cyclosporine: 93%), and were associated with superior renal function as measured by the composite renal impairment endpoint (MI: 55%; LI: 54% and cyclosporine: 78%; p < or = 0.001 MI or LI versus cyclosporine) and by the mGFR (65, 63 and 50 mL/min for MI, LI and cyclosporine; p < or = 0.001 MI or LI versus cyclosporine). Belatacept patients experienced a higher incidence (MI: 22%, LI: 17% and cyclosporine: 7%) and grade of acute rejection episodes. Safety was generally similar between groups, but posttransplant lymphoproliferative disorder was more common in the belatacept groups. Belatacept was associated with superior renal function and similar patient/graft survival versus cyclosporine at 1 year posttransplant, despite a higher rate of early acute rejection.

Balancing efficacy and toxicity of kidney transplant immunosuppression.

Late renal allograft loss is mainly the result of progressive histological damage. Both underimmunosuppression (rejection phenomena) and overimmunosuppression (calcineurin inhibitor nephrotoxicity) contribute to the progression of chronic histological damage. The current study was performed to elucidate the complementary impact of immune and nonimmune phenomena on renal allograft histology and function. By performing protocol biopsies, it was demonstrated that clinical and subclinical acute cellular rejection phenomena continue to play important roles, despite the use of the powerful combination of tacrolimus, mycophenolate mofetil, and steroids. Next to immune phenomena, the importance of nonimmune factors in renal allograft histological evolution was shown in protocol biopsy studies. Both in adult and in pediatric renal allograft recipients, the characteristics of the donor kidney (donor age, size discrepancy) appeared to be major determinants of the histological and functional evolution. This impact of donor characteristics was not only important in the immediate peritransplantation period, it was also shown that higher donor age increased the risk for progressive posttransplant histological injury and calcineurin inhibitor nephrotoxicity. Systemic levels of tacrolimus, if kept within a relatively narrow target window, were not associated with a risk for calcineurin inhibitor nephrotoxicity. However, we observed a significant association between renal allograft histology and P-glycoprotein (ABCB1) gene polymorphisms and expression, suggesting a role of this protein in the individual susceptibility to calcineurin inhibitor nephrotoxicity. Finally, the interplay between immune and nonimmune phenomena was demonstrated by the association between donor origin (deceased versus living) and local renal complement gene expression, by using whole-genome expression microarrays.

Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial.

Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC(0-24) of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC(0-24) and C(min) for both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.

Localization, etiology and impact of calcium phosphate deposits in renal allografts.

Hypercalcemia, hypophosphatemia and renal phosphate wasting are common after kidney transplantation. Animal data suggest that these alterations in mineral metabolism may contribute to calcium phosphate (CaPhos) deposition in the kidney and renal dysfunction. We tested the hypothesis that CaPhos deposition is highly prevalent in the early posttransplant period and is related to a disturbed mineral metabolism. For this purpose, biomarkers of mineral metabolism and renal calcium and phosphorus handling were prospectively assessed in 201 renal transplant recipients. CaPhos deposits were observed in 4.6, 30.4 and 24.7% of protocol biopsies obtained at the time of engraftment, and 3 and 12 months thereafter, respectively. In multivariate logistic regression analysis, high calcium and low serum phosphorus levels were independently associated with renal CaPhos deposition at month 3. The extent of CaPhos deposition correlated significantly with the severity of mineral metabolism disturbances. Renal function after a mean follow-up of 33 months was similar in patients with and without CaPhos deposition at month 3. In conclusion, our data demonstrate that CaPhos deposition is highly prevalent in the early posttransplant period and suggest that a disordered mineral metabolism is implicated in its pathogenesis. The clinical relevance of CaPhos deposition remains to be established.

Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation.

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.

Pseudoaneurysm complicating protocol renal transplant biopsies: case reports.

Pseudoaneurysm is a rare complication of a renal biopsy procedure. We describe two cases of kidney transplant recipients who were diagnosed with a pseudoaneurysm more than 48 hours after protocol renal allograft biopsy and were successfully treated by selective embolization of the afferent artery.

Living donor kidney transplantation: analysis of the first 40 cases performed in UZ Leuven.

Living donation kidney transplantation has been popular worldwide to try to increase the donor pool. In Belgium, the rate of living donation kidney transplantation has been traditionally relatively low compared to other countries. This is--in part--due to the relatively higher cadaveric organ offer that is available in Belgium (around 25 donors per million inhabitants), compared to other countries. However, the increasing waiting times on cadaveric waiting list and the superiority of the results of live donation versus cadaveric kidney transplantation have led to a reappraisal of this strategy. In our center a living donation kidney transplant programme was started in 1997. Since then 40 cases of live donation kidney transplantation have been performed and are reported herein.

Free p-cresol is associated with cardiovascular disease in hemodialysis patients.

Cardiovascular disease (CVD) is highly prevalent in chronic kidney disease, suggesting that molecules retained in uremia might contribute to this increased risk. We explored the relationship between p-cresol, a protein-bound uremic retention solute, and CVD by comparing the strength of this relationship relative to traditional and novel cardiovascular risk factors. Univariate Cox proportional hazard analysis showed that the free serum p-cresol concentration was significantly associated with CVD when the primary end point was the time to the first cardiovascular event. In multivariate analysis, free p-cresol was significantly associated with CVD in non-diabetics. In diabetic patients, however, a significant relationship between p-cresol and cardiovascular events could not be demonstrated despite their having significantly higher p-cresol levels. Our study shows that free p-cresol is a novel cardiovascular risk factor in non-diabetic hemodialysis patients.

Posttransplant Epstein-Barr virus-associated myogenic tumors: case report and review of the literature.

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of different types of malignancies. While nonmelanoma skin cancers, lymphomas and Kaposi sarcomas are the most frequently reported malignancies after solid organ transplantation, EBV-associated smooth muscle tumors (EBV-SMT) after transplantation are rare and thus far only 18 cases in kidney recipients have been reported. A case of a 51-year-old kidney transplant recipient diagnosed with EBV-SMT is reported together with a review of the literature.

Influenza vaccination is efficacious and safe in renal transplant recipients.

Whether influenza vaccination in solid-organ transplant recipients is efficacious remains a controversial issue. Furthermore, theoretical concerns have been raised regarding the safety of vaccination as it might trigger rejection of the allograft. The present prospective trial is aimed at investigating the antibody response and safety of influenza vaccination in renal transplant recipients (RTR). A total of 165 RTR and 41 healthy volunteers were vaccinated with a standard trivalent inactivated influenza vaccine. Hemagglutination-inhibiting (HI) antibodies were quantified before and 1 month after vaccination. Seroprotection (SP) and seroresponse (SR) were defined as a titer > or =40 and a 4-fold rise in HI titer, respectively. Similar SR rates were observed in both groups. Postvaccination SP rates in RTR amounted to 92.7%, 78.7% and 82.9% for A/H1N1, A/H3N2 and B, respectively. High baseline SP rates, most probably reflecting frequent preimmunizations, explain partly the high postvaccination SP rates. SR rate was independently and inversely associated with baseline SP rate. Mycophenolate mofetil (MMF) usage was associated with a 2.6-5-fold lower SR. Nonetheless, these patients showed good postvaccination SP rates. A booster dose did not enhance SP or SR rates. Influenza vaccination neither affected allograft function nor caused rejection episodes. In conclusion, influenza vaccination is efficacious and safe in renal transplantation.