Variable cyclosporine exposure: a risk factor for chronic allograft nephropathy and graft loss?

BACKGROUND: Following the introduction of ciclosporine (CsA), the 2-year survival of transplanted kidneys improved from less than 60% to over 80%. Though the introduction of this drug resulted in a marked improvement in graft survival, its use was not without problems. Variable absorption and a narrow therapeutic index resulted in the need for measurements of CsA blood concentrations to tailor the drug dose to maximize therapeutic efficacy while minimizing toxicity. METHODS: Data were available from the LOTESS study of 4948 transplant patients receiving Neoral with at least 5 years' follow-up. Potential risk factors associated with outcome in renal transplant recipients treated with CsA were explored: the primary outcome variable was graft loss. A stepwise binary logistic regression analysis was used to identify donor, recipient, and treatment variables related to outcome. RESULTS: In the initial analysis, chronic rejection was the only significant predictor of graft loss. The relative risk (RR) of graft loss was 16.9 (95% CI = 13.9-20.4). Further analysis identified four independent risk factors for chronic rejection cadaveric donor (RR, 1.50; 95% CI = 1.05-2.15), older donor (RR, 1.02; 95% CI = 1.01-1.02), younger recipient (RR, 1.02; 95% CI = 1.02-1.03), and variable predose CsA concentration (RR, 1.25; 95% CI = 1.06-1.48). CONCLUSION: With the UK kidney transplant waiting list at about 5000 patients and only 1658 transplants performed during 2002, it is important maximize graft survival. For example, perhaps marginal donors (age > 55) can be matched to older recipients without increasing the risk of chronic allograft nephropathy and therefore graft loss. Variable predose CsA concentrations may arise from at least three different sources: adherence to treatment, drug formulation, and individual variation in absorption. Therefore, it is important to emphaze to patients that erratic compliance may increase their risk of graft loss. Second, although only one CsA formulation is marketed in the UK, when generic forms of CsA are introduced it will be important to demonstrate consistent delivery of CsA from these new formulations. Third, improved monitoring of CsA using a C2 rather than a predose blood concentration measurement may be used to reduce intra-individual variations in drug exposure.     

Analysis of allograft biopsy specimens in renal transplants with proteinuria: is proteinuria a culprit of graft loss?

It has been proposed that proteinuria occurring after renal transplantation may be not only a marker but also a culprit of allograft dysfunction. We retrospectively analyzed the data from 55 patients who underwent transplant renal biopsy for proteinuria and/or azotemia occurring beyond 1 year after transplantation. Proteinuria was considered as significant when > or = 30 mg/dL, and the results of transplant biopsy were categorized according to the Banff 97 classification. Logistic regression was used to estimate odds ratios (OR) for graft loss associated with proteinuria and transplant pathology. The patients were followed for 86.0 +/- 32.8 months after transplantation, and transplant biopsy was performed at 54.1 +/- 31.0 months. Proteinuria at 1 year after transplantation noted in 29.1% of patients was not significantly associated with graft loss (OR = 1.94, 95% CI from 0.59 to 6.41). In addition, proteinuria at the time of transplant biopsy was not significantly associated with graft loss. Chronic allograft nephropathy was the most frequent transplant pathology. Only glomerulonephritis was significantly associated with proteinuria at the time of the transplant biopsy. On the other hand, graft loss was significantly associated with the presence of proteinuria both at 1 year after transplant biopsy and at the final follow-up. These results suggest that posttransplantation proteinuria is an important marker of graft dysfunction, but is not predictive of graft loss in biopsy-proven cases. Appropriate management guided by the results of a transplant biopsy may improve the outcome.     

Return to dialysis after renal allograft loss: is dialysis treatment initiated too late?

INTRODUCTION: Allograft failure is a common complication after renal transplantation. However, data describing the level of renal function and the clinical condition of patients returning to dialysis after graft failure are scarce. The purpose of this analysis was to retrospectively determine the stage of end-stage renal failure at dialysis initiation and the outcome during the first year of dialysis among patients who lost their grafts. METHODS: We analyzed deaths with a functioning graft and graft losses among patients transplanted in our center between January 1, 1994, and December 31, 2003. Weight, blood pressure, serum albumin, hemoglobin, phosphorus-calcium levels, and vascular access for dialysis were analyzed at the beginning (D(0)) and at 1 year after initiation of dialysis (M(12)). Creatinine clearance (CrCl), and hemoglobin were also studied at 3 months before beginning renal replacement therapy (M(-3)). RESULTS: Ninety-eight patients lost their grafts after a mean follow-up of 94 +/- 34 months; 37 died with a functioning graft and 61 returned to dialysis. Patient age was 62 +/- 10 years for the first group and 47 +/- 13 years for the second. At D(0), patients were hypertensive and anemic with a mean CrCl of 10 +/- 3 mL/min, suggesting that they were referred too late for dialysis. Surprisingly, at M(-3), CrCl was 19 +/- 7 mL/min and hemoglobin 10.6 +/- 3.6 g/dL. Four patients died during the first year of dialysis. CONCLUSIONS: Our data suggest that transplant patients returned to dialysis too late. CrCl and hemoglobin deteriorate rapidly during the 3 months preceding dialysis initiation.     

De novo C1q nephropathy in the renal allograft of a kidney pancreas transplant recipient: BK virus-induced nephropathy?

C1q nephropathy is a distinct entity characterized by extensive and dominant C1q mesangial deposition with associated steroid resistant proteinuria in the absence of systemic lupus erythematosus. Several morphological patterns ranging from very subtle glomerular alterations to focal/segmental glomerulosclerosis and mesangial proliferative changes have been described. Interstitial nephritis secondary to BK polyomavirus is a recently recognized complication in kidney transplant recipients. It may be associated with a tubulitis-like picture, mimicking sometimes acute tubular rejection. We report the case of a kidney pancreas transplant recipient who developed de novo C1q nephropathy, in the setting of BK polyomaviral interstitial nephritis. He presented with renal allograft dysfunction and a kidney biopsy was performed. It was interpreted as acute cellular rejection. C1q deposits were detected by immunofluorescence studies and electron microscopy. The patient did not respond clinically to appropriate anti-rejection treatment and a second renal biopsy was performed. The possibility of an interstitial nephritis secondary to BK polyomavirus mimicking rejection was suggested. Special immunohistochemical and blood/urine PCR studies for BK virus were performed, confirming the diagnosis of BK virus tubulonterstitial nephritis with a persistent, probable BK virus induced C1q nephropathy.     

Does the endothelial function change in renal transplant patients with longer duration of exposure and with higher cumulative doses of cyclosporine?

OBJECTIVE: Administration of cyclosporine (CsA) is one potential cause of endothelial dysfunction in renal transplant patients. We sought to investigate endothelial functional changes with respect to the cumulative dose and duration of exposure to CsA. METHODS: Sixty-six renal recipients and 25 healthy controls were included in the study. The recipients were classified according to their time of CsA exposure: group 1 (0 to 36 months); group 2 (36 to 72 months); and group 3 (over 72 months). Endothelial function of the brachial artery was evaluated using high-resolution vascular ultrasound. Endothelium-dependent and -independent vasodilatation (EDD and EID, respectively) were assessed by assessing the responses to reactive hyperemia and using sublingual isosorbide dinitrate (ISDN), respectively. RESULTS: There were no statistically significant differences between the groups with regard to their demographic, clinical, and most biochemical characteristics. Baseline measurements of the diameter of the brachial artery were similar in all groups. The values of mean brachial artery EDD and EID responses in groups 1, 2, and 3 were less than those in the control group (P < .05, P < .05, and P < .05, respectively). Mean brachial artery EDD and EID in group 1 were significantly impaired compared to groups 2 and 3 (for EDD: P < .05 and P < .05, respectively; for EID: P < .05 and P < .05, respectively). In contrast there was no difference between groups 2 and 3 with respect to these parameters. There were mild to moderate positive correlations between the cumulative doses of CsA and EDD and EID (r = .26 and r = .52, P < .05, respectively). CONCLUSION: Endothelial dysfunction was more prominent in the first 36-month period than later despite the longer exposure to and higher cumulative doses of CsA. This finding may reflect an extended effect of the uremic state on endothelial function or more intense doses of CsA in early posttransplant period.     

Conversion from cyclosporin (Neoral®) to tacrolimus (Prograf®) in renal allograft recipients with chronic graft nephropathy: results of an observational study

To evaluate the role of tacrolimus in the treatment of Chronic Graft Nephropathy (CGN), a pilot cross-sectional study was performed on 14 patients with deteriorating renal function and biopsy-proven CGN. Maintenance therapy was switched from cyclosporin to tacrolimus, and results of conversion on allograft function were assessed by estimated glomerular filtration rate (GFR) and clinical outcome. Minimum follow-up was 15 months. Two distinctive response patterns emerged: (i) continuing deterioration of renal function with no apparent benefit over the projected trend of GFR (nine patients), and (ii) unequivocal change in the GFR trend line equation with reduced rate of deterioration in one patient and sustained improvement of GFR in four patients (reversal of downward trend). Five out of 14 patients (36 %) benefited from replacing Neoral with Prograf. All five patients exceeded their estimated time of return to dialysis by a median of 41 weeks (range: 29–52) and their grafts continue to function. Received: 6 July 1998 Received after revision: 8 December 1998 Accepted: 18 December 1998     

Assessment of kidney transplant suitability for patients with prior cancers: is it time for a rethink?

Kidney transplant recipients have up to a 100‐fold greater risk of incident cancer compared with the age/sex‐matched general population, attributed largely to chronic immunosuppression. In patients with a prior history of treated cancers, the type, stage and the potential for cancer recurrence post‐transplant of prior cancers are important factors when determining transplant suitability. Consequently, one of the predicaments facing transplant clinicians is to determine whether patients with prior cancers are eligible for transplantation, balancing between the accelerated risk of death on dialysis, the projected survival benefit and quality of life gains with transplantation, and the premature mortality associated with the potential risk of cancer recurrence post‐transplant. The guidelines informing transplant eligibility or screening and preventive strategies against cancer recurrence for patients with prior cancers are inconsistent, underpinned by uncertain evidence on the estimates of the incidence of cancer recurrence and the lack of stage‐specific outcomes data, particularly among those with multiple myeloma or immune‐driven malignancies such as melanomas. With the advent of newer anti‐cancer treatment options, it is unclear whether the current guidelines for those with prior cancers remain appropriate. This review will summarize the uncertainties of evidence informing the current recommendations regarding transplant eligibility of patients with prior cancers.     

Donor cause of brain death in renal transplantation: a predictive factor for graft function?

Purpose

Our aim was to evaluate the influence of donor cause of brain death on the results of kidney transplantation.

Methods

This retrospective study included 896 consecutive deceased-donor renal transplantations performed between January 1, 2000, and December 31, 2009. We compared outcomes of grafts from donors after cerebrovascular accident (CVA; n = 371) versus head trauma (HT; n = 525).

Results

Univariate analysis of pretransplantation data showed statistically significant differences (P < .05): among the following variables for the HT versus CVA groups respectively: recipient age (43.63 ± 13.2 y vs 49.80 ± 12.5 y); donor age (36.06 ± 16.6 y vs 52.57 ± 13.2 y) and time on dialysis (50.67 ± 45.034 mo vs 59.39 ± 46.3 mo). Regarding transplantation results, we observed that mean serum creatinine was significantly lower among HT recipient, at 1, 3, 6, 12, and 24 months after transplantation (P < .05). Chronic allograft nephropathy (CAN) and delayed graft function were higher among the CVA group. HT group kidneys showed significantly longer mean survival times than CVA group kidneys (102.7 ± 3.9 mo vs 94.8 ± 5.6 mo; log rank: P = .04). Upon multivariate analysis donor cause of death was not identified as an independent risk factor for graft survival or occurrence of chronic allograft nephropathy.

Conclusions

Transplantation results were better among the HT group. However multivariate regression analysis indicated that donor cause of death was not an independent risk factor for graft survival or occurrence of chronic allograft nephropathy.     

Efficacy of pneumococcal immunization in patients with renal disease--what is the data?

BACKGROUND/AIMS: There is an increased incidence of invasive pneumococcal disease in patients with renal allografts, chronic renal insufficiency (CRI), or nephrotic syndrome (NS). Routine pneumococcal immunization (PI) has been recommended for these patients, but the efficacy of PI in this population is not well established. METHODS: A review was done of studies that reported the immunologic response, efficacy, or safety of PI in patients with renal allografts, CRI, or NS. RESULTS: On review of 26 published studies of PI in this population, all studies demonstrated a serologic response by the majority of patients to at least some pneumococcal serotypes. Use of steroids did not alter this response. In the studies with a greater than 6-month follow-up, declining antibody titers were consistently reported, and this decline was usually more rapid than in healthy controls. However, because the studies of the efficacy of PI in this population involve small numbers of patients and are not controlled, the significance of this decline in titers is not known. The incidence of serious adverse reactions to PI is very low. CONCLUSION: Pending more data, patients with renal transplants, CRI, or NS should continue to be offered PI.     

Tacrolimus or cyclosporine: which is the better partner for mycophenolate mofetil in heart transplant recipients?

BACKGROUND: The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage. METHODS: Sixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded. RESULTS: Baseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08). CONCLUSIONS: At the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.     

Therapeutic regulation of complement in patients with renal disease - where is the promise?

Numerous renal diseases are characterized by complement activation within the kidney, and several lines of evidence implicate complement activation as an important part of the pathogenesis of these diseases. Investigators have long anticipated that complement inhibitors would be important and effective therapies for renal diseases. Eculizumab is a monoclonal antibody to the complement protein C5 that has now been administered to patients with several types of renal disease. The apparent efficacy of this agent may herald a new era in the treatment of renal disease, but many questions about the optimal use of therapeutic complement inhibitors remain. Herein we review the rationale for using complement inhibitors in patients with renal disease and discuss several drugs and approaches that are currently under development.     

BCG for upper-tract transitional-cell carcinoma: is it safe in patients with renal compromise?

We report three cases of end-stage renal failure necessitating hemodialysis subsequent to BCG administration for the treatment of upper-urinary tract transitional-cell carcinoma in patients with a solitary kidney, one with normal renal function and two with chronic renal failure prior to BCG instillation. We discuss treatment-related issues with pertinent literature review.