Role of Magnetic Resonance Elastography as a Noninvasive Measurement Tool of Fibrosis in a Renal Allograft: A Case Report.

A major reason for poor long-term kidney transplant outcomes is the development of chronic allograft injury, characterized by interstitial fibrosis and tubular atrophy. Currently, an invasive biopsy that samples only <1% of the kidney is the gold standard for detecting kidney allograft fibrosis. We report the use of magnetic resonance elastography (MRE) to quantify tissue stiffness as a noninvasive and whole-kidney measurement tool of allograft fibrosis in a kidney transplant patient at 2 time points. The MRE whole-kidney stiffness values reflected the changes in fibrosis of the kidney allograft as assessed by histologic examination. To our knowledge, this technique is the first observation of change over time in MRE-derived whole-kidney stiffness in an allograft that is consistent with changes in histology-derived fibrosis scores in a single patient.

Kidney transplant tourism: cases from Canada.

Canada has a marked shortfall between the supply and demand for kidneys for transplantation. Median wait times for deceased donor kidney transplantation vary from 5.8 years in British Columbia, 5.2 years in Manitoba and 4.5 years in Ontario to a little over 2 years in Quebec and Nova Scotia. Living donation provides a viable option for some, but not all people. Consequently, a small number of people travel abroad to undergo kidney transplantation by commercial means. The extent to which they are aware of the potential risks to their health and the health of the kidney vendors is unclear. Travel abroad to obtain a kidney commercially i.e. transplant tourism (TT), raises ethical issues which include the exploitation of the poor, uncertainty of donor informed consent to nephrectomy, poor clinical care and lack of follow up for the donor, commodification of the body and inequity of access to medical care for donors. Also, TT widens socioeconomic disparities in access to transplantation, differing from the Canadian system of universal coverage for healthcare. The Canadian transplant community has discussed how to respond to patients who plan to travel abroad for TT or return with a purchased kidney. Unease rests in the tension between the duty to care for legitimate Canadian residents and the unwillingness to enable TT. This paper discusses three anonymized cases and the Canadian responses to TT as recorded in academic literature and a formal statement by relevant professional bodies.

Pre-transplantation glucose testing for predicting new-onset diabetes mellitus after renal transplantation.

AIM: New-onset diabetes after renal transplantation (NODAT) adversely affects graft and patient survival. However, NODAT risk based on pre-transplant blood glucose (BG) levels has not been defined. Our goal was to identify the best pre-transplant testing method and cut-off values. MATERIALS AND METHODS: We performed a case-control analysis of non-diabetic recipients who received a live donor allograft with at least 6 months post-transplant survival. Pre-transplant glucose abnormalities were excluded through 75 g oral glucose tolerance testing (OGTT) and random BG (RBG) measurement. NODAT was defined based on 2003 Canadian Diabetes Association criteria. Multivariate logistic and Cox regression analysis was performed to determine independent predictor variables for NODAT. Receiver-operating-characteristic (ROC) curves were constructed to determine threshold BG values for diabetes risk. RESULTS: 151 recipients met initial entry criteria. 12 had pre-transplant impaired fasting glucose and/or impaired glucose tolerance, among who 7 (58%) developed NODAT. In the remaining 139, 24 (17%) developed NODAT. NODAT risk exceeded 25% for those with pre-transplant RBG > 6.0 mmol/l and 50% if > 7.2 mmol/l. Pre-transplant RBG provided the highest AUC (0.69, p = 0.002) by ROC analysis. Increasing age (p = 0.025), acute rejection (p = 0.011), and RBG > 6.0 mmol/l (p = 0.001) were independent predictors of NODAT. CONCLUSION: Pre-transplant glucose testing is a specific marker for NODAT. Patients can be counseled of their incremental risk even within the normal BG range if the OGTT is normal.

Role of dietary salt intake in posttransplant hypertension with tacrolimus-based immunosuppression.

Dietary salt is an important contributor to hypertension in the general population. While its role in cyclosporine-induced hypertension is minimal, its role in tacrolimus-based immunosuppression has not been defined. We measured the 24-hour urine sodium excretion as an estimate of intake in a group of stable renal transplant recipients on tacrolimus (N = 143) who had serum creatinine fluctuations <20% during the preceding 3 months. Average clinic-measured blood pressure (BP) from before and after the 24-hour urine collection was computed. Patients with recent changes in antihypertensive medications were excluded. Average systolic BP was 126 +/- 14 and diastolic BP 76 +/- 7 mm Hg. Urine sodium was 162.6 +/- 70 mmol/d (range 50 to 351), and the sodium/creatinine ratio was 15.4 +/- 6.4. There was no correlation between urine sodium excretion and either systolic or diastolic BP (R = 0.07 and R = 0.05, P = NS) or the sodium/creatinine and systolic/diastolic BP (R = 0.13, R = 0.11, P = NS). By multiple linear regression only weight and urine protein were independently associated with both systolic BP (P < .0001 for each) and diastolic BP (P < .05 for each). In conclusion, there is no appreciable influence of dietary salt intake on BP under tacrolimus-based immunosuppression. Restricting dietary salt intake in these patients cannot be recommended at the current time.

Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen.

UNLABELLED: Modified release (MR) tacrolimus is an extended release formulation administered once daily (qD). The purpose of this pharmacokinetic (PK) study was to evaluate tacrolimus exposure in stable kidney transplant recipients converted from Prograf twice a day to MR tacrolimus qD. METHODS: This was an open-label, multicenter study with a crossover design. Eligible patients were 18 to 65 years of age, more than 6 months posttransplant with stable renal function, and received stable Prograf doses more than 2 weeks prior to enrollment. Patients received Prograf twice a day through day 7; 24-hour PK profiles were obtained on days 1 and 7. Patients were converted to the same milligram-for-milligram daily dose of MR tacrolimus qD in the morning on day 8; 24-hour PK profiles were obtained for MR tacrolimus on days 8, 14, and 21. Laboratory and safety parameters were also evaluated. RESULTS: Most patients (67 of 70) completed all 5 PK profiles. The 90% confidence intervals (CI) for the MR tacrolimus vs Prograf comparison at steady state (days 14 and 21 vs days 1 and 7) were 90.7 and 99.4 for AUC0-24 and 82.7 and 91.9 for Cmin. MR tacrolimus was well tolerated with a safety profile comparable to that of Prograf. AUC0-24 was highly correlated to Cmin for Prograf (day 1, r = 0.80; day 7, r = 0.84) and MR tacrolimus (day 14, r = 0.92; day 21, r = 0.86). Renal function remained stable after conversion to MR tacrolimus. CONCLUSION: The steady state PK of MR tacrolimus are equivalent to Prograf after a milligram-for-milligram conversion in stable kidney transplant recipients. The results provide evidence to support a safe 1:1 conversion from Prograf twice a day to MR tacrolimus.

Diltiazem use in tacrolimus-treated renal transplant recipients.

BACKGROUND: Calcium channel blockers are widely used in the treatment of post-transplant hypertension but have the potential for drug interaction with calcineurin inhibitors. Renal allograft outcomes when diltiazem is used with cyclosporine have been reported, but similar data with tacrolimus are not available. METHODS: We performed a retrospective analysis of all our renal transplant recipients from March 1997 to March 2002 who were given tacrolimus, mycophenolate mofetil and prednisone. Patients were divided into two groups based on whether diltiazem was started in the first postoperative week. Outcome measures included renal function up to 2 years post-transplant, blood pressure (BP) control, tacrolimus exposure, and costs related to tacrolimus monitoring. RESULTS: Sixty-four patients constituted the diltiazem group and 32 the control group. Their baseline characteristics were similar. The mean average daily dose of diltiazem used was 213.95 mg/day. There was no difference in renal function, graft survival, or patient survival over 2 years. BP control was similar although the diltiazem group required more medication. Diltiazem was discontinued in four patients due to side-effects. There was no difference in tacrolimus-related side-effects between the two groups. There was also no difference in tacrolimus exposure, cost related to tacrolimus monitoring, or combined costs when the expense of diltiazem was added. CONCLUSION: Diltiazem use is acceptably safe and efficacious in renal transplant recipients treated with tacrolimus-based immunosuppressive therapy. It can be considered as a first-line antihypertensive in these patients and is cost neutral for tacrolimus use.

Death with graft function in elderly patients after cadaveric renal transplantation: effect of waiting time.

Survival after kidney transplantation is better than on the waiting list, even in the elderly. However, the effects of a prolonged waiting time for an organ on death with graft function have not been critically examined in this patient group. We conducted a single-center retrospective analysis of our cadaveric renal transplant experience in patients older than 60 years who received a kidney between January 1, 1990 and December 31, 2003. Besides waiting time, the effects of recipient age, gender, and diabetes were also examined. Cox proportional hazards analysis using patient death as a time-dependent outcome was used to estimate the hazard ratio of death posttransplantation. Using Kaplan-Meier survival methodology, patients with waiting times < or =5 years had significantly better survival times posttransplantation compared with those with waiting times >5 years (6.2 vs 2.8 years; P <.001). Each year of waiting was associated with hazard ratio 1.16 (95% confidence interval [CI], 1.06-1.27) for death. Prolonged waiting time on dialysis is deleterious to patient survival in recipients older than 60 years at transplantation. Early transplantation thus should be strongly encouraged in this group of patients.

Renin-angiotensin system blockade in biopsy-proven allograft nephropathy.

Allograft nephropathy leads to progressive renal injury and ultimate graft loss. In native kidney disease, the use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) is beneficial in retarding the decline of renal function. We reviewed a cohort of renal transplant recipients who were prescribed either an ACEi or ARB for biopsy-proven allograft nephropathy. Patients were followed from time of initiation of ACEi/ARB and were stratified based on biopsy findings. Outcomes of interest included safety, allograft survival, renal function, and rate of renal function decline pre- and post-ACEi/ARB. The 5-year allograft survival after biopsy was 83%. Mean serum creatinine was 2.2 +/- 1.1 mg/dL (range 1.0 to 4.3) at time of biopsy and 2.6 +/- 1.2 mg/dL (1.2 to 6.5) at last follow-up. The mean slope of the creatinine versus time (SD) was 2.43 (7.93) in the 12 months prior to therapy and 1.45 (3.66) following therapy, with the absolute difference in slope -3.38 (6.06) (P =.0004). We conclude that treatment with ACEi/ARB is beneficial in the management of allograft nephropathy.

Seasonal variation in outpatient blood pressure in stable renal transplant recipients.

Seasonal variation in blood pressure (BP) has been described in the general and dialysis populations, with higher recordings noted in the winter than in the summer. This difference has been attributed to changes in weight, ambient temperature, and length of daylight. In this study, we sought to determine whether such seasonal differences exist in renal transplant recipients, a group with a high prevalence of hypertension. We reviewed our outpatient population of 652 adult renal transplant recipients and identified primary allograft recipients with graft survival >1 year, stable renal function, on both cyclosporine and prednisone, and who had >1 pair of post-first year "winter" (defined as the months of January and February) plus "summer" (defined as the months of July and August) outpatient BP measurements from the same year. One hundred sixty-three patients met entry criteria, from whom 432 BP pairs were obtained. When the most recent pair from each patient was analyzed (n=163), diastolic and mean BP were found to be higher in winter than summer (by 2.5 and 2.3 mmHg, respectively, P<0.01 for each) by a paired Student t test. In a separate analysis using all BP pairs (n=432), systolic, diastolic, and mean BP were found to be significantly higher in winter (by 5.3, 2.7, and 3.5 mmHg, respectively, P<0.001 for each). An effect of season was confirmed in a multiple regression model of common predictors for hypertension, controlling for number of BP pairs per patient. In conclusion, renal transplant recipients demonstrate higher BP in the winter than in the summer. This effect is independent of known predictors of hypertension in this population and may be, at least, partly related to changes in length of daylight and temperature.

A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients.

BACKGROUND: Corticosteroids have been a mainstay of rejection prophylaxis for several decades, despite the multiple adverse effects of long-term use, including weight gain, hyperlipidemia, diabetes, hypertension, and bone disease. The detrimental effect of steroids on the metabolic profile begins in the early posttransplantation period, and the complete avoidance of steroids in transplantation would therefore be optimal. We hypothesized that the addition of mycophenolate mofetil (MMF) and a humanized monoclonal anti-CD25 antibody (daclizumab) to a cyclosporine (CsA microemulsion)-based immunosuppression protocol would permit transplantation without steroids. METHODS: Steroid-free renal transplantation was attempted in 57 patients treated with daclizumab, MMF, and CsA. Twenty-eight patients received kidneys from living donors; the remaining 29 received cadaveric grafts. RESULTS: At 1 year, patient and graft survival were 95% and 89%, respectively. Fourteen patients (25%) experienced rejections, of which 13 were readily reversed with steroids; 1 patient required OKT3. Mean serum creatinine at 12 months for patients not experiencing rejection was 149+/-58 micromol/L, compared with 158+/-102 micromol/L for those experiencing rejection. Five patients required hospitalization for infection; no patients developed lymphoproliferative disease. At baseline, 17 patients required 3 or more antihypertensive medications, compared with 2 patients at 1 year. Three of 43 nondiabetic patients developed diabetes during the study. There was no significant reduction in lumbar or femoral bone density. CONCLUSIONS: On the basis of these positive results, we believe steroid avoidance with this immunosuppressive regimen merits further study.

ACE inhibitors and angiotensin II antagonists in renal transplantation: an analysis of safety and efficacy.

Angiotensin-converting enzyme inhibitors (ACEi) are a class of antihypertensive agents that decrease mortality in congestive heart failure and have established efficacy in the treatment of hypertension and the slowing of established diabetic nephropathy and other proteinuria-associated glomerulonephritides. These drugs have not gained wide acceptance in the treatment of hypertension in renal transplant recipients (RTRs) because of a potential for decreased renal blood flow and glomerular filtration rate associated with a single kidney and concomitant cyclosporine use. Experimental animal models suggest that ACEi may be of benefit in slowing the progression of chronic renal allograft rejection. We undertook a retrospective chart analysis of all RTRs in our institution who had been treated with an ACEi or an angiotensin II (AT II) antagonist, with the objectives of determining the safety, efficacy, and side effect profile of these medications. The minimum follow-up period was 6 months. One hundred seventy-seven of 642 RTRs were prescribed an ACEi or AT II antagonist. Forty-seven patients discontinued therapy, with the most common causes of discontinuation being cough (8 patients) and hyperkalemia (6 patients). The mean arterial blood pressure at each follow-up period was lower than that at the time of initiation of ACEi or AT II antagonist therapy, with a decrease from 92 +/- 12 mm Hg to 86 +/- 9 mm Hg (P < 0.05) after 3 years of treatment. The serum creatinine concentrations did not change throughout the follow-up period. There was a nonsustained increase from the baseline serum potassium of 4.4 +/- 0.5 to 4.6 +/- 0.6 mEq/L at 3 months (P < 0.05), but no further increases in potassium beyond this time. The mean hemoglobin concentration for the cohort did not change, but 13 RTRs given an ACEi for posttransplantation erythrocytosis (PTE) had a decrease in hemoglobin from 17.1 +/- 1.0 g/dL at the start of ACEi therapy to 14.8 +/- 2.2 g/dL at 3 years (P < 0.05). ACEi and AT II antagonists were generally effective antihypertensives, and were safe and well-tolerated agents in this cohort of RTRs. ACEi were also effective in the treatment of PTE.

Development of focal segmental glomerulosclerosis in the renal allograft of a patient with lupus.

Nephritis has been a recognized complication of systemic lupus erythematosus since the early 1900s. Almost all lupus patients have some degree of renal involvement related to their condition, but a considerably smaller proportion of these patients actually progress to end-stage renal disease (ESRD). However, lupus patients are also susceptible to other primary renal insults that may significantly contribute to the deterioration in their renal function. We present a case of a patient with clinical and pathological evidence of lupus nephritis that progressed to ESRD and subsequently developed "recurrent" focal segmental glomerulosclerosis in her transplant kidney. Retrospective clinicopathologic correlation suggested the possibility of more than 1 primary renal process that eventually led to her dialysis-dependent state. This case illustrates the importance of meticulously examining both clinical and renal biopsy data in patients with lupus nephritis and considering the presence of co-existing renal pathologies to resolve an otherwise discordant picture of disease progression. These considerations may have important therapeutic and prognostic implications.

Outcome of kidney transplantation from high-risk donors is determined by both structure and function.

METHOD: Despite the need to expand the donor pool, it is unclear what parameters should be used. The value of donor renal pathology and calculated creatinine clearance (CrCl) in determining recipient outcome was assessed in 57 kidney transplants from 34 donors in whom pretransplant renal biopsies were performed because of age > or =60, hypertension, and/or vascular disease. We retrospectively compared clinical outcomes in these recipients and 57 control recipients selected to have the same baseline demographics but receiving transplants from low risk donors who were significantly younger (32+/-13.9 vs. 61+/-7.3 years) and lighter weight (71+/-18.1 vs. 84+/-20.2 kg) than the high-risk donors (P<.001 for both). RESULTS: Recipients of high-risk kidneys had a higher incidence of delayed graft function, defined by a <10% fall in serum creatinine (Cr) in the first 24 hr, (56% vs. 30%, P<.01), a higher incidence of rejection (60% vs. 37%, P = .02) and a higher Cr level (197+/-64 vs. 144+/-54 micromol/L at 18 months, P<.005). Graft and patient survival were similar; 12% and 5% vs. 91% and 9% in high-risk vs. control groups, respectively (P = NS). Donor renal pathology was scored 0-3 (none to severe disease) in four areas: glomerulosclerosis, interstitial fibrosis, tubular atrophy, and vascular disease. A donor vessel score of 3/3 was associated with a 100% incidence of delayed graft function and a mean 1-year Cr level of 275+106 micromol/L (compared with 43% and 192+54 micromol/L in those with lower vessel scores, P<.05). Calculated donor CrCl <100 ml/min was associated with higher recipient Cr levels at 1 year, 240+/-95 micromol/L vs. 180+/-54 micromol/L in recipients of kidneys from donors with CrCl levels >100 ml/min (P<.05). The mean 1-year Cr level was 320+/-102 micromol/L in recipients with both a vascular score of 3/3 and a donor CrCl <100 ml/min and 184+/-63 micromol/L in those with neither factor (P = .001). CONCLUSION: Calculated donor CrCl and donor vascular pathology predict recipient graft function and may be helpful in selecting high-risk donors for single kidney transplantation.

Clinical practice guidelines: prevention of cytomegalovirus disease after renal transplantation.

OBJECTIVE: To develop a set of comprehensive, standardized, evidence-based guidelines for the use of antiviral therapy to prevent cytomegalovirus disease in adult patients having undergone renal transplantation. OPTIONS: The use of medication, at the time of induction therapy or at the earliest sign of viremia. Treatments were evaluated by patient and donor serologic groups and the induction regimen used. OUTCOMES: The control of symptoms and features of cytomegalovirus disease over the first 6 mo to 1 yr after transplantation. EVIDENCE: Articles, compiled using a MEDLINE search from 1976 to July 1997, were reviewed by representatives of nephrology, microbiology, pharmacy, and epidemiology. Additional information was obtained from recent review articles and conference abstracts, and from experts in the field. VALUES: The evidence-based methods and values of the Canadian Task Force on the Periodic Health Examinations were used. High value was placed on studies with a randomized controlled design and blinded outcome observers. Study quality was classified as poor when cointervention was present (especially with regard to immunosuppressive regimens), when more than 20% of patients were lost to follow-up, and when intention to treat analysis was not performed. Recommendations were made with a graded system (grades A and B: Use of the intervention advised, based on high or fair quality evidence, respectively; grades D and E: Use of the intervention not advised, based on high or fair quality evidence, respectively: grade C: No recommendation made because of insufficient or conflicting evidence). RECOMMENDATIONS: (1) Seropositive recipient; donor seropositive or seronegative; immunosuppression with antilymphocyte products. Prophylaxis with antiviral therapy recommended (grade A recommendation). (2) Seronegative recipient; seropositive donor; immunosuppression with antilymphocyte products. Prophylaxis with antiviral therapy recommended (grade A recommendation) (3) Seronegative recipient; seropositive donor; conventional immunosuppression. Prophylaxis with antiviral therapy recommended (grade B recommendation). (4) Seronegative recipient; seronegative donor; any immunosuppressive regimen. No prophylaxis with antiviral therapy required (grade D/E recommendation). (5) Seropositive recipient: donor seropositive or seronegative; conventional immunosuppression. Prophylaxis left to the discrimination of the physician in charge (grade C recommendation).

Efficacy of azithromycin in the treatment of cyclosporine-induced gingival hyperplasia in renal transplant recipients.

BACKGROUND: Gingival hyperplasia (GH) is a common side effect of cyclosporine . Azithromycin (Zithromax; AZI) is a macrolide antibiotic reported in case studies to reduce cyclosporine-induced gingival hyperplasia (CIGH) in renal transplant recipients (RTR). METHODS: The efficacy of AZI to treat CIGH in RTR was examined in a double-blind, randomized crossover trial. Patients (n=17) with CIGH were randomized to receive AZI and a matching placebo in alternate order for 5 days, separated by a 2-week washout period. Follow-up visits were conducted at week 6 and week 12. Changes in GH were evaluated by measuring the clinical gingival sulcus depths, tooth length, and the length of the interdental papillae to the cementum-enamel junction of two teeth in each of the four quadrants. RESULTS: Significant improvements were observed in all three types of periodontal measurements, representing reductions of gingival tissue above the medial aspect of the tooth, of the gingival sulcus depth, and of the length of the interdental papillae. Patients reported an improvement in gum bleeding. AZI was well tolerated, and 67% of the patients reported that the treatment was at least somewhat useful. CONCLUSIONS: AZI should be considered for RTR with CIGH.

Thrombotic microangiopathy in association with cytomegalovirus infection in a renal transplant patient: a new treatment strategy.

BACKGROUND: Cytomegalovirus (CMV) associated with thrombotic microangiopathy (TMA) in transplant patients has not been extensively described. This case illustrates an association between CMV and TMA in a transplant patient with resolution of the latter after treatment of the CMV. METHODS AND RESULTS: At 6 weeks after renal transplantation, a 57-year-old woman presented with TMA. Cyclosporine was discontinued, and plasmapheresis was started. However, the patient continued to deteriorate and developed CMV pneumonitis. Plasmapheresis was discontinued, and intravenous ganciclovir was initiated. Both the TMA and the CMV resolved after initiation of the ganciclovir. CONCLUSION: This case identifies another potential etiological factor in the development of TMA after renal transplantation. It is the first reported case of TMA being cured with treatment of CMV.