R. Jean Shapiro

A multi-year analysis of islet transplantation compared with intensive medical therapy on progression of complications in type 1 diabetes.

Background. We hypothesized that transplantation of islets into type 1 diabetics could improve outcomes of glucose metabolism, renal function, retinopathy, and neuropathy compared with intensive medical therapy. Methods. We conducted a prospective, crossover, cohort study of intensive medical therapy (group 1) versus islet cell transplantation (group 2) in 42 patients. All were enrolled in group 1 then 31 crossed over with group 2 when islet donation became available. Transplantation was performed by portal venous embolization of more than 12,000 islet equivalents/kg body weight under cover of immunosuppression with antithymocyte globulin, tacrolimus, and mycophenolate. Outcome measures were HbA1c, change in glomerular filtration rate (GFR), progression of retinopathy, and change in nerve conduction velocity. This report details interim analysis of outcomes after 34±18 months (group 1) and 38±18 months (group 2). Results. HbA1c (%) in group 1 was 7.5±0.9 versus 6.6±0.7 in group 2 (P<0.01). GFR (mL/min/month) declined in both groups (group 1 −0.45±0.7 vs. group 2 −0.12±0.7, P=0.1). Slope of the GFR decline in group 1 was significantly more than 0. Retinopathy progressed in 10 of 82 eyes in group 1 versus 0 of 51 in group 2 (P<0.01). Nerve conduction velocity (m/sec) remained stable in group 1 (47.8±5 to 47.1±5 m/sec) and group 2 (47.2±4.5 to 47.7±3.5). Conclusion. Islet transplantation yields improved HbA1c and less progression of retinopathy compared with intensive medical therapy during 3 years follow-up.

The effect of medical therapy and islet cell transplantation on diabetic nephropathy : An interim report

Background. The effect of islet cell transplantation (ICT) on renal function in type 1 diabetes is uncertain and some recent studies report a significant decline in estimated glomerular filtration rate (GFR) and worsening of albuminuria. Methods. We are conducting a prospective crossover study comparing medical treatment with islet transplantation on the progression of diabetic complications, including renal function. The primary endpoint is change in GFR measured by 99mTc-diethylenetriaminepentaacetate with secondary endpoints including estimated GFR and albumin excretion. Results. We have followed 21 patients after islet transplantation a median of 29 months (range 13–45) and compared their results with medically treated patients followed a median 29.5 months (range 13–56). There is no difference in the rate of decline in measured GFR between medically treated patients (–0.35±0.89; 95% CI: –0.57 to –0.13 mL/min/month/1.73 m2) and those after ICT (–0.31±1.18; 95% CI: –0.61 to –0.01) and neither is significantly different from that expected for the general population. The rate of decline in our estimated GFR results is lower than that reported in other studies and we did not find any worsening of albuminuria. Conclusions. We do not find evidence of worsening of renal function after islet transplantation compared with medically treated patients.

Reduced progression of diabetic retinopathy after islet cell transplantation compared with intensive medical therapy.

Background. Diabetic retinopathy is a major complication of type 1 diabetes and remains a leading cause of visual loss. There have been no comparisons of the effectiveness of intensive medical therapy and islet cell transplantation on preventing progression of diabetic retinopathy. Methods. The British Columbia islet transplant program is conducting a prospective, crossover study comparing medical therapy and islet cell transplantation on the progression of diabetic retinopathy. Progression was defined as the need for laser treatment or a one step worsening along the international disease severity scale. An interim data analysis was performed after a mean 36-month follow-up postislet transplantation and these results are presented. Results. The medical and postislet transplant groups were similar at baseline. Subjects after islet transplantation had better glucose control than the medically treated subjects (mean HbA1c 6.7%±0.9% vs. 7.5±1.2, P<0.01) and were C-peptide positive. Progression occurred significantly more often in all subjects in the medical group (10/82 eyes, 12.2%) than after islet transplantation (0/51 eyes, 0%) (P<0.01). Considering only subjects who have received transplants, progression occurred in 6/51 eyes while on medical treatment and 0/51 posttransplant (P<0.02). Conclusions. Progression of diabetic retinopathy was more likely to occur during medical therapy than after islet cell transplantation.

Differential impact of age on verbal memory and executive functioning in chronic kidney disease

We compared aspects of verbal memory and executive functioning in 51 community-dwelling persons with chronic kidney disease (CKD) and 55 healthy controls matched on age and education. Depressive symptoms were assessed with the Centre for Epidemiological Studies-Depression Scale (CES-D), and illness variables included glomerular filtration rate (GFR) and hemoglobin. Findings indicate that persons with CKD exhibited poorer performance on measures of memory (CVLT-II) and executive functioning (DKEFS Trailmaking Test B and Color-Word Interference Tests) in comparison with healthy controls. Furthermore, performance decrements were magnified in older CKD participants on measures of verbal memory and inhibition. Nearly half of CKD participants aged 61 and older exhibited significant impairments in verbal memory and inhibition in comparison to matched controls. Cognitive performance in CKD was not associated with measures of illness severity. The differences observed were not accounted for by depressive symptoms, which were only weakly associated with cognitive performance, and negatively associated with age. Findings highlight the need for further exploration of the etiologies and functional consequences of the neuropsychological presentation of CKD.

Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection.

Background. The purpose of this study was to determine whether screening for anti-human leukocyte antigen (HLA) antibodies (Abs) could predict development of acute rejection (AR) before clinical evidence of kidney allograft dysfunction in nonsensitized recipients. Methods. Eighty-four non-HLA identical kidney transplant recipients were prospectively tested for anti-HLA Abs (FlowPRA analysis and anti-HLA Ab specificity determination) at 0, 10, 20, 30, 60, 90, 180 and 365 posttransplantation, and at the time of clinical suspicion of AR. Allograft biopsies were performed at the time of engraftment, 3 and 12 months posttransplantation, when patients developed new anti-HLA Abs, or when clinically indicated. Results. Among the 70 patients without preformed anti-HLA Abs, 11 developed de novo anti-HLA Abs (8 donor-specific Abs) at a median of 30 days (q1-q3=10–180 days) after transplantation. Patients with de novo anti-HLA Abs had a shorter time to AR than patients without de novo anti-HLA Abs, P=0.06. However, in all cases, de novo anti-HLA Abs developed concomitantly or after a clinically evident AR. Conclusions. Although de novo anti-HLA Abs were associated with AR, routine screening for anti-HLA Abs was not useful in identifying patients at risk for AR before clinical evidence of allograft dysfunction.

Probability, Predictors, and Prognosis of Posttransplantation Glomerulonephritis

Glomerulonephritis (GN) is the leading cause of chronic kidney disease among recipients of renal transplants. Because modern immunosuppressive regimens have reduced the incidence of rejection-related graft loss, the probability and clinical significance of posttransplantation GN (PTGN) requires reevaluation. In this Canadian epidemiologic study, we monitored 2026 sequential renal transplant recipients whose original renal disease resulted from biopsy-proven GN (36%), from presumed GN (7.8%), or from disorders other than GN (56%) for 15 yr without loss to follow-up. Kaplan-Meier estimates of PTGN in the whole population were 5.5% at 5 yr, 10.1% at 10 yr, and 15.7% at 15 yr. PTGN was diagnosed in 24.3% of patients whose original renal disease resulted from biopsy-proven GN, compared with 11.8% of those with presumed GN and 10.5% of those with disorders other than GN. Biopsy-proven GN in the native kidney, male gender, younger age, and nonwhite ethnicity predicted PTGN. Current immunosuppressive regimens did not associate with a reduced frequency of PTGN. Patients who developed PTGN had significantly reduced graft survival (10.2 versus 69.7%; P < 0.0001). In summary, in the Canadian population, PTGN is a common and serious complication that causes accelerated graft failure, despite the use of modern immunosuppressive regimens.

Factors associated with progression of interstitial fibrosis in renal transplant patients receiving tacrolimus and mycophenolate mofetil.

Background. We recently reported a randomized study in renal transplant patients (RTP) receiving tacrolimus, mycophenolate mofetil, and prednisone in which patients who had early protocol biopsies (PBx) derived no benefit compared with controls (no PBx) at 6 months, likely due to the low prevalence of subclinical rejection. We report on the follow-up of these patients to 24 months at which time a repeat PBx and tests of renal function were performed. Methods. Of the 240 RTP randomized, 22 were excluded for a protocol violation. Approximately 75% of the remaining 218 (111 PBx and 107 controls) completed the study. Results. At 24 months, graft function was excellent with a mean creatinine clearance of approximately 74 mL/min and negligible proteinuria; however, the prevalence of interstitial fibrosis and tubular atrophy (IF/TA)—ci + ct more than or equal to 2—increased from approximately 3% at baseline to up to 40% to 50%. By logistic regression analysis, the only independent positive correlate of IF/TA was transplantation with a deceased donor. However, by post hoc analysis, use of angiotensin-II-converting enzyme inhibitors or angiotensin II receptor blockers was negatively correlated with both the prevalence of IF/TA at 24 months and its progression between 6 and 24 months in RTP that had paired biopsies. Conclusions. A regimen of tacrolimus, mycophenolate mofetil, and prednisone results in excellent renal function at 24 months posttransplant but with a progressive increase in IF/TA. A potential inhibitory effect of angiotensin-II-converting enzyme inhibitor/angiotensin II receptor blockers on IF/TA is suggested that requires confirmation in a randomized study.

Influence of chronic dietary acid on renal tubular handling of magnesium.

Micropuncture and clearance studies were performed on rats with chronic metabolic acidosis to evaluate the segmental handling of magnesium. Fractional magnesium excretion was 12.6±2.3% in acidemic rats (blood pH 7.17+0.2) compared to 5.1±1.3% of normal animals (blood pH 7.36±0.05). Ultrafilterable magnesium concentrations were similar in both normal and acidotic animals, 0.51±0.02 and 0.48±0.03 mM, respectively. Elevation of urinary magnesium excretion was due to diminished reabsorption in the loop of Henle and segments beyond the distal sampling site. Acute correction of the systemic acidosis with NaHCO3 infusions partially corrected the renal magnesium levels as fractional magnesium excretion fell from 12.6% to 3.1+0.75%. This was associated with enhanced reabsorption of magnesium in the loop. To determine if acidosis may compromise the renal conservation of magnesium, acidotic rats were subsequently placed on magnesium-restricted diets. Normal and acidotic animals adapted appropriately and to a similar extent when challenged by short-term magnesium-restricted diets. Accordingly, elevation of dietary acid intake and systemic acidosis leads to renal magnesium wasting which is due in part to diminished reabsorption in the loop of Henle. However, chronic acidosis does not compromise the renal adaptive response to dietary magnesium restriction.

An observational study of health literacy and medication adherence in adult kidney transplant recipients

Background There is a high prevalence of non-adherence to immunosuppressants in kidney transplant recipients. Although limited health literacy is common in kidney recipients and is linked to adverse outcomes in other medical populations, its effect on medication adherence in kidney transplant recipients remains poorly understood. The objective was to investigate the effect of lower health literacy on immunosuppressant adherence. Methods Kidney recipients who were at least 6 months post-transplant and outpatients of Vancouver General Hospital in B.C., Canada were recruited through invitation letters. A total of 96 recipients completed the Health Literacy Questionnaire, which provides a multifactorial profile of self-reported health literacy and the Transplant Effects Questionnaire-Adherence subscale measuring self-reported immunosuppressant adherence. Hierarchical linear regression was used to analyze the association between health literacy and adherence after controlling for identified risk factors of non-adherence. Results Our sample was on average 53 years old, 56% male and 9 years post-transplant. Kidney recipients reported low levels of health literacy on scales measuring active health management and critical appraisal of information and 75% reported non-perfect adherence. Worse adherence was associated with poorer overall health literacy (ΔR2 = 0.08, P = 0.004) and lower scores on six of nine of the health literacy factors. Conclusions Poorer health literacy is associated with lower immunosuppressant adherence in adult kidney transplant recipients suggesting the importance of considering a recipients level of health literacy in research and clinical contexts. Medication adherence interventions can target the six factors of health literacy identified as being risk factors for lower medication adherence.

Pharmacokinetics of mycophenolic acid and its glucuronidated metabolites in stable islet transplant recipients.

Given the paucity of data on pharmacokinetics of mycophenolic acid (MPA) in islet transplant, the aim of this study was to characterize pharmacokinetic parameters of MPA and its 2 glucuronidated metabolites in stable islet transplant recipients. Sixteen subjects were entered into this open-label study after written informed consent. Upon administration of a steady-state morning mycophenolate mofetil dose, 12-hour serial concentrations of MPA and its phenolic glucuronide (MPAG) and acyl-glucuronide (AcMPAG) were measured by a validated high-performance liquid chromatography method and pharmacokinetic parameters analyzed by noncompartmental modeling. Subjects included 11 women and 5 men who had received 2.7 ± 0.8 islet transplants. Age was 50 ± 8 years, weight 64 ± 11 kg, serum albumin 4.2 ± 0.3 g/dL, and serum creatinine 1.1 ± 0.4 mg/dL. All patients were also on tacrolimus-based steroid-free immunosuppressant regimens. Mycophenolate mofetil dosage ranged from 1 to 2 g daily (25.4 ± 6.1 mg/kg/d). Pharmacokinetic parameters for MPA were area under the curve 42.9 ± 21.6 μg h/mL; dose-normalized AUC 52.9 ± 25.4 μg h/mL/g; maximal concentration (Cmax) 13.0 ± 6.2 μg/mL; time to Cmax (tmax) 1.2 ± 0.4 hours; minimum concentration (Cmin) 1.4 ± 1.0 μg/mL; and MPA-free fraction 1.2% ± 1.0%. Area under the curve ratios of MPAG/MPA and AcMPAG/MPA were 17.8 ± 12.4 and 0.1 ± 0.1, respectively. The wide interpatient variability in all pharmacokinetic parameters of MPA and metabolites are consistent with results from the only other published pharmacokinetic study in islet transplant recipients. A population model and a search for significant covariates may help reduce this variability. Pharmacokinetic parameters calculated in the present study, coupled with findings from the only other published MPA study in islet transplant, form a preliminary base on which to build a population model for future multicenter studies of this little-studied transplant subpopulation.