The generalized aminoaciduria seen in patients with hepatocyte nuclear factor-1alpha mutations is a feature of all patients with diabetes and is associated with glucosuria.

Hepatocyte nuclear factor-1alpha (HNF-1alpha) mutations are the most common cause of maturity-onset diabetes of the young. HNF-1alpha homozygous knockout mice exhibit a renal Fanconi syndrome with glucosuria and generalized aminoaciduria in addition to diabetes. We investigated glucosuria and aminoaciduria in patients with HNF-1alpha mutations. Sixteen amino acids were measured in urine samples from patients with HNF-1alpha mutations, age-matched nondiabetic control subjects, and age-matched type 1 diabetic patients, type 2 diabetic patients, and patients with diabetes and chronic renal failure. The HNF-1alpha patients had glucosuria at lower glycemic control (as shown by HbA1c) than type 1 and type 2 diabetic patients, consistent with a lower renal glucose threshold. The HNF-1alpha patients had a generalized aminoaciduria with elevated levels of 14 of 16 amino acids and an increased mean Z score for all amino acids compared with control subjects (0.66 vs. 0.00; P < 0.0005). Generalized aminoaciduria was also present in type 1 diabetic (Z score, 0.80; P < 0.0001), type 2 diabetic (Z score, 0.71; P < 0.0002), and chronic renal failure (Z score, 0.65; P < 0.01) patients. Aminoaciduria was not associated with microalbuminuria or proteinuria but was associated with glucosuria (1.00 glucosuria vs. 0.19 no glucosuria; P = 0.002). In type 1 diabetic patients, urine samples taken on the same day showed significantly more aminoaciduria when glucosuria was present compared with when it was absent (P < 0.01). In conclusion, HNF-1alpha mutation carriers have a mutation-specific defect of proximal tubular glucose transport, resulting in increased glucosuria. In contrast, the generalized aminoaciduria seen in patients with HNF-1alpha mutations is a general feature of patients with diabetes and glucosuria. Glucose may depolarize and dissipate the electrical gradient of the sodium-dependent amino acid transporters in the proximal renal tubule, causing a reduction in amino acid resorption.

The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function.

BACKGROUND: The purpose of this study was to determine the effect of renal function on the elimination and disposition of mycophenolic acid and its glucuronide metabolite (MPAG) after oral administration of the pro-drug mycophenolate mofetil. In addition, this study sought to examine hemodialysis removal of mycophenolic acid and its MPAG. METHODS: Subjects were stratified into five groups on the basis of iohexol clearance. After an overnight fast, all subjects received a single 1 gm dose of mycophenolate mofetil. Plasma concentrations of mycophenolic acid and MPAG were measured from 0 to 96 hours after administration. Mycophenolic acid and MPAG maximum plasma concentration (Cmax) and the time to reach Cmax (tmax) for each group were determined from the mean plasma concentration-time profiles. Area under the plasma concentration-time curve values for mycophenolic acid and MPAG were calculated by the trapezoidal rule. The half-lives of mycophenolic acid and MPAG were calculated from the terminal portions of the concentration-time profiles. RESULTS: Mycophenolic acid clearance was not associated with changes in glomerular filtration rate (GFR). Cmax tended to increase as GFR declined. MPAG clearance correlated well with GFR (r2 = 0.905). Clearance of mycophenolic acid and MPAG were unaffected by hemodialysis. CONCLUSIONS: Clearance of mycophenolic acid after a single 1 gm oral dose of mycophenolate mofetil is unaffected by renal function. Clearance of mycophenolic acid is unaffected by hemodialysis. Diminished renal function should not require preemptive adjustment of 1 gm doses of mycophenolate mofetil; however dosage adjustment may be warranted on the basis of adverse effects or toxicity in individual patients. Mycophenolate mofetil can be administered irrespective of hemodialysis session without effect on mycophenolic acid exposure.

The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation.

BACKGROUND: Mycophenolate mofetil, a pro-drug for mycophenolic acid, reduces the likelihood of allograft rejection after renal transplantation. We studied the relationship between mycophenolic acid pharmacokinetics and the likelihood of rejection in a randomized concentration-controlled trial. METHODS: Under double-blind conditions, recipients of kidney transplants were followed for evidence of allograft rejection for 6 months. In addition to mycophenolate mofetil, patients received usual doses of cyclosporine (INN, ciclosporin) and corticosteroids. The dose of mycophenolate mofetil (given twice daily) was controlled by feedback, with mycophenolic acid area under the concentration-time curve (AUC) as the controlled variable. Patients were randomly assigned to 1 of 3 target AUC groups. RESULTS: Logistic regression analysis showed a significant (P < .0001) relationship between mycophenolic acid AUC and the likelihood of rejection. High mycophenolic acid values were associated with a very low probability of rejection. An AUC of 15 micrograms.h/mL yielded 50% of maximal achievable efficacy with a 4% change of efficacy for a 1 microgram.h/mL change in AUC at the midpoint of the logistic curve. Exploratory analyses showed other variables (e.g., the maximum observed plasma concentration, predose plasma concentration, and drug dose) had poorer predictive power for the rejection outcome. Bivariate regression confirmed the importance of AUC as a highly predictive variable and showed low predictive value of other variables, once the contribution of AUC had been considered. The characteristic side effects of mycophenolate mofetil therapy appeared related to drug dose but not to mycophenolic acid concentration. CONCLUSIONS: The AUC of mycophenolic acid is predictive of the likelihood of allograft rejection after renal transplantation in patients receiving mycophenolate mofetil.

A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation.

BACKGROUND: Adding a fixed dose of 1 g b.i.d. of mycophenolate mofetil (MMF) to an immunosuppressive regimen consisting of cyclosporine and prednisone results in a 50% reduction in the incidence of acute rejection after kidney transplantation. This study was designed to investigate the relationship between pharmacokinetic data (mycophenolic acid area under the curve; MPA AUC) and the prevention of rejection after kidney transplantation. METHODS: A total of 154 adult recipients of a primary or secondary cadaveric kidney graft were randomly allocated, in this double-blind trial, to receive MMF treatment aimed at three predefined target MPA AUC values (16.1, 32.2, and 60.6 microg x hr/ml). During the first 6 months after transplantation, plasma samples for nine AUCs were collected. After analysis of the samples, a coded dose adjustment advice was generated using a Bayesian algorithm, maintaining the double blinding. Immunosuppressive therapy further consisted of cyclosporine and prednisone. The primary end point of this study was the occurrence of biopsy-proven acute rejection within the 6-month study period. RESULTS: A total of 150 patients were eligible for analysis. Although after day 21, the mean MMF dose was reduced, the mean MPA AUC gradually increased and target MPA AUC values were exceeded in all three groups. The incidences of biopsy-proven acute rejection in the low, intermediate, and high target MPA AUC groups were 14 of 51 (27.5%), 7 of 47 (14.9%), and 6 of 52 (11.5%), respectively. The incidences of premature withdrawal from the study due to adverse events in the three groups were 4 of 51 (7.8%), 11 of 47 (23.4%), and 23 of 52 (44.2%), respectively. Logistic regression analysis showed a highly statistically significant relationship between median ln(MPA AUC) and the occurrence of a biopsy-proven rejection (P<0.001). The logistic regression using median ln(Cpredose) was also statistically significant for this relationship (P=0.01), whereas it was not when using mean MMF dose (P=0.082). In contrast, the logistic regression using mean MMF dose for comparison of patients who successfully completed the study versus patients experiencing premature withdrawal due to adverse events was highly significant (P<0.001), whereas this was not significant when using median ln(Cpredose) (P=0.512) or median ln(MPA AUC) (P=0.434). CONCLUSION: MPA Cpredose and MPA AUC are significantly related to the incidence of biopsy-proven rejection after kidney transplantation, whereas MMF dose is significantly related to the occurrence of adverse events.

Clinical pharmacokinetics of mycophenolate mofetil.

The pharmacokinetics of the immunosuppressant mycophenolate mofetil have been investigated in healthy volunteers and mainly in recipients of renal allografts. Following oral administration, mycophenolate mofetil was rapidly and completely absorbed, and underwent extensive presystemic de-esterification. Systemic plasma clearance of intravenous mycophenolate mofetil was around 10 L/min in healthy individuals, and plasma mycophenolate mofetil concentrations fell below the quantitation limit (0.4 mg/L) within 10 minutes of the cessation of infusion. Similar plasma mycophenolate mofetil concentrations were seen after intravenous administration in patients with severe renal or hepatic impairment, implying that the de-esterification process had not been substantially affected. Mycophenolic acid, the active immunosuppressant species, is glucuronidated to a stable phenolic glucuronide (MPAG) which is not pharmacologically active. Over 90% of the administered dose is eventually excreted in the urine, mostly as MPAG. The magnitude of the MPAG renal clearance indicates that active tubular secretion of MPAG must occur. At clinically relevant concentrations, mycophenolic acid and MPAG are about 97% and 82% bound to albumin, respectively. MPAG at high (but clinically realisable) concentrations reduced the plasma binding of mycophenolic acid. The mean maximum plasma mycophenolic acid concentration (Cmax) after a mycophenolate mofetil 1 g dose in healthy individuals was around 25 mg/L, occurred at 0.8 hours postdose, decayed with a mean apparent half-life (t1/2) of around 16 hours, and generated a mean total area under the plasma concentration-time curve (AUC infinity) of around 64 mg.h/L. Intra- and interindividual coefficients of variation for the AUC infinity of the drug were estimated to be 25% and 10%, respectively. Intravenous and oral administration of mycophenolate mofetil showed statistically equivalent MPA AUC infinity values in healthy individuals. Compared with mycophenolic acid, MPAG showed a roughly similar Cmax about 1 hour after mycophenolic acid Cmax, with a similar t1/2 and an AUC infinity about 5-fold larger than that for mycophenolic acid. Secondary mycophenolic acid peaks represent a significant enterohepatic cycling process. Since MPAG was the sole material excreted in bile, entrohepatic cycling must involve colonic bacterial deconjugation of MPAG. An oral cholestyramine interaction study showed that the mean contribution of entrohepatic cycling to the AUC infinity of mycophenolic acid was around 40% with a range of 10 to 60%. The pharmacokinetics of patients with renal transplants (after 3 months or more) compared with those of healthy individuals were similar after oral mycophenolate mofetil. Immediately post-transplant, the mean Cmax and AUC infinity of mycophenolic acid were 30 to 50% of those in the 3-month post-transplant patients. These parameters rose slowly over the 3-month interval. Slow metabolic changes, rather than poor absorption, seem responsible for this nonstationarity, since intravenous and oral administration of mycophenolate mofetil in the immediate post-transplant period generated comparable MPA AUC infinity values. Renal impairment had no major effect on the pharmacokinetic of mycophenolic acid after single doses of mycophenolate mofetil, but there was a progressive decrease in MPAG clearance as glomerular filtration rate (GFR) declined. Compared to individuals with a normal GFR, patients with severe renal impairment (GFR 1.5 L/h/1.73m2) showed 3-to 6-fold higher MPAG AUC values. In rental transplant recipients during acute renal impairment in the early post-transplant period, the plasma MPA concentrations were comparable to those in patients without renal failure, whereas plasma MPAG concentrations were 2- to 3-fold higher. Haemodialysis had no major effect on plasma mycophenolic acid or MPAG. Dosage adjustments appear to not be necessary either in renal impairment or during dialysis. (ABSTRACT TRUN

Patterns of N-acetyl-beta-D-glucosaminidase excretion after renal transplantation.

N-Acetyl-beta-D-glucosaminidase activity (NAG) was assayed in 750 early morning urine samples from 25 renal transplant patients during the post operative period. Eighty four per cent of all acute rejection episodes were preceded or accompanied by a greater than two-fold rise in NAG activity; similar increases were caused by dialysis, gentamicin therapy and ureteric dehiscence. Only 9% of all significant increases in NAG excretion could not be accounted for by any of these four processes. Analysis of the day-to-day pattern of NAG activity as opposed to individual NAG values provided a clue to the occurrence of rejection during immediate post-transplantation oliguria.

Renal vasculitis: increasingly a disease of the elderly?

BACKGROUND/AIMS: The majority of patients presenting to our district general hospital with renal vasculitis are elderly. Older patients respond less well to treatment and have a poorer prognosis. We investigated the relationship between age and outcome of renal vasculitis in our centre and examined the evidence regarding treatment of elderly patients with this condition. METHODS: Patients presenting over a 2-year period with renal vasculitis were identified by clinical and histological features and by antineutrophil cytoplasmic autoantibody positivity. They were followed for a mean of 15 months and outcomes were recorded. Results were compared with published studies. RESULTS: The mean age at presentation of 21 patients was 69 years. Forty-eight percent required dialysis and there was a 33% overall mortality. The mean age of patients in previous treatment studies has been between 50 and 55 years. CONCLUSIONS: The greater severity of disease at presentation and poorer outcome than previously described is likely to be due to the high proportion of elderly patients. The incidence of vasculitis is increasing in the elderly but as this group has been poorly represented in clinical trials in renal vasculitis, applying the findings of these trials to their treatment may be hazardous. Future research should determine which treatments are safe and effective in the elderly.

Acute renal failure in essential mixed cryoglobulinemia: precipitation and reversal by plasma exchange.

A patient with essential mixed cryoglobulinemia was treated for deteriorating renal function with plasma exchange alone. This therapy was immediately followed by acute oliguric renal failure due to precipitation of the cryoglobulin within glomerular capillary loops, probably as a result of infusion of cold plasma. The composition of the intracapillary deposits reflected not only the variety of cryoglobulin but the rapidity of deposition. Renal function returned when plasma exchange was re-introduced, this time coupled with immunosuppressive chemotherapy. After resolution of the intraluminal caogula a membranoproliferative picture remained. Replacement fluids for plasma exchange in cryoglobulinemia should be warmed before infusion.

The value of autologous indium (111In)-labelled platelets in the diagnosis of renal transplant rejection.

Serial pelvic imaging after injection of autologous platelets labelled with 111In was used to study 22 consecutive patients following cadaver renal transplantation. Increases in isotope uptake by the allografts were observed during episodes of acute rejection (12/22) but not during acute tubular necrosis (4/22). The technique was not influenced by oliguria or hemodialysis therapy. Extra-renal accumulations of labelled platelets were noted in perinephric hematomata and deep vein thromboses.

Acute renal failure: the tip of the iceberg?

This study reports the experience, during a six-year period, of the Aberdeen Renal Unit in the treatment of patients with acute renal failure. The combination of a relatively stable population base and a single regional dialysis centre has allowed the incidence of acute renal failure to be assessed. Approximately 30 patients per million population were dialysed annually for acute renal failure; 69 per cent of these patients (20.5 per million population per year) were dialysed for acute reversible intrinsic renal failure (ARIRF) and mortality in this group was 44 per cent. Patients with more severe disease at the time of presentation to the renal unit, as defined by a clinical severity score, had significantly reduced survival rates. However, it was not possible to predict the outcome in individual cases; ten of 24 patients with clinical severity scores which indicated a poor prognosis survived the period of oliguria and were discharged from hospital. The fact that other renal units dialyse fewer patients per million population per year for ARIRF probably reflects a reluctance to refer patients whose general condition appears poor. As the overall mortality rate reported in this study does not differ significantly from rates reported previously from centres treating a smaller proportion of patients, such decisions may not be correct. It is well known that facilities in Britain for treating patients with end-stage renal disease are inadequate; it now appears likely that some patients who might benefit from acute dialysis are being denied treatment for a potentially reversible disease process.

Awake renal transplantation; a realistic alternative to general anesthesia.

A 63-year-old man with profound phobia of general anesthesia recently underwent successful renal transplantation in our unit under combined spinal-epidural anesthesia (CSEA). We believe that although this is not a novel technique, it is a realistic option for renal transplantation in patients in whom general anesthesia is not feasible. The use of CSEA for surgery below the umbilicus and its postoperative pain management has increased in popularity in recent years. Its use in renal transplantation is not widely reported; however, available articles suggest that it is a safe and useful alternative to general anesthesia, with no significant difference in anesthesia or surgical time, surgical conditions, hemodynamic stability, or early postoperative renal function. The procedure was performed with no alteration to the surgical technique usually adopted by the surgeon. The patient had a largely uneventful postoperative recovery, with good pain control and no significant complications. He has achieved good stable renal function, with a serum creatinine concentration of 105 mumol/L at 6 months (preoperative serum creatinine concentration, 832 mumol/L). We believe this case demonstrates that CSEA is a practical option for renal transplantation in the United Kingdom, and would recommend CSEA as a useful alternative to general anesthesia in patients with this type of phobia. Careful preoperative planning, patient selection, and consideration of a contingency plan meant that surgically the procedure proceeded as standard, with good results. Because of the success of this case, a second patient with phobia of general anesthesia has recently been placed on the regional transplantation waiting list.

Development of a video assessment scoring method to determine the accuracy of endoscopist performance at screening flexible sigmoidoscopy.

BACKGROUND AND AIMS: Variation in the adenoma detection rate (ADR) at flexible sigmoidoscopy screening has been shown to be due to variation in endoscopist performance. There are no objective methods for scoring an endoscopist's performance reliably, and the aim of this study was to develop a valid and reliable objective scoring method using video footage of screening flexible sigmoidoscopies. METHODS: In a series of five experiments, experienced endoscopists (the scorers) independently scored a sample (n = 43) of the 40 000 flexible sigmoidoscopy extubations recorded as part of the United Kingdom Flexible Sigmoidoscopy Screening Trial (UK FSST). The scoring system, the parameters scored, and their definitions evolved over the course of the five experiments. The initial visual analogue score (range 0-100) used in the first two experiments evolved into a five-point score that ranged from 1 (E, poor) to 5 (A, excellent) in the last three experiments. The final parameters scored were: time spent viewing the mucosa, re-examination of poorly viewed areas, suctioning of fluid pools, distension of the lumen, lower rectal examination, and overall quality of the examination. The first four experiments scored one individual case per endoscopist; in experiment 5, an overall score was awarded for five cases performed by each endoscopist being assessed. RESULTS: Scoring five cases examined by an individual endoscopist using the A-E grading system was the most reliable method (interclass correlation coefficient 0.89). Cluster analysis demonstrated that the endoscopists in the high-scoring ADR group (ADR 14.7-15.9 %) could be differentiated from those in the intermediate- and low-scoring ADR groups (ADR 8.6-12.6 %). CONCLUSIONS: An objective scoring system for assessing the accuracy of performance at screening flexible sigmoidoscopy, based on video footage, is described. Endoscopists who might benefit from further training can be identified using this method.

Hypersensitivity to hemodialysis: the United Kingdom experience.

A postal survey of all U.K. hemodialysis centers was conducted to investigate the prevalence of hypersensitivity in the first use of disposable dialyzers. A total of 117 patients with 243 separate reactions were identified, suggesting that 1 in 20 to 1 in 50 patients may be susceptible to an anaphylactoid reaction to a new hemodialyzer at some time, while the risk of reaction occurring with any single hemodialysis is approximately 1 in 1,000 to 1 in 5,000. No particular brand or type of hemodialyzer nor any identifiable technique of priming procedure was associated with reactions, but in those few patients who suffered repeated reactions further problems were avoided by increasing the volume of saline in the initial rinse of the hemodialyzer or by changing to another brand of hemodialyzer. Although it is likely that many reactions are unrecognized or unreported, the scale of the problem is larger than many British nephrologists had suspected.

The impact of atherosclerotic renovascular disease on diabetic renal failure.

Atherosclerotic renovascular disease (ARVD) is common in the general population, and its prevalence increases with age. Parallel studies show it is also common in patients with diabetes. The widespread use of angiotensin converting enzyme inhibitors and angiotensin receptor antagonists for heart and kidney disease might therefore expose arteriopathic diabetic patients to potential harm if they had critical renal artery stenosis. This review looks at the natural history of ARVD in the diabetic and non-diabetic populations: while it is common, it only rarely leads to renal failure. Hence intervention to revascularize ischaemic kidney son the basis of radiological appearances alone may subject some patients to unnecessary therapy. Although untested by randomized trial, a policy of watchful waiting may be the simplest strategy for most diabetic patients with suspected ARVD, reserving angiography and angioplasty (usually backed up by a stent) for those with an abrupt decline in renal function and no other cause for renal deterioration. Future clinical trials may better define subgroups of patients who will truly benefit from renal revascularization.

Anaphylactoid reactions during haemodialysis are due to ethylene oxide hypersensitivity.

Anaphylactoid reactions during haemodialysis are unusual, but increasingly recognised. It has recently been reported that there is a significant association between such reactions and the presence of IgE to albumin exposed to ethylene oxide (ETO). Review of the clinical features and epidemiology of dialysis anaphylaxis in the light of this new data suggests that these reactions are due to ETO hypersensitivity.

Anaphylactoid reactions due to haemodialysis, haemofiltration, or membrane plasma separation.

A previously undescribed anaphylactoid reaction to haemodialysis, haemofiltration, or membrane plasma separation occurred in 15 patients receiving regular dialysis. The illness varied in severity from urticaria, sneezing, and watering of the eyes to severe bronchospasm and cardiovascular collapse, and began within a minute of blood being returned from the dialyser or filtration device to the patient. Reactions developed only when a dialyser sterilised with ethylene oxide was used for the first time and never after sterilisation with formalin. Several patients had more than one reaction while three had a reaction each time a new dialyser was used. Incorrect priming of the dialysers may be a partial explanation of these attacks, but the exact reason for their occurrence is unknown. This is a dramatic and potentially life-threatening syndrome that may not previously have been recognised as a reaction to dialysis.