Alan R. Hull

Magnesium absorption in the human small intestine. Results in normal subjects, patients with chronic renal disease, and patients with absorptive hypercalciuria.

Magnesium absorption was studied in the normal human jejunum and ileum by in vivo intestinal perfusion, using test solutions containing from 0 to 20 mM Mg (as MgCl2). As luminal Mg concentration was increased, the rate of absorption in the jejunum rose progressively with a tendency towards saturation at the higher concentrations. The kinetics and rates of Mg absorption in the ileum were comparable to those in the jejunum, with the exception that at higher luminal concentrations the ileal absorptive process was fully saturated. Using test solutions containing various combinations of Ca and Mg, we found that Ca had little or no influence on Mg absorption, even through Mg depressed Ca absorption to a modest extent. Patients with end-stage renal disease, who had a reduced rate of Ca absorption (presumably due to deficiency of 1,25-dihydroxycholecalciferol) were found to have a severe depression of Mg absorption. On the other hand, patients with absorptive hypercalciuria and nephrolithiasis, who had an increased rate of Ca absorption, were found to absorb Mg normally. These results suggest that Mg absorption in the human is mediated by a transport process different from that which facilitates Ca absorption, and that normal Mg absorption may be dependent on vitamin D. Our results do not establish whether or not the normal intestine can absorb Mg against an electrochemical gradient.

Effect of Daily Hemodialysis on Depressive Symptoms and Postdialysis Recovery Time: Interim Report From the FREEDOM (Following Rehabilitation, Economics and Everyday-Dialysis Outcome Measurements) Study

BACKGROUND Clinical depression and postdialysis fatigue are important concerns for patients with kidney failure and can have a negative impact on quality of life and survival. STUDY DESIGN The FREEDOM (Following Rehabilitation, Economics and Everyday-Dialysis Outcome Measurements) Study is an ongoing prospective cohort study investigating the clinical and economic benefits of daily (6 times per week) hemodialysis (HD). In this interim report, as part of an a priori planned analysis, we examine the long-term impact of daily HD on depressive symptoms, measured using the Beck Depression Inventory (BDI) survey, and postdialysis recovery time, measured using a previously validated questionnaire. SETTING & PARTICIPANTS Adult patients initiating daily HD with a planned 12-month follow-up. OUTCOMES & MEASUREMENTS The BDI survey and postdialysis recovery time question were administered at baseline, and changes were assessed at months 4 and 12. RESULTS 239 participants were enrolled (intention-to-treat cohort) and 128 completed the study (per-protocol cohort). Mean age was 52 years, 64% were men, 55% had an arteriovenous fistula, and 90% transitioned from in-center HD therapy. In the per-protocol cohort, there was a significant decrease in mean BDI score over 12 months (11.2 [95% CI, 9.6-12.9] vs 7.8 [95% CI, 6.5-9.1]; P<0.001). For robustness, the intention-to-treat analysis was performed, yielding similar results. The percentage of patients with depressive symptoms (BDI score>10) significantly decreased during 12 months (41% vs 27%; P=0.03). Similarly, in the per-protocol cohort, there was a significant decrease in postdialysis recovery time over 12 months (476 [95% CI, 359-594] vs 63 minutes [95% CI, 32-95]; P<0.001). The intention-to-treat analysis yielded similar results. The percentage of patients experiencing prolonged postdialysis recovery time (>or=60 minutes) also significantly decreased (81% vs 35%; P=0.001). LIMITATIONS Observational study with lack of control arm. CONCLUSIONS Daily HD is associated with long-term improvement in depressive symptoms and postdialysis recovery time.

Etiology of Liver Disease in Renal-Transplant Patients

The etiology of 72 episodes of liver disease that developed in 62 of 162 renal-transplant recipients was evaluated. Infection with hepatitis B virus was a minor problem, and none of our patients had evidence of infection with hepatitis A. Cytomegalovirus infection was ubiquitous in the population and probably accounted for many episodes of acute liver disease. This agents role in causing chronic hepatitis is less secure. Infections with other viruses including Epstein-Barr virus, adenovirus, and the herpes viruses were only rarely associated with hepatic disease. Azathioprine was responsible for some episodes of acute cholestasis but could not be incriminated as a direct cause of chronic disease. A cause could be identified for the majority of episodes of acute hepatic dysfunction, but the cause of most of the chronic hepatitis remains undetermined. It is likely that infection with non-A, non-B hepatitis virus accounts for much of this serious, often fatal, complication of renal transplantation.

Drug substitution in transplantation: A National Kidney Foundation white paper

Specific safeguards to guide the approval process and substitution practices for generic immunosuppressive agents are necessary for the effective delivery of patient care. Currently, the Food and Drug Administration (FDA) requires the demonstration of bioequivalence of generic drugs to innovator drugs in normal healthy subjects, a criterion that may be insufficient for critical-dose drugs. For generic equivalents of critical-dose drugs and for innovator critical-dose drugs, there should be a requirement for replicate studies measuring intrasubject variability and subject-treatment interactions to establish that bioequivalence holds true. Extensive testing of generic drugs in all target patient types is impractical and should not be required. However, when evidence suggests that the bioavailability of a critical-dose drug may vary substantially in certain subgroups, the FDA should require a demonstration of bioequivalence of generic versions to innovator products in these representative target populations. Changes in the approval process for generics should be accompanied by more consistent substitution practices. Pharmacists should notify the prescribing physician and patient whenever a critical-dose drug (generic or brand name) is dispensed in a different formulation from the one the patient has been taking. Therapeutic substitution for such drugs should not be made unless the prescribing physician has granted approval. The health care provider should consider instituting appropriate monitoring whenever patients are switched between generic formulations or between innovator drugs and generic formulations. Patients should be well informed about generic substitutes so that they can participate in treatment choices.

Prospective Comparative Study of Variable Dosage and Variable Frequency Regimens for Administration of Gentamicin

In patients with impaired renal function, careful adjustment of gentamicin dosage is required to achieve therapeutic yet nontoxic concentrations. Two regimens that differ in pharmacodynamic characteristics have been recommended for this purpose: prolonging the intervals between administration of equal doses (variable frequency regimen [VFR]) or administering a loading dose followed at the usual intervals by reduced maintenance doses (variable dosage regimen [VDR]). These regimens were compared in a prospective, randomized study of 20 seriously ill hospitalized patients, 10 on VFR and 10 on VDR. Wide variability in peak serum levels of gentamicin was observed both between patients and in individual patients after separate injections of the same dosage. As predicted by the design of these regimens, the trough serum levels of gentamicin correlated significantly with the serum creatinine concentrations in patients on the VDR but not in patients on the VFR. A gentamicin trough level of ≥4 μg/ml was the only variable among those tested that correlated significantly with development or progression of renal insufficiency during treatment with gentamicin, but such trough levels were observed frequently on both regimens. Whereas this study does not permit a direct comparison of the therapeutic efficacy of VDR and VFR, no difference in the risk of nephrotoxicity with these regimens was observed.

Urologic Complications in 505 Renal transplants with Early Catheter Removal

Of 505 consecutive renal transplants urologic complications occurred in 4.1 per cent of cadaver, 2.6 per cent of living related, 1.9 per cent of diabetic and 3.8 per cent of nondiabetic allografts. Over-all, patient survival and graft salvage rates were 94 and 83 per cent, respectively. Principles of prevention, diagnosis and management of these complications are discussed. In contrast to prior standards the bladder catheter was removed within 36 hours postoperatively in nearly all cases without any increase in morbidity.

Acute Nickel Intoxication by Dialysis

Nickel intoxication was observed in a group of 23 dialyzed patients when leaching of nickel-plated stainless steel water heater tank contaminated the dialysate. Symptoms occurred during and after dialysis at plasma nickel concentrations of approximately 3 mg/L. Symptoms included nausea (37 of 37), vomiting (31 of 37), weakness (29 of 37), headache (22 of 37), and palpitation (two of 37). Remission of symptoms occurred spontaneously, generally 3 to 13 hours after cessation of dialysis. The evidence indicated that the nickel became bound in the plasma after crossing the membrane, resulting in a higher concentration in the plasma than in the dialysate and preventing its removal by dialysis.

A randomized trial comparing double-drug and triple-drug therapy in primary cadaveric renal transplants

A controlled trial was carried out in 209 primary cadaveric renal transplants to compare the effects of cyclosporine and steroids (double therapy) with those of cyclosporine in lower initial dose, azathioprine, and steroids (triple therapy). Patients have been followed 1–36 months since transplantation. Actuarial two-year graft survival (double 74%, triple 76%) and two-year patient survival (double 90%, triple 93%) were similar for both groups. Further analysis of particular risk factors including age, diabetes, HLA matching, acute renal failure, and use of sequential Minnesota antilymphocyte globulin in patients with delayed graft function also showed similar outcomes with both immunosuppressive regimens. Initial hospitalization time, rate of rejection, incidence of serious infection, and rate of rehospitalization were not different. Mean CsA doses and mean trough whole-blood levels were higher in double-therapy patients at hospital discharge but not by three months posttransplant. There were no differences between the two groups in iothalamate clearance at any time. Hypertension was more frequent six months post-transplant in the triple-therapy group (p<0,05). Thus, similar results were obtained with both regimens, and except for hypertension no regimen appeared to have increased side effects up to three years posttransplant.

Spectrum of Liver Disease in Renal Transplant Recipients

An evaluation of the hepatic dysfunction which occurred in the post-transplant period in 31 of 82 renal transplant recipients managed at Parkland Memorial Hospital has revealed three different patterns of liver disease. Two patients died in acute liver failure during an acute fulminant illness. Eight other patients suffered an acute, anicteric, and completely reversible hepatic disorder. Twenty-one patients have been afflicted with a chronic form of liver disease which, in a least 5, has progressed to an active cirrhosis. Infection with cytomegalovirus and other viruses is probably responsible for most of the liver disease we have observed in these patients, while hepatotoxicity related to therapy with azathioprine and other drugs has played only a minor role.

Jejunal Absorption and Secretion of Calcium in Patients with Chronic Renal Disease on Hemodialysis

10 patients with chronic renal disease on hemodialysis and 8 normals were studied by constant jejunal perfusion of calcium gluconate solutions, using polyethylene glycol as a nonabsorbable marker. Results in normals indicated that calcium absorption from 1 and 5 mM calcium solutions is mainly active. Absorption from 5, 15, and 20 mM solutions was a linear function of luminal calcium concentration, suggesting that the active transport carrier is saturated when luminal calcium concentration is greater than 5 mM and indicating that the increment in absorption at higher luminal concentrations is mainly the result of passive absorption. With 1 mM calcium, normals absorbed calcium against a concentration gradient, whereas the patients secreted calcium. Absorption in the patients was much less than normal with 5, 15, and 20 mM luminal calcium concentrations; however, the slope of this linear (passive) portion of the curve was normal. Unidirectional calcium fluxes were measured with calcium-47. Flux out of the lumen was depressed 2.5-fold in the patients, but flux into the lumen was normal. Xylose, urea, and tritiated water were absorbed normally, indicating no generalized abnormality of jejunal transport in these patients. Endogenous calcium secretion, estimated by the amount of calcium added to a calcium-free solution, was normal in the dialysis patients. These results indicate that active calcium absorption is markedly depressed in patients with chronic renal disease who are receiving hemodialysis therapy. On the other hand, passive calcium movement and endogenous calcium secretions are normal.