Jejunal and ileal absorption in patients with chronic renal disease. Effect of 1alpha-hydroxycholecalciferol.

Calcium absorption in 30-cm segments of small intestine was measured by constant perfusion of test solutions containing different concentrations of calcium gluconate. In both the jejunum and ileum, calcium absorption rates increased progressively as luminal calcium concentration was increased stepwise between 1 and 20 mM. Although calcium transport was not saturable within these limits, unidirectional flux ratios of calcium (47Ca) suggest that calcium absorption is active in both the jejunum and ileum. Calcium absorption in patients with chronic renal disease was markedly depressed in both regions of the small intestine. This was due to decreased flux out of the lumen; flux in the reverse direction was normal. Flux ratios in the renal disease patients showed no evidence for active calcium transport. Treatment of these patients for 1 wk within 2 mug/day of 1alpha-hydroxycholecalciferol [1alpha-(OH)-D3] restored net calcium absorption and unidirectional calcium flux out of the lumen to normal values in the jejunum; in the ileum, 1alpha-(OH)-D3 increased calcium absorption 60-83% of normal at the various luminal calcium concentrations. 1alpha(OH)-D3 had no effect on unidirectional calcium flux into the lumen or on xylose and electrolyte absorption in either area of the small intestine.

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.

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.

Association between acute pancreatitis and malignant hypertension with renal failure.

Of 42 patients with malignant hypertension seen in five years in our institutions, seven (17%) had acute pancreatitis. All patients with pancreatitis were black, all had renal failure, and six received dialysis. No particular drug was received by all patients, gallstones were excluded in the majority, and alcoholism was not a factor. Clinical acute pancreatitis persisted for several weeks and five patients died, three of them with pancreatic pseudocyts. Among 259 patients on long-term hemodialysis programs in the same time period, only two additional cases of acute pancreatitis were observed and related to chronic alcoholism. Acute pancreatitis is a frequent complication of malignant hypertension, and when it happens it is severe and commonly fatal.

Rubella antibodies and adverse events late after renal transplantation.

Rubella antibody titers were determined pretransplant and then serially posttransplantation in 52 consecutive patients whose renal allografts survived at least three months. Group A patients (18) had antibody titers greater than or equal to 1:128 in the posttransplant period. Group B (24) had intermediate antibody titers that never rose higher than 1:64. Group C (10) consistently had antibody titers less than 1:8. Group A did not differ from groups B and C with respect to age, race, sex, type of transplant, underlying renal disease, or maximum complement fixation antibody titers posttransplant to cytomegalovirus or herpes simplex virus, type 1. Group A did differ from groups B and C in its frequency of hepatitis, chronic liver disease, episodes of late rejection (greater than or equal to 21 days after transplant), transplant nephrectomy required for rejection, infections whose defense involves intact cell-mediated immunity, and the number of late rejection episodes per patient. Mechanisms underlying these associations are not known but apparently are not related to HLA phenotype.

Iatrogenic arteriovenous fistula. An unusual complication of indwelling pericardial catheter and intrapericardial steroid instillation for the treatment of uremic pericarditis.

The drainage and instillation of poorly absorbable corticosteroids has recently been suggested as an laternative to the present modes of therapy for uremic pericarditis. One patient who underwent such a therapeutic approach subsequently had a left internal mammary artery to right internal mammary vein arteriovenous fistula develop. To our knowledge, this is the first report of the development of arteriovenous fistula after either pericardiocentesis or intrapericardial instillation of steroids.

Disease due to cytomegalovirus and its long-term consequences in renal transplant recipients. Correlation of allograft survival with disease due to cytomegalovirus and rubella antibody level.

We prospectively studied 52 consecutive renal allograft recipients who retained their grafts at least three months. The transplant recipients were observed for five years or longer. Disease due to cytomegalovirus (CMV) occurred in nine (17.3%). Manifestations of disease due to CMV that were significantly more common than in chronologically matched controls in comparable periods after transplantation included fever, leukopenia, hepatic function abnormalities, pneumonia, and renal dysfunction. Life-table analyses suggested a trend of decreased allograft survival with disease due to CMV, but the difference between controls was not statistically significant. A significant inverse correlation were noted between the level of hemagglutination inhibition antibody to rubella virus reached after transplantation and allograft survival. This correlation remained statistically significant even when patients with disease due to CMV were excluded from the analysis.

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 posttransplant in the triple-therapy group (p less than 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.

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.

The legislative and regulatory process in the end-stage renal disease (ESRD) program, 1973 through 1997.

Although hemodialysis began in the early 1960s, it did not begin to really grow until 1973, when the Federal government started to pay for end-stage renal disease (ESRD) treatment under Medicare. Since then, the Health Care Financing Administration (HCFA) has made a series of mistakes while maintaining this very successful program. This article traces the steps HCFA took, and the responses by the providers that produced the situation we have today. This program pays the lowest amount for hemodialysis of any industrialized nation, and most likely as a result has the highest mortality rate (23%) of any of the same countries. The problem as outlined is that HCFA attempted to ration by price while ignoring quality. This has been compounded by the providers finding more and more ways to reduce cost to continue to make a profit while not improving quality. The result is a program that could have been much better, and a patient population that has suffered.

Recommended clinical practices for maximizing peritoneal dialysis clearances.

Data from the Canada-U.S.A. (CANUSA) Study have recently confirmed a long-suspected linkage between total clearance and patient survival in peritoneal dialysis (PD). Recognizing that what we have historically accepted as adequate PD simply is not, the Ad Hoc Committee on Peritoneal Dialysis Adequacy met in January, 1996. This committee of invited experts was convened by Baxter Healthcare Corporation to prepare a consensus statement that provides clinical recommendations for achieving clearance guidelines for peritoneal dialysis. Through an analysis of 806 PD patients, the group concluded that adequate clearance delivered with PD can be achieved in almost all patients if the prescription is individualized according to the patient's body surface area, amount of residual renal function, and peritoneal membrane transport characteristics. Use of 2.5 L to 3.0 L fill volumes, the addition of an extra exchange, and giving automated peritoneal dialysis patients a "wet" day are all options to consider when increasing weekly creatinine clearance and KT/V. Rather than specify a single clearance or KT/V target, the recommended clinical practice is to provide the most dialysis that can be delivered to the individual patient, within the constraints of social and clinical circumstances, quality of life, life-style, and cost. The challenge to PD practitioners is to make prescription management an integral part of everyday patient management. This includes assessment of peritoneal membrane permeability, measurement of dialysis and residual renal clearance, and adjustment of the dialysis prescription when indicated.

Dialysis-related mortality in the United States.

BACKGROUND: In the United States, the gross mortality rate for patients undergoing dialysis in 1992 was 23.6% per year, higher than in any other industrialized country. This mortality rate has been rising slightly for the last 10 years. Wide variations in mortality rates exist among states and among dialysis centers, and smaller dialysis centers have higher mortality rates than larger ones. PURPOSE: To review the possible reasons for the high mortality rate associated with dialysis in the United States. SUMMARY: Differences in patient populations do not explain the variations in mortality rates. The incidence of new patients and the prevalence of older patients and patients with diabetes are higher in the United States than in other countries and are continuing to rise. However, these numbers are rising in other countries as well without a concomitant increase in their mortality rates. Black patients make up a disproportionate number of US dialysis patients, but they are less likely to die than white patients. US patients spend less time per week in dialysis than their European counterparts and use smaller dialyzers, resulting in lower clearance of solutes. CONCLUSION: Approximately two thirds of US patients receive inadequate dialysis. Nephrologists must examine their practices and their outcomes to improve the quality of care they give.