Kenneth Abreo

The use of deferoxamine in the management of aluminium accumulation in bone in patients with renal failure.

Aluminum frequently accumulates in patients with end-stage renal failure. We investigated the value of long-term, intermittent infusions of deferoxamine for the removal of aluminium from bone in seven patients undergoing long-term maintenance dialysis. Transient rises in serum aluminum levels occurred initially after treatment. Three patients who were studied by bone biopsy had absent or reduced levels of bone aluminum. Histologic studies of bone before and after therapy showed differences similar to those observed between patients with uremia who had an accumulation of aluminum in bone and those who did not. The diagnostic value of rises in the serum aluminum level after a single infusion of deferoxamine was studied in 12 patients with and 10 patients without aluminum accumulation in bone. All patients with bone aluminum had rises in serum aluminum levels, but rises were also observed in some patients without bone aluminum. Thus, the test cannot be used to diagnose aluminum accumulation in bone. Urinary aluminum levels increased significantly after a single infusion of deferoxamine in three patients with kidney transplants and accumulation of aluminum in bone. These findings indicate that deferoxamine is beneficial for the therapy of aluminum accumulation in the bone of patients with renal failure.

The use of contaminated donor organs in transplantation

Introduction. Organ transplantation has become an accepted means of treating end‐stage organ disease in recent years with acceptable patient and graft survival. Transplant recipients have an increased risk of infectious complications due to multiple factors including decreased host resistance from chronic end‐stage organ failure as well as from the immunosuppression required to prevent graft rejection. 
Hypothesis. Therefore, the use of contaminated allografts could result in life‐threatening infections in organ recipients. 
Method. In this study, transplant patients receiving organs from donors with positive blood or urine cultures, from 1993 to 1997, were retrospectively reviewed. 
Results. There was a total of 599 organ donors in our state. Forty‐six (7.5%) had positive blood cultures and 25 (4.5%) had positive urine cultures. A total of 179 patients received organs from these contaminated donors, 36 of which were transplanted at our center. In this group, there were 16 kidney, 9 liver, and 11 heart transplants. Both donors and recipients received prophylactic broad‐spectrum antibiotics, which were adjusted based on culture and sensitivity results. The most common organisms isolated from the blood were staphylococci followed by streptococci and Gram‐negative organisms. Three of the 9 liver transplant patients in the series died with a mortality of 33%. Two of the 3 patients who died had sepsis but the responsible organisms were different from those recovered from the donor. The rest (66%) did well and have acceptable liver function. None of the 16 renal transplant recipients developed an infection and all survived. One patient developed acute irreversible rejection requiring transplant nephrectomy. There was one death in the heart transplant group resulting in a mortality of 9%. This death was not attributed to infectious processes. Three of 11 heart transplant patients grew organisms in the post‐operative period that were similar to those found in the corresponding donors. However, no patient suffered significant morbidity or mortality from these infections and all recovered. The recipients of contaminated organs had levels of organ function similar to those of randomly chosen recipients of non‐contaminated organs, and both groups had similar lengths of hospital stay. 
Conclusion. Only 3 of 36 organ recipients had infections caused by organisms found in the contaminated donor organs for a rate of 8%. Contaminated donor organs seem to fare as well as non‐contaminated donor organs and there was no increase in morbidity or mortality. Contamination of organs should not be an absolute contraindication to the use of these organs in transplantation.

End-stage renal disease in liver transplants.

Renal dysfunction is one of the most significant problems following orthotopic liver transplantation (OLTx). Since the major risk factor for delayed renal dysfunction following OLTx is presumed to be cyclosporine (CsA) nephrotoxicity, it has been suggested that CsA is the most probably cause of end‐stage renal disease (ESRD) in this population of patients. To test this hypothesis the records of OLTx patients in our center who developed ESRD requiring dialysis were reviewed. There were 132 consecutive adult patients with end‐stage liver disease (ESLD) who received 146 OLTxs between 1990 and 2000. Five patients (3.4%) developed ESRD requiring dialysis. Four of the five patients developed nephrotic range proteinuria prior to reaching ESRD. Renal biopsy in four patients showed focal segmental glomerulosclerosis, diabetic nephropathy, membranous nephropathy and cyclosporine toxicity. The underlying hepatic and metabolic disease may have played a role in the genesis of glomerular diseases in these OLTx patients. Perhaps if more renal biopsies are performed in OLTx patients with chronic renal failure, we might discover that, although CsA/tacrolimus therapy is a definite risk factor for post‐transplantation chronic renal failure, other disease processes may also play a significant role.

Diagnosis and Treatment of Tuberculosis in Hemodialysis and Renal Transplant Patients

Background: The incidence of Mycobacterium tuberculosis in hemodialysis (HD) and renal transplant (RT) patients in developing countries is high. With the resurgence of tuberculosis in the US, insights gained in the diagnosis and treatment of this infection in HD and RT patients in developing countries should be valuable to physicians in the West. Methods: A retrospective study of 40 cases of tuberculosis, 24 in HD patients (24/177, 13.6%) and 16 in RT patients (16/109, 14.7%) diagnosed over a period of 21 months in one center. Results: The clinical features, diagnostic procedures, and management dilemmas of this group of patients are described in this report. Diabetes mellitus was the most common associated disease in both groups of patients. Fever, the most common presenting sign, was persistent low grade in 66.6% of HD patients and high intermittent in 56.2% of RT patients. Fever of unknown origin was only seen in RT patients. Pulmonary involvement was most common in both groups, presenting either as infiltrates or effusions. Tuberculous peritonitis was seen only in HD patients (33.3%). Eight HD patients were treated for tuberculosis for variable periods prior to transplantation, 4 of whom had less than 6 months of therapy. None had a recurrence of tuberculosis after transplantation. Because of the known cyclosporin-lowering effect of rifampicin resulting in an increased cost of immunosuppressive therapy, 13 patients were treated successfully with rifampicin-sparing therapy. Conclusion: Tuberculosis should be included in the differential diagnosis of fever in HD and RT patients, especially if fever is of unknown origin in the RT patient. M. tuberculosis in the renal transplant patient can present with high intermittent fever. Partial treatment of tuberculosis is sufficient prior to renal transplantation but treatment should be continued to completion after transplantation. If the cost of immunosuppressive therapy is prohibitive because of rifampicin, rifampicin-sparing antituberculosis therapy can be successfully employed in RT patients.

Liddle's syndrome, an underrecognized entity: A report of four cases, including the first report in black individuals

Liddles syndrome, a rare cause of hypokalemic hypertension, is characterized by a renal tubular sodium channel defect resulting in excessive sodium absorption and concomitant potassium wasting. In this disorder, although the clinical manifestations resemble primary aldosteronism, serum and urine aldosterone are suppressed. The syndrome is transmitted in an autosomal dominant pattern. It has been reported previously in white and oriental populations but not in the black individuals. We identified four patients (two of whom are black) in our nephrology clinic, with severe hypokalemic hypertension not correctly diagnosed for several years. All patients underwent an extensive work-up for secondary hypertension because of persistent severe hypertension (average blood pressure, 210/130 mm Hg) despite high-dose multi-drug therapy. Primary aldosteronism was excluded because of low serum aldosterone. Cushings syndrome, pheochromocytoma, renal artery stenosis, and enzymatic deficiencies of cortisol synthesis (11 beta-hydroxylase, 17 alpha-hydroxylase, 5 beta-reductase, and 11 beta-hydroxysteroid dehydrogenase) were ruled out with extensive endocrine and radiologic studies. Once the diagnosis of Liddles syndrome was suspected, all patients were treated with either triamterene or ameloride, with resolution of hypokalemia and correction of hypertension occurring within 5 to 7 days. Our findings suggest that Liddles syndrome can occur in the black population. Although the actual incidence of this syndrome remains unknown, it may be significantly more common than we are led to believe since it is inherited in a Mendelian pattern. Whether there is a subset of low-renin, salt-sensitive black hypertensive patients who have the same or similar sodium channel defect remains to be elucidated.

Lipofuscin Products, Lipid Peroxides and Aluminum Accumulation in Red Blood Cells of Hemodialyzed Patients

This study examines whether there is a relationship between aluminum overload and the accumulation of lipofuscin products (aging pigments) and lipid peroxides in red blood cells (RBC) of hemodialyzed patients. Lipid peroxides levels were assessed by the thiobarbituric acid reactivity; lipofuscin products were assessed by determining fluorescence in the lipid extracts at excitation 360 nm and emission 440 nm. Aluminum was measured by atomic absorption spectrophotometry. Controls were age-matched normal volunteers. Data show that there was a significant increase in the lipid peroxides and lipofuscin products in hemodialyzed patients compared with controls even after normalization with hemoglobin or phospholipids in RBC. Further, the increase in the lipid peroxides and lipofuscin products significantly correlated with the levels of aluminum accumulation in RBC of hemodialyzed patients. This study suggests that aluminum overload has a role in increased membrane peroxidation, which in turn can cause reduced RBC life span and contribute to anemia in chronic renal failure patients.

Effects of diabetes mellitus and aluminum toxicity on myocardial calcium transport

Diabetics have an increased risk of developing renal insufficiency, as well as congestive heart failure independent of coronary atherosclerotic or hypertensive heart disease. Aluminum toxicity is being recognized with increased frequency in patients with reduced renal function and aluminum accumulates to a greater degree in tissues of patients with diabetes. Studies in patients with end stage renal disease have implicated aluminum overload as a potential cause of reduced cardiac function. Since both diabetes and aluminum decrease the activity of (Ca + Mg)-ATPase, a key enzyme involved in myocardial calcium transport, the interaction of experimental diabetes mellitus and aluminum toxicity on myocardial sarcoplasmic reticulum calcium transport was investigated in rats. Aluminum alone had no effect on (Ca + Mg)-ATPase activity, while activities in both the diabetic ([DM]) and diabetic plus aluminum loaded ([DM + Al]) groups were significantly lower than controls ([C]). Oxalate-dependent calcium uptake in the [DM] rats was slightly, but not significantly lower than controls, however, uptake was markedly reduced in rats which were both diabetic and aluminum loaded. The calcium regulatory protein calmodulin was measured by a functional assay in the soluble fraction of myocardial tissue prepared from each of the four groups. Compared to [C], calmodulin activity was significantly reduced in both the [DM] and [DM + Al] groups but not affected by aluminum alone. These data indicate that diabetes mellitus is associated with decreased myocardial calmodulin activity that may contribute to reduced sarcoplasmic reticulum (Ca + Mg)-ATPase and calcium transport activities and that aluminium toxicity potentiates the adverse effects of diabetes on decreasing sarcoplasmic reticulum calcium uptake.

Correction of Microcytosis Following Elimination of an Occult Source of Aluminum Contamination of Dialysate

A higher prevalence of aluminum-associated microcytic anemia was noted in hemodialysis unit A (n = 67) compared to unit B (n = 39). This finding could not be explained by differences in the aluminum content of reverse osmosis (RO) water or intake of antacids containing aluminum by patients in the two units. An intermittent source of aluminum contamination was suspected when water aluminum and total dissolved solutes (TDS) were measured at several sites in the water treatment facility of unit A. A one-way valve that maintained unidirectional flow in an RO bypass circuit was found missing. Intermittent pressure changes in this circuit altered the direction of water flow causing mixing of partially purified water with RO water. Installation of the valve stopped contamination and resulted in a decrease in plasma aluminum concentration from 183 +/- 12 micrograms/L to 76 +/- 7.3 micrograms/L, erythrocyte aluminum concentration from 210 +/- 31 micrograms/L to 61 +/- 9 micrograms/L and microcytosis from 58% to 8% in patients (n = 48) when measured 6 months later. Because contamination was missed in spite of water testing at the RO site, these findings underscore the importance of measuring water aluminum and TDS content at the dialysis stations. Frequent water testing at dialysis stations, familiarity with the design of water treatment facilities, and recognition of aluminum overload can lead to early detection and correction if similar types of aluminum contamination should occur.

Use of Deferoxamine in the Treatment of Aluminum Overload in Dialysis Patients

In the past two decades, improvements in hemodialysis technology and better medical management have resulted in decreased morbidity and mortality of end-stage renal disease patients. However, prolonged survival of patients on hemodialysis has also led to the development of unique problems, one of which is aluminum overload. Fatients on chronic hemodialysis have a predilection for accumulating aluminum in brain, bone, and red blood cells resulting in encephalopathy, bone disease, and microcytic anemia. Initially the high concentration of aluminum in dialysis water was felt to be the major source of aluminum overload in dialysis patients (1-5), but th is source of aluminum has been eliminated by the use of reverse osmosis water systems. This leaves the ingestion of aluminumcontaining phosphate binders as the major cause of aluminum overload today (67 7). Once aluminum intoxication has developed, discontinuation of aluminum-containing antacids and dialysis against a low aluminum dialysate are not sufficient measures to decrease the amount of aluminum in the body. This is due to the fact that 8090% of aluminum in plasma is protein bound (81 I), leaving only 10-20% available for removal by dialysis. Deferoxamine has been extensively used as a chelating agent to facilitate aluminum removal in aluminum-overloaded dialysis patients. This review will attempt to describe the following features and uses of deferoxamine: 1) chemical structure; 2) side effects; 3) effect on aluminum clearance during hemodialysis and peritoneal dialysis; and 4) treatment of aluminum-related bone disease, encephalopathy, and microcytic anemia.

Metabolic Alkalosis After Orthotopic Liver Transplantation

To ascertain the etiology of metabolic alkalosis (MA) following orthotopic liver transplantation (OLT) the records of patients with 123 consecutive OLTs from 1995 to 2000 were reviewed. Metabolic alkalosis occurred in 51.2% of patients. Patients with MA had a larger fluid deficit (−3991 ± 4324 vs. −1018 ± 4863, p < 0.05), cumulative furosemide dose (406 ± 356 vs. 243 ± 189, p < 0.02), and citrate load from blood transfusions (9164 ± 4870 vs. 7809 ± 3967, p < 0.05). There was no difference in serum lactate concentration (3.15 ± 1.63 vs. 3.11 ± 1.91) in patients with and without MA. The duration of ICU stay was longer in patients with MA (14.9 ± 15.3 vs. 5.3 ± 3.9 days, p < 0.004). Treatment of severe MA in 19 (15.4%) patients consisted of 0.1 N hydrochloric acid and/or acetazolamide. Hypokalemia and hypomagnesemia occurred in 37.4% and 59.3% of patients, respectively. In conclusion, MA is a common post‐OLT complication that is associated with a longer ICU stay. Diuretic‐induced volume depletion, the citrate load from blood transfusions, hypokalemia, and hypomagnesemia contribute to the pathogenesis of MA in OLT.