Keep it simple: comparing functional assessments in individuals with Down syndrome.

BACKGROUND: A number of assessments exist that evaluate function in ambulatory adults. However, these assessments take for granted the cognitive abilities required for the participant to understand what is being asked of them in order to demonstrate their functional abilities. It has been shown that individuals with Down syndrome (DS) demonstrate lower functional levels when asked to perform additional tasks while walking. Therefore, measurements of function may not be reflective of actual function if the assessment requires additional tasks in those with DS. It is for these reasons the current investigation sought to evaluate four common functional assessments, two with [modified Berg balance test (mBERG) and Functional Gait Assessment (FGA)] and two without [Timed Up and Go (TUG) and Established Populations for Epidemiologic Study in the Elderly (EPESE)] complex tasks. METHODS: Adults with DS (n = 19) completed four functional assessments, which were later compared using bivariate Pearson correlation coefficients. RESULTS: There were large associations between simple assessments (TUG-EPESE: r = -0.525, P = 0.021) and complex assessments (FGA-mBERG: r = 0.612, P = 0.005), respectively. The TUG also inversely correlated with the FGA (r = -0.476, P = 0.039), and the EPESE had a large association with mBERG (r = 0.508, P = 0.027). CONCLUSIONS: The mBERG may be the best test to replicate real-world scenarios through its tasks, although it may also be confounded by the cognitive load required to perform the movements as asked. The TUG and EPESE may be more appropriate as mobility assessments because they require very little cognitive attention when completing the tasks. True assessments of mobility ought to err on the side of simple so to not confuse the outcomes with executive functionality.

Renal metabolism of alanine.

In the acidotic dog, alanine is extracted from plasma and utilized as a precursor of ammonia. Simultaneously, it is formed de novo within tubular cells and added to renal venous blood. When plasma concentration is within a normal range, production of alanine greatly exceeds utilization. Increasing the plasma concentration reduces production and increases utilization of plasma alanine. The infusion of glutamine increases the renal production of alanine without appreciable change in utilization of plasma alanine. These results are consonant with the view that alanine is metabolized by transamination with alpha-ketoglutarate to form glutamate, which is subsequently deaminated oxidatively to liberate ammonia. Conversely, alanine is formed by transamination of pyruvate with either glutamate or glutamine and is added to renal venous blood. The balance between production and utilization is dependent, at least in part, on the concentrations of the reactants.

Pathways of ammonia metabolism in the intact functioning kidney of the dog.

Studies in which (15)N-labeled precursors of urinary ammonia were infused into the artery of an intact functioning kidney of an acidotic dog have led to the following conclusions: Preformed ammonia and ammonia derived from the amide nitrogen of plasma glutamine are added directly to urine without significant incorporation into amino acid intermediates of renal tissue. Thus, reductive amination of alpha-ketoglutarate to form glutamate does not occur to an appreciable extent nor is there significant transfer of the amide nitrogen of glutamine to the corresponding keto acids to form glutamate, aspartate, alanine, or glycine. The enzyme system "glutaminase II" may participate to a significant extent in the metabolism of glutamine by forming aspartate and alanine by direct transamination of oxalacetate and pyruvate and liberating the amide nitrogen as ammonia. Renal alanine exists as a well mixed pool derived in roughly equal amounts from filtered and reabsorbed plasma alanine and newly synthesized alanine. The alanine pool of tubular cells does not equilibrate with the alanine of peritubular capillary blood. Transfer of the nitrogen of alanine to alpha-ketoglutarate and subsequent oxidative demination of the resulting glutamate can account for the ammonia formed from alanine. Glycine is not an important intermediate in renal nitrogen metabolism.

Diffusion equilibrium for ammonia in the kidney of the acidotic dog.

Inflow of preformed ammonia in arterial blood, renal production of ammonia, outflow of ammonia in renal venous blood, and urinary excretion of ammonia were measured during the infusion of (15)NH(4)Cl into one renal artery of dogs with chronic metabolic acidosis. Our results show that the specific activity of ammonia measured in the urine and that calculated in the renal pool agree within 95%. Pool specific activity is obtained by dividing the rate of infusion of isotope by the pool turnover rate, i.e., the sum of the rate of ammonia output in the urine and that in renal venous blood. An average of 35% of urinary ammonia is derived from arterial ammonia in these experiments. We conclude that ammonia is distributed evenly throughout all phases of the kidney within a period less than the transit time of blood through the kidney. Furthermore, from the proportion of urinary ammonia we found to be derived from preformed arterial ammonia (35%), and from our previous demonstration that 73% of urinary ammonia derives from deamidation and/or deamination of plasma glutamine, alanine, glycine, and glutamate, we can account for all of the ammonia that leaves the kidney in renal venous blood and in urine.

Simultaneous assay of immunoreactive beta-lipotropin, gamma-lipotropin, and beta-endorphin in plasma of normal human subjects, patients with ACTH/lipotropin hypersecretory syndromes, and patients undergoing chronic hemodialysis.

We have studied the relative concentrations of the human immunoreactive (IR) peptides gamma-lipotropin (hgammaLPH, [1-58]hbetaLPH), beta-lipotropin (hbetaLPH), and beta-endorphin (hbetaEND, [61-91]hbetaLPH) using gel exclusion chromatography together with a specific radio-immunoassay (RIA) for hgammaLPH and a RIA that (because hbetaEND is the COOH-terminus of the hbetaLPH molecule) measures both hbetaEND and hbetaLPH on an equimolar basis. In normal subjects, basal plasma IR-hgammaLPH was often undetectable (<12.5 fmol/ml), but ranged up to 21 fmol/ml, and IR-hbetaEND/hbetaLPH was 10.8+/-0.7 fmol/ml; previous studies by others suggest that most of the IR-hbetaEND/hbetaLPH was probably hbetaLPH. Both IR-hgammaLPH and IR-hbetaEND/hbetaLPH were significantly elevated (P < 0.001) in patients undergoing chronic hemodialysis (101.5+/-12.7 and 23.8+/-2.0 fmol/ml, respectively). Their IR-hgammaLPH coeluted with standard hgammaLPH as a single peak, and IR-hbetaEND/hbetaLPH coeluted with hbetaLPH; no distinct peak of IR-hbetaEND was observed. In patients with ACTH/LPH hypersecretion due to Addison's disease, Nelson's syndrome, or ectopic ACTH syndrome, IR-hgammaLPH and IR-hbetaEND/hbetaLPH were both elevated, and IR-hbetaEND/hbetaLPH eluted as two peaks, one coeluting with hbetaLPH and the other with hbetaEND. The molar concentrations of all three peptides were significantly correlated with one another. The lower concentrations of endogenous IR-hbetaEND observed may be due in part to its apparent shorter plasma half-life, as estimated in an Addison's patient given a cortisol infusion. The biologic significance of these three peptides in circulating blood is still unknown. The increased levels of hbetaLPH and hgammaLPH in plasma of patients with chronic renal failure suggest that the kidney may be an important organ for their metabolism.

Beta-2 microglobulin is an amyloidogenic protein in man.

Curvilinear fibrils with the tinctorial properties of amyloid were isolated from a patient with bone and joint involvement complicating chronic dialysis for renal disease. Subunit fractions of 24,000 and 12,000 mol wt were identified after gel filtration under dissociating conditions, the latter containing a significant amount of a dimer of the former. This was confirmed by Edman degradation of each fraction, which yielded the amino terminal sequence of normal human beta-2 microglobulin (B2M) to residues 20 and 30, respectively. The size of the subunit protein (12,000 mol wt) and the amino acid composition make it likely that intact B2M is a major constituent of the fibrils. B2M is thus another example of a low molecular weight serum protein, with a prominent beta-pleated sheet structure, that may adopt the fibrillar configuration of amyloid in certain pathologic states.

Chronic myeloid leukemia-associated membranoproliferative glomerulonephritis that responded to imatinib mesylate therapy.

There is no known clinical association between chronic myelogenous leukemia (CML) and membranoproliferative glomerulonephritis (MPGN). We present a patient who was followed in the renal clinic for proteinuria of unknown etiology (3.2 g/24 h) and normal renal function who was diagnosed with CML as well as MPGN and acute renal failure at the same time. The patient's renal function and proteinuria improved when his CML was treated with imatinib mesylate, suggesting that CML either caused or exacerbated existing MGPN. To the best of our knowledge, this is the first reported case of MPGN associated with CML that improved with imatinib mesylate therapy.

Magnesium toxicity as a cause of hypotension and hypoventilation. Occurrence in patients with normal renal function.

Symptomatic hypermagnesemia usually requires both increased intake of the ion and abnormal renal function; however, we treated two patients with iatrogenic hypermagnesemia (10.4 and 13.2 mEg/L) who had normal renal function. One received ureteral irrigation with hemiacidrin (Renacidin) to dissolve a stone, and the other was treated for ingestion of an unknown toxin with large doses of magnesium sulfate. Therapy included ventilatory support, intravenous calcium, and fluids. Dialysis was not required, and recovery was complete.

Dexamethasone suppression testing in chronic renal failure: pharmacokinetics of dexamethasone and demonstration of a normal hypothalamic-pituitary-adrenal axis.

The status of the hypothalamic-pituitary-adrenal axis in chronic renal failure (CRF) was examined by dexamethasone suppression testing (DST) using oral overnight, oral and iv 8-h daytime, and standard 48-h oral dosage protocols. Based on data obtained after iv administration of dexamethasone, the daytime study was used to calculate pharmacokinetic parameters for dexamethasone (clearance, volume of distribution at steady state, and terminal t1/2). None of a group of seven uremic patients had suppressed plasma cortisol concentrations after administration of 1 mg dexamethasone, orally, the night before. Six normal subjects and six patients with CRF participated in the pharmacokinetic study. There was no significant difference between the groups with respect to clearance, volume of distribution at steady state, or t1/2 of dexamethasone, indicating that patients with CRF metabolize dexamethasone in a fashion similar to that of normal subjects. Daily patterns of plasma cortisol determined between 0800-1600 h on a day when dexamethasone was not administered were similar in normal subjects and CRF patients. However, the degree of suppression of plasma cortisol after dexamethasone was significantly greater in the normal subjects (P less than 0.01), possibly due to a prolonged cortisol t1/2 in CRF. Nevertheless, the CRF patients did have decreased plasma cortisol levels from 4-8 h after iv and from 4-7 h after oral dexamethasone. The bioavailability of dexamethasone was not significantly different between the groups. When 48-h oral DSTs were performed in the CRF group, four of five patients had normal responses. The one patient who did not suppress had low levels of plasma dexamethasone, presumably due to decreased gastrointestinal absorption of dexamethasone. These results indicate that the metabolism of dexamethasone is similar in CRF patients and normal subjects, that normal suppression of plasma cortisol can be achieved in uremia if the duration of dexamethasone administration is prolonged sufficiently to compensate for the prolongation of cortisol t1/2 in CRF, and that it is essential to measure plasma dexamethasone as well as cortisol levels to interpret the results of a DST in CRF patients.

Massive propranolol metabolite retention during maintenance hemodialysis.

Eight outpatients on long-term hemodialysis receiving propranolol therapy were studied on a nondialysis day, 11 +/- 1 hr after the last dose. Steady-state daily dosage of propranolol averaged 225 +/- 36 mg (range, 80 to 400). Plasma concentrations of propranolol and three of its metabolites were measured by gas chromatography--mass spectrometry (x +/- SEM): propranolol, 47 +/0 17 ng/ml; propranolol glucuronide, 2.119 +/0 597 ng/ml; 4-hydroxypropranolol glucuronide, 789 +/- 149 ng/ml; and naphthoxylactic acid, 4,357 +/- 727 ng/ml. The plasma levels of these metabolites were 18, 20, and 29 times, respectively, as high as in patients with normal renal function and correlated well with the dose of propranolol. The total concentration of these metabolites exceeded the concentration of propranolol to 239 times (range 74 to 476). Four long-term hemodialysis patients on propranolol were hospitalized to ensure compliance. Plasma levels of propranolol and of the three metatolites were followed during a dosage interval. Plasma propranolol correlated well with dose (r = 0.94) and declined with approximately normal half-lifes of 3.2 to 5.4 hr. There was little variation in the extremely high plasma levels of the three metabolites during a dosage interval. The total metabolite to propranolol plasma concentration ratio in these four patients ranged from 109 to 705. The correlation between total metabolite concentrations and propranolol dose was striking (r = 0.997). Massive retention of propranolol metabolites occurs uniformly in uremia, is highly predictable from the dose, and could have important clinical implications.

Carbenicillin therapy in patients with normal and impaired renal function.

Optimun therapy with carbenicillin entails the use of high serum concentrations and the risk of significant dose-related toxicity. We report a study of serum clearance method of dose adjustment of carbenicillin patients with normal and imparied renal function. This method was found to provide serum concentrations considered to be satisfactory in every instance, by either constant-rate or intermittent infusion, and should enable greater precision in the use of the antibiotic. Implications of these findings aimed at providing dosage schedules for patients with renal failure are discussed.

Pharmacokinetics and nondialyzability of mexiletine in renal failure.

Mexiletine is an investigational antiarrhythmic drug eliminated primarily by hepatic metabolism. To evaluate its pharmacokinetics in patients with renal failure, we gave 14 subjects (creatinine clearance from 0 to 68.9 ml/min, including five subjects who required maintenance dialysis) a single, 200 mg dose of mexiletine. Serial blood samples were drawn and analyzed for mexiletine concentration by gas chromatography. The elimination t1/2 was 18.9 +/- 7.4 hours and oral clearance was 378 +/- 109 ml/min (means +/- SD). There was no correlation between these parameters and creatinine clearance. In subjects receiving dialysis, the study was also repeated during dialysis 1 week later. There was no significant difference between the AUCs either while receiving dialysis or when calculated on a day when the subject was not receiving dialysis. Thus dosing adjustments for mexiletine should not be necessary in patients with creatinine clearance values as low as 10 ml/min or in patients receiving dialysis. Furthermore, supplemental doses of mexiletine are not likely to be needed after dialysis. Evaluation of the kinetics at steady state are necessary to extrapolate further our observations after a single oral dose.

Ceforanide kinetics in renal insufficiency.

Ceforanide (500 mg) was infused intravenously over 30 min into six normal subjects, 10 nondialysis patients with renal insufficiency, and six hemodialysis patients. Dialysis patients received two ceforanide infusions, one immediately before dialysis and another during an interdialysis period. Sequential plasma samples over 24 to 72 hr were assayed for ceforanide. Peak ceforanide levels (mean = 69 +/- 12 micrograms/ml) and volumes of distribution did not vary with creatinine clearance (Clcr, ml/min/1.73 m2) and both plasma clearance and renal clearance decreased linearly as Clcr decreased. Mean nonrenal clearance (4.6 +/- 1.8 ml/min/1.73 m2) did not vary with Clcr. Mean half-life was 3 hr in the normal subjects, increasing to approximately 25 hr in patients with severe renal insufficiency. Hemodialysis resulted in a removal of approximately 21% of the dose of ceforanide. Dosing recommendations for patients with renal insufficiency are provided.

Encainide disposition in patients with renal failure.

The antiarrhythmic agent encainide undergoes extensive presystemic biotransformation to form O-desmethylencainide (ODE) and 3-methoxy-ODE (MODE) in subjects who exhibit the extensive metabolizer (EM) phenotype for debrisoquin 4-hydroxylation. These metabolites contribute significantly to the overall antiarrhythmic activity and are extensively excreted in the urine. Therefore, the effects of renal impairment on the disposition of encainide and its metabolites were studied in seven EM patients with renal failure and compared with those in eight healthy normal subjects of the same phenotype. After a single dose of encainide, its systemic and oral clearances were significantly lower and its elimination t1/2 was shorter in patients with renal failure than in healthy volunteers. This shortening was explained by a significant reduction in steady-state volume of distribution in renal failure. After chronic dosing to steady state, quantitatively similar changes were seen. Chronic oral dosing produced 80% higher levels of ODE (the most pharmacodynamically active metabolite) and 167% higher levels of MODE as compared with healthy volunteers. The prolongations in ECG intervals were similar in the two groups despite the higher encainide dose in the normal subjects. In conclusion, patients with renal failure will require lower doses of encainide because of both reduced encainide clearance and increased accumulation of active metabolites.

Overwhelming strongyloidiasis: an unappreciated opportunistic infection.

Strongyloides stercoralis is an intestinal nematode which infects a large portion of the world's population. Individuals with infection confined to the intestinal tract are often asymptomatic but may have abdominal pain, weight loss, diarrhea, and other nonspecific complaints. Enhanced proliferation of the parasite in compromised hosts causes an augmentation of the normal life-cycle. Resultant massive invasion of the gastrointestinal tract and lungs is termed the hyperinfection syndrome. If the worm burden is excessive, parasitic invasion of other tissues occurs and is termed disseminated strongyloidiasis. A variety of underlying conditions appear to predispose to severe infections. These are primarily diseases characterized by immunodeficiency due to defective T-lymphocyte function (Table 1). Individuals with less severe disorders become compromised hosts because of therapeutic regimens consisting of corticosteroids or other immunosuppressive medication. The debilitation of chronic illness or malnutrition also predisposes to systemic stronglyloidiasis. The diagnosis of strongyloidiasis can be readily made by microscopic examination of concentrates of upper small bowel fluid, stool, or sputum. Important clues suggesting this infection include unexplained gram-negative bacillary bacteremia in a compromised host who may have vague abdominal complaints, an ileus pattern on X-ray, and pulmonary infiltrates. Eosinophilia is helpful, if present, but should not be relied upon to exclude the diagnosis. The treatment of systemic infection due to Strongyloides stercoralis with either thiabensazole 25 mg/kg orally twice daily is satisfactory if the diagnosis is made early. Because of several unusual features of this illness in compromised hosts, the standard recommendation for 2 days of therapy should be abandoned in such patients. Immunodeficiency, corticosteroids, and bowel ileus reduce drug efficacy. Thus a longer treatment period of at leuch as blind loops or diverticula necessitate longer treatment. Stool specimens and upper small bowel aspirates should be monitored regularly and treatment continued several days beyond the last evidence of the parasite. In particularly difficult situations where either worm eradication is impossible or reinfection is probable, short monthly courses of antihelminthic therapy seem to be effective in averting recurrent systemic illness. Finally, prevention of hyperinfection or dissemination due to Strongyloides stercoralis can be accomplished by screening immunocompromised hosts with stool and upper small bowel aspirate examinations. These would be especially important prior to initiating chemotherapy, or before giving immunosuppressive medications or corticosteroids to patients with nonneoplastic conditions such as systemic lupus erythematosus, nephrotic syndrome, or renal allografts.

Vitamin B6 deficiency in uremia.

Significant decreases in plasma pyridoxal-5-phosphate (PLP), plasma glutamic-oxaloacetic transaminase (PGOT) and erythrocyte glutamic-oxaloacetic transaminase (EGOT) were found in 29 uremic patients including 14 who had been on hemodialysis an average of 15.8 months. The mean PLP values of the uremic patients (5.39 +/- 0.37 ng/ml) were clearly lower than the values obtained for the normal group (9.30 +/- 0.80 mg/ml). The mean PGOT values of the uremic patients (dialyzed 4.07 +/- 0.29 U/liter, undialyzed 5.31 +/- 0.49 U/liter) were significantly lower than the normal group (6.57 +/- 0.39 U/liter). The mean EGOT value of the uremic patients (325 +/- 17 U/liter) was also lower than normal subjects (416 +/-21 U/liter). Stimulation of the EGOT by exogenous PLP (EGOT index) was less in dialyzed patients (1.60) than normal subjects (1.80) while the undialyzed uremic subjects had a greater than normal stimulation (2.12). All of these results indicate that uremic patients are vitamin B6 deficient and that those undergoing hemodialysis may have decreased amounts of the EGOT apoenzyme.

Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency.

A life-threatening toxicity syndrome consisting of an erythematous, desquamative skin rash, fever, hepatitis, eosinophilia, and worsening renal function in 78 patients receiving allopurinol is described. In a majority of cases, the development of this syndrome was associated with the use of standard (200 to 400 mg per day) doses of allopurinol in patients with renal insufficiency. In pharmacologic studies, it was demonstrated that the renal clearance of the major metabolite of allopurinol, oxipurinol, is directly proportional to the renal clearance of creatinine (oxipurinol clearance = 0.22 X creatinine clearance -2.87). An inverse linear relation was noted between the serum oxipurinol half-life and the renal creatinine clearance [( serum oxipurinol half-life in hours]-1 = 0.00034 X creatinine clearance in milliliters per minute + 0.0045). Long-term use of 300 mg per day of allopurinol was found to result in elevated steady-state serum oxipurinol concentrations in patients with renal insufficiency (serum oxipurinol concentration in micromoles per liter = -2.5 X creatinine clearance in milliliters per minute + 326). Avoidance of allopurinol or use of reduced doses in patients with renal insufficiency according to proposed guidelines should be adequate to inhibit uric acid production in most patients and may reduce the incidence of life-threatening allopurinol toxicity.

Atypical herpesvirus hominis type 2 infection in uremic patients receiving immunosuppressive therapy.

In four uremic patients (three renal transplant recipients and one with idiopathic thrombocytopenia), painful, initially vesicular lesions developed in the anogenital region while they were receiving immunosuppressive drug therapy. These lesions enlarged, coalesced and ulcerated, presenting a puzzling diagnostic problem. Initial misdiagnoses often resulted in inappropriate antimicrobial therapy. Routine cultures, histologic sections and Tzanck preparations were seldom helpful. The correct diagnosis of herpesvirus hominis (HVH) infection was established within 18 to 48 hours by viral culture of swab or biopsy material. Subsequent identification of isolates as HVH type 2 was confirmed by neutralization kinetics, infectivity titers and ability to plaque in chick embryo cells. Various therapeutic regimens were ineffective. Clinical improvement best correlated with decrease in dosage of immunosuppressive agents.

Opportunistic strongyloidiasis in renal transplant recipients.

Eight patients with severe strongyloidiasis complicating renal transplantation are reported. Twenty-one additional cases from the English-language literature are reviewed. In this setting, systemic strongyloidiasis is an often baffling illness involving multiple organ systems that is frequently complicated by serious bacterial infection. Bacteremia, meningitis, urinary tract infection, and pneumonia resulting from enteric organisms are common. In order to make the diagnosis, larvae must be sought by direct microscopy of stool, upper intestinal fluid, sputum, urine, or biopsy specimens. Treatment with oral thiabendazole in prolonged or repeated courses is recommended. Effective parenteral therapy is not available. Following treatment, previously parasitized patients must be tested at regular intervals to detect therapeutic failure or reinfection. Screening of patients awaiting renal transplantation for chronic intestinal strongyloidiasis is suggested. Improvement of the observed 52% mortality will depend upon heightened awareness by physicians caring for renal transplant candidates, and upon improved therapeutic regimens.

Options for renal replacement therapy: special considerations.

The number of patients coming to end-stage renal disease (ESRD) continues to increase annually, challenging the existing system of renal replacement therapy. Moreover, these patients, on average, are older at the onset of ESRD and are living longer after the initiation of renal replacement therapy. The choice of modality of renal replacement therapy (hemodialysis, peritoneal dialysis, or transplantation) that is best suited for a particular patient is thus increasingly important. Important factors to consider include not only mortality and morbidity, but also quality of life, patient age and social circumstances, and the etiology of ESRD. Three ESRD patient populations in particular, diabetic patients, the elderly and the patients with HIV infection or acquired immunodeficiency syndrome (AIDS), present renal care providers with complex issues as to renal replacement therapy and outcomes. Motivated patients with available resources, no matter what their cause of ESRD, should be considered as excellent candidates for home hemodialysis. This modality of renal replacement therapy is associated with improved survival and quality of life when compared with other modes of dialysis.