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Detection of low-molecular-weight proteins in urine by dipsticks.

BACKGROUND: Testing of urines with dipsticks for proteinuria, glycosuria, etc., is common practice. A deficiency with currently available dipsticks is their lack of chemical sensitivity and underestimation of low-molecular-weight proteins such as light chains. METHODS: We experimented with a number of dyes that gave an easily recognized color change on dipsticks for various low-molecular-weight proteins such as alpha-1-glycoprotein, alpha-1- and beta-2-microglobulin, and kappa and lambda light chains. We were successful in formulating a dye for impregnating dipsticks that gave a color change with low-molecular-weight proteins. RESULTS: Most dipsticks will measure proteins down to about 1 g/l. Our composite of two dyes (described here as the "TPR" dipsticks) gave reproducible results for protein concentrations of >/=300 mg/l, and detected low-molecular proteins. The TPR reagent is resistant to interferences from many compounds; also, the protein results are not altered in a given urine at a pH between 5 and 8. CONCLUSIONS: We have developed a dipstick that detects low-molecular-weight proteins. The dipsticks are easy to use and are suitable for outpatient or point-of-care testing. The precision of the dipsticks is satisfactory and is only marginally lower than quantitative spectrophotometric methods using pyrogallol red (PYR).

Coloring Agents↗

Review of Metabolic Screening Program of Children's Hospital, Vancouver, British Columbia. 1971--1977.

1. Between 1971 to 1977, 74,521 urines, collected on filter paper and mailed in, were screened by the Metabolic Screening Program of the Children's Hospital. These represented 45.9% of live births in B.C. hospitals were the program has been available. The mean age of the infants was 4.4 weeks. Urines were examined by chromatography with ethyl acetate-pyridine-water for sugars. 1423 (2.13%) had an abnormal pattern necessitating a repeat urine card. A persistent abnormality was noted in 167 (0.22%) and from these a liquid urine sample was obtained for two dimensional amino acid chromatography and/or a repeat sugar chromatography. 2. In 47 (0.06%) of these a definite metabolic abnormality was confirmed. These included cases of Iminoglycinuria (8), Hartnup trait (4), Nonketotic hyperglycinemia (2), Histidinemia (1), Cystathioninuria (5), Argininosuccinic aciduria (1), Maple Syrup Urine Disease (1), Diabetes Mellitus (1), Renal glycosuria (1) and Persistent galactosuria (3). 201 infants had a slight increase of cystine and/or lysine, and 19 of these were documented to be heterozygous for cystinuria.

Amino Acids↗

The proteinuria of industrial lead intoxication.

Studies of protein excretion were undertaken in seven males, aged 35-42 years, who had more than 5 years exposure to industrial lead and had clinically established Pb intoxication. Heavy metal intoxication with Cd and Hg causes proximal tubular abnormalities, i.e., aminoaciduria, glycosuria, phosphaturia. Similar abnormalities occur in Pb intoxication except that the nature of the proteinuria remains controversial. Studies of urinary proteins included 24-hr urine protein excretion, dextran gel separations, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and beta 2 microglobulin (B2M) measurements. Creatinine clearances, and serum B2M concentrations were normal. Urine total protein distribution by SDS-PAGE and the B2M excretion rate were also normal. These data imply that the nephrotoxicity of Cd and Hg are different than that of Pb. We speculate on what might account for this difference. This study suggests that when examining a population exposed to Pb, the finding of tubular proteinuria should alert investigators to search for the presence of other toxic agents.

Adult↗

Periodic ACTH discharge.

A 9 1/2-year-old girl is presented who had cyclical attacks of abdominal pain, vomiting, emotional disturbance, and marked weight change for two years. Associated findings were facial plethora, hypertension, transient hyperglycemia and glycosuria, elevated plasma ACTH, cortisol, and urinary 17-OHCS excretion, and low plasma osmolality with hyponatremia. Urinary excretion of catecholamines and porphyrin metabolites was not increased. Between episodes, she showed no abnormal clinical signs or laboratory data. The attacks were effectively suppressed with the administration of chlorpromazine. The disorder appears to be due to the periodic release of excessive ACTH; the cause remains unknown.

Adrenocortical Hyperfunction↗

Insulin infusion with parenteral nutrition in extremely low birth weight infants with hyperglycemia.

From Nov. 7, 1983, to Nov. 6, 1986, all infants with birth weight less than or equal to 1000 gm admitted to Oregon Health Sciences University who had persistent hyperglycemia and glycosuria were treated with graded insulin infusion while energy intake was increased to at least 100 kcal/kg/day (419 kilojoules/kg/day). The records of these infants were reviewed to define the clinical characteristics of infants likely to develop hyperglycemia and to see whether insulin administration would allow goals for energy intake to be met. There were 76 surviving infants; 34 received insulin and 42 did not. Treated infants were smaller (767 +/- 161 vs 872 +/- 98 gm; p = 0.0004), were more immature (26.8 +/- 1.4 vs 27.7 +/- 2.0 weeks; p = 0.0115), and required mechanical ventilation longer (28 +/- 19 vs 17 +/- 15 days; p = 0.0196). There were no significant differences between the groups at 3, 7, 10, or 14 days for intravenously administered glucose or for total nonprotein energy intake at 3, 7, 10, 14, 28, or 56 days. Treated infants achieved an intake of 100 kcal/kg/day (419 kilojoules/kg/day) at 15 +/- 8 vs 17 +/- 11 days and regained birth weight at 12 +/- 6 vs 13 +/- 6 days (NS). There was no difference in percent change from birth weight at 7, 14, 28, or 56 days. Treated infants had a glucose concentration of 195 +/- 60 mg/dl (10.8 +/- 3.3 mmol/L) while receiving 7.9 +/- 3.0 mg/kg/min (43 +/- 17 mumol/kg/min) of glucose at the start of insulin infusion on days 1 to 14. Insulin was given for 1 to 58 days. The initial dose was 40 to 100 mU/gm of dextrose infused (57 to 142 nmol/mol) and then gradually decreased. Less than 0.5% of blood glucose values were 25 to 40 mg/dl (1.4 to 2.2 mmol/L). We conclude that insulin infusion improves glucose tolerance in extremely low birth weight infants and allows hyperglycemic infants to achieve adequate energy intake similar to that of infants who do not become hyperglycemic.

Blood Glucose↗

Postoperative management of the diabetic patient.

Diabetic patients are at increased risk for adverse outcomes of surgery. These adverse outcomes are related to pre-existing complications of diabetes, especially atherosclerotic disease, nephropathy (and perhaps increased susceptibility to other renal toxins), and peripheral and autonomic neuropathy. Hyperglycemia is associated with likely risks for poorer wound healing, increased susceptibility to infection, and probable loss of administered nutrients through glycosuria. Insulin use has the flexibility of timing and dose in the postoperative management of most diabetic patients. The combinations of intermediate-acting and long-acting insulins and short-acting insulins usually are related to the experience and preferences of the treating physicians and allied health professionals. Intravenous insulin (always R) may be limited to administration in the ICU because of the need for frequent blood glucose monitoring and rapidity of glucose response to intravenous insulin. The use of short-acting insulin analogues has been shown to work well as premeal insulin or for rapidly treating marked hyperglycemia in the outpatient setting. Meal delivery in the hospitalized patient may not be timed as precisely as in the home situation. Nurses may be responsible for many patients. The rapid-acting analogues may be associated with increased risk for hypoglycemia in the hospitalized patient if insulin cannot be given immediately before a meal. These rapid-acting insulin analogues usually are limited to circumstances in which the patient can determine the dose and self-administer just before ingestion of the meal. The long-acting insulin analogues may not afford enough flexibility in many situations in which daily dosages changes are occurring in intermediate-acting and long-acting insulins. Oral glucose-lowering agent use in the postoperative state usually is limited to selected patients, including patients who have been on such agents before surgery, who have only mild elevations of blood glucose, who are able to ingest oral medications, and who do not have significant comorbid conditions (or significant risk for such conditions) that may be contraindications to use of such agents (see Table 3). Sulfonylureas and other insulin secretagogues (e.g., meglitinide, nateglinide) lower glucoses acutely. The risk for hypoglycemia is slightly less with the nonsulfonylurea agents. Efficacy and side effects limit the use of carbohydrase inhibitors for hospitalized patients. The glucose-lowering effects of biguanides and thiazolidinediones usually are not rapid enough for hospitalized patients who have never taken these medications. For patients who have been on a biguanide or thiazolidinedione before admission, these agents often are restarted in the postoperative period when oral intake of medications is possible and hepatic and renal function are stable. The hospital period affords an opportunity to review long-term management issues related to diabetes and its complications. Instruction on the importance of medical nutrition therapy, glycemic control, management of hypertension, dyslipidemia, and aspirin use as well as basic guidelines for foot care should be carried out during the hospitalization and at the time of discharge. Similarly, appropriate arrangements for medical nutrition therapy, general diabetes education (especially for newly diagnosed diabetic patients), and regular medical follow-up are important to ensure long-term, excellent surgical and medical outcomes.

Adult↗

Urinary tract infection in the impaired host.

In general, defects in phagocytosis and in humoral or cellular immunity do not appear to predispose to the acquisition of UTI but do influence the clinical manifestations and the severity, microbiology, and complications of infection once it is established. The incidence of UTI in immunosuppressed patients other than diabetics or renal transplant recipients is not higher than the incidence in nonimmunosuppressed individuals. The higher frequencies of infection seen in diabetics and in renal transplant recipients correlate best with the duration of bladder instrumentation rather than with glycosuria or immunosuppressive regimen. Neutropenia blunts the clinical manifestations of UTI and predisposes to bacteremia. Use of broad spectrum antibiotics results in alterations in indigenous flora, promotes urinary infections with resistant nosocomial pathogens, and predisposes to fungemia with hematogenous seeding of the urinary tract. Routine screening for detection of asymptomatic bacteriuria and prompt institution of antimicrobial therapy is indicated only in renal transplant recipients within 3 months of their surgery and not in any of the other diseases discussed.

Bacterial Infections↗

Pharmacologic profile of methyl 2-tetradecylglycidate (McN-3716)--an orally effective hypoglycemic agent.

A specific inhibitor of fatty acid oxidation, methyl 2-tetradecylglycidate (McN-3716) has been found to produce a dose dependent hypoglycemic effect when administered orally to rats, mice, and dogs. In addition to being more potent than other inhibitors of fatty acid oxidation, McN-3716 was also found to be 15--20 times more potent than tolbutamide in lowering the blood glucose of fasting rats. Furthermore, evidence is presented that McN-3716 produces hypoglycemia by a mechanism which differs from that of other oral hypoglycemic agents, the biguanides and the sulfonylureas. As predicted by the Randle glucose-fatty acid cycle, McN-3716 lowered glucose concentrations only under conditions where fatty acids were being used as the major energy substrates (fasting, diabetes, and feeding of high fat diets) but not under conditions where energy was derived mainly from carbohydrate (fed state or following hypophysectomy). Administration of McN-3716 produced a remarkable lowering of the plasma glucose and the glycosuria of depancreatized dogs but did not result in complete normalization of glucose, especially the excursions of blood glucose following feeding. It did, however, produce virtually complete reversal of the ketoacidosis of alloxan diabetic rats and depancreatized dogs without worsening the plasma lipid profile. Thus, McN-3716 may have potential utility as an oral therapeutic agent for the treatment of ketosis-prone juvenile or maturity-onset diabetes.

Animals↗

The Fasting Hyperglycaemia Study: I. Subject identification and recruitment for a non-insulin-dependent diabetes prevention trial.

Subjects at increased risk for developing non-insulin-dependent diabetes mellitus (NIDDM) were encouraged via a public awareness campaign, general practitioners, or a direct approach (in the case of women with previous gestational diabetes) to attend one of three English and two French centers for fasting plasma glucose (FPG) measurement. Of 1,580 subjects (mean +/- SD age, 47 +/- 10 years), 29% were male, 56% had a diabetic relative, 20% had a history of elevated blood glucose or glycosuria, and 9% previously had gestational diabetes. Thirty-one percent (493) had an initial increased fasting glucose ([IFG] 5.5 to 7.7 mmol.L-1), 3% (41) a diabetic fasting glucose ([DFG] > or = 7.8 mmol.L-1), and 66% (1,046) a normal fasting glucose ([NFG] < 5.5 mmol.L-1). Four hundred forty-one of the 493 returned for a second FPG measurement, and 67% (293) of these had a similar value on repeat testing 2 weeks later. A 75-g, 2-hour oral glucose tolerance test (OGTT) in 223 of these subjects showed that 37% (83) had impaired glucose tolerance (IGT), 26% (58) diabetes mellitus (DM), and 37% (82) normal glucose tolerance (NGT). Seven percent of self-referred patients had NIDDM by World Health Organization (WHO) criteria. Eighty-eight percent of those with an initial DFG had an increased glycated hemoglobin (> 6.2%), and 75% an increased fructosamine (> 282 mumol.L-1). While these two glycemic measures provided good discrimination for diabetes, neither were reliable in detecting those with increased but not diabetic FPG values. In conclusion, 293 (19%) of 1,580 self-referred subjects were identified as having persistently increased FPG, and 227 have been entered into a randomized NIDDM prevention trial evaluating healthy-living advice and sulfonylurea therapy.

Adult↗

Restoration of normal lipid and aminoacid metabolism in diabetic patients treated with a portable insulin-infusion pump.

To determine whether abnormalities of lipid and aminoacid metabolism observed in diabetes are corrected when plasma-glucose levels are restored to normal, eight insulin-dependent diabetics were treated for 7-14 days with a portable infusion pump which delivers insulin subcutaneously in basal (between-meal) doses with pulse-dose increments before meals. Mean plasma-glucose (206 +/- 24 mg/dl during conventional insulin treatment) fell to 89 +/- 3 mg/dl at day 7 and 84 +/- 2 mg/dl at day 14 of pump treatment; glycosuria was eliminated. Plasma cholesterol, triglycerides, and free fatty acids were elevated during conventional insulin treatment but fell to normal after 7 days of pump treatment. Plasma-levels of branched-chain aminoacids were 50-60% above control levels during conventional treatment but fell to normal after 7 days of pump therapy. Aminoacids were reduced from their high postprandial levels to normal values after insulin-pump treatment. In addition to restoring plasma-glucose to normal, treatment of diabetes with a portable insulin-infusion system results in restoration of normal lipid and aminoacid metabolism. Long-term use of this system may determine whether metabolic changes resulting from insulin lack cause the complications of diabetes.

Adolescent↗

A high carbohydrate leguminous fibre diet improves all aspects of diabetic control.

In a randomised cross-over study 18 nondependent (NIDDM) and 9 insulin-dependent (IDDM) diabetics were put on to a high carbohydrate diet containing leguminous fibre (HL) for 6 weeks, and also a standard low carbohydrate diet (LC) for 6 weeks. During two identical 24 h metabolic profiles mean preprandial and mean 2 hour postprandial blood glucoses were significantly lower on HL in both groups, as were also several overall measures of diabetic control, including the degree of glycosuria. Total cholesterol was reduced significantly on HL in both groups, and the HDL/LDL cholesterol ratio increased significantly on HL in the NIDDM group. A diet high in complex carbohydrate and leguminous fibre improves all aspects of diabetic control, and continued use of a low carbohydrate diet no longer appears justified.

Adult↗

Casual blood glucose levels and prevalence of undiscovered diabetes mellitus in Lagos Metropolis Nigerians.

A diabetic screening exercise involving 1627 subjects (1050 males and 577 females) was carried out in the Lagos Metropolis of Nigeria. Casual capillary blood glucose and/or urine glucose were tested for by means of dipsticks. The prevalence rates of undetected diabetes in the males and females were respectively 1.5% and 1.9%. Mean (+/- SD) casual blood glucose levels were higher in the females (82.8 (+/- 19.1) mg/100 ml) than in the males (75.9 (+/- 16.2) mg/100 ml). The prevalence of renal glycosuria was 1.3% in the males and 0.2% in the females. The prevalence of diabetes mellitus in the Lagos Metropolis appears high but similar to that in many other countries. The ambient blood glucose in the non-hospitalized subjects also seems to be not significantly different from values reported in other places.

Adolescent↗

Thymic reticulum of autoimmune mice. I. Ultrastructural studies of the diabetic (db/db) mouse thymus.

The thymus of the db/db mouse, an autoimmune strain with insulin-dependent diabetes mellitus and manifesting hyperglycemia, polyuria, glycosuria and obesity, was observed by electron microscopy. Its comparison with normal thymuses and thymuses from non-diabetic obese mice has revealed two major differences: first, the presence of crystal-like structures in some of the numerous clear vacuoles in cells, and second, a modification of the cells forming the border of cystic cavities. These cells contain two types of granules which are quite plentiful. One variety is clear and big, and a second type is small and dense, with an aspect similar to that of secretion granules. It is hypothesized that the crystalloid formations found in epithelial cells, and the presence of small, dense granulations in cells bordering the cystic cavities, are a consequence of the abnormal storage of the thymic hormone, thymulin, which results from a secretory function defect. These observations suggest a possible role for the thymic reticulum in thymic function deficiencies.

Animals↗

[Angiotensin-converting enzyme and diabetes mellitus].

Elevation of serum angiotensin-converting enzyme (ACE) has been reported to occur in 25 p. 100 of diabetic patients. This finding would decrease the specificity of increased ACE level in sarcoidosis. We measured serum ACE in 90 diabetic patients with simultaneous analysis of various parameters including those appreciating the degree of metabolic control. Serum ACE values, observed in diabetics are not different from values measured in controls, respectively 22,3 +/- 6,4 and 21,1 +/- 6,7 U/ml (means +/- SD). Only 5,5 p. 100 of diabetic patients had (slightly) increased serum ACE levels, i.e.: levels above mean +/- 2 SD of values observed in controls. Serum ACE levels were higher in insulin-dependent diabetics: 24,7 +/- 6,7 (n = 34) than in non insulin-dependent diabetics: 20,8 +/- 5,9 (n = 56) (p = 0,01). In the diabetic group, there is a positive linear correlation between serum ACE level and 24h-glycosuria or glycosylated A1c hemoglobin. These are parameters appreciating middle or long-term metabolic control. In the other hand, no correlation was observed between serum ACE and glycemia, triglyceridemia, serum creatinin, blood pressure or the presence of diabetic retinopathy. These findings do not show an elevation of serum ACE in diabetic patients. However, they suggest that long-term metabolic control of diabetes influence serum ACE level.

Diabetes Mellitus↗

Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs.

Rapidly progressive fibrosing interstitial nephritis after a slimming regimen containing aristolochic acid has been identified as Chinese herbs nephropathy (CHNP). From 1995 to 1998, we observed 12 Chinese people from different areas of Taiwan who underwent renal biopsy for unexplained renal failure. Medical history gave no clue to the causes of impaired renal function except for the ingestion of traditional Chinese herbs. Although these patients ingested herbal drugs from various sources for different purposes, their renal biopsy samples showed amazingly similar histological findings, with extensive hypocellular interstitial fibrosis and atrophy and loss of tubules in all cases. Glomeruli were apparently intact. They also had similar clinical features, such as normal or mildly elevated blood pressure, early and severe anemia, low-grade proteinuria, glycosuria, and insignificant urinary sediments. Renal function deteriorated rapidly in most patients despite discontinuation of the herbal medicines. Seven patients underwent dialysis, and the remainder experienced slowly progressive renal failure. Bladder carcinoma was found in one patient. Morphologically and clinically, the nephropathy in our patients was similar to CHNP, reported in Belgium. Because of the complexity and unknown types of herbs used in different clinical situations, unidentified phytotoxins other than aristolochic acid might be responsible for this unique disease entity. We conclude that the relation of this nephropathy to the consumption of Chinese herbs is striking. Using uncontrolled herbal remedies carries a high risk for developing interstitial renal fibrosis and urothelial malignancy.

Adult↗

Ranitidine-associated interstitial nephritis and Fanconi syndrome.

Ranitidine is an H2 blocking agent widely used in the treatment of peptic ulcer disease. Although acute interstitial nephritis has been described in association with a related drug, cimetidine, this complication secondary to ranitidine has been reported only once before. We describe a patient who presented with acute renal failure and features of Fanconi syndrome in association with the use of ranitidine. Renal biopsy showed acute interstitial nephritis. The patient had renal tubular acidosis with alkaline urine, aminoaciduria, renal glycosuria, uricosuria, and phosphaturia. There was a marked disparity between the degree of elevation of urea nitrogen and creatinine concentrations in the serum that was attributable to diminished urea generation, since simultaneous measurement of inulin, creatinine, and urea clearances showed that they were comparably reduced. Urinary nitrogen loss in the form of aminoaciduria contributed significantly to decreased urea generation. Both acute renal failure and Fanconi syndrome resolved after treatment with prednisone.

Adult↗

Nonacidotic proximal tubulopathy transmitted as autosomal dominant trait.

The family of a patient with a nonacidotic and hypercalciuric proximal tubulopathy was studied. The proband showed glycosuria, aminoaciduria, tubular proteinuria, renal hypophosphatemia, and urate tubular hyporeabsorption without bicarbonate loss. He also presented increased urine calcium excretion, plasma 1,25-dihydroxyvitamin D, and enteral calcium absorption. Clinical consequences of the tubulopathy were osteopenia and calcium kidney stones. Fifteen of the proband's relatives were studied; six of them had renal hypophosphatemia, 10 presented hypercalciuria, and three showed both hypercalciuria and hypophosphatemia. No other reabsorption defects were observed. High plasma levels of 1,25-dihydroxyvitamin D were found in 13 family members; their values correlated positively with calcium excretion and negatively with tubular phosphate reabsorption. None produced stones or had reduced mineral bone density. Hypophosphatemia and hypercalciuria occurred in the two generations studied; their transmission was independent of gender, and male-to-male transmission occurred for both defects. Our findings suggest that a genetic alteration of proximal tubular function could cause multiple reabsorption defects in the proband or renal phosphate leakage in the proband's relatives. The genotypic alteration causing the proximal dysfunctions may be monogenic, with an autosomal dominant pattern of inheritance and variable expressivity. Increased calcium excretion may be due to the proximal tubular alteration; alternatively, it may be the result of a genetic background predisposing to idiopathic hypercalciuria. Phosphate and calcium loss could stimulate 1,25-dihydroxyvitamin D synthesis in proximal tubular cells.

Absorption↗

Lambda light chain induced nephropathy: a rare cause of the Fanconi syndrome and severe osteomalacia.

The Fanconi syndrome is a generalized disorder of proximal renal tubular transport characterized by wasting of phosphate, amino acids, glucose, bicarbonate, and uric acid. The association of the acquired Fanconi syndrome with lambda light-chain proteinuria is rare. We report the third case in the English language literature. A 65-year-old man presented with severe pelvic pain. Investigations showed an elevated serum creatinine level, and a 24-hour urine collection contained 2.56 g protein. The Fanconi syndrome was diagnosed, with findings of phosphaturia, glycosuria, and aminoaciduria. Bence Jones protein (lambda sub-type) was present in the urine at a concentration of 0.58 g/L. Monocytic cells in the bone marrow and proximal tubular cells in the kidney contained cytoplasmic crystalline inclusions. Undecalcified bone sections confirmed the clinical diagnosis of osteomalacia. The patient was treated with phosphate, calcium, and ergocalciferol and experienced significant symptomatic improvement. The Fanconi syndrome caused by light-chain deposition in proximal tubular cells is well described in the literature. However, it is rare for the light chains to be of the lambda subtype. This may reflect differences in the physicochemical properties of kappa and lambda light chains.

Aged↗