Effect of exercise on urinary N-acetyl-beta-D-glucosaminidase activity and albumin excretion in children with type I diabetes mellitus.

Urinary N-acetyl-beta-D-glucosaminidase (NAG), a proximal tubule lysosomal enzyme, has been used as an indicator of subtle renal injury. Since it has been positively and significantly correlated with hemoglobin A1c and microalbuminuria, it has been suggested that this enzyme may also reflect metabolic control. Albumin excretion is exacerbated in adult diabetic individuals during exercise; such exercise-induced albuminuria may be a forerunner of diabetic nephropathy. Metabolic control, degree of exertion, and duration of diabetes have been suggested to influence this increase in albuminuria during exercise. Studies of children are few and have produced inconsistent results. Thus we studied 28 insulin-dependent diabetic children ranging in age from 5 yr to 16 yr and 27 age-matched controls using treadmill exercise; two exercise periods consisting of (1) graded increases in speed and grade at 3-min intervals until exhaustion and (2) a constant speed and grade necessary to produce 2/3-3/4 maximal heart rate for 30 min were performed. Capillary blood glucose, urinary NAG/creatinine (cr) ratios (UNAG/Ucr) and urinary albumin/creatinine ratio (Ualb/Ucr) were measured before and after each exercise period; hemoglobin A1c was also measured. The latter averaged 11.8 +/- 0.6% (mean +/- SEM); contrary to previous studies, this was not correlated with pre- or postexercise UNAG/Ucr. During both exercise periods, blood glucose dropped 271 +/- 19 mg/dl to 213 +/- 21 mg/dl (period 1) and 230 +/- 22 mg/dl to 157 +/- 21 mg/dl (period 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary excretion of N-acetyl-beta-D-glucosaminidase in children with type I diabetes mellitus.

N-acetyl-beta-D-glucosaminidase (NAG), a lysosomal enzyme, has been shown to be increased in the urine of patients with various glomerulonephritides, tubulointerestitial diseases, renal allograft rejection, toxic renal injury, and diabetes mellitus. Although it has been suggested that urinary NAG may reflect blood glucose control, no studies have correlated this with other measures of metabolic control. Thirty-four children from a diabetic summer camp were found to have urinary NAG to creatinine ratios significantly above those of normal controls of similar age (5.22 +/- 1.19 versus 1.51 +/- 0.17 U). Urinary NAG was found to positively correlate with an arbitrary control index (r = 0.82; P less than 0.05) and in seven patients with hemoglobin A1c (r = 0.70; P less than 0.001). In a closely followed group of 40 clinic patients, urinary NAG to creatinine ratio was again found to be significantly increased over normal controls (7.55 +/- 0.70 versus 1.51 +/- 0.17 U; P less than 0.05). Again, urinary NAG was positively correlated with HbA1c (r = 0.62; P less than 0.001) and urinary albumin to creatinine ratio (r = 0.47; P less than 0.01). In neither group was there a correlation with UNAG:UCr and duration of disease. Thus, these data suggest that urinary NAG to creatinine ratio appears to be a reflection of blood sugar control.

Hyperphosphaturia and hypermagnesuria in children with IDDM.

Urinary excretion of calcium, inorganic phosphorus, magnesium, glucose, and creatinine was measured in first-void spot urine samples collected 4 days apart in 220 insulin-dependent diabetic (IDDM) children (mean age 11.9 yr) attending a summer camp. A single control urine sample was obtained from 33 healthy nondiabetic siblings (mean age 11.2 yr). Mean +/- SD urinary calcium-creatinine ratios (UCa/Cr) did not significantly differ between IDDM and control subjects (0.14 +/- 0.09 vs. 0.12 +/- 0.09, respectively, P = 0.156). Mean urinary magnesium-creatinine ratios (UMg/Cr) were elevated in IDDM compared with control subjects (0.15 +/- 0.06 vs. 0.08 +/- 0.03, respectively, P = 0.0001). Similarly, mean urinary phosphorus-creatinine ratios (UP/Cr) were significantly increased over those in control subjects (1.12 +/- 0.33 vs. 0.40 +/- 0.22, respectively, P = 0.0001). UCa/Cr, UMg/Cr, and UP/Cr were correlated with increasing mean urine glucose content (P = 0.0001). No correlations were found when UCa/Cr, UMg/Cr, or UP/Cr were compared with patient age, duration of diabetes, glycosylated hemoglobin, or insulin dosage. Urine losses of phosphorus and magnesium were present even when glycemic control was considered good by several methods (glycosylated hemoglobin, short-term glycemic index, or urinary glucose content). Glomerular hyperfiltration was unable to account for increased urinary mineral content. In conclusion, the data indicate that urinary excretion of phosphorus and magnesium is elevated in children with IDDM, regardless of glycemic control. In the presence of glucosuria, this loss is further enhanced. Urinary calcium excretion is significantly higher only during periods of glucosuria. The data suggest that children with IDDM could be at risk for mineral deficiencies in the absence of intensive insulin management.

Effect of dietary protein restriction on functional renal reserve in diabetic nephropathy.

PURPOSE, PATIENTS, AND METHODS: Functional renal reserve in patients with insulin-dependent diabetes mellitus, as determined by the glomerular filtration rate (GFR) response test, is a measure of the capacity of the kidney to increase glomerular filtration in response to the stimulus of a protein meal or amino acid infusion. This 12-month study evaluated the changes in functional renal reserve in eight patients with insulin-dependent diabetes mellitus with nephropathy (micro-albuminuria [greater than or equal to 30 micrograms/minute]) who chronically decreased their dietary protein intake to a mean of 0.6 g/kg/day (Group 1) compared with a group of similar patients (n = 7) who maintained their unusual dietary protein intake (1.0 g/kg/day, Group 2). Patients were evaluated and measurements taken at 3-, 6-, and 12-month intervals. Absolute and percent increases in GFR were calculated from three averaged 1-hour measurements after an 80-g protein test meal. RESULTS: Although the initial absolute mean rise (14 +/- 12 versus 18 +/- 13 mL/minute/1.73 m2) in GFR and maximal percent rise (16% +/- 16% versus 32% +/- 27%) after the meal did not differ significantly between the two groups, at 12 months, values in the lower protein group increased (27.8 +/- 9.5 mL/minute/1.73 m2 and 54.7% +/- 48.8%), whereas those in the normal protein intake group declined significantly (3.7 +/- 3.6 mL/min-ute/1.73 m2 and 6.5% +/- 6.5%) (p less than 0.05). Both urine urea and microalbuminuria decreased significantly (p less than 0.05) in the low protein group. Unstimulated GFR at the end of 12 months was significantly less (p less than 0.05) in Group 2 (47 +/- 2 mL/minute/1.73 m2) than in Group 1 (71 +/- 21 mL/minute/1.73 m2). The rate of decline in GFR was significantly greater (p less than 0.05) in the normal protein intake group than in the low protein intake group (0.68 +/- 0.4 versus 0.28 +/- 0.15 mL/minute/1.73 m2/month). CONCLUSIONS: This study indicates that sustained dietary protein restriction can help to preserve renal function, decrease albuminuria, and lower the baseline GFR while maintaining functional renal reserve in patients with insulin-dependent diabetes mellitus.

Sex of the parental donor and cellular rejection of renal allografts in children.

The survival of renal allografts of maternal and paternal origin has been assumed to be identical, and in reports concerning graft survival the outcome of parental transplants is not analyzed by sex of the donor. Fifty-five children received a parental kidney between January 1973 and March 1987 at one institution. There were 6 technical failures. Analysis of renal graft survival in the remaining 49 children indicates a disparity between maternal and paternal graft survival, with an increased propensity for loss of paternal grafts from cellular rejection. Nine of 22 parental grafts are no longer functioning; 7 were lost from cellular rejection. In comparison, cellular rejection resulted in the loss of only 2 of 27 maternal grafts. This disadvantage of paternal grafts is most conspicuous in patients followed for 2 or more years; 7 of 15 paternal but only 1 of 20 maternal grafts were lost because of cellular rejection (P = 0.01). With causes of graft loss other than cellular rejection treated as withdrawal, actuarial survival of the 27 maternal grafts at 1 and 5 years is 96% and 91%, respectively, while that of the 22 paternal grafts is 83% and 58% (P = 0.017). Analysis of data from other centers will help determine whether our observation is of clinical significance.

Research in pediatric residency programs.

BACKGROUND AND OBJECTIVES: We have required residents in pediatrics at the Cleveland Clinic Foundation to give research presentations since 1989; this article reviews our experience with this program. Additionally, we sought to determine how many other accredited pediatric programs in the United States also require this. METHODS: Retrospective review of the Cleveland Clinic program; descriptive statistics of other United States residency programs, obtained by questionnaire. RESULTS: Pediatric residents at the Cleveland Clinic have given 108 research presentations since 1989, and have developed 33 (30.5%) of them into manuscripts or abstracts. We mailed questionnaires to 215 pediatric residency program directors and received responses from 177 (82%). Of these, 48 (27%) indicated their programs had a research requirement; residents could present their findings in departmental meetings or submit an abstract or manuscript to a professional society or journal. Respondents cited several barriers to research: residents are too busy, there are too few faculty members to mentor them, financial resources are limited, and there is no residency review committee requirement. CONCLUSIONS: Even though only approximately one fourth of the pediatric residency programs in the United States require research, we feel it is worthwhile experience. Despite barriers, residents can and do perform research and publish their findings.

Adverse reactions to parenteral lincomycin.

Lincomycin use has not been reported exclusively in children and inasmuch as it has been extensively used at our institution, a chart review of 265 patients who received parenteral lincomycin at a dose of 100 mg/kg/day in four divided doses for five days or longer was undertaken. The following conditions were diagnosed: cellulitis, 39%; septic arthritis, 21%; osteomyelitis, 16%; abscess, 13%; lymphadenitis, 9%; and pneumonia, 1%. Cures were achieved in all. The majority of organisms cultured were Staphylococcus aureus and Streptococcus pyogenes. Duration of therapy ranged from five to 63 days, with a mean of 15 days. The lincomycin dose ranged from 75 to 2,400 mg every six hours. The majority of patients received the drug intravenously, but 25.7% received it only intramuscularly. There were no adverse reactions at the administration sites. Only 3% of the patients developed diarrhea, which was not felt to be secondary to the drug. There were no cases of pseudomembranous colitis. Therefore parenteral lincomycin in children appears to be a safe and effective antibiotic when used for infections due to Gram-positive cocci.

Long-term use of propranolol, ibuprofen, and spironolactone in the management of Bartter's syndrome.

This report concerns two patients with Bartter's syndrome who were treated with propranolol, spironolactone, and potassium supplements. When ibuprofen was added to this regimen, potassium supplements were no longer required. In both patients, plasma renin activity decreased, plasma volumes increased, and a "catch-up" in linear growth ensued. This report confirms others that indicate prostaglandin synthetase inhibitors are a useful adjunct in the therapy of Bartter's syndrome.

Simultaneous iothalamate, creatinine, and urea clearances in children with renal disease.

Glomerular filtration rate (GFR) is often used to evaluate and manage patients with renal disease. Few studies in children have compared accurate estimations of GFR (clearance of inulin and/or iothalamate) with the clearance of creatinine which, because of simplicity, has been used as an approximation of GFR. At reduced levels of GFR, studies in adults suggest that the mean of the creatinine and urea clearances closely approximate the GFR. The present investigation shows that the clearance of creatinine approximates the GFR at normal levels; however, at reduced levels the creatinine clearance and the mean of the creatinine and urea clearances both overestimate the GFR as measured by iothalamate. The clearance of creatinine remains a useful clinical tool if its limitations at low levels of GFR are realized.

Concentrations of prostaglandins in plasma, seminal vesicles, and ovaries of aging C57BL/6NNia mice.

Concentrations of prostaglandin E1 (PGE1), and prostaglandin E2 (PGE2) (combined in the same radioimmunoassay) and prostaglandin F2 alpha (PGF2 alpha) were analyzed in circulating plasma and seminal vesicles of 3- and 26 to 27-month-old males and in circulating plasma and ovaries of 3-, 6-, 14 to 18- and 26 to 30-month-old female C57BL/6NNia mice. The amount of PGE declined in the plasma (P less than 0.05) and seminal vesicles (P less than 0.02) of aged male mice, whereas PGF2 alpha concentrations remained unchanged. There were no statistical differences in plasma or ovarian concentrations of PGE or PGF2 alpha when comparing the various age groups of female mice. It does not appear as if age-related changes in prostaglandins play a significant role in reproductive senescence.

Renal function in children undergoing cardiac operations.

Because we sometimes observed large amounts of uric acid crystals in the urine of infants and children after open-heart operations and since renal insufficiency from any cause can be a serious complication of cardiac procedures, 8 acyanotic and 5 cyanotic children were studied prospectively by comparing several preoperative and postoperative measures of renal function. There were no significant differences between the acyanotic and cyanotic groups in terms of age, time on cardiopulmonary bypass, or other preoperative variables. Postoperatively, children in both groups had a wide range of free water clearances (CH2O), with some values in the range reported to be diagnostic of renal insufficiency in adults. Since none of these children had renal insufficiency by other criteria, CH2O may not be as reliable an indicator of renal insufficiency in children. The major difference between the cyanotic and acyanotic groups was seen in postoperative serum uric acid levels (SUA); the mean SUA levels in the acyanotic and cyanotic groups were 5.3 +/- 0.5 mg/dl (+/- standard error of the mean) and 10.4 +/- 1.7 mg/dl (range, 8.0 to 15.5 mg/dl), respectively. Since the hyperuricemia in the cyanotic children could not be related to increased exogenous administration or decreased renal excretion, it is probably caused by increased endogenous production and may be related to the resolution of the cyanotic state.

Rapid antibody production and sample preparation for radioimmunoassay of prostaglandin A.

A dialysis equilibrium method for plasma or tissue preparation for radioimmunoassay of prostaglandins is presented and compared to the silica gel column technique. The plasma or tissue is extracted, dried, redissolved in buffer and dialyzed for further purification before assay. Results comparing both methods shows that dialysis equilibrium greatly simplifies the silica gel column technique yet preserves specificity, sensitivity and reproducibility. In addition a rapid micromethod for the development of a specific antibody to prostaglandin A is detailed.

Response of urinary N-acetyl-beta-D-glucosaminidase to rapid decreases in blood glucose.

Urinary N-acetyl-beta-D-glucosaminidase (NAG) has been shown to be a sensitive indicator of blood sugar control. Twelve insulin-dependent diabetics whose blood glucoses were being controlled with the artificial pancreas had concurrent urinary NAG activity measured. Blood glucose dropped markedly from 198 +/- 22 mg/dl (x +/- SEM) to 121 +/- 7 mg/dl during the 25 h on the artificial pancreas. For the entire group UNAG: UCr dropped from 14.9 +/- 4.4 to 7.25 +/- 1.68 units. In order to determine if larger decreases in blood glucoses over the course of the study resulted in larger decreases in UNAG: UCr, an arbitrary division at 180 mg/dl was made. Six patients with blood glucoses at or above this level at the start of the study showed a drop in both blood glucoses and UNAG: UCr (261 +/- 24 to 134 +/- 12 mg/dl and 21.1 +/- 6.1 to 7.29 +/- 1.53 U, respectively). Even though the other six patients had blood glucoses below the renal threshold, both blood glucoses and UNAG: UCr declined (136 +/- 4 to 110 +/- 4 mg/dl; 8.89 +/- 2.4 to 6.2 +/- 1.64 U, respectively). Thus not only may urinary NAG activity reflect long-term control and renal complications of diabetes, but this enzyme is also responsive to acute changes in blood glucose.

Urinary kallikrein excretion in renal transplant patients.

Urinary kallikrein, as a reflection of the intrarenal kallikrein, is distinct from plasma kallikrein. The kallikrein-kinin system, activated via antigen-antibody complexes, has been implicated in the pathophysiology of acute transplant rejection. We studied urinary excretion of sodium, potassium, protein, and kallikrein following renal transplantation in nine patients, In four patients who took steroids daily and were followed from the time of transplantation (without rejection episodes), urinary kallikrein remained stable (3.7 +/- 0.5 EU/24 hr, x +/- SEM). Since sodium-retaining steroids influence urinary kallikrein excretion, two patients were studied 2 and 3 months post-transplantation while receiving alternate-day prednisone. Values from urinary kallikrein in these patients did not differ from those in patients taking steroids daily (3.7 +/- 0.5 versus 2.7 +/- 0.3 EU/24 hr). In three patients experiencing acute rejection episodes, urinary kallikrein excretion rose markedly (24 to 260 EU/24 hr) and remained elevated until the patients became oliguric. Furthermore, this rise occurred 1-3 days before the clinical diagnosis of rejection was made. For the group as a whole there was no significant correlation between urinary kallikrein excretion, the excretion of sodium or potassium, or urine volume. Although the number of patients studied is small, the increases observed in urinary kallikrein suggest that activation of the intrarenal kallikrein-kinin system is associated with acute transplant rejection.

Percutaneous renal biopsy in infants and young children.

Records of 55 percutaneous renal biopsies performed in 53 children aged 5 days to two years were reviewed. Radiographic or ultrasound imaging techniques were not utilized during the biopsy procedure. Forty-nine of 55 biopsy attempts yielded sufficient tissue for histologic evaluation (89.1%). Transient gross hematuria not requiring intervention was the sole complication and was noted in 6 of 55 biopsy attempts (10.9%). Percutaneous renal biopsy can be performed safely in very young children and the success of the procedure is comparable to that in older children.

Hyperlipidemia in uremic children: response to peritoneal dialysis and hemodialysis.

Hemodialysis and hyperlipidemia have been associated in both adults and children. The present study indicates hyperlipidemia in uremic children treated with peritoneal dialysis and implies that the cardiovascular risk felt to exist with hemodialysis also exists in peritoneal dialysis. Thirty-eight children with chronic renal insufficiency or end-stage renal disease were followed serially under varying conditions of medical management, hemodialysis, peritoneal dialysis, and transplantation. Serum triglyceride concentrations in patients on peritoneal dialysis were not significantly different from those in patients on hemodialysis, but both were significantly higher (P less than 0.01) than concentrations in patients on medical management and transplantation.

Toxic psychosis due to cyproheptadine in a child on hemodialysis: a case report.

In 1971 Simmons et al. presented evidence that children receiving regular dialysis therapy required approximately seventy percent of recommended caloric intake to achieve normal growth. Since that time, pediatric nephrologists and dietitians have strived to meet that requirement. In an effort to attain adequate caloric intake, cyproheptadine, a known appetite stimulant, was prescribed to a child on chronic hemodialysis. The following reports the unexpected complication of toxic psychosis that resulted.

Impact of a camp experience on choice of coping strategies by adolescents with insulin-dependent diabetes mellitus.

Summer camps for children with IDDM have allowed educators to expand diabetes curricula and test novel approaches to education. Yet few evaluations have been published assessing the effectiveness of these types of educational interventions. The present study was designed as a formative assessment to provide preliminary evaluation of the impact of a life skills curriculum designed to increase awareness of different techniques that may be useful in managing stress. Life skills curricula are included each year as part of the teen session at the Texas Lions Camp for Children with Diabetes. Following the intervention, campers reported an intent to use more problem-focused and fewer detachment strategies to deal with a personally identified stressor. Limitations of the current pilot study are used to illustrate problems inherent in evaluation of camp programs.

Acute response of urinary N-acetyl-beta-D-glucosaminidase to mannitol infusion in the dog.

Urinary activity of N-acetyl-beta-D-glucosaminidase (NAG) has been used as an indicator of subtle renal injury in a variety of conditions. Such enzyme activity has been shown to be increased in human and other animals with diabetes mellitus. The mechanism of this increase in urinary NAG activity is not known. To determine if the osmotic diuretic effect of the glycosuria could stimulate urinary NAG activity, mannitol was infused into the left renal artery of six dogs to cause a unilateral osmotic diuresis and compared to the right side. During three control periods of 20 minutes, each urinary NAG excretion (expressed in units as the ratio of NAG activity to urinary creatinine, NAG/Cr) was equal from both left and right kidneys, 5.0 +/- 1.5 vs 6.0 +/- 3.6 units, respectively. During the 11 mannitol infusion periods urine volume and sodium excretion rose significantly from the left kidney, .50 +/- 2 to 1.5 +/- .3 ml/min and 21 + 5 to 99 +/- 16 u Eq/min, respectively. However urinary NAG/Cr did not change, 5.0 +/- 1.5 to 5.1 +/- 1.0 units. In six control dogs not infused with mannitol, urinary NAG/Cr tended to rise with time from control to experimental collection periods, 4.7 +/- 2.0 to 8.1 +/- 3.0 respectively; however these are not significantly different. In all dogs urine volume and sodium excretion tended to rise throughout the course of the study due to hydration with normal saline; thus it is possible that the tendency for urinary NAG activity to rise may have been due to the increase in sodium excretion. However, these studies demonstrate that the osmotic diuresis induced by mannitol produced no significant change in urinary NAG activity. Thus it may be that the hyperglycemia itself, and not the glycosuria, produces the increase in urinary NAG activity seen in the diabetic.

Lovastatin preserves renal function in experimental diabetes.

Although hyperlipidemia has been associated with the progression of glomerulosclerosis, little attention has been directed toward the use of lipid-lowering agents in altering diabetic nephropathy. We tested the hypothesis that lovastatin and the combination of lovastatin and enalapril would preserve renal function in streptozotocin-induced diabetic Wistar rats. Five groups of animals were studied: group 1, nondiabetic (n = 10); group 2, diabetic, insulin only (n = 12); group 3, lovastatin, (15 mg/kg/day, n = 13); group 4, enalapril, (50 mg/L drinking water, n = 10) and group 5, lovastatin plus enalapril, (n = 14). After 8 weeks of treatment, glomerular filtration rate (GFR, insulin clearance) was measured in anesthetized animals. The diabetic group was characterized by a GFR of 0.18 +/- 0.03 ml/min/g of kidney weight (gKW), a blood glucose level of 441 +/- 36 mg/dL, plasma cholesterol and triglyceride levels of 64 +/- 6.0 and 103 +/- 26.0 mg/dL. Lovastatin preserved GFR, 0.52 +/- 0.06 ml/min/gKW compared with the diabetic control subjects (P < 0.05). Enalapril also maintained GFR (0.42 +/- 0.06 ml/min/gKW, P < 0.05). In the lovastatin plus enalapril group, GFR (0.62 +/- 0.05 ml/min/gKW) was greater than in the enalapril group (P < 0.05), but was not different from the lovastatin group. Plasma lipid levels were not altered in any of the groups. Assessment of the kidneys by histology after treatment showed that the mesangial matrix injury score was better in the lovastatin, enalapril, and lovastatin plus enalapril groups compared with the diabetic group (P < 0.05). Lovastatin, enalapril, and lovastatin plus enalapril abrogated the decline in GFR and glomerular injury in diabetic rats. Lovastatin's direct renal protective effect seems to be independent of its lipid-lowering properties.