Sarcoidosis associated with nephrocalcinosis in young children.

Three patients with nonpulmonary sarcoidosis had chronic erythema nodosum within the first 2 years of life. Each subsequently had renal sarcoidosis and nephrocalcinosis; hypercalcemia was documented in each patient and hypercalciuria in two patients. Treatment with prednisone was not uniformly successful in normalizing creatinine clearance. Nephrocalcinosis may be more common than previously reported in patients with sarcoidosis.

Targeted enzyme therapy of experimental glomerulonephritis in rats.

We sought to determine whether systemic administration of proteases ameliorates membranous nephritis induced in rats by immunization and challenge with cationic bovine gamma globulin, and whether targeting of protease to glomerular capillaries increases efficacy. Proteases substituted with biotin were targeted via the cationic protein avidin A, which by virtue of its charge has affinity for the glomerular basement membrane. Despite identical pretreatment proteinuria, rats given untargeted protease (biotin-conjugated without avidin, or unconjugated plus avidin) had significantly less proteinuria than saline-treated controls and nephrotic rats given avidin plus biotin-conjugated (targeted) protease had even less proteinuria and reduced glomerular rat IgG and C3. Among more severely nephrotic rats, targeted protease was again more effective than untargeted protease at reducing proteinuria, and also decreased the size of electron-dense glomerular deposits, hypercholesterolemia, and creatininemia. Inactivated targeted proteases had no effect on proteinuria, hypercholesterolemia, or azotemia. Finally, active targeted protease did not affect proteinuria in the nonimmune mediated nephrosis induced by puromycin aminonucleoside. We conclude that systemic protease can specifically diminish glomerular immune deposits, proteinuria, hyperlipidemia, and creatininemia associated with experimental immune complex glomerulonephritis but not toxic nephrosis, and that targeted protease is more effective than untargeted protease.

The roles of eicosanoids in experimental glomerulonephritis.

There is accumulating evidence showing alterations of renal eicosanoid synthesis in glomerular disease. Despite the complexity of their role in glomerulonephritis, these compounds appear to play a major part in the inflammatory response and in control of renal hemodynamics. The role of eicosanoids in the filtration of macromolecules has not been established, but there is indirect evidence of their involvement in mediating proteinuria. Dietary manipulation, either by high EPA, high linoleic acid, or EFA-deficient diet, in experimental glomerulonephritis have shown promising results as summarized in Table 1. The therapeutic potential of alterations in dietary fatty acid to modulate the inflammatory response appears to be of great value. Table 2 summarizes the effects of different dietary fatty acid alterations on eicosanoid synthesis. Nonetheless, we should point out that most of the studies of alterations in dietary fatty acids did not document changes in glomerular synthesis of prostaglandin, thromboxane, or HETES. Further studies examining the effects of different fatty acid regimens on glomerular eicosanoid synthesis and the role of these eicosanoids in the development of glomerulonephritis will provide valuable information. These findings could determine the specific type of dietary manipulation to inhibit or stimulate the production of selected eicosanoids.

Urinary tract infection in children.

Based on what is known of the pathogenesis of renal scarring, several therapeutic goals are important and are summarized in Figure 4. First, in children less than 5 years of age, and particularly neonates, a high index of suspicion must be combined with appropriate diagnostic techniques, including suprapubic aspiration if necessary, to obtain rapid and accurate diagnosis of urinary tract infection, thereby minimizing therapeutic delay. Although therapy can be started with broad spectrum antibiotics, culture and sensitivities are important to assure adequate antimicrobial therapy. Second, given the high incidence of vesicoureteral reflux in children with urinary tract infections, all children less than 5 years of age should have a VCUG and IV pyelogram shortly after resolution of the acute infection. In children more than 5 years of age, boys should be studied, given the very low incidence of urinary tract infection in males, and the high probability of urologic disease. Afebrile girls more than 5 years of age are exempted from diagnostic evaluation of the first episode of infection. Subsequent episodes should be investigated. Third, children with reflux should receive continuous antibiotic prophylaxis until age 6 to 8 years or until reflux resolves. Yearly evaluations are performed with radionuclide cystography, which is a nontraumatic sensitive means of detecting reflux, requiring less radiation than VCUG. Individuals of any age with recurrent urinary tract infections without reflux may benefit from a 3- to 6-month course of antimicrobial prophylaxis. Finally, antibiotic therapy should be appropriate and adjusted as necessary based the susceptibility of the bacterial pathogen. In older girls with simple uncomplicated urinary tract infections, single-dose therapy may be adequate. Younger children at increased risk for renal scarring should be treated more conservatively, receiving a 10-day course of therapy.

Diuretic therapeutics in the pediatric patient.

Careful management of fluid and electrolytes has long been an intrinsic part of pediatric practice. However, the augmentation of these manipulations through the rational use of diuretic agents requires considerable skill. In pediatric medicine, the regulation of pharmacokinetic processes and their interface with pharmacodynamic processes show dramatic age-related changes. These ontogenetic processes and their modification by various disease states must be considered carefully before selection and application of diuretic agents. The available data concerning the ontogeny of renal function and the attempts to apply diuretic therapy to pediatric disease are reviewed. It is concluded that results obtained to date suffer from the absence of a rigorous attempt to answer the fundamental therapeutic questions: What drug? What dose? What duration of therapy? A rational "target-effect" strategy is proposed for the application of diuretic agents to pediatric medicine.

Eicosanoids in experimental and human renal disease.

The renal prostaglandins and thromboxanes are powerful autacoids with potential effects on renal hemodynamics, salt and water metabolism, and the immune system. The possibility of adverse effects on renal function in certain patients with renal disease due to cyclooxygenase inhibition with nonsteroidal anti-inflammatory drugs has long been appreciated. Experimental evidence indicates that renal prostaglandin and thromboxane production is increased in several models of renal disease and that similar decrements in renal function occur with cyclooxygenase inhibition and may be due to inhibition of vasodilator prostaglandins. Additionally, several investigators have shown that administration of prostaglandins may be therapeutic in some forms of renal disease, particularly immunologically mediated diseases. Dietary modification to affect prostaglandin production has also been promising in certain experimental models. In contrast to vasodilator prostaglandins, thromboxane is a potent vasoconstrictor and would be expected to have adverse effects on renal function. Despite demonstration of elevated glomerular thromboxane, studies using inhibitors of thromboxane synthesis in immunologically mediated glomerular disease have been disappointing. There is some evidence, however, that these drugs may be of benefit in ureteric obstruction and renal transplant rejection.

Hemodynamic roles of thromboxane A2 and prostaglandin E2 in glomerulonephritis.

Eicosanoid metabolites may play a role in the pathophysiology of nephrotoxic serum nephritis (NSN), a model of immune renal disease. Our purpose was to determine the relative importance of vasoconstrictor [thromboxane A2 (TX)A2] and vasodilator [prostaglandin E2 (PG)E2] eicosanoids as mediators of hemodynamic and renal functional changes. Glomerular filtration rate (GFR; inulin clearance), and renal plasma flow (RPF; para-aminohippurate clearance/extraction) were measured in rats on day 1 and day 14 of NSN. Specific inhibitors of TXA2 synthesis and receptor binding, and cyclooxygenase inhibitors were used to determine the relative roles of TXA2 and PGE2. In vitro glomerular production of radioimmunoassayable PGE2 and TXB2 were measured after clearances. At 1 day GFR is decreased compared to control, 1.9 +/- 0.2 vs. 2.6 +/- 0.2 ml/min. RPF is numerically increased, 10.0 +/- 1.0 vs. 7.0 +/- 0.6 ml/min. By 14 days GFR is normal, 2.2 +/- 0.2 ml/min, as a consequence of significantly increased RPF, 11.7 +/- 1.0 ml/min. Glomerular production of PGE2 and TXB2 was increased 11- and 15-fold respectively at both 1 and 14 days. Pretreatment with OKY-1581, or acute treatment with UK-38,485, both inhibitors of TXA2 synthesis, had no effect on GFR or RPF in NSN rats. Addition of EP 092, a TXA2 receptor antagonist was similarly without effect. In contrast, acute treatment with the cyclooxygenase inhibitors meclofenamate or indomethacin resulted in a 50% decrease in both RPF and GFR; these inhibitors had no effect in control rats. We conclude that PGE2 (vasodilator) is of greater relative significance than TXA2 (vasoconstrictor) with respect to renal function in the NSN rat at 1 and 14 days.

Peritubular capillaries of the renal cortex in experimental diabetes mellitus in the rat.

Microangiopathy affects the peritubular capillaries in experimental diabetes. Five to six months after streptozotocin administration to induce experimental diabetes in rats, a progressive increase of lymph flow and of the entry of albumin from the renal peritubular capillaries into the interstitium was seen. Under these conditions, owing to the alteration of peritubular physical forces, the uptake of tubular reabsorbate into the capillaries can be impaired with potentially severe consequences in diabetic nephropathy.