Prostaglandin synthesis linked to phosphatidylinositol turnover in isolated rat glomeruli.

Prostaglandins produced by the glomerulus are important factors in controlling glomerular function. The controlling step, i.e., the release of arachidonic acid from the phospholipids by either phospholipase A2 and/or C, remains poorly defined. The present studies were designed to determine which factors control arachidonic acid turnover and prostaglandin synthesis in glomeruli. As tools we used the calcium ionophore A23187, mepacrine, a phospholipase inhibitor, trifluoperazine, a calmodulin antagonist, and angiotensin II. A23187 (2 microM) caused a significant stimulation of both prostaglandin E2 and prostaglandin F2 alpha synthesis (measured by radioimmunoassay), which was associated with increased phosphatidylinositol turnover (measured by [14C]arachidonic acid and [32P]orthophosphate incorporation). Surprisingly, trifluoperazine (10-100 microM) also progressively increased synthesis of both prostaglandins, which was accompanied by increased phosphatidic acid/phosphatidylinositol turnover and decreased phosphatidylinositol content. In contrast, phosphatidylcholine and phosphatidylethanolamine turnover were significantly inhibited by trifluoperazine and their total content remained unaffected. Mepacrine (1 mM) decreased prostaglandin synthesis and both phosphatidylcholine and phosphatidylethanolamine turnover, and had no consistent effect on phosphatidylinositol turnover in control glomeruli. Mepacrine did, however, inhibit both A23187 or trifluoperazine-induced increase in phosphatidylinositol turnover. Angiotensin II increased turnover of phosphatidylinositol and also phosphatidylcholine, as determined by incorporation of [14C]arachidonic acid. Thus, all agents that increased prostaglandin synthesis also enhanced phosphatidylinositol turnover. The exact pathway of arachidonic acid release remains to be determined.

"Crack" cocaine-induced syndrome mimicking sarcoidosis.

A 39-year-old man with a history of frequent "crack" cocaine use of several years' duration presented with progressive dyspnea. Evaluation revealed bilateral interstitial pulmonary infiltrates and hilar adenopathy, diffuse pulmonary uptake of gallium, and markedly elevated serum angiotensin-converting enzyme activity. Open lung biopsy revealed interstitial and perivascular collections of histiocytes containing refractile, polarizable material, presumably inhaled along with the cocaine. Paratracheal lymph nodes were enlarged, reactive, and contained similar polarizable material. The well-formed, non-necrotizing granulomata characteristic of sarcoidosis were not present in either tissue specimen. To our knowledge, the association of chronic crack cocaine inhalation with this constellation of clinical findings, typically seen in sarcoidosis, has not previously been described.

The incident patient cohort study design with uncontrolled dose. Substantial over-estimation of mortality as a function of peritoneal dialysis dose?

In the Canada-USA (CANUSA) Study, the dialysis dose was neither randomized nor held constant, was measured at 6 month intervals, and the relative risk of mortality (R) was found to correlate linearly to mean values of weekly peritoneal plus renal urea clearance normalized to volume, (KprT/ V)m, ranging from 1.5 to 2.3. A risk/dose (R/D) function was derived for continuous ambulatory peritoneal dialysis from kinetic criteria for dose equivalency in hemodialysis (HD) and peritoneal dialysis (PD) and the HD R/D function. This PD R/D function was nonlinear with breakpoint from steep to shallow slope at (KprT/V)ud = 2.00, where ud refers to uniform single doses in contrast to mean doses with wide variances on the mean. The predicted decrease in renal urea clearance KrT/V per 6 months of CANUSA follow-up was computed from serial measured KrT/V in the Randomized Dialysis Prescription and Clinical Outcomes Study and showed it to be 0.21 +/- 0.34. The CANUSA (KprT/V)m values were corrected for the distributed values of 3 months decrements in KrT/V, and the population mortality risk at each (KprT/V)m dose level reported in CANUSA was computed from summation of the product of the R/D curve and fractional distribution of (KprT/V)ud values. From these calculations, the authors conclude that maximum (KprT/V)ud level achieved in CANUSA was 2.00, and the study does not define R/D response above this level.

Altered prostaglandin synthesis by glomeruli from rats with unilateral ureteral ligation.

There is evidence that prostaglandins modulate renal hemodynamics in unilateral ureteral obstruction. We examined prostaglandin synthesis by glomeruli from rats with 24- and 72-h unilateral ureteral ligation. During prelabeling of the lipid pools with [14C]arachidonate glomeruli from the ligated kidney incorporated less 14C label than those from contralateral or normal control kidneys. However, the incorporation of [14C]arachidonate into phospholipids of glomeruli was proportionately higher in the ligated kidney. Incubation of the prelabeled glomeruli with either angiotensin II or bradykinin significantly increased release of labeled prostaglandins and turnover of [14C]arachidonate on the ligated side. Radioimmunoassay determinations showed that after 24-h ligation, glomeruli from both sides produced comparable amounts of PGF2 alpha, 6-keto-PGF1 alpha, TXB2, and PGE2. After 72 h, glomeruli from the ligated kidney produced more PGF2 alpha, 6-keto-PGF1 alpha, and TXB2 than the contralateral glomeruli. In contrast, PGE2 synthesis was higher in contralateral glomeruli. Neither angiotensin II nor bradykinin had a measurable effect on radioimmunoassayable prostaglandins. We conclude that unilateral ureteral ligation is associated with specific alterations of glomerular prostaglandin synthesis and phospholipid metabolism that are intrinsic to the glomerulus.

Prostaglandin synthesis in isolated glomeruli.

Prostaglandins are thought to play an important role in the local regulation of glomerular blood flow and in the release of renin from the juxtaglomerular apparatus. We therefore examined prostaglandin synthesis by isolated rat glomeruli. Isolated glomeruli were either prelabeled with [14C] arachidonic acid or were incubated with [14C] arachidonic acid for the entire experimental incubation in Krebs buffer. Prostaglandin synthesis was determined by thin layer radio-chromatography of acid extracts of the supernatant solutions. Indomethacin inhibitable synthesis of small amounts of 6-keto-PGF1 alpha, the metabolite of prostacyclin (PGI2,) and larger amounts of PGF2 alpha, and PGE2, and possibly thromboxane B2 (TXB2) by isolated glomeruli could be demonstrated with either prelabeling or direct incubation. These findings support the hypothesis that prostaglandins are produced within the glomerulus where they may affect local glomerular blood flow and function.

Etiologic diagnosis of renal calculus disease.

Renal calculus disease is a common cause of morbidity in industrialized societies, accounting for seven to 10 of every 1000 hospital admissions. Recent advances in surgical therapy have made operative therapy much less invasive while maintaining a high level of success. However, the need to reduce the incidence of this disease persists as more than one half of all stone formers will have recurrence. Although the etiology and therapy for several types of renal calculi are established, much remains unknown concerning the mechanisms of formation of the most prevalent form of renal calculi, calcium oxalate. This article reviews recent basic science and clinical research that attempts to identify the etiologies of renal calculus formation.

Effect of converting enzyme inhibitors on prostaglandin synthesis by isolated glomeruli and aortic strips from rats.

In addition to their effect on angiotensin and bradykinin metabolism, converting enzyme inhibitors (CEI) may also alter prostaglandin (PG) synthesis. We therefore examined two CEI, SQ 14,225 (captopril) and SQ 20,881, for their in vitro effect on PG synthesis by glomeruli and aortic strips from rats. Glomeruli incubated in test tubes produced predominantly PGE2 and PGF2 alpha. Both CEI selectively stimulated PGE2 synthesis with maximal effects at 25 microM. During superfusion of glomeruli with captopril (25 microM) synthesis of PGE2 increased 5- to 10-fold and that of 6-keto-PGF1 alpha doubled. No significant change in PGF2 alpha or thromboxane B2 occurred. This effect of CEI was independent of angiotensin or bradykinin. In contrast captopril had no effect on PG synthesis by aortic strips, which produced predominantly prostacyclin assayed as 6-keto-PGR1 alpha and little PGE2 and PGF2 alpha. These results demonstrate that CEI can directly stimulate PG synthesis in glomeruli. This additional mechanism of action of CEI may require reinterpretation of the role of angiotensin based on results obtained with CEI.

Reversible acute renal insufficiency and hyperkalemia following indomethacin therapy.

We noted five cases of reversible acute deterioration of renal function in patients with very mild to moderate renal insufficiency who received indomethacin for an acute gouty attack. This decrease in renal function was consistent with a primary decrease in renal blood flow. In addition, hyperkalemia developed in the patients, which we attribute to a decrease in renin and aldosterone secretion, a decrease in distal tubular delivery of sodium, and, more importantly, to a decrease in urine flow. This report is intended to alert physicians to the possible complications of indomethacin therapy in patients with mild renal insufficiency.

Continuous arteriovenous hemofiltration. A report of six months' experience.

Continuous arteriovenous hemofiltration using small hollow-fiber hemofilters, without pumps, was used as an alternative to conventional methods of acute dialytic therapy. During a 6-month period, 15 patients had 17 treatments. Mean treatment duration was 98.5 +/- 101.1 (SD) hours (range, 4 to 300 hours), for a total of 1673 hours. Mean output per treatment was 9.5 +/- 4.4 mL/min, which was found to be adequate to control uremia despite a considerable protein intake. Six patients had a significant hemorrhage; however, all 6 had active bleeding and existing coagulopathies before beginning treatment. Overall, continuous arteriovenous hemofiltration was found to be a convenient and safe method for providing continuous fluid, electrolyte, and acid-base balance in patients with inadequate renal function. The treatment was particularly useful in patients with vascular instability or severe fluid overload.

Prostaglandin synthesis by isolated rat glomeruli: effect of angiotensin II.

Prostaglandins play a role in the regulation of renal blood flow and glomerular filtration. In the presence of [14C]arachidonate the pattern of prostaglandins produced by isolated glomeruli was PGF2 alpha > PGE2 > PGD2 = TXB2 = 6-keto-PGF1 alpha (a metabolite of prostacyclin). Glomeruli prelabeled with [14C]arachidonate showed an additional labeled prostaglandin that co-chromatographs with 6,15-diketo-13,13-dihydro-PGF1 alpha and may represent breakdown product of prostacyclin. Thus, prostacyclin, judged by its breakdown products, was the second most abundant prostaglandin produced. These results were confirmed by specific radioimmunoassays for PGF2 alpha, PGE2, and 6-keto-PGF1 alpha. Isolated glomeruli produced 1,740 pg x 10 min-1 x mg protein-1 of PGF2 alpha, 798 of 6-keto-PGF1 alpha, and 266 od PGE2. In prelabeled glomeruli angiotensin II causes a small but significant increase in 14C-labeled prostaglandins. Radioimmunoassay for 6-keto-PGF1 alpha showed that the angiotensin stimulation was specific for prostacyclin. Angiotensin II also affected the glomerular handling of [14C]arachidonate. It decreased the uptake of extracellular [14C]arachidonate and increased the incorporation of intracellular [14C]arachidonate into glomerular phospholipids. Based on these results, we propose that in the glomerulus angiotensin increases prostaglandin synthesis and stimulates deacylation and reacylation of phospholipids.

Renal vein thrombosis treated with thrombolytic therapy: case report and brief review.

Renal vein thrombosis (RVT) can occur as a complication of the nephrotic syndrome. We present the case of a young woman with systemic lupus erythematosus with nephrotic syndrome and bilateral RVT with extension of the thrombus into the vena cava to the level of the right atrium and multiple pulmonary emboli. She was treated acutely with streptokinase, with complete resolution of the thrombi. In general, anticoagulation is the mainstay of therapy for RVT. Review of the literature reveals that thrombolytic therapy can be used safely and appears to have been reserved for those patients with the most severe disease or the more grave prognosis. we feel that thrombolytic therapy is warranted in the presence of bilateral RVT with acute renal failure, massive clot size with high risk of acute embolic events, or recurrent pulmonary emboli, in the absence of overriding contraindications.

Acute sterile peritonitis.

We have encountered a sporadic form of aseptic peritonitis, not previously described, that we refer to as acute sterile peritonitis (ASP). This syndrome, which occurs with a frequency of 0.1% of dialyses, begins abruptly during peritoneal dialysis with abdominal pain, fever, and occasionally chills and vomiting. Coincident with the onset of symptoms, the dialysate return becomes cloudy with many white blood cells. Cultures are negative and resolution occurs within hours with continued dialysis. In this report we detail the clinical features of this new syndrome.