Svend Larsen

A Prospective Double-Blind Clinically Controlled Multicenter Trial of Sodium Pentosanpolysulfate in the Treatment of Interstitial Cystitis and Related Painful Bladder Disease

Painful bladder disease, sensory bladder disease, chronic abacterial cystitis and interstitial cystitis are ill-defined conditions of unknown etiology and pathogenesis, and, therefore, they are without any rational therapy. Pathogenetic theories concerning defects in the epithelium and/or mucous surface coat (including glycosaminoglycans) of the bladder, and theories concerning immunological disturbances predominate. Sodium pentosanpolysulfate (Elmiron) acts by substituting a defective glycosaminoglycan layer and inhibits complement reactions in inflammatory processes. We compared sodium pentosanpolysulfate versus placebo in a prospective double-blind, clinically controlled multicenter trial of 115 patients with painful bladder disease. Two protocols were used. Protocol A included 43 patients with clinically and pathologically anatomically verified interstitial cystitis (28 or more mast cells per mm.2), and protocol B included 72 patients with a painful bladder and unspecific histological findings. The patients were randomized to receive either sodium pentosanpolysulfate (200 mg. twice daily) or placebo capsules for 4 months. Before and after the trial the patients were evaluated with symptom grading, urodynamics and cystoscopy with distension and deep bladder biopsies. The results showed no difference between the pre-trial and post-trial values in the sodium pentosanpolysulfate and placebo groups in both protocols in regard to symptoms, urodynamic parameters, cystoscopic appearance and mast cell counts. A significant increase in the cystoscopically determined bladder capacity in the sodium pentosanpolysulfate group in protocol A was found. We conclude that no statistically or clinically significant effect of sodium pentosanpolysulfate was found compared to placebo in patients with painful bladder disease.

Glomerular endotheliosis in normal pregnancy and pre‐eclampsia

Objective To investigate the proportion of women with findings characteristic for pre‐eclampsia, as opposed to renal disease, in a controlled study of hypertensive pregnant women undergoing antepartum renal biopsy.

Ultrasonically Guided Fine Needle Aspiration Biopsy of Renal Masses

A consecutive series of 301 ultrasonically guided fine needle aspiration biopsies of renal masses was reviewed. The retrieval rate was 95 per cent and a correct cytological diagnosis was established in 82 per cent of the cases. There were 14 false positive aspirates, for a predictive value of a malignant aspirate of only 93 per cent. All false positive results were misinterpreted as relatively well differentiated adenocarcinoma. We conclude that renal fine needle aspiration biopsy may add information but the risk of a false positive finding must always be considered.

Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre‐eclamptic pregnancies

Objective To study the correlation between serum cystatin C levels and renal structural changes in normal, hypertensive and pre‐eclamptic pregnancy to evaluate it as a marker of the degree of renal involvement in pre‐eclampsia.

Painful Bladder Disease: Clinical and Pathoanatomical Differences in 115 Patients

The diagnostic criteria for interstitial cystitis considered as a subgroup of painful bladder disease (that is sensory bladder disease and chronic abacterial cystitis) are not well established. Some urologists rely on symptoms, while others rely on cystoscopic appearance or pathological findings. Among 115 patients with painful bladder disease we compared symptoms, and cystoscopic and urodynamic findings in those with and without detrusor mastocytosis (28 or more mast cells per mm.2) and attempted to elucidate possible differences between the groups. We chose the pathological anatomical criterion of detrusor mastocytosis to be diagnostic for interstitial cystitis. A total of 43 patients had detrusor mastocytosis and other pathological anatomical signs of interstitial cystitis, and 72 had no mastocytosis but the pathological diagnoses of chronic unspecific cystitis, fibrosis of the bladder, detrusor myopathy, intestinal metaplasia and normal findings. When the 2 groups of patients were compared we found no differences in regard to symptoms (pain, dysuria, frequency, nocturia and urgency), frequency of allergy and hysterectomy, duration of symptoms, petechial bleeding during cystoscopy with bladder distension and cystometric findings. The patients with mastocytosis differed from those without mastocytosis in that they were older, and had a higher frequency of hematuria, a higher frequency of a red, scarred and richly vascularized bladder at cystoscopy before distension, and a smaller cystoscopic bladder capacity. We conclude that by dividing patients with painful bladder into 2 groups according to the mast cell counts in the detrusor, certain differences in the clinical findings in the groups can be ruled out. However, in individual patients one cannot note with certainty to which pathological anatomical group the patient belongs, since great overlapping between the groups exists. Whether only patients with detrusor mastocytosis have interstitial cystitis depends on definitions and still remains an open question.

Acute kidney graft rejection

Serial biopsies from 41 consecutive renal allotransplanted patients were evaluated in order to obtain pretransplant data as well as information on well‐functioning and acutely rejecting grafts. Each patient served as his own control. Thirty‐five patients were followed according to the schedule which included biopsy prior to transplantation, shortly after opening of reanastomosis, at least once postoperatively (days 7–10), and furthermore whenever clinically indicated. The morphological evaluation was in each case combined with immunofluorescence (to detect immunoglobulins and complement fractions) and immunohistochemistry with a wide panel of monoclonal antibodies for T cells (CD2, CD3, CD4, CD8, γφ), B cells (CD20, CD22), macrophages (CD68, MAC387) NK cells (leu‐7, CD 16), activation markers (IL‐2‐R, Ki‐67, transferrin‐R), MHC antigens (HLA‐ABC, HLA‐DR), adhesion molecules (ICAM‐1, VCAM‐1, ELAM‐1, PADGEM, VLA‐4, LFA‐1 α/β), and growth factors (EGF, TGF‐α, EGF‐R). When 132 biopsies and 10 failed allografts were examined, no specific morphological or immunohistological parameter predictive of rejection or graft outcome could be found. Morphology in follow‐up biopsies from non‐rejecting and rejecting patients revealed a continuum of inflammatory changes, and several non‐rejecting cases demonstrated cellular inflammatory infiltrates which could not be discriminated from those seen in acute rejection. Of the patients 44% had acute rejection accompanied by increased infiltration of T cells and macrophages showing enhanced IL‐2‐R expression, increased tubular and endothelial staining for MHC class II, ICAM‐1, and VCAM‐1, and strong leukocytic expression of VLA‐4 and LFA‐1 α/β.

The action of cysteinyl-leukotrienes on intracellular calcium mobilization in human detrusor myocytes

Objective To investigate the presence of leukotriene D4 receptors in fura‐2‐loaded human detrusor smooth muscle cells (DSMCs) by examining the ability of leukotriene D4 to raise intracellular‐free Ca2+ concentration ([Ca2+]i), to determine the origin of the leukotriene D4‐mediated rise in [Ca2+]i and to investigate whether the specific leukotriene D4 receptor antagonist montelukast inhibits the Ca2+ response induced by leukotriene D4.

Nonobstructive Detrusor Myopathy in a Group of Patients with Chronic Abacterial Cystitis

Chronic abacterial cystitis is clinically and pathoanatomically an ill-defined condition, presenting with a variety of urologic symptoms and often nonspecific histology. A retrospective histologic analysis of bladder biopsies from 101 patients with chronic abacterial cystitis revealed degenerative changes in the detrusor muscle cells (detrusor myopathy) in 25 of them. The changes were often very severe, and even fatty replacement of muscle tissue was seen. Retrospective analysis of the symptoms, urodynamics and cystoscopic findings in these patients showed that none had haematuria, but five (all women) had had urinary retention requiring catheterization. Significant residual urine was found in nine patients, and the cystometrograms showed a shift to the right. No patient had infravesical obstruction. At cystoscopy less than half of the patients had petechial bleeding after bladder distension. The aetiology and pathogenesis of the degenerative changes are unknown, despite theoretic speculation. The authors conclude that careful histologic examination can identify different clinical types of chronic abacterial cystitis. Such studies may assist future research into the nature of the problem and also the search for more rational therapy.

Urine profiles and kidney histology after intravenous injection of ionic and nonionic radiologic and magnetic resonance contrast media in normal rats

RATIONALE AND OBJECTIVES Previous studies showed that both high-osmolality and low-osmolality iodinated contrast media cause temporary albuminuria and enzymuria (presence of enzymes in urine) in normal rats. Whether the same is true with ionic high-osmolality and nonionic low-osmolality magnetic resonance (MR) contrast media is unknown. We studied urine profiles and histology after intravenous injection of four types of contrast media in rats with normal kidneys. METHODS Urine profiles were monitored 4, 24, 48, and 72 hr after intravenous injection of saline, diatrizoate, iohexol, gadopentetate dimeglumine, and gadodiamide (4.59 mmol/kg of body weight) in normal rats. Each group included 20 male rats. After sacrifice, both kidneys were removed for examination by light microscopy (LM) and electron microscopy (EM). RESULTS All four contrast agents caused a temporary (< 22 hr) increase in the excretion of albumin (2-5 times) and of cytoplasmic (30-100 times) and brush border (10-100 times) renal enzymes when compared with saline. The degree of albuminuria correlated well (r = 0.90) with the osmolality of the injected media, whereas the increased level of enzymuria was unrelated to the osmolality. No major differences in the enzymuric effects of the four agents were noted. LM revealed vacuoles in all kidneys exposed to radiologic contrast media but not in kidneys exposed to MR contrast media or saline. Slight vacuolation was revealed by EM after the use of MR contrast media, and significant vacuolation was evident via EM after the use of radiologic contrast media. No difference between ionic and nonionic media within each drug group was detected by either LM or EM. CONCLUSIONS Transient renal effects are induced by both ionic and nonionic high-osmolality and low-osmolality radiologic and MR contrast media in normal rats. Both osmotic (e.g., albuminuria) and chemotoxic (e.g., enzymuria) mechanisms seem to be involved. From a morphologic point of view, the chemotoxic mechanisms seem to be of major importance.

Contrast Medium Induced Nephropathy: Animal Experiments

Contrast medium induced nephropathy may be defined as an acute impairment of renal function that follows exposure to radiographic contrast materials, and for which alternative etiologies have been excluded. Acute renal insufficiency has been reported following exposure to contrast media administered by intravenous and intra-arterial routes. Contrast media may account for as many as 12% of episodes of hospital-acquired acute renal failure, thus exceeding aminoglycoside antibiotics in nephrotoxic potential (Hou et al. 1983). The incidence of contrast medium induced nephropathy is difficult to establish with certainty from the literature, since incidence figures in various reports vary depending on the population studied, the definition of acute renal failure, and differences in methodology (Jevnikar et al. 1988). Furthermore, the true incidence of nonoliguric contrast medium induced nephropathy is not known because it is not routine to systematically monitor renal function following contrast medium administration. Clinically, the glomerular filtration rate is usually assessed indirectly by measuring serum creatinine concentrations or, more precisely, by measuring creatinine clearance. This operational definition may greatly underestimate toxicity that is not severe enough to affect these rather insensitive markers of renal function. Serum creatinine concentration, the measure most often used as indicator of renal dysfunction, may not be elevated above the normal range until glomerular filtration rate falls below 50% of normal values because of its nonlinear relation to glomerular filtration rate.