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Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common Mendelian disorders and is genetically heterogeneous. Linkage studies have shown that the majority (approximately 85%) of ADPKD cases are due to mutations in PKD1 on chromosome 16p13.3, while mutations in PKD2 on chromosome 4q21-q23 are thought to account for most of the remaining cases. In this report, we describe the mutation in a large four-generation ADPKD family (TOR-PKD77) which we had mapped to the PKD2 locus by linkage analysis. In this family, we screened for mutations by directly sequencing two nested RT-PCR fragments (PKD2N1 and PKD2N2) that cover approximately 90% of the PKD2 open reading frame. In the affected members, we identified a novel single adenosine insertion (2160InsA) in the PKD2N2 fragment. This mutation occurred in the polyadenosine tract (nt2152-2159) of exon 11 and is predicted to result in a frameshift with premature translation termination of the PKD2 product, polycystin 22, immediately after codon 723. The truncated polycystin 2 is predicted to lack the calcium-binding EF-hand domain and two cytoplasmic domains required for the homodimerization of polycystin 2 with itself and for the heterodimerization of polycystin 2 with polycystin 1.

The bone morphogenetic proteins, BMP-2 and OP-1, are candidates for growth factors that control renal branching morphogenesis. We examined their effects in embryonic kidney explants and in the mIMCD-3 cell model of collecting duct morphogenesis (mIMCD-3 cells are derived from the terminal inner medullary collecting duct of the SV40 mouse). Osteogenic protein-1 (OP-1), at a dose of 0.25 nM, increased explant growth by 30% (P = 0.001). In contrast, 100-fold greater concentrations of OP-1 (28 nM) decreased explant growth by 10% (P < 0.001). BMP-2 was entirely inhibitory (maximum inhibition of 7% at 5 nM, P < 0.0004). In an in vitro model for branching morphogenesis utilizing the kidney epithelial cell line, mIMCD-3, low doses of OP-1 (< 0.5 nM) increased the number of tubular structures formed by 28 +/- 5% (P = 0.01), whereas concentrations > 0.5 nM decreased that number by 22 +/- 8% (P = 0.02). All concentrations of BMP-2 (0.05-10 nM) were inhibitory (maximum inhibition at 10 nM of 88 +/- 3%, P < 0.0001). Stimulatory doses of OP-1 increased tubular length (P = 0.003) and the number of branch points/structure (3.2-fold increase, P = 0.0005) compared with BMP-2. To determine the molecular basis for these effects, we demonstrated that BMP-2 is bound to mIMCD-3 cells by the type I serine/threonine kinase receptor, ALK-3, and that OP-1 bound to an approximately 80-kDa protein using ligand-receptor affinity assays. To demonstrate that OP-1 can exert both stimulatory and inhibitory effects within a developing kidney, embryonic explants were treated with agarose beads saturated with 2 microM OP-1. OP-1 decreased the number of ureteric bud/collecting duct branches adjacent to the beads by 58 +/- 1% (P < 0.0001). In contrast, the number of branches in tissue distal to the OP-1 beads was enhanced, suggesting a stimulatory effect at lower doses of OP-1. We conclude that OP-1 and BMP-2 directly control branching morphogenesis and that the effects of OP-1 are dependent on its local concentration within developing kidney tissue.

Aim: To study the effect of beta-carotene (beta-Car) on radiation-induced mutation., Methods: Mutant frequency at T-lymphocyte hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus in rats was measured using a T-lymphocyte cloning technique and malondialdehyde (MDA) was measured using a thiobarbituric acid (TBA)., Results: Mutant frequency at the HGPRT locus was elevated by 60Co-gamma 3.75 Gy, and was reduced by ig beta-car 20 and 10 mg.kg-1 (P < 0.05), but not by beta-Car 5 mg.kg-1. It showed a dose-dependent relationship. MDA was signifcantly reduced in plasma of rats given beta-Car after 60 Co-gamma radiation. There was positive coherence between MDA and mutant frequency at the HGPRT locus (r = 0.9978, P < 0.05)., Conclusions: Radiation-induced mutation is inhibited by beta-Car, associated with antioxidant action of beta-Car.

Genetic variability in the renin-angiotensin system may modify renal responses to injury and disease progression. We examined whether the M235T polymorphism of the angiotensinogen (AGT) gene, the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene, and the A1166--> C polymorphism of the angiotensin II type 1 receptor gene may be associated with disease progression in 168 Caucasian patients with IgA nephropathy. All patients had serial measurements of their creatinine clearance, proteinuria, and blood pressure (mean+/-SD) with a follow-up of 6.1+/-4.7 yr. The genotype frequencies for each gene were consistent with Hardy-Weinberg equilibrium, and were similar to those of 100 Caucasian control subjects. We examined two primary outcomes: (a) the rate of deterioration of Ccr, and (b) the maximal level of proteinuria. We found that patients with the AGT MT (n = 79) and TT (n = 29) genotypes had a faster rate of deterioration of Ccr than those with the MM (n = 60) genotype (i.e., median values, -6.6 and -6.2 vs. -3. 0 ml/min/yr, respectively; P = 0.01 by Kruskal-Wallis test). Similarly, patients with AGT MT and TT genotypes had higher maximal values of proteinuria than those with the MM genotype (i.e., median values, 2.5 and 3.5 vs. 2.0 g/d, respectively; P < 0.02 by Kruskal-Wallis test). Neither the ACE insertion/deletion nor angiotensin II type I A1166--> C gene polymorphism was associated with disease progression or proteinuria in univariate analysis. Multivariant analysis, however, detected an interaction between the AGT and ACE gene polymorphisms with the presence of ACE/DD polymorphism adversely affecting disease progression only in patients with the AGT/MM genotype (P = 0.008). Neither of these gene polymorphisms was associated with systemic hypertension. Our results suggest that polymorphisms at the AGT and ACE gene loci are important markers for predicting progression to chronic renal failure in Caucasian patients with IgA nephropathy.

A series of substituted ferro-cyclopentadienyl borane compounds were separated by using thin-layer chromatographic technique. The optimum mobile phase was acetone-cyclohexane-tetraethyl ammonium halide (0.59:8.24:1.18). The orthogonal array method was used to get the optimum chromatographic condition. The types and the concentrations of different kinds of ion-pair reagents, the contents of acetone and cyclohexane were considered as factors which affected the results of separation. The operating conditions for each experiment was adopted based on the L9 (3(4)) design. A statistical method of variance analysis was used to evaluate the overall degree of separation (D(S)), a criterion which reflects the degree of optimization. As a result, we found the most important factors that affected the separation and the optimum chromatographic condition for 8 compounds of this sort.

Background: Cyclosporine (CsA) is a potent immunosuppressive drug widely used in organ transplantation and in the treatment of autoimmune diseases (1, 2). However, its common nephrotoxic effect is a major limiting factor. Short-term CsA treatment has been shown to cause reversible renal vasoconstriction, whereas long-term treatment can lead to an afferent arteriolopathy and chronic renal failure., Methods: We performed a randomized controlled trial to examine the short-term renal effects of verapamil in 32 CsA-treated heart or lung transplant recipients. Sixteen patients each were randomized to receive a 6-week course of verapamil or control treatment (atenolol in hypertensive patients and placebo in normotensive patients) 1-2 months after transplantation. An 8-hr sequential clearance study of inulin and p-aminohippuric acid for estimating glomerular filtration rate and renal plasma flow, respectively, was performed at baseline and at completion of study. The integral area under the curve of the clearance parameter over 8 hr was then calculated to generate a clearance-time index., Results: There was no difference in the clearance-time indices for inulin and p-aminohippuric acid between the two groups at baseline. However, at the completion of study, the within-group change in the glomerular filtration rate clearance-time index was different between the verapamil and control groups (48+/-20 vs. -35+/-17 ml/min/1.73 m2 x hr, respectively; P=0.0038). A similar trend was seen for renal plasma flow, but did not reach statistical significance. Mean arterial blood pressure and whole-blood CsA levels did not differ between the two groups during the study. Verapamil treatment was also associated with a decrease in CsA dose requirement (7.6+/-0.58 mg/kg/day at baseline vs. 4.6+/-0.40 mg/kg/day at completion; P<0.001) without any significant change in trough whole blood CsA levels. Rejection episodes did not differ between the two groups., Conclusions: The use of verapamil in the heart or lung transplant recipients may therefore provide both renal protective effects and cost savings.

The rise of total lipid, triglyceride and total cholesterol, and the drop of cortisol in serum induced by PA can be significantly inhibited by total ginsenosides in the leaves of Panax ginseng [GSL, 60 mg/(kg.d)]. From GSL ten compounds have been isolated and identified as ginsenoside-Rb2, -Rc, -Rd, -Re, -Rg1 -F3, F2, -Rg2, 20(R)-Rg2 and -Rh1, respectively. Pharmacological study has proved ginsenoside-Re to be the chief active constituent of GSL.

Although a number of factors have consistently correlated with progression to chronic renal insufficiency (CRI) in idiopathic membranous glomerulonephropathy (IMGN), they appear late, are not quantitative in nature and have not been validated. We have determined that the highest sustained six-month period of proteinuria is an important predictor of progression. Using multiple logistic modelling, the only additional prognostic variables of importance in 184 Canadian patients were the initial creatinine clearance and the rate of change in function over this six-month interval. Independent data from Italy (101 patients) and Finland (78 patients) were obtained for comparison. Sensitivity, specificity, negative and positive predictive values and overall accuracy, as well as Pearson's goodness-of-fit and Harrell's "C" statistic were used to assess the fits of the model. Accuracy of prediction was > or = 85% in all three countries. Pearson's Chi-square goodness-of-fit showed good agreement across the spectrum and Harrell's "C" statistic was > or = 90%. Therefore, a predictive, semiquantitative algorithm in IMGN has been validated. Its relevance in patient management and in clinical trials is illustrated.

We presents a Born; iterative method, for reconstructing optical properties of turbid media by means of frequency-domain data. The approach is based on iterative solution of a linear perturbation equation, which is derived from the integral from of the Helmholtz wave equation for photon-density waves in each iteration the total field and the associated weight matrix are recalculated based on the previous reconstructed image. We then obtain a new estimate by solving the updated perturbation equation. The forward solution, also based on a Helmholtz equation, is obtained by a multigrid finite difference method. The inversion is carried out through a Tikhonov regularized optimization process by the conjugate gradient descent method. Using this method, we first reconstruct the distribution of the complex wave numbers in a test medium, from which the absorption and the scattering distributions are then derived. Simulation results with two-dimensional test media have shown that this method can yield quantitatively (in terms of coefficient valued) as well as qualitatively (in terms of object location and shape) accurate reconstructions of absorption and scattering distributions in cases in which the first-order Born approximation cannot work well. Both full-angle and limited-angle measurement schemes have been simulated to examine the effect of the location of detectors and sources. The robustness of the algorithm to noise has also been evaluated.

The pharmacology of PD 144418 (1-propyl-5-(3-p-tolyl-isoxazol-5-yl)-1,2,3,6-tetrahydropyridine) was characterized using neurochemical, biochemical and behavioral techniques. For sigma (sigma 1 and sigma 2 respectively) sites, PD 144418 affinities were determined using whole guinea pig brain membranes with [3H](+)-pentazocine and neuroblastoma x glioma cell membranes using [3H]1,3,di-O-tolylguanidine (DTG) in the presence of 200 nM (+)-pentazocine. PD 144418 exhibited an affinity for sigma 1 of 0.08 nM (Ki) versus a K1 of 1377 nM for sigma 2 site. Additional receptor binding studies indicated that PD 144418 lacked affinity for dopaminergic, adrenergic, muscarinic and a variety of other receptors. In vitro studies indicated that PD 144418 reversed the N-methyl-D-aspartate (NMDA)-induced increase in cyclic GMP (cGMP) in rat cerebellar slices without affecting the basal levels, suggesting that sigma 1 sites may be important in the regulation of glutamine-induced actions. PD 144418 potentiated the decrease in 5-hydroxytryptophan caused by haloperidol in the mesolimbic region, but by itself had no effect in 5-hydroxytrypamine (5-HT) and dopamine (DA) synthesis. Behaviorally, similar to other sigma ligands, PD 144418 antagonized mescaline-induced scratching at doses that did not alter spontaneous motor activity. This action is suggestive of potential antipsychotic property. It exhibited no anxiolytic and antidepressant properties in the models used. These results show that PD 144418 is a very selective sigma 1 agent, devoid of any significant affinity for other receptors and that sigma 1 site may modulate actions in the CNS.

Five compounds were isolated from the leaves of Panax ginseng and characterized as 20(R)-protopanaxatriol, daucosterine, ginsenoside-F2, ginsenoside-F3 and majoroside-F4 on the basis of spectral analysis and chemical evidence. Among them, majoroside-F4 is obtained from plant for the first time.

Polycystin, the product of autosomal dominant polycystic kidney disease (ADPKD) 1 gene (PKD1) is the cardinal member of a novel class of proteins. As a first step towards elucidating the function of polycystin and the pathogenesis of ADPKD, three types of information were collected in the current study: the subcellular localization of polycystin, the spatial and temporal distribution of the protein within normal tissues and the effects of ADPKD mutations on the pattern of expression in affected tissues. Antisera directed against a synthetic peptide and two recombinant proteins of different domains of polycystin revealed the presence of an approximately 400-kD protein (polycystin) in the membrane fractions of normal fetal, adult, and ADPKD kidneys. Immunohistological studies localized polycystin to renal tubular epithelia, hepatic bile ductules, and pancreatic ducts, all sites of cystic changes in ADPKD, as well as in tissues such as skin that are not known to be affected in ADPKD. By electron microscopy, polycystin was predominantly associated with plasma membranes. Polycystin was significantly less abundant in adult than in fetal epithelia. In contrast, polycystin was overexpressed in most, but not all, cysts in ADPKD kidneys.

Rise of total lipid, total cholesterol and triglyceride in rabbits were markedly inhibited by oral administration of ginsenosides from stems and leaves at a daily dose of 60mg/kg. The inhibitory rates were 66.2%, 92.8% and 58.1% respectively.

A 40-year-old male was admitted to the hospital with acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia (PCP). Two months before admission the patient had a high fever, general fatigue and mild epigastic tenderness. On admission, physical examination revealed numerous small tumors on the head, gingiva, neck, nasal ala, anterior forehead, anterior thoracic, bilateral sole and bilateral lower limbs. At that time, the CD4 cell count was 130/microliters. Upper GI endoscopy was performed because of sever epigastralgia and hematemesis. The gastric mucosa was diffusely nodular and erythematous with bleeding. This biopsy showed Kaposi's sarcoma, and the same findings were obtained from the duodenum, rectum and skin, AIDS with related cutaneous and gastrointestinal KS and PCP was diagnosed. We performed a combination of chemotherapy and Interferon-alpha therapy, and the KS almost completely disappeared within 3 months.

Plasminogen activator inhibitor 1 (PAI-1) is an important regulator of plasminogen activation, which inhibits both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). The DNA sequence encoding mature PAI-1 protein was inserted into an inducible expression vector. This gene was highly expressed to produce a soluble active protein in E. coli cells. The amount of the recombinant protein was up to 20% of total cellular protein. By efficient purification with a yield of about 15-20%, the recombinant protein could be purified to homogeneity with its specific activity up to 6.1 x 10(4) (uPA) IU/mg. Its inhibitory activity declined during incubation at 37 degrees C with a half life of about 2 hr.

The solid phase synthesis of libraries containing a 1,3,4,6-tetrasubstituted-2,5-diketo-1,4-piperazine scaffold (DKP) or a 3,4,6-trisubstituted-2,5-diketo-1,4-morpholine scaffold (DKM) from alpha-bromocarboxylic acids and amines is described. Using a design strategy which we refer to as divergent library design, both templates were prepared from a common intermediate. The general utility of this synthetic route in creating novel, non-peptidyl chemical libraries is discussed.

That bone disease accompanies renal failure has been known for over 100 years. This bone disease (renal osteodystrophy) has been variously attributed to hyperparathyroidism, vitamin D deficiency, aluminium toxicity, iron toxicity, uraemia, and a host of other aetiologies. In addition, the form the bone disease takes has been variously described as osteitis fibrosa, osteomalacia, mixed uraemic osteodystrophy and the aplastic (adynamic) lesion. In this manuscript we will focus on the aetiology, consequences, diagnosis and possible management of the aplastic form of the disease. The renal osteodystrophy study was a prospective, cross-sectional study of renal bone disease in a largely unselected population of patients receiving dialysis in three hospitals in Toronto. A variety of non-invasive data (parathyroid hormone (PTH), aluminium, etc.) and bone histology were obtained and analysed to assess pathogenesis, diagnostic criteria and management. We have defined the aplastic lesion as having low bone formation without a marked increase in unmineralized osteoid (i.e. excluding osteomalacia). We have noted that it may be associated with increased aluminium or little to no aluminium. With increased aluminium the patients have a poorer prognosis both with regards to bone disease and mortality, and they should be managed appropriately to alleviate aluminium toxicity. With lesser amounts of aluminium, morbidity and mortality are less severely impacted, but not normal. We have shown that the low bone formation, of the aplastic lesion without aluminium may be "normalized' by increasing PTH levels. It is concluded that aplastic bone disease carries adverse consequences both in terms of bone problems and survival. In the absence of aluminium toxicity the stimulation of PTH effectively corrects the bone formation abnormality. Whether this will alleviate the adverse consequences will be difficult to study. Avoiding the problem by not over-suppressing PTH seems a reasonable approach at this point.

A modified rabbit meningitis model is described for determining the PAE in vivo, which utilised a self-standing device for repeatedly sampling pure CSF. The model allowed the PAEs of ciprofloxacin and rifampicin on Escherichia coli ATCC 25922 to be determined following PAE induction in vitro, or in vivo in CSF after intrathecal injection or during the last 1.5 h of a 7 h iv continuous infusion. The estimated volumes of distribution of ciprofloxacin and rifampicin in CSF were 0.68 +/- 0.24 mL and 0.74 +/- 0.04 mL, respectively, and the terminal elimination half lives were 1.8 +/- 0.5 h and 2.2 +/- 0.3 h, respectively. PAEs of approximately 2 h were obtained in vivo and in vitro after exposing E. coli to 3 x MIC of ciprofloxacin in vitro and to 1 x MIC of drug in vivo. When the organism was exposed to rapidly declining concentrations in vivo, only a minimal PAE was observed for both antibiotics. Moreover, a PAE of 3.1 +/- 1.3 h of rifampicin was obtained in vivo, being smaller than the 4.8 h PAE observed in vitro, which might be explained by the binding of 45 +/- 6.5% rifampicin to proteins in the CSF.

With the markedly reduced usage of aluminum salts in renal failure, parathyroid hormone (PTH) has become the major determinant of currently seen bone disease. Clinicians now must consider what PTH level should be sought. Too low a level may lead to the aplastic bone lesion (low turnover bone), and too high a level may cause osteitis fibrosa. Furthermore, conventional normal PTH levels may not be a suitable target because of the well-known resistance to PTH in uremic patients. In this report, we derive the PTH levels that best distinguish patients with low and high bone formation states from those with normal bone formation in a group of 175 dialysis patients without aluminum toxicity. Using bone histological parameters, we propose that ideally PTH levels should be maintained between 10 pmol/L (100 pg/mL) and 20 to 30 pmol/L (200 to 300 pg/mL) in chronic dialysis patients, levels two to four times the upper limit of values found in normal subjects.

To evaluate the efficacy of a second generation acid pump inhibitor-lansoprazole (L) a controlled clinical trial in 72 patients of duodenal ulcer was carried out with omeprazole (O) as control. The results showed that the ulcer healing rate after 4-week treatment was 97.4% in lansoprazole group and 91.2% in omeprazole, while the effective rate was 100% and 97.1% respectively (P > 0.05). Ulcer related pain was relieved more quickly in lansoprazole group. The pain relief rate after treatment of 3 days was different significantly between the two group, being 74.3% (L) and 51.6% (O) respectively (P < 0.05). No marked side-effect was observed in lansoprazole group. It is shown that lansoprazole is effective and safe for treatment of duodenal ulcer.

To determine factors predictive of long-term graft function in patients treated prophylactically with an antilymphocyte antibody, 670 first cadaveric adult renal transplant procedures performed between 1985 and 1991 were reviewed. The actuarial 1- and 5-year patient survival in this group was 95% and 87% respectively, and graft survival was 84% and 70% respectively. The final analysis was based on a study group of 635 patients which excluded 28 patients who lost grafts to early technical failures and 8 patients who were not induced with an antilymphocyte preparation. Multivariate analysis showed that 5-year graft survival was lower in patients with delayed graft function (p = 0.0001), in those who had an acute rejection episode in the first 6 months post-transplant (p = 0.0001), recipients greater than 55 years of age at the time of transplant (p = 0.0001), in patients who were highly sensitized at the time of transplant (p = 0.0331) and, finally, in those who received a graft from an older donor (p = 0.044). The 209 patients with delayed graft function had a 16% lower long-term graft survival than 425 patients with early graft function (62% vs. 78% respectively at 5 years). One or more rejection episodes in the first 6 months post-transplant (329 patients) reduced long-term graft survival by 13% compared to those who did not have a rejection episode (67% vs. 80% respectively at 5 years).(ABSTRACT TRUNCATED AT 250 WORDS)

A phase I-II clinical trial was conducted to determine the maximum-tolerated dose (MTD) of oral cyclosporine (CsA) and vinblastine in patients with metastatic renal cell cancer (RCC) as well as to estimate the response rate. Sixteen patients received a 5 mg/kg oral loading dose of CsA followed by 3 days of CsA in 4 divided daily doses escalating from 10 mg/kg per day up to 17 mg/kg per day. Vinblastine (Vbl) was administered as an intravenous bolus on the morning of the 3rd day with dose escalation from 6 to 10 mg/m2. Cycles were repeated every 4 weeks until tumor progression. Forty-nine cycles of CsA with vinblastine were administered. The maximum tolerated dose of Vbl was 10 mg/m2, with neutropenia as the dose-limiting toxicity resulting in one death. CsA could not be escalated above 17 mg/kg per day because of nausea and vomiting. Other toxicities included constipation (100%), malaise (100%), temporary increase in pain (36%), and one seizure that may have been drug-related. There were no clinically significant changes in renal function or serum bilirubin. Mean peak whole-blood CsA level at the highest CsA dose level was 919 ng/ml (range: 414-1,827) with a trough prior to Vbl injection of 451 ng/ml (range: 128-1,229). There were no tumor responses. The combination of oral CsA and Vbl is not nephrotoxic but is poorly tolerated. In most patients optimal blood levels of CsA for reversal of MDR cannot be reliably achieved, and vinblastine dose intensity must be compromised because of the significant toxicity of this regimen.

A cDNA coding for human plasminogen activator inhibitor-2 (PAI-2) was transferred into the genome of Autographa californica nuclear polyhedrosis virus adjacent to the polyhedrin promoter. Cells infected with recombinant virus synthesized a 43-kDa PAI-2 protein, the majority of which was secreted. The recombinant PAI-2 was identical to native PAI-2 purified from human placenta with respect to interaction with polyclonal antibody and inhibition of urokinase-type plasminogen activator.

Transient decreases in glomerular filtration rate (GFR) and renal plasma flow (RPF) have been associated with each daily dose of cyclosporine (CYA) in patients with renal allografts. We examined the differential dose effects of CYA on native renal function in 24 recipients of heart or lung transplants (treated with 7.3 +/- 0.5 mg/kg/day [mean +/- SEM]) and in seven patients with psoriasis (treated with 4.2 +/- 0.7 mg/kg/day). GFR and RPF were measured by urinary inulin and para-aminohippuric acid clearances 2 hours before the morning CYA dose and for 6 hours after. The age of heart and lung transplant recipients at renal study (2 months after transplantation) was 47 +/- 2.0 years. Their serum creatinine levels rose from 80 +/- 4.0 mumol/L during the first week after transplantation to 120 +/- 4.0 mumol/L at renal study (p < 0.0001). Their GFR and RPF were decreased before the CYA dose at 64 +/- 2.4 and 340 +/- 16 ml/min per 1.73 m2 and did not vary during the study. In comparison, the age of patients with psoriasis was 51 +/- 4.6 years at renal study (24 +/- 4.0 months after CYA treatment). Their serum creatinine levels rose from 80 +/- 4.0 mumol/L before treatment to 100 +/- 10 mumol/L at renal study (p = 0.07). Transient decreases of their baseline GFR and RPF (85 +/- 7.4 and 380 ml/min per 1.73 m2) with a nadir occurring during the first 2 hours of CYA ingestion were observed together with the recovery of these parameters toward baseline by the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the risk factors associated with renal osteodystrophy, we examined the database of 256 patients who were prospectively studied in three Toronto dialysis centers between October of 1987 and 1989. The potential risk factors examined included age, sex, type and duration of dialysis, type and dose of phosphate binders, vitamin D treatment, and history of diabetes mellitus, renal allograft failure, parathyroidectomy, and bilateral nephrectomy. All patients had undergone a bone biopsy and were categorized into one of four disease groupings: (1) osteitis fibrosa and mixed bone disease, (2) aluminum bone disease, (3) mild bone disorder, and (4) aplastic bone disorder. The mean (+/- SD) age of the patients at bone biopsy was 57 +/- 15 years, and 62% were men. Forty-five percent of patients were treated by hemodialysis and 55% by peritoneal dialysis. The mean duration of dialysis was 4 +/- 4 years. Twenty-five percent were also diabetic. The most common disorder was the aplastic (or "adynamic") bone disorder, found in 34% of patients. Aluminum bone disease was found in 27%, osteitis fibrosa or mixed bone disease in 27%, and mild bone disorder in 12% of patients. Cumulative intake of aluminum gels was associated with aluminum bone disease, whereas peritoneal dialysis with supraphysiologic calcium concentrations, ingestion of calcium carbonate, and diabetes mellitus were associated with both mild bone disorder and aplastic bone disorder. These three latter risk factors may be important in predisposing patients to a low bone turnover state through modulation of parathyroid hormone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Idiopathic focal segmental glomerulosclerosis (FSGS) is an infrequent renal biopsy diagnosis in the elderly. In our single-centre referral registry there were only 17 cases seen in 822 biopsies performed in patients aged 60 or over giving an incidence of 2%. These seventeen patients ranged from age 61 to 78 at the time of biopsy and were followed a median period of 29.5 months. The incidence of nephrotic syndrome at baseline was similar to younger adults (70.5%), but both hypertension (71%) and renal insufficiency (53%) were higher. Fifty-three percent (9/17) of the patients were treated with either steroids or a combination of steroids and cytotoxic therapy. A complete remission in proteinuria was observed in 44% of the treated patients versus none in the untreated patients. No relapses were seen in those that had a complete remission. As well, none of the patients with a complete remission, versus 9/14 (63%) of the untreated or non-responsive patients progressed to renal failure during the observation period. One patient who was treated with cytotoxic therapy and steroids subsequently died of a pancreatic carcinoma. Idiopathic FSGS is an infrequent glomerulopathy in the elderly but it is important given its malignant natural history. Alternate day prednisone for up to 6 months may be a reasonable approach since a complete remission in proteinuria was seen in 44% of our treated patients and this response was closely linked to a good long-term prognosis. The risks of therapy however must be carefully weighed against the potential benefit in each case because of the advanced age of these patients.

Chronic nephrotoxicity is a major complication in high-dose cyclosporine treatment. We examined the glomerular filtration rate, renal plasma flow, and kidney biopsies of 15 psoriatic patients treated with low-dose cyclosporine (< or = 5 mg/kg/d) for 30 months (25 to 35 months) 1 month after drug withdrawal. The mean (95% confidence interval) age of the patients in the study was 44 years (38 to 50 years). Their serum creatinine levels pretreatment and at the time of the study were 0.94 mg/dL (0.85 to 1.0 mg/dL) and 1.2 mg/dL (1.1 to 1.3 mg/dL). Seven patients had a decreased glomerular filtration rate and four of them also had a reduced renal plasma flow, below the 2.5 percentile of normal. Four patients had moderate tubulointerstitial scarring and arteriolopathy, while the remaining patients had mild structural abnormalities. The severity of acute nephrotoxicity during treatment and chronic structural injury were highly correlated (r = 0.81; P < 0.0003). Recurrent episodes of severe acute nephrotoxicity (defined as reversible increase of serum creatinine > 90% of baseline value) was a marker for moderate chronic nephrotoxicity. No correlation was found between chronic structural injury and patient age, sex, pretreatment creatinine level, blood pressure (pretreatment or during treatment), cyclosporine dose and treatment duration, and cyclosporine blood levels. In seven patients continued on cyclosporine for another 12 months (10 to 14 months), repeat studies showed no interval changes. Despite 40 months (30 to 51 months) of treatment, all but one of these seven patients (with previous hypertension and atherosclerotic vascular disease) had mild functional and structural abnormalities. None had any severe acute nephrotoxicity at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated 259 dialysis patients using serum parathyroid hormone (PTH, IRMA; normal range 1 to 5.5 pM or 10 to 55 pg/ml), the deferoxamine infusion test and iliac crest bone biopsy to determine the various forms of renal osteodystrophy and their risk factors. Although half of the biopsied patients had low turnover osteodystrophy, evidence of aluminum toxicity was present in only 1/3 of them. Additional risk factors for this bone lesion included treatment with peritoneal dialysis, ingestion of calcium carbonate, diabetes mellitus and advanced age. The PTH levels in patients with the aplastic lesion were significantly lower than in patients with normal or high bone turnover lesions [7.7 +/- 6.1 vs. 36.9 +/- 3.2 pM (77 +/- 61 vs. 369 +/- 32 pg/ml), P < 0.0001]. Aside from hypercalcemia, these patients were relatively asymptomatic. In a second study, 10 patients on peritoneal dialysis with the aplastic lesion had their dialysate calcium lowered from 1.62 to 1.0 mM. This resulted in a significant increase in PTH levels, from [3.7 +/- 0.8 to 10.6 +/- 1.9 pM (37 +/- 8 to 106 +/- 19 pg/ml), P < 0.001] which persisted over the nine-month observation period. In conclusion, the aplastic lesion is the most common form of renal osteodystrophy, with aluminum intoxication implicated in only 1/3 of the cases. In the remainder, factors identified include therapy with peritoneal dialysis using supraphysiological dialysate calcium, oral CaCO3 intake and diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine A (CyA) is known to cause hyperkalemia by impairing renal potassium excretion. However, the observation of transient and severe hyperkalemia occurring within 3 to 5 hours of CyA ingestion in several organ transplant patients led us to postulate that it might also cause a potassium efflux from the intracellular to the extracellular fluid space. We tested this hypothesis by studying 22 nondiabetic, renal transplant patients with stable renal function (serum creatine < 2.25 mg/dL) who were treated with CyA (CyA group; n = 14) or imuran and prednisone (STD group; n = 8). Eight CyA and four STD patients also were treated with a beta-blocker (BB). While at rest, fasting plasma potassium levels were sampled hourly in all patients from 8:00 am to 1:00 pm. All medications (including CyA and BBs) were given after the 8:00 am blood sampling. Venous pH, osmolality, insulin, aldosterone, epinephrine, norepinephrine, and CyA levels also were determined at 8:00 am, 11:00 am, and 1:00 pm. Urine was collected from 11:00 pm to 8:00 am prior to the study (period I) and from 8:00 am to 1:00 pm during the study (period II) for measurement of potassium excretion (standardized to a 5-hour period). A significant increase in serial plasma potassium levels was noted in the CyA + BB group only (P = 0.0006 by repeated measures analysis of variance).(ABSTRACT TRUNCATED AT 250 WORDS)

A compound has been synthesized with the formula (rad)(2)Mn(2)[Cu(opba)](3)(DMSO)(2).2H(2)O, where rad(+) is 2-(4-N-methylpyridinium)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, opba is orthophenylenebis(oxamato), and DMSO is dimethyl sulfoxide. It consists of two nearly perpendicular graphite-like networks with edge-sharing Mn(II)(6)Cu(II)(6) hexagons. The two networks are fully interlocked with the same topological relationship as that between adjacent rings of a necklace. The compound has three kinds of spin carriers: Mn(II) and Cu(II) ions, antiferromagnetically coupled through oxamato bridges, and rad(+) radical cations, bridging the Cu(II) ions through the nitronyl nitroxide groups and forming Cu-rad chains. The temperature dependence of the magnetization reveals that below 22.5 K, the compound behaves as a magnet.

To assess the effects of diabetes mellitus on renal osteodystrophy, we examined the database of 256 patients (45% on hemodialysis and 55% on peritoneal dialysis) who were prospectively studied in three Toronto dialysis centers between October of 1987 and 1989. All patients had serial documentation of their clinical, laboratory and risk parameters of bone disease, and completed a series of investigations that included the deferoxamine test, measurement of intact 1-84 PTH levels, and an iliac crest bone biopsy. Twenty-five percent of these patients were diabetic. When compared to non-diabetic patients, they were on dialysis for a shorter duration (2.4 +/- 0.3 vs. 4.7 +/- 0.3 years; P < 0.0002), used calcium carbonate as the only phosphate binder more frequently (40 vs. 25%; P < 0.007), and had lower parathyroid hormone levels (12 +/- 1.4 vs. 24 +/- 2.3 pmol/liter; P < 0.002). High-turnover bone disorders (that is, osteitis fibrosa and mixed disorder) were distinctly uncommon (8 vs. 33%; P < 0.01 by Fisher's exact test), while the mild (19 vs. 9%; P = NS) and the aplastic disorders (with mean stainable bone surface aluminum of 6.5 +/- 0.7%) (46 vs. 31%; P = NS) tended to be more common in diabetic patients. The prevalence of aluminum bone disease was the same in both groups (27%). Diabetic patients ingested a smaller cumulative dose of aluminum gels (3.7 +/- 0.6 vs. 9.3 +/- 1.1 kg; P < 0.005), yet had a higher rate of aluminium accumulation on bone surfaces than non-diabetic patients (1.5 +/- 0.19 vs. 0.96 +/- 0.10% per month on dialysis; P < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)

We have assessed the bone histology in 259 chronic dialysis patients, all of whom were in the same dialysis program. All patients had bone biopsies with quantitative histomorphometry, intact parathyroid hormone (PTH) measurements, basal and deferoxamine stimulated serum aluminum levels. Results demonstrate the increased incidence of the recently described aplastic bone lesion, particularly in patients treated with peritoneal dialysis (PD). Aluminum-related bone disease is much less common than previously described, perhaps in relation to the declining use of aluminum as a phosphate binder. A different pattern of bone lesions is seen in PD as compared with hemodialysis (HD), with low turnover disorders comprising 66% of the lesions seen in PD and high turnover lesions accounting for 62% of the bone histologic findings in HD. The difference in these patterns may relate to alterations in PTH levels, as mean PTH levels in HD patients were 2-1/2 times the levels found in PD patients (P < 0.0005), while older age, higher prevalence of diabetes and a shorter duration of dialysis may also have contributed to the findings in the PD patients. We suggest that PD, perhaps by maintaining calcium at higher levels, may more effectively suppress the parathyroid gland.

End-stage lung disease has been treated successfully by lung transplantation (LTXP) at our institution since 1983. We report on the renal function of 30 LTXP recipients who were followed for at least 6 months (mean, 39 months; range, 6-60 months). All patients received quadruple immunosuppressive therapy including cyclosporine A, with a trough serum level (RIA) between 150 and 250 ng/ml for the first 6 months between 125 and 150 mg/ml after 6 months. The mean serum creatinine (SeCr) increased from a baseline value of 75 +/- 3.5 to 182 +/- 13.9 microM at the end of the follow-up. The greatest change in SeCr occurred within the first 6 months post LTXP. Fifteen of 30 patients who were initially normotensive required at least one antihypertensive medication post LTXP. By the end of the follow-up, 9 patients had SeCr > 200 microM. Two patients in this institution have progressed to end-stage renal disease requiring dialytic therapy. CsA nephrotoxicity has emerged as a major source of morbidity in the lung transplant population. Nephrotoxicity occurs early, and there does not appear to be any trend toward reversibility despite a lowering of the dose. Renal parenchymal injury may be progressive, despite an apparent plateau of the SeCr in some patients.

We developed an approach in quantifying the risk of developing chronic renal insufficiency (CRI) based on a cohort of 184 patients with idiopathic membranous glomerulonephritis (IMGN), prospectively followed by the Toronto Glomerulonephritis Registry between 1974 and 1988. After a mean follow-up period of 5.8 years, 26% of patients developed CRI (defined as persistent reduction of creatinine clearance (CCr) less than or equal to 60 ml/min/1.73 m2 for greater than or equal to 12 months). We found that when compared to the baseline probability of the unselected patients, the severity of proteinuria at kidney biopsy added only marginally to the prediction of CRI. We introduced a special test condition: persistent proteinuria (PP) (that is, duration of proteinuria, g/day, above different cut-off levels). We examined the positive predictive value (PPV) and sensitivity (SEN) of 15 arbitrarily chosen levels of PP (that is, proteinuria greater than or equal to 4, 6 or 8 g/day persisting for greater than or equal to 6, 9, 12, 18 or 24 months) to select levels with optimal predictive characteristics. We found that PP greater than or equal to 8 g/day for greater than or equal to six months was a simple and useful predictor of CRI with a PPV and SEN of 66%. To further improve our prediction, we tested the following parameters: age, sex, initial SCr and CCr, proteinuria, serum albumin, hypertension, rate of change of CCr over time, and therapy (steroids +/- immunosuppressive drugs) in a multivariate analysis. Proteinuria, initial CCr, and rate of change of CCr were most important in predicting CRI.(ABSTRACT TRUNCATED AT 250 WORDS)

Between October 1987 and October of 1989, we conducted a prospective study to evaluate non-invasive test strategies for predicting aluminum bone disease (ABD) in a group of largely unselected dialysis patients based on their deferoxamine (DFO) test alone, or the combined results of their DFO test and intact 1-84 parathyroid hormone (PTH) levels. These test parameters were evaluated against the pathological diagnosis of ABD based on bone biopsy ("gold standard"). A total of 445 patients in three dialysis centers in Toronto were serially followed for their clinical, laboratory and risk parameters for renal osteodystrophy during the study, and 259 (142 PD and 117 HD) patients underwent a series of investigations which included the DFO test, measurement of intact 1-84 PTH levels, and an iliac crest bone biopsy. Serum aluminum ([Al]) level greater than or equal to 3700 nM (or 100 micrograms/liter) had a positive predictive value (PPV) of 75% for ABD in our PD and 88% in our HD patients, but its sensitivity was low (10 and 37%). Delta [Al] (that is, incremental rise of serum [Al] from baseline post-DFO) was useful in predicting ABD in our PD but not HD patients. Test combination based on delta [Al] greater than or equal to 5550 nM (or 150 microgram/liter) and PTH levels less than 20 pM (or 200 pg/ml) yielded the best PPV greater than or equal to 95% for ABD in both PD and HD patients. This test cut-off would remain highly predictive of ABD even if the prevalence of ABD decreases to as low as 5% for the PD patients and 10% for the HD patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A clinical trial of misoprostol, an analog of PGE1 produced by G.D. Searle & Co., on treatment of duodenal ulcer was carried out in five hospitals in Beijing, Shanghai, and Guangzhou. Totally 94 cases were treated with misoprostol 200 micrograms q.i.d. for 4 weeks. A parallel comparison was made, using cimetidine 200 mg q.i.d. A double-blind, double-dummy study was conducted. The result showed that the therapeutic efficacy of misoprostol in duodenal ulcer is similar to that of cimetidine. The ulcer healing rate in four weeks being 60.7% and 67.9% respectively, while the overall effectiveness rate being 77.7% and 80.2%. There was no statistically significant difference between the two medication groups. The side effect of misoprostol is mainly mild diarrhea (6.4%), but it disappears despite the continued use of medication. To our impression, misoprostol represents a new therapeutic approach for treatment of peptic ulcer in addition to acid controlling H2 blockers.

20(S)-Ginsenoside-Rg2 and its 20(R) epimer were successfully separated using reversed-phase low pressure column (Rp-18) chromatography. The method has proved very convenient and rapid.

Seizures produced by intracerebral injection of zinc sulfate in rabbits are a new chronic model of experimental epilepsy. The main features of this model are: the animals are easily controlled, the electrocorticogram is conveniently recorded, the endpoints are definite, and the rate of seizure is higher than with other methods. The commonly used antiepileptic drugs, such as phenobarbital (30 mg/kg), diphenylhydantoin (30 mg/kg), nitrazepam (3 mg/kg), and sodium valproate (300 mg/kg), have therapeutic effects in treating this experimental epilepsy, when they are given intravenously. But they can not protect the rabbits from death, except phenobarbital.

During the past 11 years, the Metro Toronto Glomerulonephritis Registry has prospectively followed all cases of glomerulonephritis starting from the time of biopsy. Focal segmental glomerulosclerosis was diagnosed by strict histologic criteria in 103 patients. Exclusion of patients with follow-up of less than 12 months reduced the number to 93 (55 adults and 38 children). Mean length of follow-up from the time of biopsy was 61 months. Ninety percent of children, but only 33 percent of adults received treatment with steroids, with or without cytotoxic drugs (p less than 0.001). Complete remission, defined as daily proteinuria of less than 250 mg, was not different in adults (39 percent) from that in children (44 percent), with a mean remission duration for all patients of 38 months. Chronic renal insufficiency, defined as a creatinine clearance of less than 0.8 ml/second/1.73 m2 for more than 12 months, was similar in adults (40 percent) and children (34 percent). Five-year renal actuarial survival, defined as the absence of chronic renal insufficiency, was 96 percent for patients with a history of complete remission, and 55 percent for those without (p less than 0.0002). Logistic regression analysis showed treatment to be the only significant factor for complete remission (p less than 0.001). Complete remission, in turn, was important for renal preservation, defined as the absence of chronic renal insufficiency (p less than 0.001). Age did not affect the treatment response or long-term renal outcome in focal segmental glomerulosclerosis. yet, the percent of adults treated was much lower than that of children, despite the fact that the majority of the untreated adults had the same clinical parameters as the treated adults and children. Thus, a judicious course of treatment is as much indicated in adults as in children with this disorder.

A patient with end-stage renal failure, two previously failed kidney transplants and high serum lymphocytotoxic antibody levels was transplanted electively with an ABO-mismatched, HLA-identical kidney from his sibling. Immunosuppression consisted of pretransplant splenectomy and plasma exchange, followed by rabbit antithymocyte serum, azathioprine, prednisone and plasma exchange in the early post-transplant period. He is now 3 years post-transplant with normal renal function on conventional immunosuppressive therapy. This case, and a review of the literature, suggest that ABO blood group incompatibility need not be an absolute barrier to successful kidney transplantation. ABO incompatible kidney transplantation may be a potentially fruitful area for further research as the demand for donor organs continues to outstrip the supply.

In two patients right atrial ball thrombi developed following prolonged subclavian cannulation for hemodialysis. One patient died, the other had the ball thrombus removed by open heart surgery. It appears that repeated friction of the catheter tip may have damaged the endothelium of the right atrial wall. This hitherto unrecognised complication might be prevented by ensuring that subclavian hemodialysis catheters are never allowed to reach as far as the right atrium.