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PubMed2002

Deaths associated with inappropriate intravenous colchicine administration.

Intravenous (IV) colchicine is occasionally prescribed for the treatment of acute gouty arthritis. The Food and Drug Administration (FDA) recently received a report of death in a patient that was associated with inappropriate IV dosing of colchicine. This report prompted further investigation of other deaths associated with IV colchicine use in the FDA Adverse Event Reporting System (AERS) and the medical literature. A total of 20 deaths were identified. Eight patients were females, 11 were males, and the gender was unknown in 1. In all cases, the recommended maximum cumulative dose of 2 to 4 mg during a course of therapy was exceeded. Dose reductions are recommended in patients with renal or hepatic disease and in the elderly. All reported adverse events were associated with colchicine toxicity, including thrombocytopenia, leukopenia, pancytopenia, agranulocytosis, aplastic anemia, acute renal failure, and disseminated intravascular coagulopathy. Death occurred within 1 to 40 days after drug administration. Therapeutic guidelines exist for use of IV colchicine and these guidelines should be followed to prevent serious toxicities and death.

Acute Disease↗
PubMed2001

Colchicine and griseofulvin inhibit VCAM-1 expression on human vascular endothelial cells - evidence for the association of VCAM-1 expression with microtubules.

We have previously reported that griseofulvin inhibits VCAM-1 expression on human vascular endothelial cells. Since griseofulvin interferes with microtubule assembly, we used colchicine as another microtubule antagonist and compared it with griseofulvin to further characterize this inhibition. By flow cytometry, colchicine inhibited VCAM-1 induction on TNFalpha-stimulated human dermal microvascular endothelial cells (HDMEC) dose-dependently. Colchicine also inhibited VCAM-1 induction on both TNFalpha- and IL-1alpha-stimulated human umbilical vein endothelial cells (HUVEC). Although this inhibition was reversible, colchicine-treated cells showed slower restoration of its expression than griseofulvin-treated cells. Moreover, co-incubation with a microtubule stabilizer paclitaxel blocked this inhibition, and colchicine-treated cells were more resistant to this blocking than griseofulvin. RT-PCR of HDMEC showed inhibition of the transcript level of VCAM-1 by both antagonists. These results indicate intimate association between VCAM-1 expression and microtubules.

Cells, Cultured↗
PubMed1992

Colchicine photosensitizes covalent tubulin dimerization.

Pure rat brain tubulin can be cross-linked by ultraviolet irradiation of tubulin-colchicine complexes at the high-wavelength maximum of colchicine to form covalent dimers greater than trimers greater than tetramers. With colchicine concentrations approximately 3 x 10(-4) M (mole ratio to tubulin 3-12) and irradiation for 5-10 min at 95-109 mW/cm2, the yield of dimers is 11-17% and of trimers is 4-6% of the total tubulin. The oligomers show polydispersity and anomalously high apparent molecular masses that converge toward expected values in low-density gels. Maximal dimer yields are obtained with MTC and the decreasing photosensitizing potency is MTC greater than colchicine greater than colchicide greater than isocolchicine greater than thiocolchicine. Single-ring troponoids also promote dimerization. Evidence is presented suggesting that the initial, low-affinity, binding step of colchicine and its analogues is sufficient to photosensitize tubulin dimerization.

Animals↗
PubMed1992

Mechanism of binding of the new antimitotic drug MDL 27048 to the colchicine site of tubulin: equilibrium studies.

MDL 27048 [trans-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2- methyl-2-propen-1-one] fluoresces when bound to tubulin but not in solution. This effect has been investigated and found to be mimicked by viscous solvents. Therefore, MDL 27048 appears to be a fluorescent compound whose intramolecular rotational relaxation varies as a function of microenvironment viscosity. The binding parameters of MDL 27048 to tubulin have been firmly established by fluorescence of the ligand, quenching of the protein fluorescence, and gel equilibrium chromatography. The apparent binding equilibrium constant was (2.75 +/- 0.45) x 10(6)M-1, and the binding site number was 0.81 +/- 0.12 (10 mM sodium phosphate-0.1 mM GTP, pH 7.0, at 25 degrees C). The binding is exothermic. The binding of MDL 27048 overlaps the colchicine and podophyllotoxin binding sites. Binding of MDL 27048 to the colchicine site was also measured by competition with MTC [2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-one] , a well-characterized reversibly binding probe of the colchicine site [Andreu et al. (1984) Biochemistry 23, 1742-1752; Bane et al., (1984) J. Biol. Chem. 259, 7391-7398]. In contrast with close analogues of colchicine, MDL 27048 and podophyllotoxin neither affected the far-ultraviolet circular dichroism spectrum of tubulin, within experimental error, nor induced tubulin GTPase activity. Like podophyllotoxin, an excess of MDL 27048 over tubulin induced no abnormal cooperative polymerization of tubulin, which is characteristic of colchicine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Molecular mechanism of colchicine action: induced local unfolding of beta-tubulin.

Colchicine, the classic antimitotic poison, disrupts cell division by preventing proper assembly of microtubules in the mitotic spindle. Colchicine is known to act by binding to tubulin, the heterodimeric subunit of microtubules. How this binding to tubulin changes the structure of the protein and results in polymerization poisoning has not been characterized. The structural locus of spectroscopically detected conformational changes induced by colchicine is unknown. We report here that colchicine induces the unfolding of a small region in the carboxyl-terminal region of beta-tubulin, around Arg-390. This unfolding is detected by proteolysis with trypsin and chymotrypsin. Chymotrypsin cleaves this region after Phe-389, and trypsin cleaves after Lys-392. The unfolded region appears to be the carboxyl end of an amphipathic helix in the absence of colchicine, and we propose that this unfolding prevents contacts necessary for assembly. Our results suggest that beta-tubulin is exposed on the growing end of the microtubule, which provides a mechanism for coupling GTP hydrolysis to polymerization.

Amino Acid Sequence↗
PubMed1984

Interaction of tubulin with bifunctional colchicine analogues: an equilibrium study.

The interaction of tubulin with simple analogues of colchicine that contain both its tropolone and trimethoxyphenyl rings has been characterized, and the results were analyzed in terms of the simple bifunctional ligand model developed for the binding of colchicine [ Andreu , J. M., & Timasheff , S. N. (1982) Biochemistry 21, 534-543] on the basis of interactions of tubulin with single-ring analogues. The compound 2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6- cycloheptatrien -1-one has been found to bind reversibly to 0.86 +/- 0.06 site of purified calf brain tubulin with an equilibrium constant of (4.9 +/- 0.3) X 10(5) M-1 (25 degrees C), delta H degrees app = -1.6 +/- 0.7 kcal mol-1, and delta S degrees app = 20.5 +/- 2.5 eu. The binding appears specific for the colchicine site. The closely related compound 2-methoxy-5-[[3-(3,4,5-trimethoxyphenyl)-propionyl]amino] -2,4,6- cycloheptatrien -1-one interacts weakly with tubulin. Binding of the first analogue is accompanied by ligand fluorescence appearance, quenching of protein fluorescence, perturbation of the far-ultraviolet circular dichroism of tubulin, and induction of the tubulin GTPase activity, similarly to colchicine binding. Substoichiometric concentrations of the analogue inhibit microtubule assembly in vitro. Excess analogue concentration under microtubule-promoting conditions induces an abnormal cooperative polymerization of tubulin, similar to that of the tubulin-colchicine complex.

Animals↗
PubMed1986

Interaction of tubulin with octyl glucoside and deoxycholate. 2. Protein conformation, binding of colchicine ligands, and microtubule assembly.

The structural change induced by binding of mild detergents to cytoplasmic calf brain tubulin and the effects on the functional properties of this protein have been characterized. Massive binding of octyl glucoside or deoxycholate monomers induces circular dichroism changes indicating a partial alpha-helix to disordered structure transition of tubulin. The protein also becomes more accessible to controlled proteolysis by trypsin, thermolysin, or V8 protease. This is consistent with the looser protein structure proposed in previous binding and hydrodynamic studies [Andreu, J. M., & Muñoz, J. A. (1986) Biochemistry (preceding paper in this issue)]. Micelles of octyl glucoside and deoxycholate bind colchicine and its analogue 2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-one (MTC). This impedes the determination of colchicine binding in the presence of detergents. Both detergents cause a reduction in the number of tubulin equilibrium binding sites for the colchicine site probe MTC. Deoxycholate monomers bind poorly to the tubulin-colchicine complex, but deoxycholate above the critical micelle concentration effectively dissociates the complex. Microtubule assembly in glycerol-containing buffer is inhibited by octyl glucoside, which raises the critical protein concentration. Low concentrations of deoxycholate enhance tubulin polymerization, allowing it to proceed without glycerol. The polymers formed are microtubules, pairwise associated open microtubular sheets, and macrotubules possibly generated by helical folding of the sheets, as indicated by the optical diffraction patterns. Saturation of tubulin with octyl glucoside, followed by full dissociation of the detergent, allowed the recovery of binding to the colchicine site and microtubule assembly, indicating the reversibility of the protein structural change.

Animals↗
PubMed1990

The carboxy terminus of the alpha subunit of tubulin regulates its interaction with colchicine.

Controlled proteolysis of goat brain tubulin by subtilisin was carried out to investigate regulatory aspects of the binding of colchicine to tubulin. Tubulin S, obtained by the cleavage of the carboxyl termini of both the alpha- and beta-subunits of tubulin by subtilisin, exhibited the following differences compared to native tubulin: (a) Reaction with colchicine, which has an optimum pH of 6.8, becomes independent of pH (in the range 5.7-8.0). (b) The colchicine-binding site, which is labile at 37 degrees C (t1/2 = 4-5 h), becomes highly stable (t1/2 greater than 12 h). (c) The affinity for colchicine is lowered. (d) This lowering of affinity arises from a faster dissociation (higher off rate) of the complex. The above characteristics of tubulin S were not shown by a partially digested hybrid in which the C-terminus of the beta-subunit alone was cleaved. The hybrid behaved very much like the undigested native protein. These results strongly suggest that the regulatory switch for colchicine-tubulin interaction is located in a small region (about 15 residues) of the C-terminus of the alpha-subunit of tubulin. Possibilities of the C-termini being involved in nonbonded contacts with the main body of tubulin are also noticed from the change in conformation between tubulin and tubulin S.

Animals↗
PubMed2000

Antitumor agents. 199. Three-dimensional quantitative structure-activity relationship study of the colchicine binding site ligands using comparative molecular field analysis.

Inhibitors of tubulin polymerization interacting at the colchicine binding site are potential anticancer agents. We have been involved in the synthesis of a number of colchicine site agents, such as thiocolchicinoids and allocolchicinoids, which are colchicine analogues, and 2-phenyl-quinolones and 2-aryl-naphthyridinones, which are the amino analogues of cytotoxic antimitotic flavonoids. The most cytotoxic of the latter compounds strongly inhibit binding of radiolabeled colchicine to tubulin, and these agents therefore probably bind in the colchicine site of tubulin. We have applied conventional CoMFA and q(2)-GRS CoMFA to identify the essential structural requirements for increasing the ability of these compounds to form tubulin complexes. The CoMFA model for the training set of 51 compounds yielded cross-validated R(2) (q(2)) values of 0.637 for conventional CoMFA and 0.692 for q(2)-GRS CoMFA. The predictive power of this model was confirmed by successful activity prediction for a test set of 53 compounds with known potencies as inhibitors of tubulin polymerization. The activities of 88% of the compounds were predicted with absolute value of residuals of less than 0.5. The predictive q(2) values were 0.546 for conventional CoMFA and 0.426 for q(2)-GRS CoMFA. The conventional CoMFA model with the highest predictive q(2) (0.546) was analyzed in detail in terms of underlying structure-activity relationships.

Antineoplastic Agents↗
PubMed2004

Synthesis and characterization of a cobalamin-colchicine conjugate as a novel tumor-targeted cytotoxin.

Colchicine was derivatized at C7 with p-alkoxyacetophenone and conjugated to cobalamin (vitamin B(12)) through an acid-labile hydrazone linker. The cobalamin moiety leads to preferential uptake of the cobalamin-colchicine prodrug by cancer cells, whereupon the hydrazone linker undergoes hydrolysis in the lysosome to unmask colchicine, which acts as a potent cytotoxin by stabilizing microtubules and causing cell death. The bioconjugate is stable in cell culture media and at neutral pH but undergoes hydrolysis with a half-life of 138 min at pH 4.5. The colchicine-cobalamin bioconjugate exhibits nanomolar LC(50) values against breast, brain, and melanoma cancer cell lines in culture. Attachment of colchicine to cobalamin is expected to increase the therapeutic index of the drug by limiting the side effects caused by the current nonselective administration of tubulin-targeted chemotherapeutic drugs.

Cell Line, Tumor↗
PubMed2002

Dexamethasone attenuates by colchicine induced Fos expression in the rat deep cerebellar and vestibular nuclei.

1. The intent of the present study was to find out whether dexamethasone pretreatment may affect the induction of Fos protein in cell nuclei of the cerebellar vestibular neuronal complex (CVNC) elicited by central administration of colchicine. Specifically, the rate of the dexamethasone-sensitive cell population was analyzed and compared at different levels of the CVNC using a light microscopic avidin-biotin peroxidase immunohistochemistry. 2. Male Wistar rats were pretreated with dexamethasone 3 days prior (2.5 mg/kg/day, s.c.) and 24 h after an intracerebroventricular delivery of colchicine (60 microg/10 microL). Animals were sacrificed 48 h after colchicine treatment by a transcardial perfusion with fixative. 3. Dexamethasone in itself had no effect on the activity of cells of the CVNC. However, in colchicine treated animals, which exhibited a large number of Fos-positive cells over the entire CVNC, the dexamethasone elicited a substantial reduction in the number of the Fos-immunoreactive cells over the CVNC. Distinct dexamethasone dependent reduction (50-90%) of Fos-immunoreactivity was observed in each of the deep cerebellar nuclei. On the other hand, less number of dexamethasone-sensitive cells were recognized in the vestibular structures. From these, maximal Fos-inhibition by dexamethasone was recognized in the medial vestibular nucleus, however, even in this case the number of suppressed cells did not exceed 50%. 4. The results provide for the first time evidence about the dexamethasone dependent reduction of Fos-immunoreactivity in the cells of the CVNC in response to stimulation elicited by colchicine. The data also indicate that the glucocorticoids might be involved in the regulation of some functions of the CVNC under stress conditions.

Animals↗
PubMed1980

Colchicine kinetics in patients with familial Mediterranean fever.

Serum colchicine levels were determined by radioimmunoassay after a 1-mg bolus injected intravenously in 4 patients with familial Mediterranean fever and in 6 normal subjects. Mean elimination half-life (t1/2) (+/- SEM) was 157 +/- 20 min in the patients and 65 +/- 15 min in the normal subjects (p less than 0.005). Total clearance was 239 +/- 50 ml/min in the patients and 601 +/- 155 ml/min in the normal subjects (p less than 0.05). Volume of distribution (Vdarea) was 76 +/- 16 and 49 +/- 91 and did not differ significantly. In 8 patients receiving colchicine prophylactically with good clinical response, serum colchicine ranged from 0.3 to 2.4 ng/ml after daily doses of 1 mg orally. In 2 responding patients 2-mg doses orally induced levels from 4 to 10 ng/ml, and in one (a nonresponder) a 3-mg dose induced levels of 7.5 to 13 ng/ml. Of 3 patients receiving 2 mg daily with unsatisfactory clinical responses, serum levels were not detectable in one and in the low range of 1.5 to 5.4 ng/ml in the others. It is suggested that lack of response to colchicine orally in some nonresponders could result from inadequate absorption or altered disposition of colchicine.

Adult↗
PubMed2004

Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain.

Microtubules are cytoskeletal polymers of tubulin involved in many cellular functions. Their dynamic instability is controlled by numerous compounds and proteins, including colchicine and stathmin family proteins. The way in which microtubule instability is regulated at the molecular level has remained elusive, mainly because of the lack of appropriate structural data. Here, we present the structure, at 3.5 A resolution, of tubulin in complex with colchicine and with the stathmin-like domain (SLD) of RB3. It shows the interaction of RB3-SLD with two tubulin heterodimers in a curved complex capped by the SLD amino-terminal domain, which prevents the incorporation of the complexed tubulin into microtubules. A comparison with the structure of tubulin in protofilaments shows changes in the subunits of tubulin as it switches from its straight conformation to a curved one. These changes correlate with the loss of lateral contacts and provide a rationale for the rapid microtubule depolymerization characteristic of dynamic instability. Moreover, the tubulin-colchicine complex sheds light on the mechanism of colchicine's activity: we show that colchicine binds at a location where it prevents curved tubulin from adopting a straight structure, which inhibits assembly.

Amino Acid Sequence↗
PubMed2004

Therapeutic effects of colchicine in the management of Peyronie's disease: a randomized double-blind, placebo-controlled study.

To determine effectiveness and safety of colchicine in Peyronie's disease. In all, 84 patients with Peyronie's disease who did not have calcified plaque were entered into study. The mean disease duration was 15 months. A medical history was obtained, and physical examination, penile X-ray, and dynamic penile duplex ultrasound were performed. Patients were randomly divided into group 1, those who received 0.5-2.5 mg colchicine daily for 4 months and group 2, who received placebo for the same period. Response to therapy was assessed objectively, during dynamic penile duplex ultrasound, as well as subjectively using International Index of Erectile Function (IIEF) questionnaire and measurements of pain, duration of disease, penile curvature, and plaque size. Differences before and after treatment and among the three Kelami classification groups were assessed. In total, 78 (92.8%) completed the whole treatment schedule. Pain resolved in 60 and 63.6% of the patients treated with colchicine and placebo, respectively (P > 0.05). After therapy, in subjects and controls a reduction in the penile deformity was observed by 17.1 and 18.4% of the patients (P > 0.05), and a decrease in plaque size was noticed by 10.5 and 10%, respectively (P > 0.05). Objective measurements did not demonstrate any difference in plaque size or penile curvature. There were no substantial differences in response to treatment based on duration of disease or within the three Kelami classification groups. Significant drug-related adverse effects occurred in colchicine group and in two cases was treatment discontinued. Colchicine is no better than placebo in improvement of pain, curvature angle, or plaque size in patients with Peyronie's disease.

Adult↗
PubMed1975

Evidence for the coupling of biosynthesis and secretion of serum albumin in the rat. The effect of colchicine on albumin production.

1. By using isotopic-dilution techniques it was found that colchicine causes a slight increase in the proalbumin content of liver, from 0.63+/-0.06 to 0.83+/-0.10mg/g of liver, but has no effect on albumin content (0.50+/-0.05mg/g of liver). All the proalbumin and 67% of the albumin is found in vesicles from which they are liberated by detergents. 2. Colchicine inhibits secretion of albumin, decreases the rate of conversion of proalbumin into albumin and decreases the rate of incorporation of l-[1-(14)C]leucine into proalbumin. 3. Balance studies in vivo show that all the (14)C appearing in serum albumin can be accounted for by the flow of (14)C through the proalbumin, in the presence or absence of colchicine. 4. When cycloheximide is given to the rats, 2min after [(14)C]leucine, further synthesis of protein stops. The label in proalbumin disappears and the proalbumin content of the liver falls, so as to account for the albumin appearing in the plasma. This occurs both in the presence and in the absence of colchicine. By contrast, there is little change in liver albumin. Studies with isolated perfused livers are in agreement with the above. Lumicolchicine has no effect on any of these systems at doses at which colchicine exerts its action. 5. These results suggest that biosynthesis and conversion of proalbumin into albumin, and secretion of serum albumin are controlled at each step.

Amino Acids↗
PubMed1979

Synthesis of membrane glycoproteins in rat small-intestinal villus cells. Effect of colchicine on the redistribution of L-[1,5,6-3H]fucose-labelled membrane glycoproteins among Golgi, lateral basal and microvillus membranes.

To define the role of cytoplasmic microtubules in the biogenesis of plasmalemma glycoproteins of rat small-intestinal villus cells, we studied the effect of colchicine on the incorporation of L-[1,5,6-3H]fucose into Golgi, lateral basal and microvillus membranes. Colchicine was administered intraperitoneally before or after injection of radioactive fucose. The incorporation of radioactivity into Golgi membranes was little affected by colchicine, which did not prevent the redistribution of most of the labelled glycoproteins from the Golgi complex into other parts of the villus cell. The incorporation of labelled glycoproteins into the microvillus membrane was greatly inhibited by colchicine given 2 h or 10 min before the radioactive fucose: all labelled glycoproteins present in this membrane were equally affected. In contrast, the administration of colchicine considerably increased the incorporation of radioactivity into the lateral basal part of the plasmalemma, and prevented the disappearance of most of the labelled glycoproteins from this membrane at late times after fucose injection. These results suggest that cytoplasmic microtubular structures are important for the polarization of the intestinal villus cell and the biogenesis of the microvillus membrane, although playing little or no role in the movement of membrane components from the Golgi complex to the lateral basal part of the plasmalemma.

Animals↗
PubMed2002

NHE3 and NHERF are targeted to the basolateral membrane in proximal tubules of colchicine-treated rats.

BACKGROUND: Depolymerization of microtubules in proximal tubule (PT) cells of colchicine-treated rats causes disruption of vesicle recycling and redistribution of some brush-border membrane (BBM) transporters into cytoplasmic vesicles. NHE3, an isoform of the Na+/H+ exchanger in the PT cell BBM, is acutely regulated by a variety of mechanisms, including protein trafficking and interaction with the PDZ protein, NHERF. The effects of microtubule disruption by colchicine on NHE3 trafficking in PT and the potential role of NHERF in this process have not been studied. METHODS: Immunofluorescence and immunogold cytochemistry were performed on cryosections of kidney tissue, and immunoblotting of BBM isolated from the renal cortex and outer stripe of control and colchicine-treated (3.2 mg/kg, IP, a single dose 12 hours before sacrifice) rats. RESULTS: In cells of the convoluted PT (S1/S2 segments) of control rats, NHE3 was located mainly in the BBM; subapical endosomes were weakly stained. In cells of the straight PT (S3 segment), NHE3 was present in the BBM and in lysosomes. In colchicine-treated rats, there was a marked redistribution of NHE3 from the BBM into intracellular vesicles and the basolateral plasma membrane in the S1/S2 segments. In the S3 segment, the abundance of BBM NHE3 was not visibly changed, but NHE3-positive intracellular organelles largely disappeared, and the antigen was detectable in the basolateral plasma membrane. The PDZ protein NHERF followed a similar pattern: in control animals, it was strong in the BBM and negative in the basolateral membrane in cells along the PT. After colchicine treatment, expression of NHERF in the basolateral membrane strongly increased in all PT segments, where it colocalized with NHE3. CONCLUSIONS: The data indicate that: (a) microtubules are involved in the apical targeting of NHE3 and NHERF in renal PT cells, and (b) the parallel basolateral insertion of NHE3 and NHERF may represent an indirect targeting pathway that involves transient, microtubule-independent basolateral insertion of these proteins, followed by microtubule-dependent, vesicle-mediated transcytosis to the BBM.

Animals↗
PubMed1986

Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever.

To determine whether colchicine prevents or ameliorates amyloidosis in patients with familial Mediterranean fever, we followed 1070 patients with the latter disease for 4 to 11 years after they were advised to take colchicine to prevent febrile attacks. Overall, at the end of the study, the prevalence of nephropathy was one third of that in a study conducted before colchicine was used to treat familial Mediterranean fever. Among 960 patients who initially had no evidence of amyloidosis, proteinuria appeared in 4 who adhered to the prophylactic schedule and in 16 of 54 who admitted non-compliance. Life-table analysis showed that the cumulative rate of proteinuria was 1.7 percent (90 percent confidence limits, 0.0 and 11.3 percent) after 11 years in the compliant patients and 48.9 percent (18.8 and 79.0 percent) after 9 years in the noncompliant patients (P less than 0.0001). A total of 110 patients had overt nephropathy when they started to take colchicine. Among 86 patients who had proteinuria but not the nephrotic syndrome, proteinuria resolved in 5 and stabilized in 68 (for more than eight years in 40). Renal function deteriorated in 13 of the patients with proteinuria and in all of the 24 patients with the nephrotic syndrome or uremia. We conclude that colchicine prevented amyloidosis in our high-risk population and that it can prevent additional deterioration of renal function in patients with amyloidosis who have proteinuria but not the nephrotic syndrome.

Actuarial Analysis↗