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Biomedical subjects

Alain Meyrier

Publications and source records attributed to Alain Meyrier.

18 recordsLinked to original sources
PubMed2005

[Atherosclerosis and the kidney].

Diffuse atherosclerosis entails a 15-30% risk of plaques on renal arteries (ARAS), with a correlation with coronary atherosclerosis. Ischemia induces generation of angiotensin II (Ang II) that maintains sufficient hydrostatic pressure within the tuft to preserve the GFR. Ang II inhibition suppresses this protective mechanism. In fact, any antihypertensive drug may lead to reaching a "critical perfusion pressure". ARAS should be suspected in case of renal asymmetry. It should also be envisaged in case of "flash pulmonary edemas". Ultrasonography and renal tomography show aortic calcifications and often the outline of an abdominal aortic aneurysm. Tomodensitometry may detect large aorto-renal plaques. Spiral scanner tomography represents a progress, in terms of renal artery imaging and of renal cortical atrophy. Magnetic resonance imaging is less accurate but avoids iodine toxicity. The best noninvasive method is pulsed echo-doppler. It is particularly useful for evaluating stenoses progression. Some stenoses progress to renal atrophy and renal artery thrombosis, whereas others follow a stable course. Pulsed Doppler helps predict whether revascularization will improve renal function, according to the resistance index. Renal arteriography entails a high risk of cholesterol crystal embolism. However, it is the obligatory first step for angioplasty and stent positioning, indicated when the kidney is not atrophic. The indication for revascularization essentially depends on evaluation of the benefits vs risks of angioplasty or surgery. Some publications underscore the frequent stability of renal function and the fact that, revascularized or not, most patients will shortly die of myocardial infarction. Renal cholesterol crystal embolism (CCE) is a severe condition, which occurs when large arteries undergo surgery, aortography or interventional radiology. Anticoagulants are a frequent cause of CCE. CCE may also occur spontaneously, resulting in slowly progressive renal insufficiency. Migration of crystals in small caliber intrarenal arteries induces obstruction, followed by an inflammatory reaction. The clinical picture resembles angiitis, with laboratory evidence of inflammation along with high eosinophil counts and hypocomplementemia. Diagnosis rests on: 1) a iatrogenic event in a patient with an atherosclerotic background; 2) examination of the skin disclosing purple toes, small necrotic lesions and livedo of the lower limbs. Crystals may also be found by funduscopy. Skin or muscle biopsy are contributive in showing crystals and help avoid renal biopsy; 3) other localizations involve the mesenteric circulation and the central nervous system. Until recently, the prognosis was considered disastrous. However, a recently published treatment schedule proved efficient in reducing mortality. A last issue regarding the relationships between atherosclerosis and the kidney deserves mention. In an autopsy-based study it was shown that atherosclerosis per se is accompanied by an increase in the glomerular surface area along with a greater proportion of obsolescent glomeruli by comparison with matched controls. Finally, it should be recalled that atherogenic hyperlipidemia usually aggravates the course of any renal disease, including ARAS. Treatment with statins is indicated in all forms of atherosclerotic renal disease.

Atherosclerosis↗
PubMed2005

Mechanisms of disease: focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS), a subtype of "idiopathic nephrotic syndrome", is not a single disease, but a lesion that initially affects the glomerulus followed by the tubulointerstitium and renal vessels. The term 'FSGS' does not accurately encompass the various pathologic features of the glomerulus, which are not always focal, segmental or sclerotic. Particular variants of FSGS, such as collapsing glomerulopathy and the glomerular tip lesion, exemplify the nosologic uncertainty inherent in the classification of glomerular lesions. Pathologic variation notwithstanding, all pathologic processes that affect the podocyte lead to one of the histologic subtypes of FSGS. This specialized cell type has essential roles in maintaining the integrity of glomerular architecture, resisting endocapillary hydraulic pressure and hindering egress of proteins into the urinary space. Once initiated, podocyte lesions and ensuing fibrosis are usually irreversible, at least in human forms of FSGS. Remarkable progress has been made in unraveling the mechanisms of podocyte dysregulation that accompany the cellular variants of FSGS and in identifying genetic mutations affecting proteins of the slit diaphragm. Hopefully, this progress will drastically improve treatments for what is one of the most difficult therapeutic challenges to confront the nephrologist.

Animals↗
PubMed2005

Podocyte involvement in human immune crescentic glomerulonephritis.

BACKGROUND: The role of podocytes in human crescentic glomerulonephritis (GN) has been underestimated. This may be due to the confounding fact that "dysregulated" podocytes are able to proliferate, lose their markers, and acquire new epitopes. Moreover, in experimental anti-glomerular basement membrane (GBM) crescentic GN, podocytes participate in the crescent formation. The aim of this study was to investigate the involvement of podocytes in human immune crescentic GN. METHODS: Renal biopsies from 12 patients with anti-GBM disease and 14 with class IV lupus GN were studied by immunohistochemistry for the following markers: (1) synaptopodin, GLEPP1, podocalyxin, podocin, alpha-actinin-4, and vimentin for podocyte identification; (2) PCNA, Ki-67, and p57 for cell cycle assessment; (3) cytokeratins for identifying epithelial cells but not normal podocytes; (4) CD68 for tagging a macrophagic epitope; (5) alpha-smooth-muscle actin (alpha-SMA), a phenotypic marker of myofibroblasts. RESULTS: "True" (capsular) crescents lining Bowman's capsule and (tuft) "pseudocrescents" covering the glomerular tuft with a persistent patent urinary space were present in the 2 types of crescentic GN in similar percentages. Several features indicated that podocytes were involved in the formation of the both crescent types. Identifiable podocytes expressed proliferation markers. Podocyte cytoplasmic expansions and racket-like podocytes bridged between the tuft and Bowman's capsule. True and pseudocrescents contained labeled podocytes. In addition, podocytes located outside of the crescents had often lost their markers (dedifferentiation) and acquired new epitopes (cytokeratins and CD68). CONCLUSION: In human immune crescentic GN, podocytes undergo proliferation and dysregulation that are indicative of a podocytopathy. Podocytes contribute to crescent formation.

Actins↗
PubMed2005

Treatment of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is not a disease, but a lesion affecting the podocyte. Secondary FSGS may be due to a host of various factors, and patients are rarely nephrotic, requiring symptomatic treatment only. The best prognostic feature of nephrotic FSGS is its response to corticosteroids. Some forms are most likely of immunological origin, relapse in a renal transplant and justify immunosuppressive treatment. In a growing number of cases, genetic profiling of molecules that contribute to the podocyte slit diaphragm permselectivity to albumin has identified defects that do not represent indications for immunosuppression. In the other forms, corticosteroids and cyclosporin A (CsA) remain the mainstay of treatment, with better efficacy when CsA is associated with steroids. The renal tolerability of CsA is reasonably good when the dosage is low. CsA dependency is not constant. Alkylating agents are reluctantly indicated in steroid-sensitive forms, which are rare. They are mostly ineffective in steroid-resistant forms. Tacrolimus seems a promising therapy with low toxicity, but it is usual for dependency on the drug to occur. Sirolimus seems to be ineffective. Azathioprine is not considered indicated, despite rare reports with favourable results, which would deserve further controlled trials. Recent publications indicate that mycophenolate mofetil might usefully find a place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the elusive substance that causes the nephrotic syndrome and its relapse on a transplant has not led to practical treatment options.

Alkylating Agents↗
PubMed2005

[Podocytopathie and transdifferentiation of the podocytes in human glomerulonephritis. An immunomorphological study].

Transdifferentiation is characterized by a loss of normal epitopes by differentiated cells, accompanied by the acquisition of new epitopes and new functions. Podocytes are differentiated epithelial cells that cover and adhere to the outer surface of the glomerular basement membrane (GBM). The podocyte/GBM complex contributes to the selective filter function of the glomerular tuft. We have shown that, in various human glomerulonephritides, "dysregulated" podocytes acquire the potential to proliferate and multiply, undergo profound morphologic changes, detach from the GBM, and show phenotypic changes indicative of transdifferentiation. In the course of these events they lose their original epitopes and acquire macrophagic markers.

Basement Membrane↗
PubMed2003

[Acute pyelonephritis].

Acute pyelonephritis is frequent. Its usual signs and symptoms comprise renal pain, fever, inflammation, and pyuria. Simple acute E. coli pyelonephritis is frequent in the young female and in most cases is a benign condition. A typical pyelonephritis may be painless, or without high fever, or lacking bacterial growth in the urine due to previous inappropriate treatment. Severe, complicated pyelonephritis is mainly observed in diabetic, alcoholic or immunocompromised patients. In occasional cases, a common form of pyelonephritis may progress to formation of a renal abscess requiring drainage. When secondary to urinary tract abnormalities, pyelonephritis may be complicated with septicemia and can induce early and severe renal tissue damage. This form warrants emergency urologic treatment. Simple pyelonephritis of the young female without febrile UTI history requires little imaging. Conversely, extensive imaging workup is mandatory in the male, the elderly, when treatment is not rapidly effective or in case of early relapse. In some cases, acute pyelonephritis leads to the development of cortical scars, the long-term prognosis of which remains to be determined.

Acute Disease↗
PubMed2003

In vivo expression of putative LMX1B targets in nail-patella syndrome kidneys.

The nail-patella syndrome (NPS) is characterized by nail and bone abnormalities, associated with glomerular involvement in approximately 40% of patients. Typical glomerular changes consist of fibrillar material in the irregularly thickened glomerular basement membrane. NPS is inherited as an autosomal dominant trait and caused by heterozygous loss of function mutations in LMX1B, a member of the LIM homeodomain protein family. Mice with homozygous inactivation of the gene exhibit nail and skeletal defects, similar to those observed in patients, associated with glomerular abnormalities. Strong reduction in the glomerular expression of the alpha3 and alpha4 chains of type IV collagen, and of podocin and CD2AP, two podocyte proteins critical for glomerular function, has been observed in Lmx1b null mice. The expression of these proteins appeared to be regulated by Lmx1b. To determine whether these changes in podocyte gene expression are involved in the development of NPS nephropathy, using immunohistological techniques, we analyzed the podocyte phenotype and the renal distribution of type IV collagen chains in the kidneys of seven NPS patients with severe glomerular disease. We also examined the nature of the fibrillar material present within the glomerular extracellular matrix. The glomerular basement membrane fibrillar material was specifically labeled with anti-type III collagen antibodies, suggesting a possible regulation of type III collagen expression by LMX1B. The expression of the alpha3 and alpha4 chains of type IV collagen, and of podocin and CD2AP, was found to be normal in the seven patients. These findings indicate that heterozygous mutations of LMX1B do not appear to dramatically affect the expression of type IV collagen chains, podocin, or CD2AP in NPS patients.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Clinical and morphological prognostic factors in membranous nephropathy: significance of focal segmental glomerulosclerosis.

BACKGROUND: Progression of idiopathic membranous glomerulonephritis (IMGN) to renal insufficiency depends on various clinical and laboratory factors that have been taken into account in most therapeutic trials based on such aggressive drugs as alkylating agents or cyclosporine. However, few studies have envisaged the prognostic significance of morphological factors and their importance for stratification of patients enrolled in therapeutic trials. METHODS: Records of patients with membranous glomerulonephritis (MGN) from 1976 to 2001 from five nephrology units were reviewed retrospectively. Secondary causes were ruled out, especially occult malignancy. Eligible cases were analyzed according to clinical profile, abundance of proteinuria, blood pressure, and standard renal pathological characteristics, including MGN staging, vascular lesions, and degree of interstitial fibrosis on a semiquantitative scale. Renal survival curves from renal insufficiency were calculated by the Kaplan-Meier method. Mean follow-up was 68 months. RESULTS: Initial multiple regression analysis showed that the most significant prognostic variable was the presence of focal segmental glomerulosclerosis (FSGS)-type glomerular lesions (P < 0.001), and patients therefore were divided into two groups: 42 patients had MGN only (group I) and 30 patients had superimposed FSGS (group II). Group II patients were more hypertensive, and all renal lesions were significantly more severe, with a higher mean stage of membranous lesions, more obsolescent glomeruli, greater mesangial proliferation, and worse interstitial fibrosis and vascular lesions. Renal survival for group II was significantly lower (P < 0.001, log-rank test). Only one remission occurred in group II, whereas 38% of group I patients experienced remission (P = 0.002). We pooled our results with those of three previous studies in the literature, totaling 282 patients (156 patients, MGN alone; 126 patients, MGN plus FSGS). Remission rates were 32% and 12.7%, respectively (P < 0.001). The prognostic value of hypertension was noted in three of the four series, including ours. CONCLUSION: FSGS lesions superimposed on IMGN are common and portend a significantly worse outcome in terms of nephrotic syndrome and renal insufficiency. Therefore, we consider that future therapeutic trials of IMGN should include case stratification based on the presence or absence of FSGS on pretreatment biopsy.

Adolescent↗
PubMed2003

E pluribus unum: The riddle of focal segmental glomerulosclerosis.

A recent consensus conference proposed a new classification for focal segmental glomerulosclerosis (FSGS). Five patterns have been defined: FSGS not otherwise specified, perihilar variant, cellular variant, tip variant, and collapsing variant. In light of the multiplicity of classification schemes in use, the promise of a rational and uniform scheme for FSGS pathology is most welcome. This approach has worked extremely well for the classification of lupus nephritis. It does not necessarily mean, however, that this new classification scheme will help to select treatment protocols according to histopathologic subsets of FSGS. In fact, one renal biopsy examination may show multiple variants and this classification, despite many merits, still lumps categories that should be split and splits categories that should be lumped together. It has become clear that despite its histologic diversity FSGS begins as a podocyte disease that progresses from a cellular to a scar lesion. Recent years have brought about astonishing insight into the complex molecular array of proteins forming the slit diaphragm between podocyte foot processes, a narrow space essential for restricting glomerular permeability to albumin. Concentrating on the podocyte rather than on the glomerular tuft is helpful for abolishing the classic distinction between primary versus secondary forms of FSGS, a distinction that crumbles away with each new evidence of genetic, ischemic, or viral etiologies of FSGS, despite similar lesions. In fact, recent studies focusing on the podocyte changes that occur in various subsets of FSGS have unraveled the striking phenomena of podocyte dedifferentiation and transdifferentiation along with differential expression of cyclin-dependent kinase inhibitors. Interestingly, the latter showed that expression of cyclin-dependent kinase inhibitors p21 and proliferation marker Ki-67 are the same in cellular FSGS, collapsing glomerulopathy, and human immunodeficiency virus-associated FSGS. Taken together these findings lead to a reassuring unitary interpretation of the pluralistic appearance of FSGS by histopathology. Clearly, further studies of the podocyte will lead to improved understanding of FSGS and to improved classification schemes that are grounded in molecular understanding of glomerular injury and that will guide the clinician in the choice of treatment and prognosis.

Animals↗
PubMed2003

Treatment of idiopathic nephrosis by immunophillin modulation.

Until 1985, glucocorticoids and cytotoxic drugs were the only treatments available for idiopathic nephrotic syndrome (nephrosis), that is, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). Trials of cyclosporine (CsA) treatment of nephrosis, the rationale of which was based on pathophysiologic considerations, have shown that this immunophillin modulator is effective in inducing and maintaining remission in patients suffering from idiopathic nephrotic syndrome. It appears that the best results, in the order of 80% remission rate, are obtained in steroid-sensitive cases, essentially MCD, and that in steroid-resistant FSGS the drug obtains remission in no more than 20% of the cases. Addition of glucocorticoids increases the success rate to approximately 30% of cases. Renal toxicity is proportional to previous impairment of renal function, primary renal disease (FSGS vs MCD) dosage >5.5 mg/kg/day and duration of treatment. The better bioavailability of the new formulation of CsA (Neoral), implies that the former dosage recommendations be reconsidered for distinctly lower figures. Repeat renal biopsy after 1 year of continuous CsA treatment is advisable, as stable serum creatinine levels may be falsely reassuring. CsA dependency is the rule during the first year of treatment. However, in some 25% of cases stable remission may be maintained after slow tapering off following 3-4 years of treatment. Other immunophillin modulators have been tried in the treatment of idiopathic nephrotic syndrome. Despite few preliminary reports indicating some success of tacrolimus the effects of this drug do not seem convincingly superior to CsA in terms of remission rate, toxicity and dependency. Rapamycin has not been tried in the treatment of nephrosis. Anecdotal cases of de novo FSGS induced by rapamycin in transplanted patients might indicate that this drug is in fact contraindicated in the treatment of nephrosis.

Cyclosporine↗
PubMed2003

Glomerular epithelial-mesenchymal transdifferentiation in pauci-immune crescentic glomerulonephritis.

BACKGROUND: Among the cellular changes occurring in renal fibrosis, epithelial-mesenchymal cell transdifferentiation or transition (EMT) is a phenomenon characterized in epithelial cells by loss of epithelial markers and acquisition of mesenchymal phenotype and of fibrosing properties. METHODS: To test the hypothesis that EMT is involved in human pauci-immune crescentic glomerulonephritis (PICGN), we studied 17 renal biopsies from 11 PICGN patients for: (i) proliferating cell nuclear antigen (PCNA) and cell cycle inhibitors (cyclin-dependent kinase inhibitors) p27 and p57; (ii) cell lineage phenotype markers: podocalyxin, synaptopodin and GLEPP-1 for podocytes; CD68 for macrophagic epitope; CD3 for T lymphocytes; alpha-smooth muscle actin (alpha-SMA) for myofibroblasts; vimentin for mesenchymal cells; and cytokeratins (CKs) for parietal epithelial cells (PECs); (iii) glomerular fibrosis by labelling collagens I, III and IV, and heat-shock protein 47 (HSP47), a marker of collagen-synthesizing cells; and (iv) co-localization of alpha-SMA, CK and HSP47 using confocal laser microscopy. RESULTS: The crescent cells proliferated greatly. They did not express p27 and p57. Different cell lineage markers could be identified in crescents: the major component was made of 'dysregulated' PECs negative for CK, followed by PECs positive for CK, macrophagic cells and myofibroblasts. Furthermore, some cells co-expressed CK and alpha-SMA. This latter co-expression suggests a transitional phase in the dynamic phenomenon of EMT. Therefore, proliferative and dysregulated glomerular epithelial cells could be a possible cellular source of myofibroblasts via EMT. In addition, HSP47 labelled many crescent cells and frequently co-localized in CK-positive epithelial cells and in alpha-SMA-positive myofibroblasts, indicating that these cells were involved in glomerular accumulation of collagens. CONCLUSION: EMT is a transient cellular phenomenon present in glomeruli in human PICGN contributing to the formation of myofibroblasts from epithelial cells and to glomerular fibrosis.

Adult↗
PubMed2002

New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes.

Mutations of CIAS1 have recently been shown to underlie familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS), in three families and one family, respectively. These rare autosomal dominant diseases are both characterized by recurrent inflammatory crises that start in childhood and that are generally associated with fever, arthralgia, and urticaria. The presence of sensorineural deafness that occurs later in life is characteristic of MWS. Amyloidosis of the amyloidosis-associated type is the main complication of MWS and is sometimes associated with FCU. In FCU, cold exposure is the triggering factor of the inflammatory crisis. We identified CIAS1 mutations, all located in exon 3, in nine unrelated families with MWS and in three unrelated families with FCU, originating from France, England, and Algeria. Five mutations--namely, R260W, D303N, T348M, A439T, and G569R--were novel. The R260W mutation was identified in two families with MWS and in two families with FCU, of different ethnic origins, thereby demonstrating that a single CIAS1 mutation may cause both syndromes. This result indicates that modifier genes are involved in determining either a MWS or a FCU phenotype. The finding of the G569R mutation in an asymptomatic individual further emphasizes the importance of such modifier a gene (or genes) in determining the disease phenotype. Identification of this gene (or these genes) is likely to have significant therapeutic implications for these severe diseases.

Adolescent↗
PubMed2001

Posttransplantation relapse of FSGS is characterized by glomerular epithelial cell transdifferentiation.

This study examined six cases of idiopathic nephrotic syndrome with primary lesions of focal segmental glomerulosclerosis (FSGS) that relapsed after renal transplantation. The glomerular lesions comprised the cellular, the collapsing, and the scar variants of FSGS and showed shedding of large round cells into Bowman's space and within the tubular lumens. Immunohistochemistry and confocal laser microscopy carried out on kidneys with FSGS relapse disclosed several phenomena. (1) Some podocytes that expressed podocalyxin, synaptopodin, and glomerular epithelial protein-1 were detached from the tuft and were free in the urinary space. (2) In the cellular variant, most podocytes had lost podocyte-specific epitopes (podocalyxin, synaptopodin, glomerular epithelial protein-1, Wilm's tumor protein-1, complement receptor-1, and vimentin). In the scar variant, these podocyte markers were absent from cobblestone-like epithelial cells and from pseudotubules. (3) Podocytes had acquired expression of various cytokeratins (CK; identified by the AE1/AE3, C2562, CK22, and AEL-KS2 monoclonal antibodies) that were not found in the podocytes of control glomeruli. Parietal epithelial cells expressed AE1/AE3 CK that were faintly, if ever, found on the parietal epithelial cells of normal glomeruli. (4) Numerous cells located at the periphery of the tuft or free in Bowman's space and within tubular lumens expressed macrophagic epitopes (identified by PGM1 [CD68], HAM56, and 25F9 monoclonal antibodies). These macrophage-like cells expressed the activation epitopes HLA-DR and CD16. (5) A number of these cells coexpressed podocalyxin + AE1/AE3 CK, podocalyxin + CD68, and CD68 + AE1/AE3. These findings suggest that in primary FSGS relapsing on transplanted kidneys, some "dysregulated" podocytes, occasionally some parietal epithelial cells, and possibly some tubular epithelial cells undergo a process of transdifferentiation. This process of transdifferentiation was especially striking in podocytes that acquired macrophagic and CK epitopes that are absent from normal adult and fetal podocytes.

Antigens, CD↗