Kidney involvement in Takayasu arteritis.

OBJECTIVE: To evaluate whether the presence of glomerulonephritis is or is not associated with the extent of arterial wall inflammatory cell infiltrate in Takayasu arthritis (TA). METHODS: Retrospective chart and pathology review of large artery and kidney specimens of TA autopsy cases. Kidney specimens were classified, according to their histopathological findings, in those with specific glomerular entities and those with non-specific, ischemic and/or hypertensive, glomerular changes. A control group of autopsy kidney specimens was utilized for comparison. Morphometric analysis was used to assess the extent of the arterial inflammatory infiltrates; results were compared among the different groups with kidney lesions. RESULTS: We included 25 kidney specimens from 25 autopsies. Specific glomerular entities were present in 14 specimens; 10 (40%) were classified as diffuse mesangial proliferative glomerulonephritis (DMPG [Group A]), and 4 (16%) as other associated glomerulopathies (Group B). Non-specific changes were observed in 11 (44%) specimens (Group C). The arterial inflammatory infiltrate proportion was 9.4 % for group A, 1.4% for group B, and 2.7% for group C. Furthermore, a larger proportion of vascular inflammation was confirmed for group A when compared with the other groups (p<0.05). Group A patients were younger than those in groups B and C (p<0.005) and exhibited shorter disease duration. CONCLUSION: The presence of DMPG was associated with a larger extent of vascular inflammatory cell infiltrate, suggesting a relationship between both phenomena.

Morphology of vascular, renal, and heart lesions in the antiphospholipid syndrome: relationship to pathogenesis.

A growing body of evidence suggests that aPL are not only serological markers of the antiphospholipid syndrome (APS), but may also directly contribute to the development of thrombosis and other manifestations, including the APS vasculopathy. The latter has been documented in leptmeninges, lung, skin, myocardium, peripheral arteries, and kidney. Renal lesions, a common feature of primary antiphospholipid syndrome (PAPS), include occlusion of principal renal arteries or their main branches, TMA, cortical ischemia, and renal vein thrombosis. Within the cardiac manifestations associated with aPL, valvular involvement is the most common. Histologic findings in valve specimens are consistent with a noninflammatory lesion characterized by intravalvular capillary thrombosis, laminar or verrucous superficial thrombosis, vascular proliferation, fibrosis, and calcification. Even though there is general consensus that endothelial damage triggers the chain of events that results in valve thickening, fusion, rigidity, and ultimately functional abnormalities, we believe that more experimental work remains to be done on the initial valve insult in APS.

Alport syndrome and diffuse leiomyomatosis. Clinical aspects, pathology, molecular biology and extracellular matrix studies. A synthesis.

The Alport syndrome-diffuse leiomyomatosis association can be defined as a hereditary disease of type IV collagen combining features of Alport syndrome (hematuric nephropathy, deafness and ocular abnormalities: anterior lenticonus, maculopathy) and leiomyomatosis involving oesophagus (diffuse type), tracheobronchial tree, and genitals (only in women). This entity is transmitted as an X-linked dominant trait. Mutations of both the COL4A5 and COL4A6 genes, located head to head in Xq22 encoding the alpha 5 and alpha 6(IV) chains are responsible for the abnormalities. Molecular studies have shown deletions of the 5' end of both COL4A5 and COL4A6 including the intergenic region. The breakpoint in COL4A6 is always located within intron 2. Immunohistochemistry has shown significant alterations of basement membranes in the kidney and esophageal leiomyomas. Leiomyomas lack alpha 5 and alpha 6(IV) chains, fibronectin and laminin beta 1 chains in the muscle basement membranes where they are normally expressed. The tumors also show myocyte anomalies: irregular expression of the alpha 5 integrin subunits, and disorganization of actin and desmin filaments. It is hypothesized that a third as yet unknown gene, situated within the large intron 2 in a critical 90 kb region, is responsible for the smooth muscle proliferation. Abnormalities of the basement membranes could destabilize interactions between muscular cells and the extracellular matrix.

Increased endothelial cell expression of alpha3beta1 integrin in cardiac valvulopathy in the primary (Hughes) and secondary antiphospholipid syndrome.

The objective of this work was to determine markers of endothelial cell activation in valves from patients with antiphospholipid syndrome (APS) and heart valve involvement, in order to establish a role for endothelial cells in the pathogenesis of the valvular disease. Sixteen valves from ten patients with APS, obtained from autopsies or removed during valve replacement, were studied. Two groups of valves were used as controls. One group included seven normal valves from patients who died from non-cardiac diseases. The other group of valves were obtained from patients with bacterial endocarditis during autopsies or valve replacement operations. Immunoperoxidase and immunofluorescence stainings with antibodies to human immunoglobulins, endothelial cells, alpha3beta1 integrin, collagen IV, laminin and fibronectin were employed. Three histopathological patterns were apparent: normal valves, valves with verrucous endocarditis and valves with fibrocalcific changes. In all the valves with verrucous endocarditis the following findings were observed: (1) increased expression of the alpha3beta1 integrin on the endothelial cells, (2) increased amount of collagen IV, laminin and fibronectin, (3) proliferation of blood vessels and (4) linear subendothelial deposition of immunoglobulins and complement. The valves with fibrocalcific changes were deformed and showed a thick layer of collagen IV, laminin and fibronectin, yet in two valves the indothelial cells showed an expression of the alpha3beta1 integrin. The control valves did not express the integrin and had only a thin subendothelial band of collagen IV. In valves from patients with APS, 1 markers of endothelial cell activation are upregulated while the inflammatory exudate is scant. There is also a prominent deposition of immunoglobulins in the valves from patients with APS, suggesting a possible association between the deposition of the antibodies and the activation of the endothelial cells in APS.

[Does heart sarcoma mimick lupus erythematosus and vasculitis? Report of 2 cases]. / El sarcoma cardiaco simula lupus eritematoso y vasculitis? Informe de 2 casos.

Primary heart tumors are rare. The most common one is myxoma. It may synthetize IL-6 and frequently shown systemic clinical manifestations that confuse the diagnosis. Primary heart sarcomas are even more rare, as far as we know they have been not associated with systemic illnesses. We observed two cases with a presumptive diagnosis of systemic lupus erythematosus who were identified as primary sarcomatous heart neoplasms after surgical excision.

Role of NO in cyclosporin nephrotoxicity: effects of chronic NO inhibition and NO synthases gene expression.

The role of nitric oxide (NO) during cyclosporin renal vasoconstriction was evaluated by glomerular hemodynamic and histological changes produced by chronic NO synthesis inhibition and neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) NO syntheses mRNA expression in renal cortex and medulla. Uninephrectomized rats treated during 7 days with vehicle (Veh), cyclosporin A (CsA) 30 mg/kg, CsA + nitro-L-arginine methyl ester (L-NAME), and Veh + L-NAME (10 mg/dl) in the drinking water were studied. Increase in arterial pressure and afferent and efferent resistances, as well as decrease in glomerular plasma flow, ultrafiltration coefficient, and single-nephron glomerular filtration rate were significantly greater with CsA + L-NAME than with CsA alone. The increase in afferent resistance was higher with CsA + L-NAME than with Veh + L-NAME. In addition, glomerular thrombosis, proximal tubular vacuolization, and arteriolar thickening were more prominent. In renal cortex, eNOS mRNA expression exhibited a 2.7-fold increase in CsA, whereas, in medulla, nNOS and iNOs expression were lower in CsA than in Veh, while eNOS tended to increase. Our results support the hypothesis that NO synthesis is enhanced at cortical level during CsA nephrotoxicity, counterbalancing predominantly preglomerular vasoconstriction. Higher NO production could be the result of increased eNOS mRNA expression.

Absence of ANCA in Mexican patients with Takayasu's arteritis.

Antineutrophil cytoplasmic autoantibodies (ANCA) were sought in 43 sera from 39 Mexican patients with typical Takayasu's arteritis (TA), (5 with active and 34 with inactive disease), and in a comparative group comprising 50 sera. Results were negative in all cases. This suggests that ANCA are not a serologic feature in TA per se, even during its active stage. ANCA positivity in TA, when present, may be a non-related phenomenon and probably identifies a subset of patients with atypical forms of TA or a polyangiitis overlap syndrome.

Primary antiphospholipid syndrome presenting as chronic thromboembolic pulmonary hypertension. Treatment with thromboendarterectomy.

Pulmonary hypertension may occur in the antiphospholipid syndrome as a result of recurrent pulmonary embolism or microthrombosis of pulmonary vessels. We describe 3 cases of primary antiphospholipid syndrome (APS) and cor pulmonale that fulfilled the criteria for chronic major vessel thromboembolic pulmonary hypertension. Pulmonary thromboendarterectomy was performed in all 3 patients and it was successful in 2. One patient died in the immediate postoperative period from hemorrhagic pulmonary edema. Chronic thromboembolic pulmonary hypertension should be added to the list of pulmonary vascular complications of primary APS. Despite its risk, pulmonary thromboendarterectomy represents a treatment option for this otherwise lethal condition.

Valvular heart disease in primary antiphospholipid syndrome (PAPS): clinical and morphological findings.

PURPOSE: To describe clinically and pathologically the valvular lesion of the primary antiphospholipid syndrome (PAPS). PATIENTS AND METHODS: We studied six patients with PAPS and valvulopathy. Four of them died and had autopsy and two had valvular replacement. The study comprised 18 heart valves, 16 from autopsy and two, one mitral and one aortic, resected at surgery. RESULTS: Murmurs and echocardiographic findings kept correlation with gross pathology. Abnormalities were found in one or more valves in all patients including two of five aortic, two of five mitral, one of four pulmonary and two of four tricuspid. Co-existence of new and old lesions was observed. Pathologic findings included intravalvular thrombosis with focal necrosis, and hemorrhage, vascular proliferation, mild histiocytic/fibroblastic infiltration, laminated and verrucous fibrin deposits, laminated and/or nodular fibrosis, and focal calcification. CONCLUSION: The PAPS valvular lesion consists mainly of superficial or intravalvular fibrin deposits and its subsequent organization: vascular proliferation, fibroblast influx, fibrosis and calcification. This results in valve thickening, fusion and rigidity leading to functional abnormalities. Inflammation is not a prominent feature of this lesion.

Role of nitric oxide in renal hemodynamic abnormalities of cyclosporin nephrotoxicity.

To evaluate the participation of nitric oxide (NO) in chronic cyclosporin A (CsA) nephrotoxicity, the glomerular hemodynamic response to NO inhibition with N-nitro-L-arginine-methyl-ester (NAME) and stimulation of NO production with L-arginine was studied in uninephrectomized rats. Chronic CsA administration produced renal vasoconstriction, characterized by increased afferent (AR) and efferent (ER) resistances, decrease of glomerular plasma flow (QA) and ultrafiltration coefficient (Kf) that resulted in a 53% fall of single-nephron glomerular filtration rate (SNGFR). NAME infusion in vehicle group (V) elevated mean arterial pressure (MAP), AR and ER, reduced qA and Kf, and increased glomerular capillary pressure (PGC), resulting in a 28.9% fall of SNGFR. In the CsA group, NAME also increased MAP, but renal vasoconstriction was more intense; a greater rise of AR lowered PGC (P < 0.05 vs. V) further decreasing SNGFR by 38.9%. In control rats, L-arginine infusion induced a vasodilatory response of AR and ER, and elevation of QA and Kf, which resulted in a 72.6% increase in SNGFR. In the CsA group, greater vasodilation was observed and SNGFR rose by 114.9%. NO2-/NO3- urinary excretion was similar in CsA and V groups, and it was not modified by NAME in either group, but it increased five- to sixfold during L-arginine infusion in both groups. In conclusion, in CsA nephrotoxicity NO production seems to be normal and the ability of the renal endothelium to produce NO is maintained. Therefore renal vasoconstriction associated with CsA is not mediated by NO deficiency, although NO appears to attenuate it.

Recurrent renal thrombotic angiopathy after kidney transplantation in two patients with primary antiphospholipid syndrome (PAPS).

Renal artery and venous thrombosis and thrombotic microangiopathy have been related to PAPS. This condition may lead to end-stage renal disease (ESRD). We present 2 patients with PAPS and ESRD who received a living unrelated kidney transplant. Despite intensive anticoagulant therapy, the disease recurred in the grafts.

Renal biopsy in systemic lupus erythematosus: significance of glomerular thrombosis. Analysis of 108 cases.

We investigated the frequency and distribution of glomerular thrombosis (GT) in 108 renal biopsies of lupus patients and correlated this finding with the presence of anticardiolipin antibodies (ACLA). GT was present mainly in the diffuse proliferative form. The activity index was higher in those patients with GT (12.9 +/- 4.7 vs 5.4 +/- 4.1, P < 0.01). The more severe histologic features, necrosis and extracapillary proliferation were also related with GT. In 18 cases with repeated biopsy the best predictors for the subsequent development of glomerular sclerosis were fibrinoid necrosis (P < 0.01), glomerular infiltration (P < 0.01) and an activity index of 10 or more (P < 0.05). GT also showed to be an important prognostic factor for sclerosis, although no statistically significant. ACLA were investigated in 36 patients at the time of renal biopsy. There were nine positive cases and in three of them this finding was related to GT. We can conclude that GT is a relevant feature showing active lupus nephritis and that it is not related to the presence of ACLA.

Alport-leiomyomatosis syndrome: an update.

Alport-leiomyomatosis syndrome is a polygenic syndrome with a dominant X-linked inheritance pattern resulting from a large deletion in the 5' end of the COL4A5 gene coding for the type IV collagen alpha 5 chains. Hypothetically, the deletion extends beyond the 5' end and probably includes a second contiguous gene responsible for leiomyomatosis (the DL gene) and even a third one coding for congenital cataract (the CCT gene).

[Alport's syndrome: new findings]. / Síndrome de Alport: nuevos conocimientos.

The Alport's syndrome is a disease characterized by a symptomatic triad: nephropathy, hypoacusia and ocular alterations. This syndrome is genetically heterogeneous and results from numerous mutations in COL4A5 gene, whose locus resides on the long arm of the X chromosome (Xq22). This gene codifies for IV collagen alpha 5 chain, which is a fundamental constituent of the glomerular, lens and Corti's organ basal membranes. Present knowledge on molecular genetics and the characterization of the different mutations that affect the Alport's gene will lead to classification of this syndrome in subtypes, according to those mutations, and to its phenotypic expressions; in addition, some syndromes, phenotypically similar, will probably have to be distinguished from Alport's disease, in a future, if a genetic alteration is found in genes other than COL4A5.

Mechanisms involved in the progression to glomerular sclerosis induced by systemic hypertension during mild puromycin aminonucleoside nephrosis.

To evaluate the contribution of systemic hypertension in the progression of nephropathies to glomerular sclerosis, a mild form of puromycin aminonucleoside (PAN) nephrosis was associated with Goldblatt hypertension and studied after 18 weeks. We studied four groups: Group I, controls; Group II, Goldblatt hypertension; Group III, PAN nephrosis; and Group IV, both conditions. Systolic blood pressure, 24-h proteinuria, serum cholesterol, triglycerides, glomerular hemodynamics, and histological studies were compared among the groups. Rats in groups II and IV developed systemic hypertension, but only group IV rats showed persistent proteinuria. No alterations in lipid metabolism were present in any of the groups. The most striking findings in the micropuncture studies were a significant increase of glomerular capillary pressure in group IV rats (63.15 +/- 1.34 mm Hg) as compared to controls (48.74 +/- 0.97 mm Hg) and to groups II and III (55.31 +/- 2.11 and 48.17 +/- 1.23 mm Hg, respectively), and a marked fall in Kf in groups III and IV. Only group IV showed significant histological alterations such as glomerular sclerosis, interstitial damage, and increased glomerular area. These results suggest that, in the presence of an underlying nephropathy, a greater fraction of systemic pressure is transmitted to the glomerular capillaries when systemic hypertension is present; the resulting elevation in glomerular pressure and proteinuria seems to be responsible for the progression to glomerular sclerosis.

Renal involvement in primary antiphospholipid syndrome.

Our objective was to define the renal involvement in primary antiphospholipid syndrome (APS). We studied 20 patients with primary APS. Fourteen were women, mean age 34.4 years. None met ARA criteria for systemic lupus erythematosus. All patients underwent complete renal function studies. The presence of hypertension was also investigated. Renal disease was found in 5 patients, and was characterized by proteinuria, hypertension and renal failure. Kidney biopsy was performed in these 5 patients, showing thromboses of the microvasculature, mesangiolysis, mesangial interposition, electron lucent subendothelial material and ischemic obsolescence of glomeruli. Arterioles showed luminal narrowing due to medial hypertrophy, mucoid thickening of the intima, thrombosis and fibrosis. We found renal disease in 25% of our patients with primary APS. Biopsy findings were consistent with a thrombotic microangiopathy involving both arterioles and glomerular capillaries.

[Drash's syndrome and its variants. A report of 3 cases]. / Síndrome de Drash y sus variantes. Informe de 3 casos.

Three cases of Drash syndrome (DS) are presented. Two of them were 2 years old, the third one a newborn. Two are autopsy cases, one of the patients is alive. All three of them had nephrotic syndrome and renal failure, with mesangial sclerosis. All three had ambiguous genitalia, abdominal testes with variable degrees of dysgenesis and bilateral gonadoblastoma. Two cases had 46XY karyotype, in one case it was not performed. Two patients had nephroblastoma, one of them after several months of nephropathy, in the other it was the cause of consultation. The patient without nephroblastoma died at the age of 26 days with renal failure. We think that the original triad of DS: nephroblastoma, pseudohermaphroditism and nephropathy should be more precisely described and expanded to include related alterations in each one of its 3 elements: nephroblastomatosis, hamartomas, probably mesoblastic nephroma and pyelocaliceal malformations in addition to Wilms' tumor, variable disorders of sexual differentiation, gonadal dysgenesis and neoplasia, in addition to pseudohermaphroditism and superficial cortical renal dystrophy and increased reniculi, in addition to mesangial sclerosis. The various clinical forms of the syndrome are combinations of the triad in which a component can be missing and/or other related malformations be present. Chromosome anomalies are possibly responsible for this phenomena. Splitting into separate syndromes should not be done until the chromosome alterations and the regions and genes involved are identified.