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Gary S Hill

Publications and source records attributed to Gary S Hill.

7 recordsLinked to original sources
PubMed2006

Parietal podocytes in normal human glomeruli.

Although parietal podocytes along the Bowman's capsule have been described by electron microscopy in the normal human kidney, their molecular composition remains unknown. Ten human normal kidneys that were removed for cancer were assessed for the presence and the extent of parietal podocytes along the Bowman's capsule. The expression of podocyte-specific proteins (podocalyxin, glomerular epithelial protein-1, podocin, nephrin, synaptopodin, and alpha-actinin-4), podocyte synthesized proteins (vascular endothelial growth factor and novH), transcription factors (WT1 and PAX2), cyclin-dependent kinase inhibitor p57, and intermediate filaments (cytokeratins and vimentin) was tested. In addition, six normal fetal kidneys were studied to track the ontogeny of parietal podocytes. The podocyte protein labeling detected parietal podocytes in all of the kidneys, was found in 76.6% on average of Bowman's capsule sections, and was prominent at the vascular pole. WT1 and p57 were expressed in some parietal cells, whereas PAX2 was present in all or most of them, so some parietal cells coexpressed WT1 and PAX2. Furthermore, parietal podocytes coexpressed WT1 and podocyte proteins. Cytokeratin-positive cells covered a variable part of the capsule and did not express podocyte proteins. Tuft-capsular podocyte bridges were present in 15.5 +/- 3.7% of the glomerular sections. Parietal podocytes often covered the juxtaglomerular arterioles and were present within the extraglomerular mesangium. Parietal podocytes were present in fetal kidneys. Parietal podocytes that express the same epitopes as visceral podocytes do exist along Bowman's capsule in the normal adult kidney. They are a constitutive cell type of the Bowman's capsule. Therefore, their role in physiology and pathology should be investigated.

Adult↗
PubMed2005

Class IV-S versus class IV-G lupus nephritis: clinical and morphologic differences suggesting different pathogenesis.

BACKGROUND: A recently proposed reclassification of lupus nephritis divides class IV (diffuse proliferative) lupus nephritis into those cases with predominantly segmental proliferative lesions (class IV-S) and those with predominantly global proliferative lesions (class IV-G). This report explores the validity of this distinction and possible differences in pathogenesis between the 2 types of lesions. METHODS: Patients from a previously reported series of severe lupus nephritis, with initial biopsies (Bx1) and control biopsies (Bx2) at 6 months after induction therapy were reclassified according to the newly proposed classification. From the original series of 65 patients, 15 patients were reclassified as having class IV-S lesions and 31 patients class IV-G lesions. Clinical data at both biopsies and follow-up were available on all patients selected. RESULTS: Patients with IV-G lesions had worse proteinuria, lower serum hemoglobins, lower CH50s, and likely higher SCrs (P = .06) and lower C3s (P = .08) than class IV-S patients. Serum CH50 and C3 correlated negatively with severity of class IV-G lesions, but not at all with class IV-S lesions. Patients with class IV-G lesions had greater overall immune deposits and subendothelial deposits on IF and greater hyaline deposits on light microscopy. By contrast, class IV-S showed predominant mesangial deposits and a much higher rate of glomerular fibrinoid necroses (13.3 +/- 15.3% vs. 5.6 +/- 8.0% of viable glomeruli, P = .03). Other distinctions included the fact that membranoproliferative features were found only in class IV-G lesions, and glomerular monocyte/macrophages were much more frequent in this group than in class IV-S lesions (1.77 +/- 0.92 vs. 0.86 +/- 0.77, P = .008). Finally, class IV-G frequently involved all viable glomeruli (74.2% of cases), whereas segmental proliferative lesions never did (P < .0001). Survivals from doubling of SCr at 10 years did not differ between the 2 types at Bx1: 72.5% segmental versus 60.4% global, P= .53. However, among those with persistent lesions at Bx 2 (11 IV-S and 9 IV-G), there was a dramatic difference in 10-year survivals between IV-S lesions (63.6%) and IV-G lesions (0%), P = .08. CONCLUSION: There are definite clinical and morphologic differences between class IV-S and IV-G lesions. Data suggest that class IV-G lesions behave as an immune complex disease, having positive correlations with extent of immune deposits and negative correlations with serum complement levels, the model traditionally assumed for lupus nephritis as a whole. However, in class IV-S lesions, the presence of proportionally greater glomerular fibrinoid necroses and lack of correlation with extent of immune deposits suggest that these lesions may have a different pathogenesis.

Adult↗
PubMed2003

Morphometric study of arterioles and glomeruli in the aging kidney suggests focal loss of autoregulation.

BACKGROUND: In the past it was widely assumed that hyaline afferent arteriolosclerosis was responsible for ischemic glomerulosclerosis in the aging and hypertensive kidney. However, glomerular lesions of focal segmental glomerulosclerosis are now recognized in essential hypertension. Experimentally, such lesions are associated with loss of autoregulation of blood flow and glomerular hyperperfusion, as well as initial glomerular hypertrophy. These observations challenge the notion of ischemia as a unitary explanation for glomerulosclerosis. METHODS: A morphometric study was performed on normal portions of eight kidneys removed for tumors in aging, normotensive patients. Measurements were made of 126 pairs of afferent arterioles and their associated glomeruli. In addition, the amount of extracellular matrix (ECM) in the immediate periglomerular region was quantitated. RESULTS: Afferent arterioles were divided into three types according to the presence or absence of hyaline deposits and whether these did or did not obstruct the lumen. Arterioles with nonobstructive hyaline deposits had lumens over twice as large as those without deposits (482 +/- 240 micro2 vs. 204 +/- 160 micro2, P=0.0000). Their associated glomeruli had significantly greater total capillary area, particularly the hilar capillaries (1276 +/- 797 micro2 vs. 667 +/- 492 micro2, P=0.002), but with larger individual capillaries elsewhere as well (P=0.03). Arterioles with obstructive deposits differed from those with nonobstructive deposits by their smaller lumens (P=0.001) and walls (P=0.004), with a higher proportion of ECM in the periglomerular region (P=0.001), all consistent with a later stage of lesion. Glomeruli were divided into four basic types: normal, hypertrophic, glomeruli with features of focal segmental glomerulosclerosis (FSGS-type), and ischemic. Compared to normal glomeruli, hypertrophic glomeruli were larger, with greater total capillary area (P=0.0005), particularly the hilar capillaries (P=0.0000), and larger capillaries in the remainder of the tuft (P=0.003), but showed no evident lesions. FSGS-type glomeruli were also larger, with larger hilar capillaries (P=0.0005), but showed an increase in ECM due to sclerotic lesions (P=0.004). The remaining capillaries showed an inverse relation with the amount of mesangial matrix, showing a spectrum of sizes from enlarged to shrunken. As anticipated, ischemic glomeruli were significantly smaller than normal ones in every parameter measured. There was a strong association between hypertrophic/FSGS-type glomeruli and hyaline arteriolosclerosis, found in 90.3% of such glomeruli, versus 29.1% for the remaining glomeruli (P=0.0001). The great majority of hyaline deposits were of the nonobstructive variety (86.2%), but some were obstructive (13.8%), particularly in FSGS-type glomeruli, consistent with a more advanced lesion. CONCLUSIONS: We believe we have demonstrated in the aging kidney of humans the morphologic correlates of loss of autoregulation, occurring on a focal basis, with afferent arteriolar dilatation and increase in glomerular capillary size and subsequent focal segmental glomerulosclerosis. Hyaline arteriolosclerosis of the nonobstructive sort is strongly associated with these changes and may play a role in their pathogenesis.

Adult↗
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

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

Outcome of relapse in lupus nephritis: roles of reversal of renal fibrosis and response of inflammation to therapy.

BACKGROUND: Renal relapse in lupus nephritis has been shown to have ominous prognostic significance with the majority of patients progressing to doubling of serum creatinine (CRX2). However, not all patients do so. This report explores the roles of response of inflammation to therapy and of glomerular scarring and interstitial fibrosis and their potential reversal to outcome of renal relapse. METHODS: Renal biopsies from 71 patients with lupus nephritis with an initial biopsy (Bx1) and systematic control biopsy (Bx2) after six months of therapy, as well as subsequent biopsies for clinical indications, were studied. The relationships of morphologic factors to renal relapse and its outcome as well as to CRX2 and end-stage renal disease (ESRD) were analyzed. Cox proportional hazards modeling was used to assess association of morphologic variables with outcomes. RESULTS: Renal interstitial fibrosis and glomerular segmental scarring were partially reversible in 17 and 11 patients, respectively. This decline was associated with an excellent prognosis, with only one patient in each group (5.9% and 9.1% respectively) progressing to CRX2. All 18 patients who progressed to CRX2 either failed to respond to therapy (7 patients) as defined by normalization of serum creatinine (SCr) and reduction of proteinuria to < or =1 g/day, or relapsed after initial response (11 patients), as defined by recent rise of SCr > 50% and/or proteinuria > 3.5 g/day. However, relapse also occurred in 11 of 47 other patients without progression to CRX2. These patients showed a greater initial response of inflammation and deposits to therapy and fibrous lesions partially reversed in the period prior to relapse, so that active lesions were superimposed on a lower level of chronic lesions. By contrast, chronic lesions mounted steadily in those who progressed to CRX2. Cox proportional hazards modeling indicated a strong association of inflammatory variables with renal relapse, CRX2 and ESRD. However, the extent of immunoglobulin deposits was not significantly associated with any outcome. Finally, we found that failure of disease to remit also is associated with a high rate of CRX2 (64.8% vs. 13.0%, P = 0.00034). CONCLUSIONS: Interstitial fibrosis and glomerular scarring in systemic lupus erythematosus are partially reversible, and this reversal is attended by an excellent outcome. The outcome of renal relapse is determined by the initial response of inflammatory and chronicity elements to therapy, those with prior partial reversal of interstitial and glomerular scarring having a good outcome, and those in whom fibrotic lesions have continued to increase and have a poor outcome. Inflammatory variables appear to be more important in determining outcome than immunoglobulin deposits.

Chronic Disease↗