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• W2104771467 abstract "Global glomerulosclerosis can be divided in the vascular (obsolescent) type and the glomerulopathic (solidified) type. In biopsies from children with recurrent nephrotic syndrome owing to minimal change nephropathy (MCN), we noticed small, globally sclerosed glomeruli that appeared to be distinct from global glomerulosclerosis. These small sclerosed glomeruli are best described as involuted glomeruli. We have characterized these involuted glomeruli in detail. We studied biopsies of 18 children (11 male, 7 female) with frequently relapsing MCN and evaluated possible explanatory variables. The involuted glomeruli can be differentiated from the other types of global glomerulosclerosis. Most notable is the presence of vital podocytes and parietal epithelial cells, which have retained their staining characteristics, in between the matrix, and the absence of periglomerular and tubulo-interstitial fibrosis. We observed involuted glomeruli in 12 out of 18 biopsies; the median percentage of involuted glomeruli was 6% (range 0–33%). The percentage of involuted glomeruli correlated with age at renal biopsy and the interval between onset of disease and time of renal biopsy, but not with gender, age at onset of disease, or prednisone dose. Multivariate analysis revealed that the interval between onset of disease and time of renal biopsy was the only independent predictor. In conclusion, glomerular involution is a special form of global glomerulosclerosis. The absence of periglomerular and tubulo-interstitial fibrosis suggests a different pathogenesis. Glomerular involution is a slow process. The clinical data suggest that involution is related to the duration of the disease process. Global glomerulosclerosis can be divided in the vascular (obsolescent) type and the glomerulopathic (solidified) type. In biopsies from children with recurrent nephrotic syndrome owing to minimal change nephropathy (MCN), we noticed small, globally sclerosed glomeruli that appeared to be distinct from global glomerulosclerosis. These small sclerosed glomeruli are best described as involuted glomeruli. We have characterized these involuted glomeruli in detail. We studied biopsies of 18 children (11 male, 7 female) with frequently relapsing MCN and evaluated possible explanatory variables. The involuted glomeruli can be differentiated from the other types of global glomerulosclerosis. Most notable is the presence of vital podocytes and parietal epithelial cells, which have retained their staining characteristics, in between the matrix, and the absence of periglomerular and tubulo-interstitial fibrosis. We observed involuted glomeruli in 12 out of 18 biopsies; the median percentage of involuted glomeruli was 6% (range 0–33%). The percentage of involuted glomeruli correlated with age at renal biopsy and the interval between onset of disease and time of renal biopsy, but not with gender, age at onset of disease, or prednisone dose. Multivariate analysis revealed that the interval between onset of disease and time of renal biopsy was the only independent predictor. In conclusion, glomerular involution is a special form of global glomerulosclerosis. The absence of periglomerular and tubulo-interstitial fibrosis suggests a different pathogenesis. Glomerular involution is a slow process. The clinical data suggest that involution is related to the duration of the disease process. With advancing age the number of globally sclerosed glomeruli in the human kidney increases. This is a more or less physiological phenomenon that is related to arteriosclerosis. More than 10% globally sclerosed glomeruli is considered as pathological for persons over the age of 40 years.1.Kappel B. Olsen S. Cortical interstitial tissue and sclerosed glomeruli in the normal human kidney, related to age and sex. A quantitative study.Virchows Arch A Pathol Anat Histol. 1980; 387: 271-277Crossref PubMed Scopus (139) Google Scholar,2.Kaplan C. Pasternack B. Shah H. Gallo G. Age-related incidence of sclerotic glomeruli in human kidneys.Am J Pathol. 1975; 80: 227-234PubMed Google Scholar Two types of global glomerulosclerosis can be distinguished: the vascular type (also referred to as obsolescent type) and the glomerulopathic type (also referred to as solidified type).3Jennette J.C. Olson J.L. Schwartz M.M. Heptinstall's Pathology of the Kidney. 5th edn. Lippincott Williams & Wilkins, Philadelphia, New York1998: 137-167Google Scholar Vascular glomerulosclerosis is characterized by a retracted glomerular tuft without tuft adhesions, surrounded by a hypocellular homogeneous collagenous matrix in the former Bowman's space (only recognizable in a silver or periodic acid-Schiff stain). Glomerulopathic sclerosis is characterized by a solidified non-retracted glomerular tuft with often recognizable tuft adhesions and without the homogeneous collagenous matrix in Bowman's space. The former is mostly associated with decreased perfusion resulting from arterial intimal fibrosis in aging or hypertension, whereas the latter form is the result of ongoing damage in glomerular diseases. It has been suggested that global sclerosis may also occur without renal disease as part of a normal damage and repair process. In fact, globally sclerosed glomeruli have been found in children below the age of 2 years.4.Emery J.L. Macdonald M.S. Involuting and scarred glomeruli in the kidneys of infants.Am J Pathol. 1960; 36: 713-723PubMed Google Scholar Notably, global glomerulosclerosis is always accompanied by tubulo-interstitial fibrosis. In recent years, Kriz et al.5.Kriz W. Hartmann I. Hosser H. et al.Tracer studies in the rat demonstrate misdirected filtration and peritubular filtrate spreading in nephrons with segmental glomerulosclerosis.J Am Soc Nephrol. 2001; 12: 496-506PubMed Google Scholar have proposed the concept of misdirected filtration as a mechanism by which glomerulosclerosis leads to periglomerular and tubulo-interstitial fibrosis. We recently noticed globally sclerosed glomeruli that appeared to be distinct from either vascular or glomerulopathic glomerulosclerosis in biopsies from children with recurrent nephrotic syndrome. These sclerosed glomeruli are characterized by a marked reduction in size and apparent lack of accompanying tubular atrophy and interstitial fibrosis. Small globally sclerosed glomeruli in the setting of congenital or childhood nephrotic syndrome in children <1 year have been previously noticed by others and were referred to as ‘microglomeruli’ in the old literature.6.Sibley R.K. Mahan J. Mauer S.M. Vernier R.L. A clinicopathologic study of forty-eight infants with nephrotic syndrome.Kidney Int. 1985; 27: 544-552Abstract Full Text PDF PubMed Scopus (51) Google Scholar However, it has not been investigated whether these glomeruli truly represent a distinct type of sclerosis. It was reported that their presence does not predict prognosis in the setting of congenital nephrotic syndrome, but other than that their potential meaning has not been addressed. In the present study, we have characterized these glomeruli in detail by light microscopy, immunostainings, and electron microscopy, and made a comparison with the classical vascular type of glomerulosclerosis and the glomerulopathic type of glomerulosclerosis in the setting of focal and segmental glomerulosclerosis (FSGS). In addition, we have studied biopsies of children with a frequently relapsing minimal change nephrotic syndrome (MCNS) for the presence of involuted glomeruli and evaluated possible explanatory variables. Our findings indicate that the small globally sclerosed glomeruli in the setting of childhood nephrotic syndrome represent a unique type of glomerular injury, best described by the term glomerular involution. We hypothesize that this is a special form of glomerulosclerosis with a different pathogenesis. We initially noticed the presence of small globally sclerosed glomeruli without accompanying interstitial changes in biopsies of children with recurrent nephrotic syndrome. Of note, these small sclerosed glomeruli were not seen in five biopsies from children with non-nephrotic kidney disease. We have characterized these small sclerosed glomeruli, which will be referred to as glomerular involution, in detail and made comparison with globally sclerosed glomeruli of the glomerulopathic type and vascular type. As compared to the classical forms of global sclerosis, in involution there is a marked reduction in diameter (approximately a quarter of the diameter of an open glomerulus). In the silver stainings with low power magnification, involuted glomeruli appear as small black nodules without apparent accompanying interstitial changes (Figure 1a). For comparison see Figure 2a and b for globally sclerosed glomeruli of the glomerulopathic and vascular type, respectively. In fact, if present in low numbers involuted glomeruli can easily be overlooked. They are mostly evenly distributed throughout the cortex, although sometimes there is a predominant subcapsular localization. On closer examination, involuted glomeruli are made up of strong staining (non-hyalinized) extracellular matrix, comparable to the matrix observed in glomerulopathic sclerosis. This matrix, likely composed of remnants of the glomerular basement membrane (GBM) and Bowman's capsule, has the appearance of an interconnecting network in continuity with the former glomerular tuft and Bowman's capsule (Figure 1b and c). In addition, a small number of vital appearing cells are usually seen unlike in vascular sclerosis, where the contracted tuft does usually not contain any cells (see below). Remarkably, there is no splitting or duplication of Bowman's capsule, as is usually observed in glomerulopathic sclerosis. Also, there is no stromal reaction or hypercellularity of the surrounding interstitium, which is usually markedly present in glomerulopathic sclerosis and to a lesser extent also in vascular sclerosis. A few atrophic tubular structures, probably remnants of the tubular apparatus, can often be identified in proximity of involuted glomeruli (Figure 1b, arrow). Electron microscopy confirmed the presence of vital appearing cells that cover either the GBM or Bowman's capsule in the involuted glomeruli, whereas these are absent in the other types of global glomerulosclerosis (data not shown). Identifiable interrupted stretches of GBM are seen and both the GBM and Bowman's capsule are in part thickened (Figure 3, arrows).Figure 2(a) Types of global glomerulosclerosis: an example of glomerulopathic glomerulosclerosis also referred to as solidified type as shown in panel a. Glomerulopathic glomerulosclerosis is characterized by a solidified non-retracted glomerular tuft with often recognizable tuft adhesions, splitting of Bowman's capsule, and prominent periglomerular fibrosis. (b) An example of vascular glomerulosclerosis is shown in panel b. This type is characterized by the retracted glomerular tuft, surrounded by a hypocellular homogeneous collagenous matrix in the former Bowman's space, without tuft adhesions. There usually is moderate periglomerular fibrosis (original magnification a, b: × 500).View Large Image Figure ViewerDownload (PPT)Figure 3Transmission electron microscopy of an involuted glomerulus: the observations by light microscopy (Figure 1) are confirmed at high magnification by electron microscopy. Involuted glomeruli show an interconnecting network of GBM and Bowman's capsule. Vital appearing cells are present. Cells that cover the GBM show foot process effacement and sometimes a single cell forms bridges between Bowman's capsule and the GBM (arrows). The former GBM and Bowman's capsule are thickened by irregular duplication and matrix deposition (original magnification × 7000).View Large Image Figure ViewerDownload (PPT) We characterized the three types of global glomerulosclerosis, glomerular involution (Figures 4 (a–d), 5 (a–d) and 6 (a–d)), glomerulopathic glomerulosclerosis (Figures 4 (e–h), 5 (e–h) and 6 (e–h)), and vascular glomerulosclerosis (Figures 4 (i–l), 5 (i–l) and 6 (i–l)), by immunostainings for synaptopodin and CD10 (podocytes), CK8 and PAX2 (parietal cells), CD68 (macrophages), α-smooth muscle actin, (myofibroblasts, mesangial cells), CD34 (endothelium), vimentin and extracellular matrix components collagen I, III, and IV, and the α1 and α5 chain of collagen IV (Table 1).Figure 5Extracellular matrix characteristics in (a–d) glomerular involution, (e–h) glomerulopathic glomerulosclerosis, and (i–l) vascular glomerulosclerosis. Collagen IV stains all of the matrix in (a) glomerular involution, (e) glomerulopathic sclerosis, and only the contracted glomerular tuft in (i) vascular glomerulosclerosis. Collagen I only stains the hyalinized extracellular matrix filling Bowman's space in (j) vascular glomerulosclerosis. (c and d) The interconnecting network in involuted glomeruli stains for both the α-1 and α-5 chain of collagen IV. (g and h) Staining of the α-1 and α-5 chain of collagen IV was also seen in glomerulopathic glomerulosclerosis, whereas in (k) vascular glomerulosclerosis Bowman's capsule stains for the α-1 chain and (l) the contracted tuft stains for the α-5 chain of collagen IV (original magnification a–d: × 400; e–l: × 250).View Large Image Figure ViewerDownload (PPT)Figure 6Staining characteristics of the periglomerular region in (a–d) glomerular involution, (e–h) glomerulopathic glomerulosclerosis, and (i–l) vascular glomerulosclerosis. (a, e, and i) CK8 is an activation marker of PECs in FSGS and is not expressed within the different types of sclerosed glomeruli but only stains tubular epithelium. In glomerulopathic and vascular sclerosis, the periglomerular fibrosis is highlighted by staining for vimentin and SMA (smooth muscle actin) (myofibroblasts) and CD34 (periglomerular capillaries). (b and d) Note the absence of interstitial reaction in glomerular involution (original magnification a–d: × 400; e–l: × 250).View Large Image Figure ViewerDownload (PPT)Table 1Antibodies used for the detection of glomerular antigensAntigenPrimary antibodyDilutionSupplier/referencePodocyte components SynaptopodinMouse anti-synaptopodin1Progen, Heidelberg, Germany CD10Mouse anti-human CD1050Monosan, Caltag lab., BurlinggamePEC components PAX-2Rabbit anti-human PAX-250Zymed laboratories Inc., San Francisco, CA, USA CytokeratinMouse anti-human CAM 5.2 (CK8)50BD Biosciences, San Diego, CA, USAMiscellaneous α-SMAMouse anti-human SMA15 000Sigma, St Louis, MO, USA EndotheliumMouse anti-human CD3440Monosan, Caltag lab., Burlinggame VimentinMouse anti-human vimentin800Biogenex, Ramon, CA, USA Collagen IVMouse anti-human collagen IV1250Sigma, St Louis, MO, USA Collagen IV α-1Mouse anti-α-1 collagen40Wieslab, Lund, Sweden Collagen IV α-5Mouse anti-α-5 collagen10Wieslab, Lund, Sweden Collagen IRabbit anti-human collagen I40Monosan, Caltag lab., Burlinggame Collagen IIIMouse anti-human collagen III10Monosan, Caltag lab., Burlinggame MacrophageMouse anti-human CD682000Dako, Glostrup, DenmarkCAM, anti-cytokeratin (cam 5.2); PAX-2, paired box gene 2 (transcription factor); PEC, parietal epithelial cell; SMA, smooth muscle actin. Open table in a new tab CAM, anti-cytokeratin (cam 5.2); PAX-2, paired box gene 2 (transcription factor); PEC, parietal epithelial cell; SMA, smooth muscle actin. Remarkably, in involuted glomeruli some of the remaining cells stained for podocyte markers synaptopodin (Figure 4b) and CD10 (Figure 4c) and for parietal epithelial cell (PEC) marker paired box gene 2 (transcription factor) (PAX-2) and (Figure 4d), whereas cells positive for these markers were neither seen in glomerulopathic sclerosis nor in vascular sclerosis (parallel panels). The extracellular matrix characteristics of the different types are depicted in Figure 5. Collagen III was negative in all types of sclerosis (data not shown). The hyalinized extracellular matrix filling Bowman's space in vascular sclerosis was strongly positive for collagen I (Figure 5j), whereas collagen I was not detected in involuted glomeruli (Figure 5b) or glomerulopathic sclerosis (Figure 5f). Collagen IV stains all of the matrix in involution and glomerulopathic sclerosis and only the contracted glomerular tuft in vascular sclerosis (Figure 5a, e, and i). There was staining for both the α-1 and α-5 chain of collagen IV in involuted glomeruli (Figure 5c and d) and glomerulopathic sclerosis (Figure 5g and h), whereas in vascular sclerosis the Bowman's capsule was stained for the α-1 chain (Figure 5k) and the contracted tuft stained only for α-5 (Figure 5l). CK8 positivity, a marker for activated PECs, was not seen (Figure 6a). CK8 is not normally expressed in glomeruli, but can become expressed on parietal cells in FSGS.7.Dijkman H. Smeets B. van der L.J. et al.The parietal epithelial cell is crucially involved in human idiopathic focal segmental glomerulosclerosis.Kidney Int. 2005; 68: 1562-1572Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar We observed residual staining in involuted glomeruli for smooth muscle actin (Figure 6b) and CD34 (Figure 6c), possibly representing residual endothelial cells and mesangial cells. Intriguingly, smooth muscle actin staining was almost absent in the periglomerular region of the involuted glomeruli (Figure 6b), this in contrast to the staining, which was very pronounced in glomerulopathic sclerosis and in vascular sclerosis (Figure 6f and j). Staining of capillary remnants for CD34 was observed in vascular sclerosis and involuted glomeruli, but not in glomerulopathic sclerosis (Figure 6g and k). The remarkable absence of interstitial changes accompanying glomerular involution was further highlighted by vimentin (Figure 6d, h, and l), staining that showed prominent periglomerular expression in glomerulopathic sclerosis, but not in involuted glomeruli. All typical glomerular characteristics of the three forms of glomerulosclerosis are listed in Table 2.Table 2Typical characteristics of the different typesGlomerular componentsNormalInvolutionGlomerulopathic sclerosisVascular sclerosisPodocyte components Synaptopodin++== CD10++==PEC components PAX-2++== Cytokeratin 8====Proliferation KI 67====Miscellaneous Macrophage (CD68)==== α-SMA Intra glomerular++++ Peri glomerular==++ Endothelium (CD34)++=+ Collagen IV+++=(BS)/+T Collagen I===+(BS) Collagen III==== Glomerular volumeNormal 150–250 μmVery small 30–40 μmNormal 150–250 μmNormal 150–250 μmBS, Bowman's space; SMA, smooth muscle actin; T, glomerular tuft. =, stands for negative. Open table in a new tab BS, Bowman's space; SMA, smooth muscle actin; T, glomerular tuft. =, stands for negative. We have studied the biopsies of 18 children with a steroid-dependent or frequently relapsing MCNS. Clinical characteristics of the patients are given in Table 3. There were 11 boys and seven girls. Median age at disease onset was 2.8 years (1.6–10.6 years) and at biopsy 5.2 years (2.3–10.9 years). Most patients expressed a frequently relapsing course of the nephrotic syndrome. All patients had received prednisone. Other immunosuppressive agents had not been used before the renal biopsy. All patients were initially treated according to the guidelines of the ISKDC. Some patients with steroid-dependent nephrotic syndrome were treated with low-dose prednisone for prolonged time periods with titration of the prednisone dose against proteinuria assessed by urinary dipstick. The biopsies contained 19 (5–35) glomeruli. Many biopsies contained small, globally sclerosed glomeruli, with the characteristics of involuted glomeruli. The median percentage of involuted glomeruli was 6% (range 0–33%). Biopsies of six patients did not show involuted glomeruli. When comparing patients without and with involuted glomeruli, we observed a significant difference in the age at renal biopsy (without involution: 3.9±1.1 year, with involution 6.5±2.6 years; P<0.05) and the interval between onset of disease and the renal biopsy (0.44±0.43 years vs 3.8±3.3 years; P<0.01). There were no significant differences in gender distribution, maximal proteinuria at onset, serum albumin, and number of recurrences or selectivity index. There was a significant correlation between the percentage of involuted glomeruli and the interval between onset of disease and renal biopsy (Figure 7, Spearman R=0.64; P<0.01), and a trend between age at biopsy and percentage involution (r=0.41; P=0.09). By logistic regression analysis, the interval between disease onset and the renal biopsy was the only independent significant predictor. We also have evaluated the relation between glomerular involution and outcome. Percentage involution was not related to outcome. All but two patients were treated with cyclophosphamide. Recurrences of the nephrotic syndrome occurred in three of six patients without involuted glomeruli and in four of eight patients with >5% involuted glomeruli. At the end of follow-up, all patients but one were in remission.Table 3Clinical characteristics of the patientsPatients (N)18Sex (M/F)11/7Age at onset (years)2.8 (1.6–10.6)Age at biopsy (years)5.2 (2.3–10.9)Interval onset–biopsy (years)1.5 (0.2–6.7)Number of relapses2 (1–16)Number of glomeruli19 (5–35)Involuted glomeruli (%)6 (0–33)F, female; M, male.Values are given as medians (range). Open table in a new tab F, female; M, male. Values are given as medians (range). Our findings justify the conclusion that glomerular involution is a type of glomerulosclerosis distinct from glomerulopathic and vascular glomerulosclerosis. The most evident distinguishing features are reduced size, remaining vital cells that stain for podocyte and parietal markers, and a remarkable absence of periglomerular fibrosis or interstitial damage. These involuted glomeruli are regularly found in patients with frequently relapsing or steroid-dependent MCNS. In our series, these glomeruli were observed in the majority (two-thirds) of the renal biopsies and were not found in the controls. It is likely that glomerular involution has been noted by other investigators although a clear description is lacking. Emery and Macdonald4.Emery J.L. Macdonald M.S. Involuting and scarred glomeruli in the kidneys of infants.Am J Pathol. 1960; 36: 713-723PubMed Google Scholar described glomerular involution and scarring in children, a process unlikely to be the result of vascular injury. They observed these scarred glomeruli in children, occurring predominantly in children aged <2 years, with preferential localization in the subcapsular region and in approximity to the arcuate vessels. In the paper, glomerular involution is described as the presence of small solid masses of connective tissue-like material lacking epithelial cells. Similar findings have been reported by Herxheimer,8.Herxheimer G. Über hyaline glomeruli der neugeborenen und Sauglinge.Frankfurter Zeitschrift Pathologie. 1909; 2: 138-152Google Scholar who noted hyalinized glomeruli in children <1 year. Both reports do not mention the tubulo-interstitium. However, based on the description (lacking epithelial cells) and the predominant occurrence at very young age, it is unlikely that these glomeruli may match our findings. Sibley et al.6.Sibley R.K. Mahan J. Mauer S.M. Vernier R.L. A clinicopathologic study of forty-eight infants with nephrotic syndrome.Kidney Int. 1985; 27: 544-552Abstract Full Text PDF PubMed Scopus (51) Google Scholar described the occurrence of microglomeruli in children with a congenital nephrotic syndrome. The microglomeruli averaged 20–40 μm in diameter and contained capillaries. The description of the glomeruli fits our findings, although no mention is made of tubulo-interstitial injury.6.Sibley R.K. Mahan J. Mauer S.M. Vernier R.L. A clinicopathologic study of forty-eight infants with nephrotic syndrome.Kidney Int. 1985; 27: 544-552Abstract Full Text PDF PubMed Scopus (51) Google Scholar Many studies have addressed global glomerulosclerosis.9.Tracy R.E. Ishii T. What is ‘nephrosclerosis’? Lessons from the US, Japan, and Mexico.Nephrol Dial Transplant. 2000; 15: 1357-1366Crossref PubMed Scopus (34) Google Scholar It was shown that the number of obsolescent glomeruli increased with age, and correlated with interstitial fibrosis and arteriolar intimal hyperplasia.9.Tracy R.E. Ishii T. What is ‘nephrosclerosis’? Lessons from the US, Japan, and Mexico.Nephrol Dial Transplant. 2000; 15: 1357-1366Crossref PubMed Scopus (34) Google Scholar Glomerular involution appears to be very different from vascular glomerulosclerosis as there is no contraction of the glomerular tuft and no deposition of collagen I but rather production of collagen IV. Moreover, we did not detect any vascular changes in the renal tissue of patients with involuted glomeruli. The random distribution of the involuted glomeruli also argues against a vascular cause. Thus, whereas vascular sclerosis is thought to occur secondary to hypoperfusion, such a pathogenesis is unlikely in glomerular involution. It is intruiging that glomerular involution occurs in the setting of MCN in patients with relapses (recurrent nephrotic syndrome) and therefore like FSGS is seen in the context of proteinuria. Therefore, one could ask if glomerular involution and glomerulopathic sclerosis in FSGS are related processes. From a histological point of view, the most apparent similarity is that in both types of glomerulosclerosis solidification is the result of matrix deposition by residual glomerular cells, which results in an ‘inflated’ glomerulus and tuft adhesions. In the last years, the pathogenesis of glomerulosclerosis in FSGS has become much clearer.10.Kriz W. Elger M. Nagata M. et al.The role of podocytes in the development of glomerular sclerosis.Kidney Int Suppl. 1994; 45: S64-S72Abstract Full Text PDF PubMed Scopus (151) Google Scholar, 11.Kriz W. Kretzler M. Nagata M. et al.A frequent pathway to glomerulosclerosis: deterioration of tuft architecture–podocyte damage–segmental sclerosis.Kidney Blood Press Res. 1996; 19: 245-253Crossref PubMed Scopus (66) Google Scholar, 12.Kriz W. Gretz N. Lemley K.V. Progression of glomerular diseases: is the podocyte the culprit?.Kidney Int. 1998; 54: 687-697Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar, 13.Kriz W. LeHir M. Pathways to nephron loss starting from glomerular diseases – insights from animal models.Kidney Int. 2005; 67: 404-419Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar It is generally accepted that in FSGS the podocyte is the cell that is initially injured, causing proteinuria. Studies in animal models have elucidated the following sequence of events, which contribute to the characteristic lesions of FSGS: podocytes loose their differentiation markers and disappear, there is activation and proliferation of PECs or dedifferentiated podocytes, and deposition of matrix with the formation of the characteristic scar. The adhesions between the glomerular tuft and Bowman's capsule are responsible for misdirected filtration, moving ultrafiltrate in the periglomerular space, stimulating myofibroblast proliferation. This periglomerular ultrafiltrate typically spreads to the peritubular space. We have confirmed these abnormalities in human FSGS, and proposed that injury to PECs is important in this process.7.Dijkman H. Smeets B. van der L.J. et al.The parietal epithelial cell is crucially involved in human idiopathic focal segmental glomerulosclerosis.Kidney Int. 2005; 68: 1562-1572Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar In glomerular involution, there is also deposition of extracellular matrix by cells of glomerular origin, causing consolidation and tuft adhesions. However, in involuted glomeruli there is no evidence of cell proliferation, podocyte markers remain present, there is no activation of PECs, and no periglomerular fibrosis or interstitial fibrosis. Based on these findings, we hypothesize that misdirected filtration does not occur in the process of glomerular involution. Apparently, glomerular involution occurs in the setting of podocyte injury with proteinuria, resulting in production of matrix by glomerular epithelial cells, but insufficient to cause PEC damage and allowing misdirected filtration. Alternatively, it cannot be excluded that factors produced by activated PECs and/or podocytes directly induce periglomerular fibrosis in FSGS and that during glomerular involution such stimulating factors are not produced. We have noticed these involuted glomeruli in children with minimal change disease, who were biopsied because of a relapsing cause of the disease. Therefore, we looked for clinical variables that could be associated with glomerular involution. We observed a significant relation between the percentage of glomerular involution and the interval between onset of disease and time of renal biopsy. Thus, involuted glomeruli are predominately observed in children who are biopsied several years after onset of the disease. We did not find a relation with number of recurrences, proteinuria selectivity index, maximal proteinuria at onset, or serum albumin. Obviously, our study has the limitations of a retrospective study. In particular, it was impossible to obtain accurate and meaningful data on time-averaged proteinuria. Especially, patients with a more protracted course were advised to check their urine by dipstick and adjust the dose and duration of prednisone therapy accordingly. Detailed information obviously cannot be retrieved from the patient records. Therefore, we cannot draw conclusions on possible mechanisms of glomerular involution. Glomerular involution may be the consequence of the initial glomerular injury, slowly developing afterward. Alternatively, it is quite possible that glomerular involution is the consequence of ongoing subtle injury, reflected by continuous recurrences of proteinuria, suggesting a progressive pathology, which increases in time. The prolonged use of prednisone may offer a third explanation. In an animal model of MCN, the so-called puromycin aminonucleoside model, chronic administration of methylprednisolone caused glomerulosclerosis,14.Garcia D.L. Rennke H.G. Brenner B.M. Anderson S. Chronic glucocorticoid therapy amplifies glomerular injury in rats with renal ablation.J Clin Invest. 1987; 80: 867-874Crossref PubMed Scopus (69) Google Scholar an effect attributed to hyperfiltration. Chronic steroid treatment has also been implicated as cause of glomerulosclerosis. Prospective studies are needed to determine the best explanation. Obviously, involuted glomeruli have lost their function. The observation that up to 30% of glomeruli are involuted in biopsies of children with MCNS thus suggests that MCN is not so benign as suggested. Although renal function abnormalities were not detected in these children by standard creatinine assays, loss of functional nephrons may cause problems in the future. Therefore, more information is needed on the pathogenesis of this process, to further clarify the relation between proteinuria, treatment, and the development of glomerular involution. In conclusion, we describe a distinct type of global sclerosis that is observed in the setting of children with recurrences of MCNS. This type of glomerulosclerosis without periglomerular and interstitial fibrosis is best described as glomerular involution, a special form of glomerulosclerosis with a different pathogenesis. Small glomeruli are often recognized in renal biopsies of children with minimal change disease. We have evaluated renal biopsies of children with a frequently relapsing nephrotic syndrome. These children were biopsied in the process of preparation for cyclophosphamide therapy. We only included biopsies classified as MCN by appropriate histological techniques (light microscopy, immunofluorescence, and electronmicroscopy). We have counted the number of small globally sclerosed glomeruli in the biopsies of 18 children (age 3–9 years) with MCN. All patients had presented with a nephrotic syndrome and were biopsied because of a frequent relapsing or steroid-dependent course. The clinical data of the patients were studied with particular emphasis on age of onset of disease, number of relapses, type and duration of immunosuppressive treatment, and relapse-free interval. For comparison, we studied five biopsies from children without proteinuria. Their primary diagnosis was hyperoxaluria and thin basement membrane nephropathy. To investigate the involuted glomeruli in more detail, we used biopsies of three patients with minimal change disease. For comparison, we used nephrectomy specimens with evidence of the other types of global glomerulosclerosis. Vascular sclerosis was investigated in the normal cortex of a male, 74-year-old patient, nephrectomized because of a renal clear cell carcinoma. We studied the solidified type of global sclerosis in a nephrectomized kidney from a patient with end-stage FSGS. For light microscopy, kidney fragments were fixed in Bouin's solution or formaldehyde, dehydrated, and embedded in paraplast (Amstelstad, Amsterdam, The Netherlands). Two-micrometer sections were stained with periodic acid-Schiff, and with silver methenamine. Involuted glomeruli were identified by high-power magnification. Glomeruli were scored and counted by one of us (HD), who was unaware of the clinical data of the patients. Immunohistochemical staining was performed on kidney sections fixed in 4% buffered formaldehyde for 24 h fixation and embedded in paraffin. Four-micrometer sections were incubated with monoclonal antibodies and polyclonal antibodies directed at various markers for podocytes, PECs, macrophages, endothelium, myofibroblasts, and matrix components such as collagen as detailed in Table 2. As secondary antibody, we used powervision Poly-HRP-anti Mouse/Rabbit/Rat IgG (Immunologic, Klinipath, Duiven, The Netherlands). Detection was carried out with the use of peroxidase as label and diaminobenzidine as substrate. For electron microscopy, we used immersion fixation. Small fragments of cortex were fixed in 2.5% glutaraldehyde, dissolved in 0.1 M sodium cacodylate buffer, pH 7.4, overnight at 4°C, and washed in the same buffer. The tissue fragments were post-fixed in palade-buffered 2% OsO4 for 1 h, dehydrated, and embedded in Epon812, Luft's procedure (Merck, Darmstadt, Germany). Ultrathin sections were contrasted with 4% uranyl acetate for 45 min and subsequently with lead citrate for 5 min at room temperature. Sections were examined in a Jeol 1200 EX2 electron microscope (JEOL, Tokyo, Japan). Comparisons were performed using t-test. For correlation analysis, we used Spearman test. Logistic regression analysis was performed to evaluate independent predictors. P-values less than 0.05 were considered significant. All statistics were performed using SPSS statistical software (SPSS 12.0 for Windows, SPSS Inc., Chicago, IL, USA). We thank the members of the EM and Immuno/ISH laboratories (all of the Department of Pathology, Radboud University Medical Center Nijmegen, Nijmegen) for their expert technical assistance." @default.
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• W2104771467 date "2007-01-01" @default.
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• W2104771467 title "Glomerular involution in children with frequently relapsing minimal change nephrotic syndrome: An unrecognized form of glomerulosclerosis?" @default.
• W2104771467 cites W1971498397 @default.
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