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Kidney pathology precedes and predicts the pathological cascade of cerebrovascular lesions in stroke prone rats.

Schreiber S, Bueche CZ, Garz C, Kropf S, Kuester D, Amann K, Heinze HJ, Goertler M, Reymann KG, Braun H - PLoS ONE (2011)

Bottom Line: The combined increase of intravasal erythrocyte aggregations and protein cylinders accompanied by glomerulosclerosis and thrombotic renal microangiopathy in kidneys of older SHRSP predicts the final stages of SHRSPs' cerebrovascular lesions marked by microbleeds and thrombotic infarcts.Our results illustrate a close association between structural brain and kidney pathology and support the concept of small vessel disease to be an age-dependent systemic pathology.Further, an improved joined nephrologic and neurologic diagnostic may help to identify patients with CSVD at an early stage.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany. stefanie.schreiber@med.ovgu.de

ABSTRACT

Introduction: Human cerebral small vessel disease (CSVD) has been hypothesized to be an age-dependent disease accompanied by similar vascular changes in other organs. SHRSP feature numerous vascular risk factors and may be a valid model of some aspects of human CSVD. Here we compare renal histopathological changes with the brain pathology of spontaneously hypertensive stroke-prone rats (SHRSP).

Material and methods: We histologically investigated the brains and kidneys of 61 SHRSP at different stages of age (12 to 44 weeks). The brain pathology (aggregated erythrocytes in capillaries and arterioles, microbleeds, microthromboses) and the kidney pathology (aggregated erythrocytes within peritubular capillaries, tubular protein cylinders, glomerulosclerosis) were quantified separately. The prediction of the brain pathology by the kidney pathology was assessed by creating ROC-curves integrating the degree of kidney pathology and age of SHRSP.

Results: Both, brain and kidney pathology, show an age-dependency and proceed in definite stages whereas an aggregation of erythrocytes in capillaries and arterioles, we parsimoniously interpreted as stases, represent the initial finding in both organs. Thus, early renal tubulointerstitial damage characterized by rather few intravasal erythrocyte aggregations and tubular protein cylinders predicts the initial step of SHRSPs' cerebral vascular pathology marked by accumulated erythrocytes. The combined increase of intravasal erythrocyte aggregations and protein cylinders accompanied by glomerulosclerosis and thrombotic renal microangiopathy in kidneys of older SHRSP predicts the final stages of SHRSPs' cerebrovascular lesions marked by microbleeds and thrombotic infarcts.

Conclusion: Our results illustrate a close association between structural brain and kidney pathology and support the concept of small vessel disease to be an age-dependent systemic pathology. Further, an improved joined nephrologic and neurologic diagnostic may help to identify patients with CSVD at an early stage.

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Structural damage of the kidney medulla and kidney cortex in SHRSP.Figure 5 demonstrates the main histopathological changes in the kidney of SHRSP. A shows an area of dilated peritubular capillaries with intravasal erythrocyte aggregations in the kidney medulla (marked by white dotted lines). Note tubular protein cylinders (white asterisks) in the kidney medulla (A) and kidney cortex (E) indicating tubular damage. In addition, tubular damage is characterized by flattening and atrophy of the tubular epithelial cells (black arrows, E). Note in contrast the normal cubic epithelium of non damaged tubules (black arrow heads, E). In B–E chronological stages of thrombotic microangiopathy are illustrated. B & E demonstrate early, C & D demonstrate advanced stages. In B & E occluded arterioles with concentric thickened and hemorrhagic tunica media (“onion-skin”; black arrow head in B; black cross in E) are shown. C demonstrates a fresh microthrombosis (black cross) with excentric hemorrhage and D shows an older microthrombosis (black cross). Note the accompanying leukocyte leakage into the perivascular interstitium (black arrow heads, C & D). In E–H chronological stages of glomerulosclerosis are illustrated. F demonstrates an early stage marked by erythrocyte sticking in glomerular capillaries (black arrow head); in E, G & H advanced stages with capillary obliteration and increased mesangial matrix (black x, E) leading to a segmental (G) or more global (H) glomerulosclerosis. A005-32: animal number 5, 32 weeks old.
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pone-0026287-g005: Structural damage of the kidney medulla and kidney cortex in SHRSP.Figure 5 demonstrates the main histopathological changes in the kidney of SHRSP. A shows an area of dilated peritubular capillaries with intravasal erythrocyte aggregations in the kidney medulla (marked by white dotted lines). Note tubular protein cylinders (white asterisks) in the kidney medulla (A) and kidney cortex (E) indicating tubular damage. In addition, tubular damage is characterized by flattening and atrophy of the tubular epithelial cells (black arrows, E). Note in contrast the normal cubic epithelium of non damaged tubules (black arrow heads, E). In B–E chronological stages of thrombotic microangiopathy are illustrated. B & E demonstrate early, C & D demonstrate advanced stages. In B & E occluded arterioles with concentric thickened and hemorrhagic tunica media (“onion-skin”; black arrow head in B; black cross in E) are shown. C demonstrates a fresh microthrombosis (black cross) with excentric hemorrhage and D shows an older microthrombosis (black cross). Note the accompanying leukocyte leakage into the perivascular interstitium (black arrow heads, C & D). In E–H chronological stages of glomerulosclerosis are illustrated. F demonstrates an early stage marked by erythrocyte sticking in glomerular capillaries (black arrow head); in E, G & H advanced stages with capillary obliteration and increased mesangial matrix (black x, E) leading to a segmental (G) or more global (H) glomerulosclerosis. A005-32: animal number 5, 32 weeks old.

Mentions: A–C: SHRSP (animal 2, 34 weeks old) with cerebral microbleeds. D–F: SHRSP (animal 4, 31 weeks old) with cerebral infarctions containing small vessel occlusions. There is a strong correlation between an advanced kidney pathology, i.e. peritubular aggregations of erythrocytes, protein cylinders and different stages of glomerulosclerosis with cerebral infarctions accompanied by either microbleeds (here hippocampus, C) or small vessel occlusions with surrounding necrotic tissue (F). A & D: kidney medulla, B & E: kidney cortex, peritubular aggregations of erythrocytes are marked by black dashed lines (A & D), protein cylinders by white asterisks (A, B & D). Different stages of glomerulosclerosis are marked in B & E (o, x; see also Figure 5). In addition kidney vessels are affected by thrombotic microangiopathy (+ in B). B corresponds to Figure 5 E. A002-34: animal number 2, 34 weeks old.


Kidney pathology precedes and predicts the pathological cascade of cerebrovascular lesions in stroke prone rats.

Schreiber S, Bueche CZ, Garz C, Kropf S, Kuester D, Amann K, Heinze HJ, Goertler M, Reymann KG, Braun H - PLoS ONE (2011)

Structural damage of the kidney medulla and kidney cortex in SHRSP.Figure 5 demonstrates the main histopathological changes in the kidney of SHRSP. A shows an area of dilated peritubular capillaries with intravasal erythrocyte aggregations in the kidney medulla (marked by white dotted lines). Note tubular protein cylinders (white asterisks) in the kidney medulla (A) and kidney cortex (E) indicating tubular damage. In addition, tubular damage is characterized by flattening and atrophy of the tubular epithelial cells (black arrows, E). Note in contrast the normal cubic epithelium of non damaged tubules (black arrow heads, E). In B–E chronological stages of thrombotic microangiopathy are illustrated. B & E demonstrate early, C & D demonstrate advanced stages. In B & E occluded arterioles with concentric thickened and hemorrhagic tunica media (“onion-skin”; black arrow head in B; black cross in E) are shown. C demonstrates a fresh microthrombosis (black cross) with excentric hemorrhage and D shows an older microthrombosis (black cross). Note the accompanying leukocyte leakage into the perivascular interstitium (black arrow heads, C & D). In E–H chronological stages of glomerulosclerosis are illustrated. F demonstrates an early stage marked by erythrocyte sticking in glomerular capillaries (black arrow head); in E, G & H advanced stages with capillary obliteration and increased mesangial matrix (black x, E) leading to a segmental (G) or more global (H) glomerulosclerosis. A005-32: animal number 5, 32 weeks old.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198774&req=5

pone-0026287-g005: Structural damage of the kidney medulla and kidney cortex in SHRSP.Figure 5 demonstrates the main histopathological changes in the kidney of SHRSP. A shows an area of dilated peritubular capillaries with intravasal erythrocyte aggregations in the kidney medulla (marked by white dotted lines). Note tubular protein cylinders (white asterisks) in the kidney medulla (A) and kidney cortex (E) indicating tubular damage. In addition, tubular damage is characterized by flattening and atrophy of the tubular epithelial cells (black arrows, E). Note in contrast the normal cubic epithelium of non damaged tubules (black arrow heads, E). In B–E chronological stages of thrombotic microangiopathy are illustrated. B & E demonstrate early, C & D demonstrate advanced stages. In B & E occluded arterioles with concentric thickened and hemorrhagic tunica media (“onion-skin”; black arrow head in B; black cross in E) are shown. C demonstrates a fresh microthrombosis (black cross) with excentric hemorrhage and D shows an older microthrombosis (black cross). Note the accompanying leukocyte leakage into the perivascular interstitium (black arrow heads, C & D). In E–H chronological stages of glomerulosclerosis are illustrated. F demonstrates an early stage marked by erythrocyte sticking in glomerular capillaries (black arrow head); in E, G & H advanced stages with capillary obliteration and increased mesangial matrix (black x, E) leading to a segmental (G) or more global (H) glomerulosclerosis. A005-32: animal number 5, 32 weeks old.
Mentions: A–C: SHRSP (animal 2, 34 weeks old) with cerebral microbleeds. D–F: SHRSP (animal 4, 31 weeks old) with cerebral infarctions containing small vessel occlusions. There is a strong correlation between an advanced kidney pathology, i.e. peritubular aggregations of erythrocytes, protein cylinders and different stages of glomerulosclerosis with cerebral infarctions accompanied by either microbleeds (here hippocampus, C) or small vessel occlusions with surrounding necrotic tissue (F). A & D: kidney medulla, B & E: kidney cortex, peritubular aggregations of erythrocytes are marked by black dashed lines (A & D), protein cylinders by white asterisks (A, B & D). Different stages of glomerulosclerosis are marked in B & E (o, x; see also Figure 5). In addition kidney vessels are affected by thrombotic microangiopathy (+ in B). B corresponds to Figure 5 E. A002-34: animal number 2, 34 weeks old.

Bottom Line: The combined increase of intravasal erythrocyte aggregations and protein cylinders accompanied by glomerulosclerosis and thrombotic renal microangiopathy in kidneys of older SHRSP predicts the final stages of SHRSPs' cerebrovascular lesions marked by microbleeds and thrombotic infarcts.Our results illustrate a close association between structural brain and kidney pathology and support the concept of small vessel disease to be an age-dependent systemic pathology.Further, an improved joined nephrologic and neurologic diagnostic may help to identify patients with CSVD at an early stage.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany. stefanie.schreiber@med.ovgu.de

ABSTRACT

Introduction: Human cerebral small vessel disease (CSVD) has been hypothesized to be an age-dependent disease accompanied by similar vascular changes in other organs. SHRSP feature numerous vascular risk factors and may be a valid model of some aspects of human CSVD. Here we compare renal histopathological changes with the brain pathology of spontaneously hypertensive stroke-prone rats (SHRSP).

Material and methods: We histologically investigated the brains and kidneys of 61 SHRSP at different stages of age (12 to 44 weeks). The brain pathology (aggregated erythrocytes in capillaries and arterioles, microbleeds, microthromboses) and the kidney pathology (aggregated erythrocytes within peritubular capillaries, tubular protein cylinders, glomerulosclerosis) were quantified separately. The prediction of the brain pathology by the kidney pathology was assessed by creating ROC-curves integrating the degree of kidney pathology and age of SHRSP.

Results: Both, brain and kidney pathology, show an age-dependency and proceed in definite stages whereas an aggregation of erythrocytes in capillaries and arterioles, we parsimoniously interpreted as stases, represent the initial finding in both organs. Thus, early renal tubulointerstitial damage characterized by rather few intravasal erythrocyte aggregations and tubular protein cylinders predicts the initial step of SHRSPs' cerebral vascular pathology marked by accumulated erythrocytes. The combined increase of intravasal erythrocyte aggregations and protein cylinders accompanied by glomerulosclerosis and thrombotic renal microangiopathy in kidneys of older SHRSP predicts the final stages of SHRSPs' cerebrovascular lesions marked by microbleeds and thrombotic infarcts.

Conclusion: Our results illustrate a close association between structural brain and kidney pathology and support the concept of small vessel disease to be an age-dependent systemic pathology. Further, an improved joined nephrologic and neurologic diagnostic may help to identify patients with CSVD at an early stage.

Show MeSH
Related in: MedlinePlus