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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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Related in: MedlinePlus

Association between the kidney pathology and age in SHRSP and Wistar rats.Regression lines. The regression lines in Figure 6 demonstrate the positive association between the severity of the kidney pathology (y-axis) and the age (x-axis) in SHRSP (blue) and Wistar (green) group. The extent of peritubular aggregated erythrocytes and the extent of tubular protein cylinders is separately assessed in the kidney medulla and cortex and is captured in a semiquantitative manner (0–3, y-axis; see also Figure 1 and Material and Methods, kidney). Note the increase of the severity of the kidney pathology with age in SHRSP (cortex: erythrocyte aggregations, regression coefficient [rc] 0.042, CI 0.019-0.065, p = 0.001; protein cylinders, rc 0.04, CI 0.025–0.055, p = <0.001; medulla: erythrocyte aggregations, rc 0.074, CI 0.057–0.090, p = <0.001; protein cylinders, rc 0.093, CI 0.079–0.107, p = <0.001) and to a lesser extent in the Wistar group (cortex: erythrocyte aggregations, rc 0.07, CI -0.001–0.015, p = 0.08; protein cylinders, rc 0.008, CI 0.005–0.011, p = <0.001; medulla: erythrocyte aggregations, rc 0.024, CI 0.014–0.034, p = <0.001; protein cylinders, rc 0.047, CI 0.033–0.061, p = <0.001) resulting in significant group differences (cortex: erythrocyte aggregations p = 0.045, protein cylinders p = 0.004; medulla: erythrocyte aggregations p = <0.001, protein cylinders p = <0.001).
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pone-0026287-g006: Association between the kidney pathology and age in SHRSP and Wistar rats.Regression lines. The regression lines in Figure 6 demonstrate the positive association between the severity of the kidney pathology (y-axis) and the age (x-axis) in SHRSP (blue) and Wistar (green) group. The extent of peritubular aggregated erythrocytes and the extent of tubular protein cylinders is separately assessed in the kidney medulla and cortex and is captured in a semiquantitative manner (0–3, y-axis; see also Figure 1 and Material and Methods, kidney). Note the increase of the severity of the kidney pathology with age in SHRSP (cortex: erythrocyte aggregations, regression coefficient [rc] 0.042, CI 0.019-0.065, p = 0.001; protein cylinders, rc 0.04, CI 0.025–0.055, p = <0.001; medulla: erythrocyte aggregations, rc 0.074, CI 0.057–0.090, p = <0.001; protein cylinders, rc 0.093, CI 0.079–0.107, p = <0.001) and to a lesser extent in the Wistar group (cortex: erythrocyte aggregations, rc 0.07, CI -0.001–0.015, p = 0.08; protein cylinders, rc 0.008, CI 0.005–0.011, p = <0.001; medulla: erythrocyte aggregations, rc 0.024, CI 0.014–0.034, p = <0.001; protein cylinders, rc 0.047, CI 0.033–0.061, p = <0.001) resulting in significant group differences (cortex: erythrocyte aggregations p = 0.045, protein cylinders p = 0.004; medulla: erythrocyte aggregations p = <0.001, protein cylinders p = <0.001).

Mentions: Single erythrocytes seemed to migrate throughout the vessel wall into the tubulointerstitial tissue; a process we also detected in the brain and we referred to as diapedesis. Aggregated erythrocytes were detected in kidneys of SHRSP and controls. However, in controls those intravasal erythrocyte aggregations occurred with a significant lower frequency (Figure 6). In both, SHRSP and controls, there was an age-dependent increase of the erythrocyte aggregations in kidney cortex and medulla (Figure 6).


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)

Association between the kidney pathology and age in SHRSP and Wistar rats.Regression lines. The regression lines in Figure 6 demonstrate the positive association between the severity of the kidney pathology (y-axis) and the age (x-axis) in SHRSP (blue) and Wistar (green) group. The extent of peritubular aggregated erythrocytes and the extent of tubular protein cylinders is separately assessed in the kidney medulla and cortex and is captured in a semiquantitative manner (0–3, y-axis; see also Figure 1 and Material and Methods, kidney). Note the increase of the severity of the kidney pathology with age in SHRSP (cortex: erythrocyte aggregations, regression coefficient [rc] 0.042, CI 0.019-0.065, p = 0.001; protein cylinders, rc 0.04, CI 0.025–0.055, p = <0.001; medulla: erythrocyte aggregations, rc 0.074, CI 0.057–0.090, p = <0.001; protein cylinders, rc 0.093, CI 0.079–0.107, p = <0.001) and to a lesser extent in the Wistar group (cortex: erythrocyte aggregations, rc 0.07, CI -0.001–0.015, p = 0.08; protein cylinders, rc 0.008, CI 0.005–0.011, p = <0.001; medulla: erythrocyte aggregations, rc 0.024, CI 0.014–0.034, p = <0.001; protein cylinders, rc 0.047, CI 0.033–0.061, p = <0.001) resulting in significant group differences (cortex: erythrocyte aggregations p = 0.045, protein cylinders p = 0.004; medulla: erythrocyte aggregations p = <0.001, protein cylinders p = <0.001).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198774&req=5

pone-0026287-g006: Association between the kidney pathology and age in SHRSP and Wistar rats.Regression lines. The regression lines in Figure 6 demonstrate the positive association between the severity of the kidney pathology (y-axis) and the age (x-axis) in SHRSP (blue) and Wistar (green) group. The extent of peritubular aggregated erythrocytes and the extent of tubular protein cylinders is separately assessed in the kidney medulla and cortex and is captured in a semiquantitative manner (0–3, y-axis; see also Figure 1 and Material and Methods, kidney). Note the increase of the severity of the kidney pathology with age in SHRSP (cortex: erythrocyte aggregations, regression coefficient [rc] 0.042, CI 0.019-0.065, p = 0.001; protein cylinders, rc 0.04, CI 0.025–0.055, p = <0.001; medulla: erythrocyte aggregations, rc 0.074, CI 0.057–0.090, p = <0.001; protein cylinders, rc 0.093, CI 0.079–0.107, p = <0.001) and to a lesser extent in the Wistar group (cortex: erythrocyte aggregations, rc 0.07, CI -0.001–0.015, p = 0.08; protein cylinders, rc 0.008, CI 0.005–0.011, p = <0.001; medulla: erythrocyte aggregations, rc 0.024, CI 0.014–0.034, p = <0.001; protein cylinders, rc 0.047, CI 0.033–0.061, p = <0.001) resulting in significant group differences (cortex: erythrocyte aggregations p = 0.045, protein cylinders p = 0.004; medulla: erythrocyte aggregations p = <0.001, protein cylinders p = <0.001).
Mentions: Single erythrocytes seemed to migrate throughout the vessel wall into the tubulointerstitial tissue; a process we also detected in the brain and we referred to as diapedesis. Aggregated erythrocytes were detected in kidneys of SHRSP and controls. However, in controls those intravasal erythrocyte aggregations occurred with a significant lower frequency (Figure 6). In both, SHRSP and controls, there was an age-dependent increase of the erythrocyte aggregations in kidney cortex and medulla (Figure 6).

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