Int Urol Nephrol DOI 10.1007/s11255-016-1229-8
NEPHROLOGY - ORIGINAL PAPER
Effects of various stages of nephropathy on wound healing in patients with diabetes: an observational cohort study encompassing 731 diabetics Paula Loewe1 · Ioannis Stefanidis1 · Peter R. Mertens1 · Christos Chatzikyrkou1
Received: 1 October 2015 / Accepted: 25 January 2016 © Springer Science+Business Media Dordrecht 2016
Abstract Background and objective In diabetics genetic predisposition, poor glycemic control and arterial hypertension contribute to nephropathy development in patients affected by diabetes mellitus. We set up the hypothesis that diabetic nephropathy and incisional hernia formation may have in common alterations of collagen composition and tested whether the occurrence of diabetic nephropathy coincides with wound healing disturbance (incisional herniation) or connective tissue diseases (inguinal herniation, umbilical herniation, aortic aneurysm, varicose veins, disc herniation). Design A questionnaire on surgical procedures, wound healing and connective tissue disorders was performed with 731 diabetics. Furthermore, test results for kidney function and damage (creatinine clearance, proteinuria) and blood sugar control (HbA1c) were recorded. Correlations between aforementioned connective tissue diseases and “advanced” diabetic nephropathy were calculated. “Advanced” diabetic nephropathy was assumed in patients with macroproteinuria, CKD stage 5 and/or end-stage renal disease. All diabetics with CKD stages 1 and 2 without proteinuria were included in the “control” group. A subgroup analysis on incisional hernia formation coinciding with diabetic nephropathy was performed in patients with previously performed abdominal surgery. Results In patients with advanced nephropathy, some diseases with connective tissue alterations, such as inguinal
* Paula Loewe [email protected] 1
Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
herniation, aortic aneurysms and varicose veins, did not occur more frequently than in patients without nephropathy. In diabetics with nephropathy, umbilical herniation (3 vs. 8.2 %, p = 0.04) and disc herniation rates (5.7 vs. 16.1 %, p = 0.002) were significantly lower. Subgroup analysis of patients with previously performed abdominal surgery (n = 381) revealed significantly higher incisional herniation rates when “advanced” diabetic nephropathy was present (16 % compared to 5.7 % without nephropathy, p = 0.016). Conclusion Our findings support the hypothesis that incisional hernia formation and diabetic nephropathy are positively correlated. Conversely, umbilical and disc herniation pathomechanisms are distinct, as these negatively correlate with the presence of advanced diabetic nephropathy. Keywords Diabetic nephropathy · Chronic kidney disease · Incisional hernia · Connective tissue disease · Risk factor
Introduction Diabetic nephropathy is a microvascular complication characterized by albuminuria, arterial hypertension and a progressive decline in glomerular filtration rate [1]. With chronic kidney disease, high cardiovascular morbidity and mortality rates are prevalent. Approximately 25–30 % of all diabetics eventually develop kidney damage that mostly is of progressive nature [2, 3]. Diabetic nephropathy is the major cause of end-stage renal disease in Western societies; nevertheless, aetiology and pathogenesis of the observed kidney damage are incompletely understood. Differential diagnosis for chronic kidney diseases in diabetics is ample, given that arterial hypertension is highly prevalent and may
13
contribute to the pathogenesis of kidney alterations and/or itself cause nephrosclerosis. Furthermore, it is well known that about 30–40 % of diabetics suffer from other kidney diseases than diabetic nephropathy [4, 5]. Without retrieval of kidney tissue, such a differentiation is not possible with certainty; furthermore, the range of proteinuria may only provide a hint at the extent of glomerular damage. In recent years, several studies report on a subgroup of patients with progressive diabetic nephropathy that lack significant proteinuria at any stage of disease [6, 7]. Notwithstanding, the hypothesis to be tested in this project is a deranged underlying collagen metabolism due to genetic traits favouring progressive kidney disease. These tests are similarly applicable in cohorts encompassing nephrosclerosis or other (immunological) kidney diseases. Main predictors of progression to end-stage renal disease (ESRD) include genetic predisposition [8, 9], an insufficiently controlled glucose metabolism [10], arterial hypertension, dyslipidemia and nicotine consumption [11, 12]. In order to prevent and treat incipient and overt diabetic nephropathy, understanding of the underlying pathogenesis is essential. The focus of different research groups has been a dysregulated inflammatory response, matrix composition or regeneration of connective tissue [13, 14]. Our research group and others found alterations of the collagen composition of kidneys in patients with diabetic nephropathy similar to those of the scar tissue of patients with incisional herniation [15–17], where the ratio of collagen type I and collagen type III is balanced in favour of the less stable collagen type III fibrils. These observations led us to the question if alterations in wound healing contribute to the pathogenesis of diabetic nephropathy and/or if impaired wound healing is a risk factor for diabetic nephropathy development. Chronic connective tissue diseases, such as varicose veins, aortic aneurysms, inguinal herniation, umbilical herniation and disc herniation, exhibit an altered extracellular matrix [18]. Some of them are associated with wound healing disorders [19]. Patients with abdominal aortic aneurysms that undergo reconstructive surgery more often suffer from incisional herniation than patients undergoing other operations [19]. Bode et al. [20] detected a raised turnover of collagen type III in the aortic vessel wall of abdominal aneurysms by immunohistochemistry. Fachinelli et al. [15] found a decrease in total collagen and collagen type I in the linea alba of patients with ventral herniation. Raffeto et al. compared patients with abdominal aortic aneurysms to patients with aortoiliac occlusive disease undergoing surgery. Patients with abdominal aortic aneurysms more commonly had abdominal wall and inguinal herniations as well as a higher risk of developing an incisional herniation [21]. Given that most of the diabetics suffering from nephropathy also develop arterial hypertension, it may be
13
Int Urol Nephrol
envisioned that repetitive elevated intraglomerular pressure is translated into glomerular injury that has to be confined. Reparative processes within the glomerular architecture have been described in diabetics [1]. Classifications on diabetic nephropathy, such as the one by Taervert et al. [22], describe glomerular fibrosis and mesangial cell proliferation features resembling a wound healing process.
Materials and methods Patient enrolment and data collection took place at a tertiary medical centre (University Hospital Aachen), and outpatient private practices specialized in Diabetes and Nephrology. The ethical committee of the University Hospital RWTH Aachen approved the study (EK Nr. 68/09). Upon informed written consent, standardized interviews were performed with patients that address wound healing (incisional herniation) and connective tissue (inguinal herniation, umbilical herniation, aortic aneurysm, varicose veins and disc herniation) disorders. Laboratory testing included serum creatinine, HbA1c and proteinuria (daily protein excretion rate in 24-h urine samples). Information on biometric data (gender, age, BMI) and known risk factors for the development of diabetic nephropathy (diabetes mellitus duration, smoking habits, arterial hypertension and dyslipidemia/usage of lipid-lowering drugs) and risk factors for incisional hernia development [angiotensin-converting enzyme (ACE)-inhibitor/angiotensin receptor (AT)1-antagonist medication, non-steroidal anti-inflammatory drug (NSAID) intake, history of glucocorticoid intake and incidence as well as number of previous abdominal surgeries] were collected. Estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease (MDRD) formula. Amongst the 731 patients enrolled in the study those with macroproteinuria (>300 mg/day), impaired eGFR 60 ml/ min/1.73 m2 and lack of proteinuria ( 15 ml/min/1.73 m2 and 60 ml/min/1.73 m2 and microalbuminuria were excluded for the initial main statistical analyses and only used as comparator group in a subanalysis for disc herniation. Kidney biopsy for diagnosis of diabetic nephropathy was not enforced, given that this is not commonly accepted due to potential complications (bleeding, infection) and the lack of therapeutic consequences. A subgroup analysis regarding the correlation of incisional hernia formation and advanced diabetic nephropathy
Int Urol Nephrol Table 1 Factors influencing the development of “advanced” diabetic nephropathy
Normal kidney function n = 353
“Advanced” kidney disease n = 141
p value
Age (median) HbA1c (%)
60 7.3
70 6.5
NEPHROLOGY - ORIGINAL PAPER
Effects of various stages of nephropathy on wound healing in patients with diabetes: an observational cohort study encompassing 731 diabetics Paula Loewe1 · Ioannis Stefanidis1 · Peter R. Mertens1 · Christos Chatzikyrkou1
Received: 1 October 2015 / Accepted: 25 January 2016 © Springer Science+Business Media Dordrecht 2016
Abstract Background and objective In diabetics genetic predisposition, poor glycemic control and arterial hypertension contribute to nephropathy development in patients affected by diabetes mellitus. We set up the hypothesis that diabetic nephropathy and incisional hernia formation may have in common alterations of collagen composition and tested whether the occurrence of diabetic nephropathy coincides with wound healing disturbance (incisional herniation) or connective tissue diseases (inguinal herniation, umbilical herniation, aortic aneurysm, varicose veins, disc herniation). Design A questionnaire on surgical procedures, wound healing and connective tissue disorders was performed with 731 diabetics. Furthermore, test results for kidney function and damage (creatinine clearance, proteinuria) and blood sugar control (HbA1c) were recorded. Correlations between aforementioned connective tissue diseases and “advanced” diabetic nephropathy were calculated. “Advanced” diabetic nephropathy was assumed in patients with macroproteinuria, CKD stage 5 and/or end-stage renal disease. All diabetics with CKD stages 1 and 2 without proteinuria were included in the “control” group. A subgroup analysis on incisional hernia formation coinciding with diabetic nephropathy was performed in patients with previously performed abdominal surgery. Results In patients with advanced nephropathy, some diseases with connective tissue alterations, such as inguinal
* Paula Loewe [email protected] 1
Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
herniation, aortic aneurysms and varicose veins, did not occur more frequently than in patients without nephropathy. In diabetics with nephropathy, umbilical herniation (3 vs. 8.2 %, p = 0.04) and disc herniation rates (5.7 vs. 16.1 %, p = 0.002) were significantly lower. Subgroup analysis of patients with previously performed abdominal surgery (n = 381) revealed significantly higher incisional herniation rates when “advanced” diabetic nephropathy was present (16 % compared to 5.7 % without nephropathy, p = 0.016). Conclusion Our findings support the hypothesis that incisional hernia formation and diabetic nephropathy are positively correlated. Conversely, umbilical and disc herniation pathomechanisms are distinct, as these negatively correlate with the presence of advanced diabetic nephropathy. Keywords Diabetic nephropathy · Chronic kidney disease · Incisional hernia · Connective tissue disease · Risk factor
Introduction Diabetic nephropathy is a microvascular complication characterized by albuminuria, arterial hypertension and a progressive decline in glomerular filtration rate [1]. With chronic kidney disease, high cardiovascular morbidity and mortality rates are prevalent. Approximately 25–30 % of all diabetics eventually develop kidney damage that mostly is of progressive nature [2, 3]. Diabetic nephropathy is the major cause of end-stage renal disease in Western societies; nevertheless, aetiology and pathogenesis of the observed kidney damage are incompletely understood. Differential diagnosis for chronic kidney diseases in diabetics is ample, given that arterial hypertension is highly prevalent and may
13
contribute to the pathogenesis of kidney alterations and/or itself cause nephrosclerosis. Furthermore, it is well known that about 30–40 % of diabetics suffer from other kidney diseases than diabetic nephropathy [4, 5]. Without retrieval of kidney tissue, such a differentiation is not possible with certainty; furthermore, the range of proteinuria may only provide a hint at the extent of glomerular damage. In recent years, several studies report on a subgroup of patients with progressive diabetic nephropathy that lack significant proteinuria at any stage of disease [6, 7]. Notwithstanding, the hypothesis to be tested in this project is a deranged underlying collagen metabolism due to genetic traits favouring progressive kidney disease. These tests are similarly applicable in cohorts encompassing nephrosclerosis or other (immunological) kidney diseases. Main predictors of progression to end-stage renal disease (ESRD) include genetic predisposition [8, 9], an insufficiently controlled glucose metabolism [10], arterial hypertension, dyslipidemia and nicotine consumption [11, 12]. In order to prevent and treat incipient and overt diabetic nephropathy, understanding of the underlying pathogenesis is essential. The focus of different research groups has been a dysregulated inflammatory response, matrix composition or regeneration of connective tissue [13, 14]. Our research group and others found alterations of the collagen composition of kidneys in patients with diabetic nephropathy similar to those of the scar tissue of patients with incisional herniation [15–17], where the ratio of collagen type I and collagen type III is balanced in favour of the less stable collagen type III fibrils. These observations led us to the question if alterations in wound healing contribute to the pathogenesis of diabetic nephropathy and/or if impaired wound healing is a risk factor for diabetic nephropathy development. Chronic connective tissue diseases, such as varicose veins, aortic aneurysms, inguinal herniation, umbilical herniation and disc herniation, exhibit an altered extracellular matrix [18]. Some of them are associated with wound healing disorders [19]. Patients with abdominal aortic aneurysms that undergo reconstructive surgery more often suffer from incisional herniation than patients undergoing other operations [19]. Bode et al. [20] detected a raised turnover of collagen type III in the aortic vessel wall of abdominal aneurysms by immunohistochemistry. Fachinelli et al. [15] found a decrease in total collagen and collagen type I in the linea alba of patients with ventral herniation. Raffeto et al. compared patients with abdominal aortic aneurysms to patients with aortoiliac occlusive disease undergoing surgery. Patients with abdominal aortic aneurysms more commonly had abdominal wall and inguinal herniations as well as a higher risk of developing an incisional herniation [21]. Given that most of the diabetics suffering from nephropathy also develop arterial hypertension, it may be
13
Int Urol Nephrol
envisioned that repetitive elevated intraglomerular pressure is translated into glomerular injury that has to be confined. Reparative processes within the glomerular architecture have been described in diabetics [1]. Classifications on diabetic nephropathy, such as the one by Taervert et al. [22], describe glomerular fibrosis and mesangial cell proliferation features resembling a wound healing process.
Materials and methods Patient enrolment and data collection took place at a tertiary medical centre (University Hospital Aachen), and outpatient private practices specialized in Diabetes and Nephrology. The ethical committee of the University Hospital RWTH Aachen approved the study (EK Nr. 68/09). Upon informed written consent, standardized interviews were performed with patients that address wound healing (incisional herniation) and connective tissue (inguinal herniation, umbilical herniation, aortic aneurysm, varicose veins and disc herniation) disorders. Laboratory testing included serum creatinine, HbA1c and proteinuria (daily protein excretion rate in 24-h urine samples). Information on biometric data (gender, age, BMI) and known risk factors for the development of diabetic nephropathy (diabetes mellitus duration, smoking habits, arterial hypertension and dyslipidemia/usage of lipid-lowering drugs) and risk factors for incisional hernia development [angiotensin-converting enzyme (ACE)-inhibitor/angiotensin receptor (AT)1-antagonist medication, non-steroidal anti-inflammatory drug (NSAID) intake, history of glucocorticoid intake and incidence as well as number of previous abdominal surgeries] were collected. Estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease (MDRD) formula. Amongst the 731 patients enrolled in the study those with macroproteinuria (>300 mg/day), impaired eGFR 60 ml/ min/1.73 m2 and lack of proteinuria ( 15 ml/min/1.73 m2 and 60 ml/min/1.73 m2 and microalbuminuria were excluded for the initial main statistical analyses and only used as comparator group in a subanalysis for disc herniation. Kidney biopsy for diagnosis of diabetic nephropathy was not enforced, given that this is not commonly accepted due to potential complications (bleeding, infection) and the lack of therapeutic consequences. A subgroup analysis regarding the correlation of incisional hernia formation and advanced diabetic nephropathy
Int Urol Nephrol Table 1 Factors influencing the development of “advanced” diabetic nephropathy
Normal kidney function n = 353
“Advanced” kidney disease n = 141
p value
Age (median) HbA1c (%)
60 7.3
70 6.5
