Subgroup analysis of patients with previously performed abdominal surgery n = 381 revealed significantly higher incisional herniation rates when “advanced” diabetic nephropathy was pre
Trang 1DOI 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 Loewe 1 · Ioannis Stefanidis 1 · Peter R Mertens 1 · Christos Chatzikyrkou 1
Received: 1 October 2015 / Accepted: 25 January 2016
© Springer Science+Business Media Dordrecht 2016
herniation, aortic aneurysms and varicose veins, did not occur more frequently than in patients without nephropa-thy 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 inci-sional hernia formation and diabetic nephropathy are posi-tively 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
Abstract
Background and objective In diabetics genetic
predis-position, poor glycemic control and arterial
hyperten-sion 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
her-niation) 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
Correla-tions 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
pro-teinuria were included in the “control” group A subgroup
analysis on incisional hernia formation coinciding with
diabetic nephropathy was performed in patients with
previ-ously performed abdominal surgery
Results In patients with advanced nephropathy, some
dis-eases with connective tissue alterations, such as inguinal
* Paula Loewe
paula.holstiege@med.ovgu.de
1 Department of Nephrology and Hypertension, Diabetes
and Endocrinology, Otto-von-Guericke-University
Magdeburg, Leipziger Str 44, 39120 Magdeburg, Germany
Trang 2contribute 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
pro-teinuria at any stage of disease [6 7] Notwithstanding, the
hypothesis to be tested in this project is a deranged
under-lying collagen metabolism due to genetic traits favouring
progressive kidney disease These tests are similarly
appli-cable in cohorts encompassing nephrosclerosis or other
(immunological) kidney diseases Main predictors of
pro-gression 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
com-position 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
her-niation and disc herher-niation, exhibit an altered extracellular
matrix [18] Some of them are associated with wound
heal-ing disorders [19] Patients with abdominal aortic
aneu-rysms 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
sur-gery Patients with abdominal aortic aneurysms more
com-monly 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
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 dia-betic nephropathy, such as the one by Taervert et al [22], describe glomerular fibrosis and mesangial cell prolifera-tion features resembling a wound healing process
Materials and methods
Patient enrolment and data collection took place at a ter-tiary medical centre (University Hospital Aachen), and out-patient private practices specialized in Diabetes and Neph-rology 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 (inci-sional herniation) and connective tissue (inguinal hernia-tion, umbilical herniahernia-tion, 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 bio-metric data (gender, age, BMI) and known risk factors for the development of diabetic nephropathy (diabetes mellitus duration, smoking habits, arterial hypertension and dys-lipidemia/usage of lipid-lowering drugs) and risk factors for incisional hernia development [angiotensin-converting enzyme (ACE)-inhibitor/angiotensin receptor (AT)1-antag-onist medication, non-steroidal anti-inflammatory drug (NSAID) intake, history of glucocorticoid intake and inci-dence as well as number of previous abdominal surgeries] were collected Estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Dis-ease (MDRD) formula
Amongst the 731 patients enrolled in the study those with macroproteinuria (>300 mg/day), impaired eGFR < 15 ml/min/1.73 m2 or dialysis dependency was regarded as “advanced” diabetic nephropathy For statisti-cal analyses and as comparator, a control group was defined which consisted of diabetics with an eGFR > 60 ml/ min/1.73 m2 and lack of proteinuria (<30 mg/day) The diabetics with eGFR > 15 ml/min/1.73 m2 and <60 ml/ min/1.73 m2 or those with eGFR > 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 diag-nosis of diabetic nephropathy was not enforced, given that this is not commonly accepted due to potential com-plications (bleeding, infection) and the lack of therapeutic consequences
A subgroup analysis regarding the correlation of inci-sional hernia formation and advanced diabetic nephropathy
Trang 3was performed in patients that previously underwent
abdominal surgery (n = 381).
Since patients on dialysis are bound to rest for
pro-longed periods during renal replacement therapy more
fre-quently, the tested relationship between advanced diabetic
nephropathy and herniated discs may be confounded Thus,
for comparison a group consisting of diabetics with an
eGFR between 15 and 60 ml/min/1.73 m2 or
microprotein-uria (30–300 mg per day) was defined in order to compare
patients without nephropathy and moderate,
non-dialysis-dependent nephropathy with regard to disc herniation
Statistics
Metrical variables were assessed for normal distribution
using the Kolmogorov–Smirnov test Depending on the data
distribution, t tests or Mann–Whitney U tests were used for
group comparisons Nominal data were examined using
chi-square test Since the development of diabetic
nephropa-thy is subject to several confounding factors, multivariate
analyses were performed Therefore, binary logistic
regres-sion was executed for independence of risk factors Known
risk factors or possible new modifiers were considered if
reaching a p value < 0.1 in univariate analysis
Addition-ally, known risk factors for the genesis of incisional hernias
were included A p value <0.05 was regarded as statistically
significant The statistical analysis was accomplished using
SPSS (version 15.0, IBM SPSS Inc., Somer, NY, USA)
Results
Following informed written consent, 731 diabetics were
enrolled in the study: 410 (56.1 %) of these were male
and 321 (43.9 %) female Kidney function was calculated
above an estimated glomerular filtration rate of 60 ml/
min/1.73 m2 in 353 patients, whereas 212 patients suffered
from moderate (stages III/IV or microalbuminuria) and
141 from advanced nephropathy defined by dependency on
dialysis, CKD stage V or macroalbuminuria
Diabetics with “advanced” nephropathy were older, had
a lower HbA1c (6.5 vs 7.3 %), were diagnosed for a longer
time period with diabetes mellitus, suffered more often from arterial hypertension, smoked less frequently and took lipid-lowering drugs more often (Table 1) Some connec-tive tissue diseases (inguinal herniation, aortic aneurysm and varicose veins) were similarly often diagnosed in the control group as well as in those patients with “advanced” nephropathy (Table 2) Diabetics with preserved kid-ney function (eGFR > 60 ml/min/1.73 m2) reported about umbilical herniation more often than patients with
“advanced” nephropathy (Table 2) Disc herniation is sig-nificantly less often diagnosed in diabetics with “advanced” nephropathy (Fig 1; Table 2) Comparing diabetics with normal kidney function to those with moderately impaired kidney function (eGFR 15–60 ml/min/1.73 m2 or micro-proteinuria) revealed that disc herniation is significantly
less prevalent in the latter group (8 vs 16.1 %, p = 0.008;
Figs 1 2)
Abdominal surgery had previously been performed in
381 patients Appendectomy (n = 158) was by far the most common operation, followed by hysterectomy (n = 58), cholecystectomy (n = 57) and inguinal hernia opera-tion (n = 56) Gynaecological operaopera-tions other than
hys-terectomies were recorded in 74 cases Eighteen patients had received kidney or kidney and pancreas transplants Subgroup analysis of these patients demonstrated inci-sional hernia formation was significantly more frequent
Table 1 Factors influencing
the development of “advanced”
diabetic nephropathy
Normal kidney function
n = 353
“Advanced” kidney disease
n = 141
p value
Diabetes duration ≥ 10 [n (%)] 184 (52.4 %) 103 (75.2 %) <0.001
Table 2 Outcome regarding connective tissue disorders of diabetics
with preserved kidney function and “advanced” kidney disease
Preserved kidney function
n = 353
“Advanced”
kidney disease
n = 141
p value
Aortic aneurysm
[n (%)]
Varices [n (%)] 80 (22.7 %) 26 (18.4 %) 0.3 Inguinal hernia
[n (%)]
Umbilical herniation
[n (%)]
Disc herniation
[n (%)]
Trang 4when “advanced” nephropathy was concomitantly present (16.0 %), whereas only 5.7 % of patients suffered from incisional herniation without “advanced” nephropathy The potential risk factors for the development of inci-sional herniation considered in the statistical analysis are shown in Table 3 A significant association in the univariate analysis could only be found between kidney function and incisional hernia formation as well as a history of glucocor-ticoid treatment and incisional hernia formation
Variables considered in multivariate analysis were age, duration of diabetes mellitus since diagnosis, nicotine consumption, arterial hypertension, usage of lipid-low-ering drugs, incisional hernia formation and therapy with glucocorticoids
By means of binary logistic regression, we could iden-tify incisional herniation as an independent risk factor (OR
3.5, p = 0.022) for the development of “advanced” diabetic
nephropathy Other independent risk factors were age (OR
2.6, p = 0.04), diabetes mellitus duration since diagnosis (OR 2.5, p = 0.019) and arterial hypertension (OR 1.1,
p < 0.001, Table 4)
Discussion
The pathophysiology of diabetic nephropathy is still not resolved, although enormous effort has been made to elu-cidate common underlying modes of damage [23, 24] The coincidence of arterial hypertension may aggravate kidney disease The mainstay of histological alterations consists of thickened basement membranes; furthermore, a pathologi-cal classification has been described that is based on glo-merular changes [22]
The initial hypothesis of our study was that diabetic nephropathy and incisional hernia development may have similar underlying pathophysiology, that is, a tissue regen-eration disorder with altered collagen metabolism and com-position For recurring incisional hernia formation excess collagen type III over collagen type I expression has been described [25]; similarly, alterations of collagen synthesis have been described for kidney fibroblasts grown under hyperglycaemic conditions [26, 27] However, based on the data on hand, it is not possible to give a statement con-cerning the causality for disease onset and perpetuation The tensile strength of type III collagen differs consider-ably from type I collagen, which is the main constituent of mature scar tissue Wound healing may be skewed by such dysregulations [28]; furthermore, loss of organ function may be incited by recurring injuries and misguided wound
83.1%
92%
94.3%
16.9%
8%
5.7%
0
50
100
150
200
250
300
350
CKD stage I/II, no
albuminuria CKD stage III/IV ormicroalbuminuria CKD stage V and/ormacroalbuminuria
n
no disc herniation disc herniation
Fig 1 Frequency of disc herniation in dependency of kidney
func-tion The share of diabetics with disc herniation was higher in
patients with preserved kidney function and lower in patients with
moderately or markedly “advanced” kidney disease
94.3%
84.0%
0
20
40
60
80
100
120
140
160
180
200
CKD stage I/II no
albuminuria CKD stage V and/or macroalbuminuria
n
no incisional herniation incisional herniation
Fig 2 Frequency of incisional herniation in dependency of kidney
function The percentage of patients with incisional herniation in the
group with preserved kidney function demonstrates a lower share of
5.7 % when compared with those with “advanced” kidney disease
(16.0 %)
Trang 5healing One may simplify the underlying
pathomecha-nism as wounding with ensuing wound repair that results in
immature scarring and excessive collagenous tissue
deposi-tion in the kidneys
Our statistical analysis revealed an association between
“advanced” diabetic nephropathy and incisional hernia
development within the subgroup of patients that had a
pre-ceding abdominal surgery Diabetics with a positive past
medical history for incisional abdominal herniation had an
increased relative risk of 3.5-fold for the development of
“advanced” diabetic nephropathy Several endogenous
fac-tors (age, gender, obesity, anaemia and diabetes mellitus) as
well as exogenous factors (glucocorticoids, ACE-inhibitors,
NSAID and smoking) promote incisional hernia
forma-tion [29] Our study did not identify a significant difference
within the gender distribution and the body mass index
(BMI) was not higher in patients with incisional abdominal
herniation The number of preceding abdominal operations
was about the same in both groups, the ones with and
with-out incisional hernia formation
Our study shows a borderline significant correlation
between ACE-inhibitor or AT-1 receptor antagonist intake
and the occurrence of incisional herniation (p = 0.07)
Uni-variate analysis showed an association between the usage
of glucocorticoids and a history of incisional herniation
Both did not reach levels of significance in the multivariate analysis
By multivariate analysis, we identified incisional her-niation as independent risk factor for “advanced” diabetic nephropathy development In addition, diabetic nephropa-thy was independently associated with age, duration of dia-betes mellitus and arterial hypertension
Patients with end-stage kidney disease have complex mechanisms involved in poor wound healing [30, 31]
We therefore performed another statistical analysis with patients suffering from CKD and macroproteinuria, exclud-ing those with end-stage kidney disease A significant posi-tive association between advanced diabetic nephropathy
and incisional herniation rates (p = 0.002) was still found,
whereas with other connective tissue alterations, no corre-lations were present
Thus, our results support the assumption that both dis-eases underlie similar pathomechanisms leading to an impaired regeneration of connective tissue
The gene expression profile of fibroblasts outgrown from the skin of patients with inguinal hernias also exhib-ited a reduced ratio of type I/III collagen [18] Neverthe-less, our data do not provide a positive correlation between inguinal herniation and “advanced” diabetic nephropathy development
Umbilical herniation was less frequent in diabetics with advanced nephropathy (3.0 %) compared to the cohort of patients with preserved kidney function (8.2 %) Fach-inelli et al showed a reduction in total collagen as well as
a reduced collagen type I in the linea alba of patients with ventral herniation (umbilical, epigastric and incisional her-niation) compared to healthy controls Differences in the amount of collagen type III were not described [15] Varia-tions in the composition of the connective tissue in the dif-ferent types of herniation were not considered
Table 3 Factors influencing
the development of incisional
herniation
a Preserved kidney function
b Advanced kidney disease
No incisional herniation n = 224 Incisional hernia n = 19 p value
Number of previous operations [median]
Kidney function
Gender
Table 4 Binary logistic regression with diabetic nephropathy risk
factors
p univariate OR (CI 95 %) p multivariate Incisional herniation 0.016 3.5 (1.2–10.3) 0.022
Diabetes duration <0.001 2.5 (1.2–5.3) 0.02
Hypertension <0.001 1.1 (1.0–1.1) <0.001
Trang 6Furthermore, disc herniation was less frequent in
diabet-ics with “advanced” nephropathy One possible
explana-tion is that patients undergoing renal replacement therapy
have to rest in supine position for several hours during each
dialysis session and may thus be protected from spine
pres-sure expopres-sure However, a similar negative correlation was
also found for patients that had not yet progressed to
end-stage renal disease and suffered from moderately impaired
kidney function (defined as eGFR 15–60 ml/min/1.73 m2,
microproteinuria) when compared to diabetics with normal
kidney function The pathomechanism of diabetic
nephrop-athy and disc herniation seem to be opposing; that is,
patients with “advanced” nephropathy were protected from
disc herniation From experimental and genetic studies, it
is known that matrix metalloproteinase (MMP) activities
are lowered in diabetic nephropathy [32] The gene
expres-sion of gelatinase B is reduced when a poorly controlled
diabetic metabolism prevails and glomerulosclerosis
coex-ists [33] A dinucleotid repeat polymorphism within the
matrix metalloproteinase-9 (MMP-9 or gelatinase B) gene
was found, the presence of which was associated with
dia-betic nephropathy [34] Conversely, increased activities
of gelatinase and stromelysin activities were detected in
humans with lumbar and cervical disc herniation [35, 36]
Dogs with acute disc herniation exhibited elevated
gelati-nase B enzymatic activity in the cerebrospinal fluid [37]
Park et al [38] showed that the concentration of the
tis-sue inhibitor of matrix metalloproteinase 2 (TIMP-2) was
lower in the ligamentum flavum of patients with disc
herni-ation when compared to the ligamentum flavum of patients
with spinal stenosis
Our study has several limitations The data collection
has been standardized; however, it has been performed in
a retrospective manner by questionnaires The follow-up
and observation period since diagnosis of diabetes mellitus
differed considerably for the recruited patients and ideally
should be at least 15 years, a time period when the
inci-dence of diabetic nephropathy development peaks
Fur-thermore, the “classification” as diabetic nephropathy may
not be justified, given that a considerable share of patients
suffers from coinciding other kidney pathologies that may
not be excluded without performance of kidney biopsies
The frequencies of normoalbuminuria observed in patients
with low GFR have been reported to be 22–24 % in type
1 diabetes mellitus and 32–71 % in type 2 diabetes
melli-tus [39] Thus, our classification with macroalbuminuria as
indicator of “advanced” diabetic nephropathy may not be
justified in all patients; however, it seems the best available
indicator of kidney damage besides impaired glomerular
filtration rate The study may be subject to various forms
of bias: 1 Reporting bias As the primary end-point
(her-nia, etc.) is based on a standardized interview, some cases
may be overlooked, others falsely included 2 Selection
bias Only patients admitted to the surgery ward of a ter-tiary medical centre were approached and asked for partici-pation in the interview Most of the patients were enrolled; however, some denied participation without providing rea-sons 3 Information bias It is not clear whether the sur-gical procedures (e.g appendectomy) were performed at a time when the patient fulfilled the criteria for (advanced) diabetic nephropathy Hence, some patients may have been misclassified 4 Confounding bias The effects of advanced diabetic nephropathy may be confounded by different BMI/ medication/diet/occupation However, BMI for the patients with and without incisional herniation was similar (see Table 3) The healthy worker effect Patients with diabetes mellitus and stage I/II nephropathy are by far more likely to have different occupations than patients with stage V All these effects may be operative in the study and may confound our results The standardized interview has been chosen to minimize differences in questionnaires, and only
a single person performed the questionnaire to exclude dif-ferences in interviewing between groups
Conclusion
Our study strongly underscores that in diabetics connec-tive tissue composition and related diseases share under-lying pathophysiology that may affect integrity of kidney architecture and function The occurrence of incisional herniation positively correlates with “advanced” kidney disease development, whereas umbilical herniation and disc herniation indicate “protection” from perpetuated kid-ney damage
Acknowledgments We are thankful for the collaboration and
sup-port with patient recruitment by Dr Heddeus, Dr Weidemann and Dr Böhm.
Funding The study was supported by SFB/TR57 (Project TP4),
SFB854(TP01) and Me1365/9-1 to PRM.
Compliance with ethical standards Conflict of interest The results presented in this paper have not been
published previously in whole or part, except in abstract format.
Ethical approval The study protocol was approved by the
ethical-committee of the RWTH University Aachen.
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