JOURNAL
OF SURGICAL
23, 31-42 (1977)
RESEARCH
The Effect
of Uremia on Wound Tensile and Collagen Formation’
Strength
ELROY D. KURSH, M.D. ,* LEROY KLEIN, M.D. ,JOHN SCHMITT, SAADKAYAL, M.D., AND LESTERPERSKY, M.D.
B.S.,
Division of Urology, Department of Surgery, Case Western Reserve University, University Hospitals, Cleveland, Ohio Submitted for publication January 27. 1977
of cellular proliferation in the An increased incidence of wound de- hibition hiscence has been noted in uremic patients fibroblasts and endotheial cells of the gran[I, 131. This phenomenon has also been ulation tissue. demonstrated in uremic animals [8, 91. A number of studies have demonstrated In spite of this, the effect of uremia on that urea effects the polymerization and wound healing has been neglected and is strength of collagen in vitro. Gross and Kirk seldom discussed in the literature. In a re- [3] have shown that a number of low moleccent extensively referenced review on the ular weight electrolytes and nonelecfactors affecting the tensile strength of trolytes, including urea (0.04 to 0.16 M) wounds, uremia was not mentioned [ 151. exert a rate regulating effect on the polyThere has been very little investigative merization of collagen fibrils in warming effort evaluating the effect of uremia on neutral solutions of collagen. Urea-denaturwound healing, and a reduction in healing ation of soluble collagen with 1 to 10 M urea capacity associated with uremia has not as evaluated by Steven and Tristram is been documented in the laboratory. Pea- thought to be the result of rupturing hydrocock [l I] showed a decrease in tensile gen bond cross-links [14]. Urea-sensitive strength in wounds of rats drinking urea cross-linking was also evaluated by Peacock solutions. Since the urea-fed rats became and Biggers using 3.3 M urea who demonextremely dehydrated, control groups of de- strated that the urea rupture times were hydrated rats in the absence of markedly approximately twice as long as the majority elevated levels of blood urea nitrogen were of primary wounds compared to secondary also studied. These rats developed a similar wounds, suggesting that urea interferes with decrease in the tensile strength of their collagen assembly [12]. In all of these exwounds making it difficult to determine if periments the concentration of urea utilized uremia or dehydration caused the reduction was considerably greater than the concenin wound tensile strength. McDermott and tration that would be anticipated in the his co-workers [7] showed that granulation uremic patient or laboratory animal. For tissue was reduced in uremic mice when example, a BUN of 100 mg% is equal to wounds were examined histologically at 5 0.017 M urea and a BUN of 200 mg% days. Autoradiographic studies with tri- equals 0.033 it4 urea. It has not been tiated thymidine also demonstrated an in- determined, therefore, if the lower concentration of urea occurring in viva affects ’ Supported by a grant from The Kidney Foundation collagen assembly or strength. of Ohio, Inc., and U.S. Public Health Service Grant On the basis of this knowledge, this No. HD-00669 from the National Institutes of Health. experiment was designed to investigate the 2 Present address: 2065 Adelbert Road, Cleveland, Ohio 44106. effect of uremia on wound healing in the 37 Copyright All rights
0 1977 by Academic Press. Inc. of reproduction in any form reserved.
ISSN 0022-4804
38
JOURNAL
OF SURGICAL
RESEARCH: TABLE
VOL. 23, NO. 1, JULY 1977 1
EFFECTOFUREMIAONTENSILESTRENGTH,COLLAGENFORMATION,CALORICINTAKE, AND BODYWEIGHT~
Serum creatinine b3%)
Days after wounding
Tensile strength (g)
Hydroxyproline/ sponge (I%9 102 37b
caloric intake/day (cd)
Final body weight (B)
91.5 5w
291 19ob
5
Controls Uremics
0.51 1.09
286 24ob
10
Controls Uremics
0.48 1.23
638 459
1106 2lW
92 61b
308 193*
15
Controls Uremics
0.51 1.31
1232 823”
2247 1506*
96 63*
334 214b
(1Data represents the mean values when n = 12. b Difference between controls and uremics is statistically significant (p < 0.05) when using the t test.
rat. Two types of wound models were utilized, a closed wound model to determine the tensile strength of wounds and a dead space model to quantify the biochemical effects of uremia on collagen formation in a sponge implanted subcutaneously. The dead space model was chosen since it is impossible to know how much collagen was present before wounding compared to the amount synthesized after wounding, and the physical limits of a given wound cannot be accurately ascertained. Since the polyvinyl sponges stimulate and accumulate 1400 z E 1200 E 2 $
z 5 800 E tiw 400 2z 200 = 800I
q q
CON'TROL UREMIC * p 1.4.
The wound tensile strength was determined in 12 control and 12 uremic rats 5, 10, and 15 days after wounding. A modification of the tensiometer described by Williams and his associates [ 161 was used to measure wound tensile strength. Sponges were removed at the time of testing wound tensile strength. The removal of sponges and extraction and purification of collagen were done as described previously [4, 61. The extracted collagen was hydrolyzed in 6 N HCI for 3 hr at 120°C. The chromatographic isolation and quantification of hydroxyprohne [5] was used to determine collagen content per sponge, since nearly all of the hydroxyproline found in mammals is present in collagen [IO]. RESULTS
The mean values for tensile strength, hydroxyproline content, caloric intake, and final body weight are seen in Table 1. The uremic rats had a significant reduction in the tensile strength of their wounds compared to the control animals at each test period (Fig. 1). There was also a statistically significant reduction in the hydroxyproline content at each test period.
In order to evaluate the effect of the degree of uremia on wound healing, the mean tensile strength and hydroxyproline content were compared at various levels of uremia for each test period (Table 2). Severe uremia (creatinine > 1.4 mg%) was associated with a considerable reduction in tensile strength and collagen accumulation at the lo- and 15-day test periods but not at Day 5. The effect of the degree of uremia was also evaluated by comparing the mean tensile strength and hydroxyproline content in the six least and six most uremic rats. The results along with the mean creatinine values in each group are seen in Table 3. A statistically significant difference was not found at any test period for hydroxyproline content and was noted at only the 15-day test period for tensile strength. A marked and statistically significant difference in caloric intake and final body weight was observed in the uremic rats compared to the controls (Table 1). Figure 2 demonstrates the marked reduction in final body weight in the uremic rats. Accordingly, in order to evaluate the effect of the final body weight which reflects the state of nutrition on wound healing in uremia,
40
JOURNAL
OF SURGICAL
RESEARCH: TABLE
EFFECT
OF DEGREE
OF UREMIA
Days after wounding
AND BODY
VOL. 23, NO. 1, JULY 1977 3
WEIGHT
ON HEALING
CAPACITY
Serum creatinine bg%)
Final body weight (Id
Tensile strength 63)
IN UREMIC
RATS=
Hydroxyproline/ sponge kit)
5
Least uremic Most uremic Heaviest Lightest
0.90 1.28b 1.04 1.15
201 180 214 166
242 237 241 237
35 39 37 37
10
Least uremic Most uremic Heaviest Lightest
1.04 1.43” 1.07 1%
212 175 230 1576
481 438 509 410
202 217 323 75b
15
Least uremic Most uremic Heaviest Lightest
1.20 1.446 1.22 1.47
220 207 248 179
898 74@ 916 73ob
1865 1146 2000 10126
a Data represents the mean values when n = 6. * Difference is statistically significant (p < 0.05) when using the t test.
the mean tensile strength and hydroxyproEvaluation of the effect of the degree of line content were compared in the six uremia or an individual value of the serum on the results was heaviest and six lightest uremic rats for creatinine determination each test period (Table 3). There was a also done by calculating the correlation coefficients (r) for the serum creatinine in statistically significant difference for tensile strength at the 15-day test period and the uremic rats against final body weight, for hydroxyproline content at the lO- and tensile strength, and hydroxyproline conIS-day test periods, tent (Table 4). The only significant correlation coefficient for the serum creatinine 340 level was found for the final body weight * n CONTROL 2 E at 10 days. There was no significant corq UREMIC z 320 relation between serum creatinine and ten*pc.oos c L sile strength or hydroxyproline. Similarly, ri correlation coefficients were also computed for the final body weights in the uremic rats against caloric intake, tensile strength, and hydroxproline content (Table 4). As anticipated, a significant r value was determined at all test periods for final body weight against caloric intake. A significant 5 IS correlation was also found between the final o:“vs body weight and tensile strength at 15 days FIG. 2. Comparison of final body weight in the and the hydroxyproline content at 10 days.
I I,
control and uremic rats. There was a marked and statistically significant reduction in the mean final body weights of the uremic rats compared to the controls. The mean creatinine values are demonstrated inside the bars.
DISCUSSION
This uremia
experiment demonstrates that has an adverse affect on healing
KURSH ET AL .: WOUND TENSILE TABLE
41
STRENGTH
4
CORRELATION COEFFICIENTS(~) FORSERUM CREATININE~ALUES ANDFINALBODY WEIGHTS IN THEUREMICRATS Days after wounding X
Y
5
10
VS
Final body weight (g) Tensile strength (g) Hydroxyproline (pg)
0.17 0.10 0.44
0.68” 0.57 0.43
0.20 0.38 0.14
vs
Caloric intake (Cal) Tensile strength (g) Hydroxyproline (pg)
0.75” 0.24 0
0.82” 0.50 0.78”
0.88” 0.63” 0.40
Serum creatinine (mg%)
Final body weight
15
u Statistically significant when n = 12.
capacity. A statistically significant reduction in tensile strength was noted in the wounds placed on the backs of uremic rats compared to control animals. A significant reduction in the collagen accumulation as determined by quantifying the hydroxyproline content in polyvinyl sponges implanted subcutaneously was also noted in the uremic animals. Therefore, the clinical impression that uremia reduces wound strength is substantiated. The degree of uremia affected the healing capacity since severe uremia was associated with poorer healing except at the 5-day test period (Table 3). Dunphy and Udupa [2] equated the tensile strength of wounds to collagen formation. Since there is little collagen formation until 5 days postwounding, the 5-day-old wound remains weak. Therefore, it is not surprising that the serum creatinine value had little effect on wound tensile strength and the small amount of hydroxyproline accumulated in the polyvinyl sponges at the 5-day test period. Throughout the experiment it was noted that the uremic animals had a much lower caloric intake than the control animals (Table 1). Weight gain was substantially less in the uremic rats. In fact, many of the uremic rats failed to gain or even lost weight. It was noted that the mean final body weight in the severely uremic rats
was less than the animals at the start of the experiment (Table 2). Therefore, the reduced state of nutrition may be responsible for the confirmed poor healing capacity associated with uremia as opposed to the uremia per se. When the mean tensile strength and hydroxyproline content were compared in the six least and six most uremic rats for each test period, a statistically significant difference was found for only the tensile strength at 15 days. On the other hand, when the tensile strength and hydroxyproline content were compared in the six heaviest and six lightest uremic rats, there was a statistically significant difference for tensile strength at 15 days and for hydroxyproline content at 10 and 15 days (Table 3). Computation of the correlation coefficients also demonstrated that there was greater correlation between final body weights and the results for wound tensile strength and hydroxyproline content than the individual serum creatinine values (Table 4). Therefore, the data suggest that the state of nutrition as determined by the final body weight appears to have a greater role in determining the healing capacity in uremic rats than the serum creatinine value. SUMMARY
The effect of uremia on wound healing in the rat was investigated by measuring the tensile strength of wounds and the
42
JOURNAL
OF SURGICAL
RESEARCH:
amount of collagen formation in polyvinyl sponges implanted subcutaneously. Uremia had an adverse affect on healing capacity since there was a significant reduction in tensile strength and collagen formation in the uremic animals. Reduced healing was noted in the more severely uremic rats indicating that the degree of uremia was important. The uremic animals had a marked reduction in caloric intake and final body weight compared to control groups, and there was greater correlation between the results for tensile strength and collagen accumulation and the final body weights than the serum creatinine values. Therefore, the data suggest that nutritional factors are responsible for the demonstrated poor healing capacity associated with uremia. REFERENCES 1. Bluemle, L. W., Jr., Webster, C. D., Jr., and Elkinton, J. R. Acute tubular necrosis. Arch. Intern. Med. 104: 180, 1959. 2. Dunphy, J. E., and Udupa, K. N. Chemical and histochemical sequences in the normal healing of wounds. N. Engl. .I. Med. 253: 847, 1955. 3. Gross, J., and Kirk, D. The heat precipitation of collagen from neutral salt solutions: Some rate regulating factors. .I. Biol. Chem. 233: 355, 1958. 4. Klein, L. Reversible transformation of fibrous collagen to a soluble state in viva. Proc. Nutl. Acad. Sci. USA 62: 920, 1%9. 5. Klein, L. Hydroxyproline in urine and tissues. Stand. Meth. Clin. Chem. 6: 41, 1970.
VOL. 23, NO. 1, JULY 1977
6. Klein, L., and Weiss, P. H. Induced connective tissue metabolism in viva: Reutilization of preexisting collagen. Proc. Natl. Acad. Sci. USA 56: 277, 1966. 7. McDermott, F. T., Nayman, J., and deBoer, W. G. R. M. The effect of acute renal failure upon wound healing: Histological and autoradiographic studies in the mouse. Ann. Surg. 168: 142, 1968. 8. Nayman, J. Effect of renal failure on wound healing: An experimental study. Ann. Surg. 164: 227, 1966. 9. Nayman, J., McDermott, F. T., and deBoer, W. G. R. M. Effect of acute renal failure upon wound healing in the mouse. Rev. Surg. 23: 453, 1966. 10. Neuman, R. E., and Logan, M. A. Determination of collagen and elastin in tissues. J. Biol. Chem.
186: 549,
1950.
11. Peacock, E. E., Jr. Production and polymerization of collagen in healing wounds of rats: Some regulating factors. Ann. Surg. 155: 251, 1%2. 12. Peacock, E. E., Jr., and Biggers, P. W. Measurement and significance of heat-labile and ureasensitive cross-linking mechanisms in collagen of healing wounds. Surgery 54: 144, 1963. 13. Stern, A. A., and Wiersum, J. The role of renal dysfunction in abdominal wound dehiscence. J. Ural. 82; 27 1) 1959. 14. Steven, F. S., and Tristram, G. R. The denaturation of acetic acid-soluble calf-skin collagen: Changes in optical rotation, viscosity and susceptibility toward enzymes during serial denaturation in solutions of urea. Biochem. J. 85: 207, 1%2. 15 Van Winkle, W. The tensile strength of wounds and factors that influence it. Surg. Gynecol. O&ret. 129: 819, 1%9. 16. Williams, R. W., Mason, L. B., and Bradshaw, M. D. Factors affecting wound healing. Surg. Forum, p. 410. W. B. Saunders, Philadelphia, 1951.
OF SURGICAL
23, 31-42 (1977)
RESEARCH
The Effect
of Uremia on Wound Tensile and Collagen Formation’
Strength
ELROY D. KURSH, M.D. ,* LEROY KLEIN, M.D. ,JOHN SCHMITT, SAADKAYAL, M.D., AND LESTERPERSKY, M.D.
B.S.,
Division of Urology, Department of Surgery, Case Western Reserve University, University Hospitals, Cleveland, Ohio Submitted for publication January 27. 1977
of cellular proliferation in the An increased incidence of wound de- hibition hiscence has been noted in uremic patients fibroblasts and endotheial cells of the gran[I, 131. This phenomenon has also been ulation tissue. demonstrated in uremic animals [8, 91. A number of studies have demonstrated In spite of this, the effect of uremia on that urea effects the polymerization and wound healing has been neglected and is strength of collagen in vitro. Gross and Kirk seldom discussed in the literature. In a re- [3] have shown that a number of low moleccent extensively referenced review on the ular weight electrolytes and nonelecfactors affecting the tensile strength of trolytes, including urea (0.04 to 0.16 M) wounds, uremia was not mentioned [ 151. exert a rate regulating effect on the polyThere has been very little investigative merization of collagen fibrils in warming effort evaluating the effect of uremia on neutral solutions of collagen. Urea-denaturwound healing, and a reduction in healing ation of soluble collagen with 1 to 10 M urea capacity associated with uremia has not as evaluated by Steven and Tristram is been documented in the laboratory. Pea- thought to be the result of rupturing hydrocock [l I] showed a decrease in tensile gen bond cross-links [14]. Urea-sensitive strength in wounds of rats drinking urea cross-linking was also evaluated by Peacock solutions. Since the urea-fed rats became and Biggers using 3.3 M urea who demonextremely dehydrated, control groups of de- strated that the urea rupture times were hydrated rats in the absence of markedly approximately twice as long as the majority elevated levels of blood urea nitrogen were of primary wounds compared to secondary also studied. These rats developed a similar wounds, suggesting that urea interferes with decrease in the tensile strength of their collagen assembly [12]. In all of these exwounds making it difficult to determine if periments the concentration of urea utilized uremia or dehydration caused the reduction was considerably greater than the concenin wound tensile strength. McDermott and tration that would be anticipated in the his co-workers [7] showed that granulation uremic patient or laboratory animal. For tissue was reduced in uremic mice when example, a BUN of 100 mg% is equal to wounds were examined histologically at 5 0.017 M urea and a BUN of 200 mg% days. Autoradiographic studies with tri- equals 0.033 it4 urea. It has not been tiated thymidine also demonstrated an in- determined, therefore, if the lower concentration of urea occurring in viva affects ’ Supported by a grant from The Kidney Foundation collagen assembly or strength. of Ohio, Inc., and U.S. Public Health Service Grant On the basis of this knowledge, this No. HD-00669 from the National Institutes of Health. experiment was designed to investigate the 2 Present address: 2065 Adelbert Road, Cleveland, Ohio 44106. effect of uremia on wound healing in the 37 Copyright All rights
0 1977 by Academic Press. Inc. of reproduction in any form reserved.
ISSN 0022-4804
38
JOURNAL
OF SURGICAL
RESEARCH: TABLE
VOL. 23, NO. 1, JULY 1977 1
EFFECTOFUREMIAONTENSILESTRENGTH,COLLAGENFORMATION,CALORICINTAKE, AND BODYWEIGHT~
Serum creatinine b3%)
Days after wounding
Tensile strength (g)
Hydroxyproline/ sponge (I%9 102 37b
caloric intake/day (cd)
Final body weight (B)
91.5 5w
291 19ob
5
Controls Uremics
0.51 1.09
286 24ob
10
Controls Uremics
0.48 1.23
638 459
1106 2lW
92 61b
308 193*
15
Controls Uremics
0.51 1.31
1232 823”
2247 1506*
96 63*
334 214b
(1Data represents the mean values when n = 12. b Difference between controls and uremics is statistically significant (p < 0.05) when using the t test.
rat. Two types of wound models were utilized, a closed wound model to determine the tensile strength of wounds and a dead space model to quantify the biochemical effects of uremia on collagen formation in a sponge implanted subcutaneously. The dead space model was chosen since it is impossible to know how much collagen was present before wounding compared to the amount synthesized after wounding, and the physical limits of a given wound cannot be accurately ascertained. Since the polyvinyl sponges stimulate and accumulate 1400 z E 1200 E 2 $
z 5 800 E tiw 400 2z 200 = 800I
q q
CON'TROL UREMIC * p 1.4.
The wound tensile strength was determined in 12 control and 12 uremic rats 5, 10, and 15 days after wounding. A modification of the tensiometer described by Williams and his associates [ 161 was used to measure wound tensile strength. Sponges were removed at the time of testing wound tensile strength. The removal of sponges and extraction and purification of collagen were done as described previously [4, 61. The extracted collagen was hydrolyzed in 6 N HCI for 3 hr at 120°C. The chromatographic isolation and quantification of hydroxyprohne [5] was used to determine collagen content per sponge, since nearly all of the hydroxyproline found in mammals is present in collagen [IO]. RESULTS
The mean values for tensile strength, hydroxyproline content, caloric intake, and final body weight are seen in Table 1. The uremic rats had a significant reduction in the tensile strength of their wounds compared to the control animals at each test period (Fig. 1). There was also a statistically significant reduction in the hydroxyproline content at each test period.
In order to evaluate the effect of the degree of uremia on wound healing, the mean tensile strength and hydroxyproline content were compared at various levels of uremia for each test period (Table 2). Severe uremia (creatinine > 1.4 mg%) was associated with a considerable reduction in tensile strength and collagen accumulation at the lo- and 15-day test periods but not at Day 5. The effect of the degree of uremia was also evaluated by comparing the mean tensile strength and hydroxyproline content in the six least and six most uremic rats. The results along with the mean creatinine values in each group are seen in Table 3. A statistically significant difference was not found at any test period for hydroxyproline content and was noted at only the 15-day test period for tensile strength. A marked and statistically significant difference in caloric intake and final body weight was observed in the uremic rats compared to the controls (Table 1). Figure 2 demonstrates the marked reduction in final body weight in the uremic rats. Accordingly, in order to evaluate the effect of the final body weight which reflects the state of nutrition on wound healing in uremia,
40
JOURNAL
OF SURGICAL
RESEARCH: TABLE
EFFECT
OF DEGREE
OF UREMIA
Days after wounding
AND BODY
VOL. 23, NO. 1, JULY 1977 3
WEIGHT
ON HEALING
CAPACITY
Serum creatinine bg%)
Final body weight (Id
Tensile strength 63)
IN UREMIC
RATS=
Hydroxyproline/ sponge kit)
5
Least uremic Most uremic Heaviest Lightest
0.90 1.28b 1.04 1.15
201 180 214 166
242 237 241 237
35 39 37 37
10
Least uremic Most uremic Heaviest Lightest
1.04 1.43” 1.07 1%
212 175 230 1576
481 438 509 410
202 217 323 75b
15
Least uremic Most uremic Heaviest Lightest
1.20 1.446 1.22 1.47
220 207 248 179
898 74@ 916 73ob
1865 1146 2000 10126
a Data represents the mean values when n = 6. * Difference is statistically significant (p < 0.05) when using the t test.
the mean tensile strength and hydroxyproEvaluation of the effect of the degree of line content were compared in the six uremia or an individual value of the serum on the results was heaviest and six lightest uremic rats for creatinine determination each test period (Table 3). There was a also done by calculating the correlation coefficients (r) for the serum creatinine in statistically significant difference for tensile strength at the 15-day test period and the uremic rats against final body weight, for hydroxyproline content at the lO- and tensile strength, and hydroxyproline conIS-day test periods, tent (Table 4). The only significant correlation coefficient for the serum creatinine 340 level was found for the final body weight * n CONTROL 2 E at 10 days. There was no significant corq UREMIC z 320 relation between serum creatinine and ten*pc.oos c L sile strength or hydroxyproline. Similarly, ri correlation coefficients were also computed for the final body weights in the uremic rats against caloric intake, tensile strength, and hydroxproline content (Table 4). As anticipated, a significant r value was determined at all test periods for final body weight against caloric intake. A significant 5 IS correlation was also found between the final o:“vs body weight and tensile strength at 15 days FIG. 2. Comparison of final body weight in the and the hydroxyproline content at 10 days.
I I,
control and uremic rats. There was a marked and statistically significant reduction in the mean final body weights of the uremic rats compared to the controls. The mean creatinine values are demonstrated inside the bars.
DISCUSSION
This uremia
experiment demonstrates that has an adverse affect on healing
KURSH ET AL .: WOUND TENSILE TABLE
41
STRENGTH
4
CORRELATION COEFFICIENTS(~) FORSERUM CREATININE~ALUES ANDFINALBODY WEIGHTS IN THEUREMICRATS Days after wounding X
Y
5
10
VS
Final body weight (g) Tensile strength (g) Hydroxyproline (pg)
0.17 0.10 0.44
0.68” 0.57 0.43
0.20 0.38 0.14
vs
Caloric intake (Cal) Tensile strength (g) Hydroxyproline (pg)
0.75” 0.24 0
0.82” 0.50 0.78”
0.88” 0.63” 0.40
Serum creatinine (mg%)
Final body weight
15
u Statistically significant when n = 12.
capacity. A statistically significant reduction in tensile strength was noted in the wounds placed on the backs of uremic rats compared to control animals. A significant reduction in the collagen accumulation as determined by quantifying the hydroxyproline content in polyvinyl sponges implanted subcutaneously was also noted in the uremic animals. Therefore, the clinical impression that uremia reduces wound strength is substantiated. The degree of uremia affected the healing capacity since severe uremia was associated with poorer healing except at the 5-day test period (Table 3). Dunphy and Udupa [2] equated the tensile strength of wounds to collagen formation. Since there is little collagen formation until 5 days postwounding, the 5-day-old wound remains weak. Therefore, it is not surprising that the serum creatinine value had little effect on wound tensile strength and the small amount of hydroxyproline accumulated in the polyvinyl sponges at the 5-day test period. Throughout the experiment it was noted that the uremic animals had a much lower caloric intake than the control animals (Table 1). Weight gain was substantially less in the uremic rats. In fact, many of the uremic rats failed to gain or even lost weight. It was noted that the mean final body weight in the severely uremic rats
was less than the animals at the start of the experiment (Table 2). Therefore, the reduced state of nutrition may be responsible for the confirmed poor healing capacity associated with uremia as opposed to the uremia per se. When the mean tensile strength and hydroxyproline content were compared in the six least and six most uremic rats for each test period, a statistically significant difference was found for only the tensile strength at 15 days. On the other hand, when the tensile strength and hydroxyproline content were compared in the six heaviest and six lightest uremic rats, there was a statistically significant difference for tensile strength at 15 days and for hydroxyproline content at 10 and 15 days (Table 3). Computation of the correlation coefficients also demonstrated that there was greater correlation between final body weights and the results for wound tensile strength and hydroxyproline content than the individual serum creatinine values (Table 4). Therefore, the data suggest that the state of nutrition as determined by the final body weight appears to have a greater role in determining the healing capacity in uremic rats than the serum creatinine value. SUMMARY
The effect of uremia on wound healing in the rat was investigated by measuring the tensile strength of wounds and the
42
JOURNAL
OF SURGICAL
RESEARCH:
amount of collagen formation in polyvinyl sponges implanted subcutaneously. Uremia had an adverse affect on healing capacity since there was a significant reduction in tensile strength and collagen formation in the uremic animals. Reduced healing was noted in the more severely uremic rats indicating that the degree of uremia was important. The uremic animals had a marked reduction in caloric intake and final body weight compared to control groups, and there was greater correlation between the results for tensile strength and collagen accumulation and the final body weights than the serum creatinine values. Therefore, the data suggest that nutritional factors are responsible for the demonstrated poor healing capacity associated with uremia. REFERENCES 1. Bluemle, L. W., Jr., Webster, C. D., Jr., and Elkinton, J. R. Acute tubular necrosis. Arch. Intern. Med. 104: 180, 1959. 2. Dunphy, J. E., and Udupa, K. N. Chemical and histochemical sequences in the normal healing of wounds. N. Engl. .I. Med. 253: 847, 1955. 3. Gross, J., and Kirk, D. The heat precipitation of collagen from neutral salt solutions: Some rate regulating factors. .I. Biol. Chem. 233: 355, 1958. 4. Klein, L. Reversible transformation of fibrous collagen to a soluble state in viva. Proc. Nutl. Acad. Sci. USA 62: 920, 1%9. 5. Klein, L. Hydroxyproline in urine and tissues. Stand. Meth. Clin. Chem. 6: 41, 1970.
VOL. 23, NO. 1, JULY 1977
6. Klein, L., and Weiss, P. H. Induced connective tissue metabolism in viva: Reutilization of preexisting collagen. Proc. Natl. Acad. Sci. USA 56: 277, 1966. 7. McDermott, F. T., Nayman, J., and deBoer, W. G. R. M. The effect of acute renal failure upon wound healing: Histological and autoradiographic studies in the mouse. Ann. Surg. 168: 142, 1968. 8. Nayman, J. Effect of renal failure on wound healing: An experimental study. Ann. Surg. 164: 227, 1966. 9. Nayman, J., McDermott, F. T., and deBoer, W. G. R. M. Effect of acute renal failure upon wound healing in the mouse. Rev. Surg. 23: 453, 1966. 10. Neuman, R. E., and Logan, M. A. Determination of collagen and elastin in tissues. J. Biol. Chem.
186: 549,
1950.
11. Peacock, E. E., Jr. Production and polymerization of collagen in healing wounds of rats: Some regulating factors. Ann. Surg. 155: 251, 1%2. 12. Peacock, E. E., Jr., and Biggers, P. W. Measurement and significance of heat-labile and ureasensitive cross-linking mechanisms in collagen of healing wounds. Surgery 54: 144, 1963. 13. Stern, A. A., and Wiersum, J. The role of renal dysfunction in abdominal wound dehiscence. J. Ural. 82; 27 1) 1959. 14. Steven, F. S., and Tristram, G. R. The denaturation of acetic acid-soluble calf-skin collagen: Changes in optical rotation, viscosity and susceptibility toward enzymes during serial denaturation in solutions of urea. Biochem. J. 85: 207, 1%2. 15 Van Winkle, W. The tensile strength of wounds and factors that influence it. Surg. Gynecol. O&ret. 129: 819, 1%9. 16. Williams, R. W., Mason, L. B., and Bradshaw, M. D. Factors affecting wound healing. Surg. Forum, p. 410. W. B. Saunders, Philadelphia, 1951.
