Diet and Renal Failure
Effect of Modified Protein Diets in Dogs and Cats with Chronic Renal Failure: Current Status1 DAVID J. POLZin,2
CARL A. OSBORNE
AND LARRY G. ADAMS
University of Minnesota, College of Veterinary Medicine, Department Small Animal Clinical Sciences, St. Paul, MM 55108
a combination of these techniques, results in a syn drome of progressive azotemia, proteinuria, arterial hypertension and, eventually, death due to uremia (6). Progression occurs despite the fact that surviving renal tissue was initially normal, but reduced in quantity. Similarly, renal insufficiency in humans often pro gresses predictably to renal failure, regardless of dif ferent initiating causes of renal damage (6, 7). Pro gression occurs even when the initiating cause of renal dysfunction is no longer present or active. These ob servations in rats and humans suggest that irreversible loss of renal mass results in spontaneous progression of renal failure. Reducing dietary protein intake has been shown to minimize proteinuria, glomerular injury and the pro gressive decline in renal function that develops in rats after reducing renal mass (5, 8). Dietary protein re striction also minimizes development of glomerular lesions and/or progression of renal dysfunction in a variety of other experimental models of renal disease, including post-salt hypertension, mineralocorticoid hypertension and nephrotoxic serum nephritis in rats, and the mouse model of systemic lupus erythematosus (6). Protein restriction has also been reported to limit progression of spontaneous chronic renal failure in humans (7). Although most studies have focused on the role of dietary protein intake in limiting progressive renal in jury, other dietary factors have also been implicated in promoting progression of chronic renal failure, in-
ABSTRACT Studies in rodents indicate that diet influ ences progression of renal failure. Excessive dietary intakes of protein, fat, energy and phosphorus have been implicated in promoting progression of renal fail ure, while restriction of some or all of these dietary constituents limits progressive renal injury. Studies confirm that renal failure is progressive in some dogs with moderate-to-advanced renal dysfunction. Recent studies also indicate that unrestricted intakes of protein promotes proteinuria in dogs and cats and glomerular injury in cats. J. Nutr. 121: S140-S144, 1991.
INDEXINGKEY WORDS: •symposium •dogs •cats •renal failure •kidney •protein
Nutritional therapy has been the mainstay of med ical management of canine and feline chronic renal failure for decades. Dietary protein and other nutrients are known to influence clinical signs of uremia, elec trolyte and mineral balance, as well as the overall nu tritional status of renal-failure patients (1-4). Renewed interest in dietary management of renal failure has been stimulated by the observation that modification of diet may reduce the rate of progression of chronic renal failure (5). The focus of this discussion is the potential impact of diet on renal function, proteinuria and progression of renal failure.
RENAL INJURY, PROGRESSIVE RENAL FAILURE AND THE ROLE OF DIET
1Presented as part of the Waltham International
Symposium on
Nutrition of Small Companion Animals, at University of California, Davis, CA 95616, on September 4-8, 1990. Guest editors for the symposium were James G. Morris, D'Ann C. Finley and Quinton
In rodents, progression to end-stage renal failure becomes inevitable once a critical mass of functioning nephrons has been damaged or lost (5, 6). Removal of approximately three-quarters or more of the functional renal mass of rats by surgical resection, infarction or 0022-3166/91
of
R. Rogers. 1 To whom correspondence
should be addressed: University
of
Minnesota, College of Veterinary Medicine, Department of Small Animal Clinical Sciences, 1352 Boyd Avenue, Room C-325, St. Paul, MN 55108.
S3.00 ©1991 American Institute of Nutrition.
S140 Downloaded from https://academic.oup.com/jn/article-abstract/121/suppl_11/S140/4744110 by University of Wyoming Libraries user on 19 June 2018
MODIFIED PROTEIN DIETS IN DOGS AND CATS
eluding energy, lipids, phosphorus, sodium, potassium and acid content (9-17). Mechanisms of progression of renal fail ure. Progressive renal damage may result from 1}per sistence of the renal disease(s) responsible for initiating renal failure, 2) different or additional causes of renal injury and/or 3) a variety of complications and se quelae of chronic renal failure, such as urinary tract infection, systemic hypertension and intrarenal min eral deposition. In addition to these causes of pro gression of chronic renal failure, spontaneous, selfperpetuating nephron damage may occur (as described above) (5). Compensatory phenomena that develop in an attempt to sustain renal function and homeostasis may contribute to self-perpetuation of renal dysfunc tion (8, 18). Examples of such factors include glomerular capillary hypertension and hyperfiltration, renal growth (hypertrophy), increased renal oxygen con sumption and increased renal ammoniagenesis. Nonadaptive factors may also be potentially injurious to surviving nephrons in chronic renal failure, including altered phosphate metabolism, altered lipid compo sition and increased activity of the coagulation system. Detection and therapeutic manipulation of these fac tors may retard progression of chronic renal failure. Many of these factors may be influenced by diet for mulation (9). Dietary protein intake and glomerular hypernitration/hypertension. Experimentally induced or naturally occurring reduction in renal mass results in increased glomerular capillary perfusion and glo merular capillary hypertension which in turn pro mote increased glomerular filtration rate (GFR) in individual remaining functional nephrons (often re ferred to as increased single-nephron glomerular fil tration rate and abbreviated SNGFR) (5, 6, 8). This increase in SNGFR is termed glomerular hyperfil tration. Although total GFR is reduced after loss of renal mass, the increase in SNGFR in surviving nephrons causes total GFR to be greater than would have been predicted based on knowledge of the mag nitude of reduction in renal mass. Presumably, glo merular hyperfiltration is as a compensatory phe nomenon designed to maximize GFR in failing kid neys. Although this compensatory adaptation may initially be beneficial, there is evidence that persis tent hemodynamic changes resulting in glomerular capillary hypertension and glomerular hyperfiltra tion may eventually damage surviving nephrons and lead to progressive deterioration of renal function. Considerable evidence implicates systemic hyper tension in promoting progressive glomerular injury associated with glomerular hypertension (19). Restricting dietary protein intake minimizes he modynamic changes that occur after spontaneous or induced reduction in renal mass (8, 18). Normaliza tion of hemodynamics by feeding reduced protein
S141
diets limits proteinuria, development of glomerular lesions and progression of renal dysfunction in a variety of experimental models of renal disease (5, 8,18). Renal hypertrophy. Results of recent studies suggest that glomerular sclerosis may develop in rats with reduced renal mass in the absence of glomerular hypertension. This observation suggests that glomer ular hypertension may not be the sole mechanism re sponsible for development of glomerular lesions in end-stage renal disease (20, 21 ). A possible association between hypertrophy of the glomerulus and devel opment of glomerular sclerosis has been hypothesized, suggesting an alternative or additional mechanism of glomerular injury (21, 22). It has been suggested that altered local hormonal growth regulation may promote glomerular sclerosis, although the mechanisms in volved and glomerular cell types affected have not been determined (22). Growth factors such as interleukin 1, platelet-derived growth factor and epidermal growth factor promote mesangial cell proliferation, and growth promoters such as endothelin may increase extracellular matrix from mesangial cells. Dietary protein, energy and phosphorus intakes as well as a host of other dietary factors may influence renal growth and hypertrophy. Dietary energy. Food restriction, and particularly energy restriction, has been shown to improve the outcome of several forms of experimental renal disease in rodents (10). Restricted energy, fat and mineral (ex cept for calcium and phosphorus) intake retarded growth and prevented development of end-stage renal pathology in rats with reduced renal mass, regardless of whether protein intake was restricted (11). In con trast, protein restriction without restriction of any other dietary component failed to retard growth or prevent development of glomerular sclerosis. Renal injury may have been ameliorated in rats fed energyand mineral-restricted diets as a result of limited renal growth and hypertrophy. Because dietary protein re striction is often associated with reduced food con sumption, the question has been raised as to whether the benefit of dietary protein restriction in limiting renal injury may in fact result from energy and mineral restriction (10). Dietary phosphate, hyperphosphatemia and hyperparathyroidism. Altered calcium and phos phate metabolism and subsequent renal secondary hy perparathyroidism result in deposition of calcium and phosphate in the renal parenchyma of animals with chronic renal failure (15, 23). Renal deposition of cal cium and phosphate causes inflammation, scarring and subsequent loss of nephrons. Studies of rats with ex perimentally induced chronic renal failure suggest that proportional restriction of dietary phosphate intake may minimize or prevent proteinuria, renal mineral ization, renal histologie alterations, renal functional
Downloaded from https://academic.oup.com/jn/article-abstract/121/suppl_11/S140/4744110 by University of Wyoming Libraries user on 19 June 2018
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deterioration and death due to uremia that occur when higher phosphate diets are fed (15). Dietary phosphate restriction also slows progres sion and prolongs survival in dogs with induced chronic renal failure (24). In cats with induced chronic renal failure, normal dietary phosphate con sumption was associated with microscopic evidence of renal mineralization, fibrosis and mononuclear cell infiltration (17). Dietary phosphate restriction prevented these abnormalities. However, evidence of progressive renal dysfunction was not detected in either normal or restricted phosphate groups of cats in this study. Renal ammoniagenesis. Spontaneous and in duced chronic renal failure are characterized by wide spread tubulo-interstitial lesions, the origin of which remains undetermined. Reduction in renal mass is as sociated with compensatory hyperfunction of renal tubules, including increased renal ammoniagenesis. Increased renal ammoniagenesis is attended by a rise in renal tissue ammonia concentration. Local toxic and inflammatory effects of ammonia may include trig gering of the alternative complement pathway by the reaction of ammonia with the third component of complement, culminating in deposition of comple ment proteins and initiation of complement-mediated cellular infiltration and tissue injury (16). These effects further impair tubular function and may promote a self-perpetuating cycle of adaptation and injury. In rats with induced renal failure, dietary supplementation with sodium bicarbonate has been shown to lower tissue ammonia concentrations, reduce peritubular deposition of complement components and dimin ish functional and structural tubulo-interstitial le sions (16). Dietary lipids and progression of renal fail ure. Several recent studies have suggested a role for lipids in modulating progression of experimental renal disease in rodents; mechanisms responsible for these modulating effects are currently the subject of inten sive study (12, 13). Lipid abnormalities are commonly observed in human patients with renal disease. Fur thermore, there appears to be an association between proteinuria, lipid abnormalities and atherosclerosis (12). It is noteworthy that hypercholesterolemia was among the most common serum biochemical abnor malities reported in a retrospective study of cats with chronic renal disease (25). The role of lipids in modulating progression of renal failure may be related, in part, to renal prostaglandin synthesis. The composition of dietary lipids may in fluence systemic blood pressure, blood lipid compo sition, platelet aggregation, blood viscosity, the im mune system and fibrinolytic activity. It has also been hypothesized that certain lipids may promote pro gressive damage to the glomerular basement mem brane and mesangial structures. Downloaded from https://academic.oup.com/jn/article-abstract/121/suppl_11/S140/4744110 by University of Wyoming Libraries user on 19 June 2018
PROGRESSION OF CANINE AND FELINE CHRONIC RENAL FAILURE In contrast to rats and humans, the progressive na ture of canine and feline chronic renal failure is less well documented. Two long-term studies designed to determine if reduced renal mass promotes progressive deterioration of renal function in dogs did not reveal progressive reduction in renal function (1, 26). Despite stable renal function, renal lesions consistent with progressive renal injury (glomerular sclerosis charac terized by subendothelial and mesangial deposition of hyaline material, increased mesangial matrix and col lapse of glomerular capillaries with adhesions of the tuft to Bowman's capsule) were observed in both stud ies. In one of these studies, renal mass was reduced by | and renal function monitored for ¿48mo (26). It is likely that the extent of renal mass reduction in this study was insufficient to initiate progressive deterio ration in renal function. In the other study, renal mass was reduced by g, but renal function was monitored for only 40 wk. This study may have been of insuffi cient duration for progressive deterioration of renal function to develop. Other studies have provided more direct evidence of the progressive nature of canine renal failure. Bourgoignie and colleagues (27) have shown that reduction of renal mass in dogs results in glomerular proteinuria, the severity of which appears to be proportional to the amount of renal mass ablated and which precedes de cline in renal function. During 15-39 mo of study, renal function remained stable in seven dogs and pro gressively declined in only three dogs. The progressive nature of canine chronic renal failure is further sug gested by the observation that progressive decline in renal function occurs in some dogs with spontaneous chronic renal failure (28). However, findings in this report are limited by the fact that renal function was determined by serial assessment of serum creatinine concentrations, which may be influenced by factors other than renal function. A progressive decline in renal function was also ob served in another study of induced canine chronic renal failure in which dogs were fed a low protein, high phosphate diet after }| renal mass ablation (24). Brown and Finco (29) reported that a pattern of de clining renal function developed over 2 y in 9 of 12 dogs after $ renal ablation. Renal function progres sively increased over the 2 y of study in the remaining three dogs. Variables reported to have a significant linear relationship with the rate of decline of renal function included tissue calcium concentration; plasma concentrations of triglycéridesand cholesterol; and renal histologie scores for fibrosis, mineralization and mesangial expansion. We recently completed a study of 15 dogs with | reduction in renal mass in which renal function and
MODIFIED PROTEIN DIETS IN DOGS AND CATS
proteinuria were monitored for 2 y. Seven of these dogs were fed a 39.7% protein diet and eight dogs were fed a 14.1% protein diet. These two diets3 differed only in protein and carbohydrate content. The 39.7% protein diet contained (in g/100 g) 25.3 fat, 29.8 car bohydrate, 0.74 calcium, 0.32 phosphorus, 0.4 potas sium and 0.23 sodium. The 14.1% protein diet con tained (in g/100 g) 23.9 fat, 54.9 carbohydrate, 0.80 calcium, 0.32 phosphorus, 0.4 potassium and 0.24 so dium. After an initial period of stable or increasing renal function, a pattern of declining renal function developed in three dogs fed the 39.7% protein diet and one dog fed the 14.1% protein diet. Renal function progressively increased or remained stable during the first 40 wk of study in all dogs in this study, suggesting that 40 wk is insufficient to assess changes in renal function in dogs with I nephrectomy. Increasing mag nitude of proteinuria typically preceded the onset of declining renal function. In cats, renal function has been found to remain stable for ail y after f reduction in renal mass (30). Proteinuria and glomerular injury were not detected in cats with reduced renal mass fed a 27.6% protein diet. However, cats fed a 51.7% protein diet developed proteinuria and microscopic evidence of glomerular injury. These two diets4 differed only in protein and carbohydrate content. The 51.7% protein diet con tained ¡ing/100 g) 36 fat, 8.7 carbohydrate, 0.47 cal cium, 0.54 phosphorus, 0.4 potassium and 0.27 so dium. The 27.6% protein diet contained (in g/100 g) 37.1% fat, 30.7 carbohydrate, 0.47 calcium, 0.54 phosphorus, 0.4 potassium and 0.29 sodium. Cats with more severe glomerular lesions had more marked pro teinuria. We interpret these observations to indicate that proteinuria and renal structural lesions observed in this study suggest a pattern of declining renal func tion would ultimately have developed in cats fed the 51.7% protein diet. LITERATURE
CITED
1. POLZIN, D. }., OSBORNE,C. A., HAYDEN, D. W. & STEVENS, J. B. (1984) Influence of reduced protein diets on morbidity, mortality, and renal function in dogs with induced renal failure. Am. I Vet. Res. 45: 506-517. 2. POLZIN, D. J. & OSBORNE,C. A. (1986) Update-Conservative medical management of chronic renal failure. In: Current Vet erinary Therapy IX (Kirk, R. W., ed.). pp. 1167-1173, W. B. Saunders Co, Philadelphia, PA. 3. POLZIN, D. J., OSBORNE,C. A., HAYDEN, D. W. & STEVENS, 3 The diets contained
cornstarch, chicken fat, casein, sucrose,
solka floe, calcium carbonate, dicalcium phosphate, potassium chloride, mineral mixture, choline, sodium chloride, vitamin mix ture, d,l-methionine and water. 4 The diet contained comstarch, chicken fat, casein, sucrose, solka floe, dicalcium phosphate, calcium carbonate, potassium chloride, sodium chloride, mineral mixture, choline, vitamin mixture, d,lmethionine and water.
4.
5.
e. 7.
8.
9.
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J. B. (1983) Effects of modified protein diets in dogs with chronic renal failure. /. Am. Vet. Med. Assoc. 173: 980-986. POLZIN, D. J., OSBORNE, C. A., STEVENS,J. B. & HAYDEN, D.W. (1983) Influence of modified protein diets on the nutri tional status of dogs with induced chronic renal failure. Am. ]. Vet. Res. 44: 1694-1702. BRENNER,B. M., MEYER,T. W. & HOSTETTER,T. H. (1982) Dietary protein intake and the progressive nature of kidney dis ease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, ablation, and intrinsic renal disease. N. Engl. ]. Med. 297: 652659. HOSTETTER,T. H. (1984) The hyperfiltering glomerulus. Med. Clin. North Am. 68: 387-398. IHLE, B. U., BECKER,G. J., WHITWORTH, J. A., CHARLWOOD, R. A. & KINCAID-SMITH,P. S. (1989) The effect of protein re striction on the progression of renal insufficiency. N. Eng/. /. Med. 321: 1773-1777. HOSTETTER,T. H., OLSON, J. L., RENNKE, H. G., VENKATACHALAM,M. A. & BRENNER,B. M. (1981) Hyperfiltration in remnant nephrons: a potentially adverse response to renal abla tion. Am. /. Physioi. 241: F85-F93. POLZIN, D. J., OSBORNE, C. A., ADAMS, L. & O'BRIEN,
T. D. (1989) Dietary management of canine and feline chronic renal failure. Vet. Clin. North Am. 19: 539-560. 10. TAPP,D. C., KOBAYASHI, S., FERNANDES, G. &.VENKATCHALAM, M. A. (1989) Protein restriction or calorie restriction? A critical assessment of the influence of selective calorie restriction on the progression of experimental renal disease. Semin. Nephrol. 9: 343-353. 11. TAPP, D. C., WORTHAM,W. G., ADDISON, J. F., HAMMONDS, D. N., BARNES,J. L. & VENKATCHALAM, M. A. (1989) Food re striction retards body growth and prevents end-stage renal pa thology in remnant kidneys of rats regardless of protein intake. Lab. Invest. 60: 184-195. 12. SCHMITZ,P. G., KASISKE,B. L., O'DONNELL,M. P. & K.EANE, W. F. (1989) Lipids and progressive renal injury. Semin. Nephroi. 9: 354-369. 13. KASISKE,B. L., O'DONNELL,M. P. & COWARDIN,W. (1990) Lipids and the Kidney. Hypertension 15: 443-450. 14. KLAHR,S., PURKERSON, M. L. & HEIFETS, M. (1987) Factors that may retard the progression of renal disease. Kidney Int. 32(Suppl. 22): S-35-S-39. 15. LAU,K. (1989) Phosphate excess and progressive renal failure: the precipitation-calcification hypothesis. Kidney Int. 36: 918937. 1Õ.NATH, K. A., HOSTETTER,M. & HOSTETTER,T. (1985) Pathophysiology of chronic tubulo-interstitial disease in rats. /. Clin. Invest. 76: 667-675. 17. Ross, L. A., FINCO, D. R. & CROWELL,W. A. (1982) Effect of dietary phosphorus restriction on the kidneys of cats with re duced renal mass. Am. J. Vet. Res. 43: 1023-1026. 18. OLSON,J. L., HOSTETTER,T. H., RENNKE,H. G., BRENNER,B. M. & VENKATCHALAM, M. A. (1982) Altered glomerular permselectivity and progressive glomerular sclerosis following extreme ablation of renal mass. Kidney Int. 21: 112-126. 19. BIDANI,A. K., MITCHELL,K. D., SCHWARTZ,M. M., NAVAR, G. &.LEWIS,E. J. (1990) Absence of glomerular injury or nephron loss in a normotensive remnant kidney model. Kidney Int. 38: 28-38. 20. O'DONNELL,M. P., KASISKE, B. L. & KEANE,W. F. (1987) Nonhemodynamic factors contribute to accelerated glomerular injury in nephrectomized rats fed a high protein diet. Kidney Int. 31: 390(abst.|. 21. FOGO,A., YOSHIDA,Y., CLICK,A. D., HOMMA,T., & ICHIKAWA, I. (1988) Serial micropuncture analysis of glomerular function in two rat models of glomerular sclerosis. /. Clin. Invest. 82: 322-330.
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22. Foco, A. & ICHIKAWA,I. (1989) Evidence for the central role of glomerular growth promoters in the development of sclerosis. Semin. Nephrol. 9: 328-342. 23. STENVINK.EL,P., ALVESTRAND,A. & BERGSTROM,J. (1989] Factors influencing progression in patients with chronic renal failure. /. Intern. Med. 216: 183-188. 24. BROWN, S., FINCO, D. R., CROWELL,W., CROWELL,W. & BARSANTI,J. A. (1987) Beneficial effect of moderate phosphate re striction in partially nephrectomized dogs on a low protein diet. Kidney Int. 31: 380 (abst.). 25. DIBARTOLA, S. P., RUTGERS, H. C., ZACK, P. M. & TARR, M. J. (1987) Clinicopathologic findings associated with chronic renal disease in cats: 74 cases (1973-1984). /. Am. Vet. Med. Assoc. 190: 1196-1192. 26. BOVEE,K. C., KRONFELD,D. S., RAMBERG,C. & GOLDSCHMIDT, M. (1979) Long-term measurement of renal function in par
Downloaded from https://academic.oup.com/jn/article-abstract/121/suppl_11/S140/4744110 by University of Wyoming Libraries user on 19 June 2018
AND ADAMS
27.
28.
19. 30.
tially nephrectomized dogs fed 56, 27, or 19% protein. Invest. UTO!. 16: 378-384. BOURGOIGNIE,J. J., GAVELLAS,G., MARTINEZ, E. & PARDO, V. (1987) Glomerular function and morphology after renal mass reduction in dogs. /. Lab. Clin. Med. 109: 380388. ALLEN,T. A., JAENKE,R. S. & FETTMAN,M. J. (1987) A tech nique for estimating progression of chronic renal failure in the dog. /. Am. Vet. Med. Assoc. 190: 866-888. BROWN, S. A. & FINCO, D. R. (1990) The chronic course of renal function following Ãœnephrectomy in dogs. /. Vet. Intern. Med. 4: 124(abs.). ADAMS, L. G., POLZIN, D. J., OSBORNE, C. A. & O'BRIEN, T. D. (1990) Effects of reduced dietary protein with induced chronic renal failure. /. Vet. Intern. 125|abs.).
in cats Med. 4:
Effect of Modified Protein Diets in Dogs and Cats with Chronic Renal Failure: Current Status1 DAVID J. POLZin,2
CARL A. OSBORNE
AND LARRY G. ADAMS
University of Minnesota, College of Veterinary Medicine, Department Small Animal Clinical Sciences, St. Paul, MM 55108
a combination of these techniques, results in a syn drome of progressive azotemia, proteinuria, arterial hypertension and, eventually, death due to uremia (6). Progression occurs despite the fact that surviving renal tissue was initially normal, but reduced in quantity. Similarly, renal insufficiency in humans often pro gresses predictably to renal failure, regardless of dif ferent initiating causes of renal damage (6, 7). Pro gression occurs even when the initiating cause of renal dysfunction is no longer present or active. These ob servations in rats and humans suggest that irreversible loss of renal mass results in spontaneous progression of renal failure. Reducing dietary protein intake has been shown to minimize proteinuria, glomerular injury and the pro gressive decline in renal function that develops in rats after reducing renal mass (5, 8). Dietary protein re striction also minimizes development of glomerular lesions and/or progression of renal dysfunction in a variety of other experimental models of renal disease, including post-salt hypertension, mineralocorticoid hypertension and nephrotoxic serum nephritis in rats, and the mouse model of systemic lupus erythematosus (6). Protein restriction has also been reported to limit progression of spontaneous chronic renal failure in humans (7). Although most studies have focused on the role of dietary protein intake in limiting progressive renal in jury, other dietary factors have also been implicated in promoting progression of chronic renal failure, in-
ABSTRACT Studies in rodents indicate that diet influ ences progression of renal failure. Excessive dietary intakes of protein, fat, energy and phosphorus have been implicated in promoting progression of renal fail ure, while restriction of some or all of these dietary constituents limits progressive renal injury. Studies confirm that renal failure is progressive in some dogs with moderate-to-advanced renal dysfunction. Recent studies also indicate that unrestricted intakes of protein promotes proteinuria in dogs and cats and glomerular injury in cats. J. Nutr. 121: S140-S144, 1991.
INDEXINGKEY WORDS: •symposium •dogs •cats •renal failure •kidney •protein
Nutritional therapy has been the mainstay of med ical management of canine and feline chronic renal failure for decades. Dietary protein and other nutrients are known to influence clinical signs of uremia, elec trolyte and mineral balance, as well as the overall nu tritional status of renal-failure patients (1-4). Renewed interest in dietary management of renal failure has been stimulated by the observation that modification of diet may reduce the rate of progression of chronic renal failure (5). The focus of this discussion is the potential impact of diet on renal function, proteinuria and progression of renal failure.
RENAL INJURY, PROGRESSIVE RENAL FAILURE AND THE ROLE OF DIET
1Presented as part of the Waltham International
Symposium on
Nutrition of Small Companion Animals, at University of California, Davis, CA 95616, on September 4-8, 1990. Guest editors for the symposium were James G. Morris, D'Ann C. Finley and Quinton
In rodents, progression to end-stage renal failure becomes inevitable once a critical mass of functioning nephrons has been damaged or lost (5, 6). Removal of approximately three-quarters or more of the functional renal mass of rats by surgical resection, infarction or 0022-3166/91
of
R. Rogers. 1 To whom correspondence
should be addressed: University
of
Minnesota, College of Veterinary Medicine, Department of Small Animal Clinical Sciences, 1352 Boyd Avenue, Room C-325, St. Paul, MN 55108.
S3.00 ©1991 American Institute of Nutrition.
S140 Downloaded from https://academic.oup.com/jn/article-abstract/121/suppl_11/S140/4744110 by University of Wyoming Libraries user on 19 June 2018
MODIFIED PROTEIN DIETS IN DOGS AND CATS
eluding energy, lipids, phosphorus, sodium, potassium and acid content (9-17). Mechanisms of progression of renal fail ure. Progressive renal damage may result from 1}per sistence of the renal disease(s) responsible for initiating renal failure, 2) different or additional causes of renal injury and/or 3) a variety of complications and se quelae of chronic renal failure, such as urinary tract infection, systemic hypertension and intrarenal min eral deposition. In addition to these causes of pro gression of chronic renal failure, spontaneous, selfperpetuating nephron damage may occur (as described above) (5). Compensatory phenomena that develop in an attempt to sustain renal function and homeostasis may contribute to self-perpetuation of renal dysfunc tion (8, 18). Examples of such factors include glomerular capillary hypertension and hyperfiltration, renal growth (hypertrophy), increased renal oxygen con sumption and increased renal ammoniagenesis. Nonadaptive factors may also be potentially injurious to surviving nephrons in chronic renal failure, including altered phosphate metabolism, altered lipid compo sition and increased activity of the coagulation system. Detection and therapeutic manipulation of these fac tors may retard progression of chronic renal failure. Many of these factors may be influenced by diet for mulation (9). Dietary protein intake and glomerular hypernitration/hypertension. Experimentally induced or naturally occurring reduction in renal mass results in increased glomerular capillary perfusion and glo merular capillary hypertension which in turn pro mote increased glomerular filtration rate (GFR) in individual remaining functional nephrons (often re ferred to as increased single-nephron glomerular fil tration rate and abbreviated SNGFR) (5, 6, 8). This increase in SNGFR is termed glomerular hyperfil tration. Although total GFR is reduced after loss of renal mass, the increase in SNGFR in surviving nephrons causes total GFR to be greater than would have been predicted based on knowledge of the mag nitude of reduction in renal mass. Presumably, glo merular hyperfiltration is as a compensatory phe nomenon designed to maximize GFR in failing kid neys. Although this compensatory adaptation may initially be beneficial, there is evidence that persis tent hemodynamic changes resulting in glomerular capillary hypertension and glomerular hyperfiltra tion may eventually damage surviving nephrons and lead to progressive deterioration of renal function. Considerable evidence implicates systemic hyper tension in promoting progressive glomerular injury associated with glomerular hypertension (19). Restricting dietary protein intake minimizes he modynamic changes that occur after spontaneous or induced reduction in renal mass (8, 18). Normaliza tion of hemodynamics by feeding reduced protein
S141
diets limits proteinuria, development of glomerular lesions and progression of renal dysfunction in a variety of experimental models of renal disease (5, 8,18). Renal hypertrophy. Results of recent studies suggest that glomerular sclerosis may develop in rats with reduced renal mass in the absence of glomerular hypertension. This observation suggests that glomer ular hypertension may not be the sole mechanism re sponsible for development of glomerular lesions in end-stage renal disease (20, 21 ). A possible association between hypertrophy of the glomerulus and devel opment of glomerular sclerosis has been hypothesized, suggesting an alternative or additional mechanism of glomerular injury (21, 22). It has been suggested that altered local hormonal growth regulation may promote glomerular sclerosis, although the mechanisms in volved and glomerular cell types affected have not been determined (22). Growth factors such as interleukin 1, platelet-derived growth factor and epidermal growth factor promote mesangial cell proliferation, and growth promoters such as endothelin may increase extracellular matrix from mesangial cells. Dietary protein, energy and phosphorus intakes as well as a host of other dietary factors may influence renal growth and hypertrophy. Dietary energy. Food restriction, and particularly energy restriction, has been shown to improve the outcome of several forms of experimental renal disease in rodents (10). Restricted energy, fat and mineral (ex cept for calcium and phosphorus) intake retarded growth and prevented development of end-stage renal pathology in rats with reduced renal mass, regardless of whether protein intake was restricted (11). In con trast, protein restriction without restriction of any other dietary component failed to retard growth or prevent development of glomerular sclerosis. Renal injury may have been ameliorated in rats fed energyand mineral-restricted diets as a result of limited renal growth and hypertrophy. Because dietary protein re striction is often associated with reduced food con sumption, the question has been raised as to whether the benefit of dietary protein restriction in limiting renal injury may in fact result from energy and mineral restriction (10). Dietary phosphate, hyperphosphatemia and hyperparathyroidism. Altered calcium and phos phate metabolism and subsequent renal secondary hy perparathyroidism result in deposition of calcium and phosphate in the renal parenchyma of animals with chronic renal failure (15, 23). Renal deposition of cal cium and phosphate causes inflammation, scarring and subsequent loss of nephrons. Studies of rats with ex perimentally induced chronic renal failure suggest that proportional restriction of dietary phosphate intake may minimize or prevent proteinuria, renal mineral ization, renal histologie alterations, renal functional
Downloaded from https://academic.oup.com/jn/article-abstract/121/suppl_11/S140/4744110 by University of Wyoming Libraries user on 19 June 2018
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deterioration and death due to uremia that occur when higher phosphate diets are fed (15). Dietary phosphate restriction also slows progres sion and prolongs survival in dogs with induced chronic renal failure (24). In cats with induced chronic renal failure, normal dietary phosphate con sumption was associated with microscopic evidence of renal mineralization, fibrosis and mononuclear cell infiltration (17). Dietary phosphate restriction prevented these abnormalities. However, evidence of progressive renal dysfunction was not detected in either normal or restricted phosphate groups of cats in this study. Renal ammoniagenesis. Spontaneous and in duced chronic renal failure are characterized by wide spread tubulo-interstitial lesions, the origin of which remains undetermined. Reduction in renal mass is as sociated with compensatory hyperfunction of renal tubules, including increased renal ammoniagenesis. Increased renal ammoniagenesis is attended by a rise in renal tissue ammonia concentration. Local toxic and inflammatory effects of ammonia may include trig gering of the alternative complement pathway by the reaction of ammonia with the third component of complement, culminating in deposition of comple ment proteins and initiation of complement-mediated cellular infiltration and tissue injury (16). These effects further impair tubular function and may promote a self-perpetuating cycle of adaptation and injury. In rats with induced renal failure, dietary supplementation with sodium bicarbonate has been shown to lower tissue ammonia concentrations, reduce peritubular deposition of complement components and dimin ish functional and structural tubulo-interstitial le sions (16). Dietary lipids and progression of renal fail ure. Several recent studies have suggested a role for lipids in modulating progression of experimental renal disease in rodents; mechanisms responsible for these modulating effects are currently the subject of inten sive study (12, 13). Lipid abnormalities are commonly observed in human patients with renal disease. Fur thermore, there appears to be an association between proteinuria, lipid abnormalities and atherosclerosis (12). It is noteworthy that hypercholesterolemia was among the most common serum biochemical abnor malities reported in a retrospective study of cats with chronic renal disease (25). The role of lipids in modulating progression of renal failure may be related, in part, to renal prostaglandin synthesis. The composition of dietary lipids may in fluence systemic blood pressure, blood lipid compo sition, platelet aggregation, blood viscosity, the im mune system and fibrinolytic activity. It has also been hypothesized that certain lipids may promote pro gressive damage to the glomerular basement mem brane and mesangial structures. Downloaded from https://academic.oup.com/jn/article-abstract/121/suppl_11/S140/4744110 by University of Wyoming Libraries user on 19 June 2018
PROGRESSION OF CANINE AND FELINE CHRONIC RENAL FAILURE In contrast to rats and humans, the progressive na ture of canine and feline chronic renal failure is less well documented. Two long-term studies designed to determine if reduced renal mass promotes progressive deterioration of renal function in dogs did not reveal progressive reduction in renal function (1, 26). Despite stable renal function, renal lesions consistent with progressive renal injury (glomerular sclerosis charac terized by subendothelial and mesangial deposition of hyaline material, increased mesangial matrix and col lapse of glomerular capillaries with adhesions of the tuft to Bowman's capsule) were observed in both stud ies. In one of these studies, renal mass was reduced by | and renal function monitored for ¿48mo (26). It is likely that the extent of renal mass reduction in this study was insufficient to initiate progressive deterio ration in renal function. In the other study, renal mass was reduced by g, but renal function was monitored for only 40 wk. This study may have been of insuffi cient duration for progressive deterioration of renal function to develop. Other studies have provided more direct evidence of the progressive nature of canine renal failure. Bourgoignie and colleagues (27) have shown that reduction of renal mass in dogs results in glomerular proteinuria, the severity of which appears to be proportional to the amount of renal mass ablated and which precedes de cline in renal function. During 15-39 mo of study, renal function remained stable in seven dogs and pro gressively declined in only three dogs. The progressive nature of canine chronic renal failure is further sug gested by the observation that progressive decline in renal function occurs in some dogs with spontaneous chronic renal failure (28). However, findings in this report are limited by the fact that renal function was determined by serial assessment of serum creatinine concentrations, which may be influenced by factors other than renal function. A progressive decline in renal function was also ob served in another study of induced canine chronic renal failure in which dogs were fed a low protein, high phosphate diet after }| renal mass ablation (24). Brown and Finco (29) reported that a pattern of de clining renal function developed over 2 y in 9 of 12 dogs after $ renal ablation. Renal function progres sively increased over the 2 y of study in the remaining three dogs. Variables reported to have a significant linear relationship with the rate of decline of renal function included tissue calcium concentration; plasma concentrations of triglycéridesand cholesterol; and renal histologie scores for fibrosis, mineralization and mesangial expansion. We recently completed a study of 15 dogs with | reduction in renal mass in which renal function and
MODIFIED PROTEIN DIETS IN DOGS AND CATS
proteinuria were monitored for 2 y. Seven of these dogs were fed a 39.7% protein diet and eight dogs were fed a 14.1% protein diet. These two diets3 differed only in protein and carbohydrate content. The 39.7% protein diet contained (in g/100 g) 25.3 fat, 29.8 car bohydrate, 0.74 calcium, 0.32 phosphorus, 0.4 potas sium and 0.23 sodium. The 14.1% protein diet con tained (in g/100 g) 23.9 fat, 54.9 carbohydrate, 0.80 calcium, 0.32 phosphorus, 0.4 potassium and 0.24 so dium. After an initial period of stable or increasing renal function, a pattern of declining renal function developed in three dogs fed the 39.7% protein diet and one dog fed the 14.1% protein diet. Renal function progressively increased or remained stable during the first 40 wk of study in all dogs in this study, suggesting that 40 wk is insufficient to assess changes in renal function in dogs with I nephrectomy. Increasing mag nitude of proteinuria typically preceded the onset of declining renal function. In cats, renal function has been found to remain stable for ail y after f reduction in renal mass (30). Proteinuria and glomerular injury were not detected in cats with reduced renal mass fed a 27.6% protein diet. However, cats fed a 51.7% protein diet developed proteinuria and microscopic evidence of glomerular injury. These two diets4 differed only in protein and carbohydrate content. The 51.7% protein diet con tained ¡ing/100 g) 36 fat, 8.7 carbohydrate, 0.47 cal cium, 0.54 phosphorus, 0.4 potassium and 0.27 so dium. The 27.6% protein diet contained (in g/100 g) 37.1% fat, 30.7 carbohydrate, 0.47 calcium, 0.54 phosphorus, 0.4 potassium and 0.29 sodium. Cats with more severe glomerular lesions had more marked pro teinuria. We interpret these observations to indicate that proteinuria and renal structural lesions observed in this study suggest a pattern of declining renal func tion would ultimately have developed in cats fed the 51.7% protein diet. LITERATURE
CITED
1. POLZIN, D. }., OSBORNE,C. A., HAYDEN, D. W. & STEVENS, J. B. (1984) Influence of reduced protein diets on morbidity, mortality, and renal function in dogs with induced renal failure. Am. I Vet. Res. 45: 506-517. 2. POLZIN, D. J. & OSBORNE,C. A. (1986) Update-Conservative medical management of chronic renal failure. In: Current Vet erinary Therapy IX (Kirk, R. W., ed.). pp. 1167-1173, W. B. Saunders Co, Philadelphia, PA. 3. POLZIN, D. J., OSBORNE,C. A., HAYDEN, D. W. & STEVENS, 3 The diets contained
cornstarch, chicken fat, casein, sucrose,
solka floe, calcium carbonate, dicalcium phosphate, potassium chloride, mineral mixture, choline, sodium chloride, vitamin mix ture, d,l-methionine and water. 4 The diet contained comstarch, chicken fat, casein, sucrose, solka floe, dicalcium phosphate, calcium carbonate, potassium chloride, sodium chloride, mineral mixture, choline, vitamin mixture, d,lmethionine and water.
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J. B. (1983) Effects of modified protein diets in dogs with chronic renal failure. /. Am. Vet. Med. Assoc. 173: 980-986. POLZIN, D. J., OSBORNE, C. A., STEVENS,J. B. & HAYDEN, D.W. (1983) Influence of modified protein diets on the nutri tional status of dogs with induced chronic renal failure. Am. ]. Vet. Res. 44: 1694-1702. BRENNER,B. M., MEYER,T. W. & HOSTETTER,T. H. (1982) Dietary protein intake and the progressive nature of kidney dis ease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, ablation, and intrinsic renal disease. N. Engl. ]. Med. 297: 652659. HOSTETTER,T. H. (1984) The hyperfiltering glomerulus. Med. Clin. North Am. 68: 387-398. IHLE, B. U., BECKER,G. J., WHITWORTH, J. A., CHARLWOOD, R. A. & KINCAID-SMITH,P. S. (1989) The effect of protein re striction on the progression of renal insufficiency. N. Eng/. /. Med. 321: 1773-1777. HOSTETTER,T. H., OLSON, J. L., RENNKE, H. G., VENKATACHALAM,M. A. & BRENNER,B. M. (1981) Hyperfiltration in remnant nephrons: a potentially adverse response to renal abla tion. Am. /. Physioi. 241: F85-F93. POLZIN, D. J., OSBORNE, C. A., ADAMS, L. & O'BRIEN,
T. D. (1989) Dietary management of canine and feline chronic renal failure. Vet. Clin. North Am. 19: 539-560. 10. TAPP,D. C., KOBAYASHI, S., FERNANDES, G. &.VENKATCHALAM, M. A. (1989) Protein restriction or calorie restriction? A critical assessment of the influence of selective calorie restriction on the progression of experimental renal disease. Semin. Nephrol. 9: 343-353. 11. TAPP, D. C., WORTHAM,W. G., ADDISON, J. F., HAMMONDS, D. N., BARNES,J. L. & VENKATCHALAM, M. A. (1989) Food re striction retards body growth and prevents end-stage renal pa thology in remnant kidneys of rats regardless of protein intake. Lab. Invest. 60: 184-195. 12. SCHMITZ,P. G., KASISKE,B. L., O'DONNELL,M. P. & K.EANE, W. F. (1989) Lipids and progressive renal injury. Semin. Nephroi. 9: 354-369. 13. KASISKE,B. L., O'DONNELL,M. P. & COWARDIN,W. (1990) Lipids and the Kidney. Hypertension 15: 443-450. 14. KLAHR,S., PURKERSON, M. L. & HEIFETS, M. (1987) Factors that may retard the progression of renal disease. Kidney Int. 32(Suppl. 22): S-35-S-39. 15. LAU,K. (1989) Phosphate excess and progressive renal failure: the precipitation-calcification hypothesis. Kidney Int. 36: 918937. 1Õ.NATH, K. A., HOSTETTER,M. & HOSTETTER,T. (1985) Pathophysiology of chronic tubulo-interstitial disease in rats. /. Clin. Invest. 76: 667-675. 17. Ross, L. A., FINCO, D. R. & CROWELL,W. A. (1982) Effect of dietary phosphorus restriction on the kidneys of cats with re duced renal mass. Am. J. Vet. Res. 43: 1023-1026. 18. OLSON,J. L., HOSTETTER,T. H., RENNKE,H. G., BRENNER,B. M. & VENKATCHALAM, M. A. (1982) Altered glomerular permselectivity and progressive glomerular sclerosis following extreme ablation of renal mass. Kidney Int. 21: 112-126. 19. BIDANI,A. K., MITCHELL,K. D., SCHWARTZ,M. M., NAVAR, G. &.LEWIS,E. J. (1990) Absence of glomerular injury or nephron loss in a normotensive remnant kidney model. Kidney Int. 38: 28-38. 20. O'DONNELL,M. P., KASISKE, B. L. & KEANE,W. F. (1987) Nonhemodynamic factors contribute to accelerated glomerular injury in nephrectomized rats fed a high protein diet. Kidney Int. 31: 390(abst.|. 21. FOGO,A., YOSHIDA,Y., CLICK,A. D., HOMMA,T., & ICHIKAWA, I. (1988) Serial micropuncture analysis of glomerular function in two rat models of glomerular sclerosis. /. Clin. Invest. 82: 322-330.
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22. Foco, A. & ICHIKAWA,I. (1989) Evidence for the central role of glomerular growth promoters in the development of sclerosis. Semin. Nephrol. 9: 328-342. 23. STENVINK.EL,P., ALVESTRAND,A. & BERGSTROM,J. (1989] Factors influencing progression in patients with chronic renal failure. /. Intern. Med. 216: 183-188. 24. BROWN, S., FINCO, D. R., CROWELL,W., CROWELL,W. & BARSANTI,J. A. (1987) Beneficial effect of moderate phosphate re striction in partially nephrectomized dogs on a low protein diet. Kidney Int. 31: 380 (abst.). 25. DIBARTOLA, S. P., RUTGERS, H. C., ZACK, P. M. & TARR, M. J. (1987) Clinicopathologic findings associated with chronic renal disease in cats: 74 cases (1973-1984). /. Am. Vet. Med. Assoc. 190: 1196-1192. 26. BOVEE,K. C., KRONFELD,D. S., RAMBERG,C. & GOLDSCHMIDT, M. (1979) Long-term measurement of renal function in par
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AND ADAMS
27.
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tially nephrectomized dogs fed 56, 27, or 19% protein. Invest. UTO!. 16: 378-384. BOURGOIGNIE,J. J., GAVELLAS,G., MARTINEZ, E. & PARDO, V. (1987) Glomerular function and morphology after renal mass reduction in dogs. /. Lab. Clin. Med. 109: 380388. ALLEN,T. A., JAENKE,R. S. & FETTMAN,M. J. (1987) A tech nique for estimating progression of chronic renal failure in the dog. /. Am. Vet. Med. Assoc. 190: 866-888. BROWN, S. A. & FINCO, D. R. (1990) The chronic course of renal function following Ãœnephrectomy in dogs. /. Vet. Intern. Med. 4: 124(abs.). ADAMS, L. G., POLZIN, D. J., OSBORNE, C. A. & O'BRIEN, T. D. (1990) Effects of reduced dietary protein with induced chronic renal failure. /. Vet. Intern. 125|abs.).
in cats Med. 4:
