Kidney International, Vol. 24 (1983), pp.

579—587

EDITORIAL REVIEW

Role of dietary factors in the progression of chronic

renal disease
In diseases of the kidney characterized by irreversible injury, provocative studies of Brenner, Meyer, and Hostetter [7] and
it appears that once a critical level of renal functional deteriora- Brenner [8] regarding the potential mechanisms by which
tion is reached, progression to endstage disease invariably protein intake may affect the progression of renal disease.
occurs even if the initiating event or condition is resolved or
eradicated. Immunopathogenetic mechanisms probably ac- Effect of dietary protein on renal function and structure in
count for most forms of primary glomerular disease in humans. experimental animals
Although immunologic events and the mediators of glomerular In 1919 and 1923 Newburgh [9] and Newburgh and C .rkson
damage that they induce might be responsible for initiating most [101 reported the production of renal structural damage in
glomerular diseases, certain clinical and experimental observa- rabbits fed diets containing large amounts of protein. These
tions suggest that the rate of progression of these diseases is experiments were criticized on four scores: (1) The frequent
influenced by several nonimmunologic factors. In certain dis- spontaneous occurrence of renal lesions in the rabbit made it
eases, such as proliferative glomerulonephritis, the relentless difficult to prove that any given injury was caused by the
decrease in renal function is due very likely to the initial experimental procedure; (2) the herbivorous rabbit, habituated
underlying process; in other entities characterized mainly by to a diet low in protein, was a poor test animal; (3) the diets
interstitial scarring and glomerular sclerosis, the cause of pro- were nutritionally inadequate; (4) the lesions were due to the
gressive loss of renal function is less apparent. Recent experi- acidity of the urine in an animal which normally excretes an
mental evidence suggests that dietary manipulations, such as alkaline urine. In reply to these criticisms Newburgh and Curtis
reductions in protein and/or phosphate intake, can halt or [111 in 1928 reported the development of similar lesions in white
attenuate the progression of chronic renal insufficiency in rats fed "adequate" diets, containing varying kinds of protein.
experimental animal models. Therefore, the exciting possibility Further, both the quantity and "quality" of dietary protein
exists that the natural history of some renal diseases may be seemed important in the development of renal disease. Rats fed
altered by changes in the diet. We review current information diets containing 75% dry liver developed renal lesions in less
regarding the role of manipulations of dietary protein, phospho- than 1 year, but the same amount of casein fed for 16 months
rus, or lipid content on the progression of chronic renal disease. caused only moderate tubular injury. A diet containing protein
Most of the experimental observations to be reviewed have from beef muscle was intermediate in its renal effects.
been made in animal models of renal disease. The literature on In the l920s Osborne et al [12, 13] reported that renal
the role of dietary manipulations on the progression of renal hypertrophy occurred consistently in rats fed a diet in which
disease in patients is somewhat limited and will not be empha- protein intake exceeded about one third of the "food fuel in the
sized here. ration." This renal response was found with all proteins tested
but not with equivalent amounts of urea [131. Neither Osborne
Role of protein intake et al [131 or Jackson and Riggs [14] found evidence of renal
The observation that ingestion of protein aggravates the disease in their rats fed high protein diets. Berg and Simms [15,
clinical condition of patients with renal insufficiency dates back 16] showed later that rats receiving a moderately restricted diet
to the turn of the century. Ambard [1] noted that uremic (54% of ad libitum food intake) lived longer and had a lower
patients are often wasted and do poorly, particularly when they incidence of degenerative disease than animals fed ad libitum.
ingest meat. The clinical experience led to efforts to alleviate The combined incidence of renal, vascular, and myocardial
"toxicity of uremia" by reducing dietary intake of protein. lesions in males fed a restricted diet increased with advancing
Volhard 121 wrote that "in cases with chronic renal insufficien- age from 24% at 800 days of age to 60% at 900 days and to 75%
cy, a reduction in nitrogen intake to levels of 3—5 grams per day at 1100, but the frequency of lesions in males fed an ad libitum
(about 20—30 grams of protein) prevents the rise in blood urea diet was 100% at 800 and 900 days. In females fed a restricted
for long periods of time; . . . considerably elevated urea, diet, the combined incidence of renal, vascular or myocardial
indican and xanthoprotein values decrease and initial signs of lesions was zero at 800 days and 24% at 1100 days as compared
uremic intoxication disappear." These observations, and many with 60 and 90% in rats fed ad libitum. Thus, onset of disease
others since, have clearly established that a reduction in protein was earlier, and incidence and severity of lesions were greater
intake ameliorates many manifestations of the uremic syndrome in males than in females both on a restricted or ad libitum food
[3—61.
Less well appreciated, until the last 3 or 4 years, is the
substantial literature of the previous six decades related to the
potential harmful effects of dietary protein on renal function in Received for publication March 8, 1983
normal animals or animals after nephrectomy. Interest in this and in revised form May 23, 1983
area has been rekindled, in great measure, by the elegant and © 1983 by the International Society of Nephrology

579
580 Klahr et a!

intake. These studies indicate that partial dietary restriction of All of the above studies indicated an important deleterious
all nutrients in rats in captivity markedly delays the develop- role for protein in the progression of renal insufficiency; howev-
ment of renal lesions. er, since the content of sodium, phosphate, and calcium was
Numerous investigators have reported a deleterious effect of higher in the high protein diets, an exclusive role of protein was
dietary protein on the course of experimental nephritis and on not established.
the progressive renal failure that occurs after subtotal renal The mechanism by which high protein intake accelerates the
ablation. On balance the available evidence indicates that high development and severity of glomerular sclerosis in animals
protein intake accelerates the progression of renal insufficiency with experimental nephritis, with subtotal renal ablation or during
in both models. Moise and Smith [17] found that renal lesions aging, is unclear. Studies in the 1930s showed that urea clear-
develop rapidly in uninephrectomized rats eating a high protein ance, GFR, and renal blood flow could be acutely increased
diet. Chanutin and Ludewig [181 varied the dietary protein of two- to threefold in the dog by high protein feeding [30—32].
partially nephrectomized rats from 10 to 80% and found that the Higher inulin-clearance values were found in rats fed 40%
degree of proteinuria, the severity of renal insufficiency, and casein than in rats fed 6% casein [33]. Pennell et al [34] also
mortality increased progressively with high dietary protein. found decreased GFR values in weanling rats fed a low protein
Lalich and Allen [19] found excessive proteinuria followed by diet. Protein restriction in these weanling rats reduced kidney
structural changes and eventual sclerosis of glomeruli in unin- mass, which may have been the main factor responsible for the
ephrectomized rats fed diets containing 30% protein. In 1939, decrease in GFR. Lower GFR and renal plasma flow values
Farr and Smadel [20, 21] reported that in rats with nephrotoxic were reported in sheep fed a low protein diet (4.9%) as
serum nephritis fed a 5% protein diet, clinical renal disease compared to sheep fed a high protein diet (14.9%) [35]. Ichika-
subsided rapidly and glomerular and tubular injury resolved. By wa et al [36] found lower values for glomerular capillary plasma
contrast, rats fed a diet containing 40% protein uniformly flow and Kf in rats fed a low protein diet than in rats fed a high
developed renal failure and died within 1 year. It should be protein diet. The fall in glomerular capillary plasma flow rate
noted that the low protein diet (5%) used in the studies of Farr was due to increased afferent and efferent arteriole resistances.
and Smadel is insufficient to sustain growth or maintain a The rats fed a low protein diet also had a reduction in glomeru-
nitrogen balance in rats. This is also the case in several other lar cross sectional area which accounted, at least partially, for
studies which have employed extremely low protein, phosphate the decline in Kf.
or fatty acid intakes (see below). In such instances growth A potential role for increased glomerular perfusion and
impairment, negative nitrogen balance, osteomalacia, phos- hyperfiltration in the causation of glomerular sclerosis has been
phate depletion, and malnutrition may represent a poor trade off suggested from studies performed in an experimental model of
for delaying the progression of chronic renal disease. uremia produced by partial infarction or resection of one kidney
Dubois and Strain [22] first demonstrated a beneficial effect and contralateral nephrectomy. Chanutin and Ferris [37] first
of diet (low phenylalanine and low tyrosine) on survival and described in 1932, to our knowledge, that this rat model
nephropathy of a mouse model of systemic lupus (NZB-NZW developed proteinuria, hypertension, and progressive renal
Fl mice). Subsequently, Friend et al [23] reported that NZB disease, an observation confirmed subsequently by other inves-
and NZW F1 mice initiated on calorie restriction when weaned, tigators [38—40]. Dog studies from our laboratory [41] demon-
at 4 to 5 months of age, or fed a moderately restricted protein strated that glomerular hyperfiltration and hyperperfusion oc-
intake at weaning were afforded significant protection from the cur as renal mass is reduced. These observations were con-
development of immune nephritis. These findings suggest that firmed subsequently in the rat [42]. The extent of functional
diet may influence the course of autoimmune disease and adaptation is proportional to the amount of renal mass removed
associated immune complex nephritis even after the onset of and more extensive renal ablation results in a greater increase in
serologic abnormalities and tissue injury. In 1937 Medlar and single nephron GFR [43]. Micropuncture studies 1 week after a
Blatherwick [24, 25] and in 1957 Kennedy [26] suggested that 90% reduction of renal mass [441 in Munich-Wistar rats indicate
glomerular sclerosis occurring with aging, uninephrectomy, or that the increase in single nephron GFR to values about twice
both could be accelerated by high protein feeding in rats. those seen in normal rats is due to a striking increase in
Wachtel, Cole, and Rosen [27] showed that the rapidity and glomerular plasma flow rate and an increased glomerular trans-
severity of the glomerular sclerosis that occurs in weanling rats capillary hydraulic pressure gradient. Arteriolar vasodilatation,
after irradiation were increased by unilateral nephrectomy and rather than major increments in systemic arterial pressure, was
were slowed by retardation of renal growth produced by low responsible for the increase in glomerular capillary hydraulic
food intake. Ritz et al [28] fed rats that were made uremic by pressure. Although the increments in single nephron GFR and
partial nephrectomy and irradiation of the remaining parenchy- its determinants observed 3 weeks after unilateral nephrectomy
ma diets containing either 51% protein with 3% fat; 14.5% were less extreme [45], these changes were in the same direc-
protein, 3% fat; or 17.5% protein with 20% fat. All rats fed the tion as those seen after greater reductions in renal mass. In
high protein diet were dead 11 days after partial renal ablation. conjunction with this increase in GFR in the remnant kidney,
By contrast, most animals fed a high fat diet and 75% of the rats there were striking structural alterations. All three glomerular
fed a high carbohydrate diet were alive 30 days after surgery cell types showed abnormalities. However, changes in the
and irradiation. More recently, Kleinknecht et al [29] examined epithelial cells were the most remarkable. Two weeks after
the effects of various protein diets on growth, renal function, renal ablation, adhesions of epithelial cells to Bowman's cap-
and survival in Wistar rats with 85% renal ablation. A diet sule were seen in severely involved glomeruli. In some areas,
containing 37% protein led to anorexia, growth failure, and epithelial cells were detached from the underlying basement
rapid deterioration of renal function in these rats. membrane. All glomeruli showed a prominent increase in
 Dietary factors in chronic renal disease
mesangial cells and matrix [44, 46]. Despite the reduction in
total GFR, the absolute excretion of protein, primarily albumin
by the remnant kidneys, was increased. Studies of fractional
clearances of neutral dextrans [46] and PVP [47] demonstrated
alterations in the size selective properties of glomerular capil-
laries in remnant kidneys. Fractional clearances of anionic,
neutral, and cationic horseradish peroxidases and of dextran
sulfates revealed a reduction in charge selective properties [46].
Since albumin is a polyanion protein, defects in the charge
selectivity of glomeruli in the remnant kidney will contribute to
the development of albuminuria.
A close linkage between glomerular hyperfiltration and struc-
tural changes was suggested in studies involving dietary protein
restriction. Feeding a low protein diet to rats with remnant
kidneys largely prevents the striking increase in glomerular
plasma flow and capillary pressures which leads to hyperfiltra-
tion. Also the accompanying proteinuria and structural alter-
ations of epithelial cells are less severe [44, 46]. It has been
proposed that the progression of chronic renal insufficiency
after a critical reduction in renal mass may be actively depen-
dent on a final common pathway: glomerular hyperfiltration [7].
As the functional contribution of the scierosing glomeruli is
lost, less severely affected glomeruli undergo further compensa-
tory hyperfiltration with subsequent injury, favoring progres-
sion and eventual total loss of glomeruli.
Although these studies [44, 46] provide a logical explanation
for a relationship between dietary protein intake and the
progressive loss of renal function, the mechanisms by which a
low protein diet attenuates the progression of renal disease have
not been clarified completely. More work is necessary to
establish the fact that hyperfiltration" constitutes the major
link between excessive dietary protein intake and glomerular
pathology. It is possible that changes in dietary protein may
affect the levels of vasoconstrictor and/or vasodilatory sub-
stances produced by the kidney, the levels of serum lipids, and
the secretion and/or glomerular response to a number of hor-
mones 148]. These and other effects of dietary protein on the
kidney, as yet not described, may contribute to the progression
of renal disease. However, it seems clear from these studies in
experimental animals that excessive dietary protein accelerates
the functional deterioration in chronic renal disease. Additional
work is required to clarify the mechanisms by which restriction
of protein intake modifies the progression of renal disease in
certain experimental animal models. It is also clear, however,
that guidelines need to be established and more information is
required as to the safe limits for protein restriction. To what
extent can protein intake be restricted to obtain maximal effects
on the progression of renal disease, but without impairing
growth and/or producing prolonged negative nitrogen balance
and malnutrition?
Other maneuvers, besides protein restriction, can affect the
progression of renal disease in rats with subtotal nephrectomy.
Harter, Davis, Tegtmeyer, and Karl (unpublished observations)
found that endurance exercise training decreased BUN signifi-
cantly (31.2 1.9 mg/dl vs. 46 6.0 mg/dl) and serum
creatinine (0.57 0.04 vs. 0.72 0.05 mgldl) levels in rats with
five-eighths nephrectomy, when compared to sedentary rats
with a similar degree of renal ablation. Whether the lower levels
of BUN and serum creatinine observed in exercised rats reflect
preservation of renal function or are due to other mechanisms
581
Table 1. Influence of dietary protein intake on GFR and effective
renal plasma flow in normal humansa
Diet GFR ERPF
(g protein/kg body weight/day) (mi/mm) (mi/mm)
2.3 to 3.0 117.3 4.3 640.2 18.5
1.0 to 1.4 104.2 2.9 570.8 17.6
O.ltoQ.4 95.2± 3.1 538.2±21.1
Abbreviation: ERPF, effective renal plasma flow.
a Data are mean and SEM. The table is adapted from Pullman et al
[50].
remains to be established. Both heparin and warfarin administra-
tion prevent the development of glomerular sclerosis and renal
insufficiency in rats with partial renal ablation [40, 49]. Thus, it
appears that coagulation may play a role in the deterioration of
renal function in partially nephrectomized rats. Whether antico-
agulant administration or endurance exercise training attenu-
ates the progression of kidney disease in these rats by prevent-
ing the development of hyperfiltration is not known.
Influence of dietary protein intake on renal function in
humans
Pullman et a! [50] found that GFR and effective renal plasma
flow decreased when normal individuals were fed a low protein
diet and both increased with a high protein diet. Table 1
summarizes the results of these studies. On the other hand,
Nielson and Bank [51] reported that inulin and iodopyracet
(Diodrast) clearances in normal subjects were relatively unaf-
fected by changes in dietary protein. Sargeant and Johnson [52]
found a reduction in GFR, measured by creatinine clearance, in
normal subjects fed a calorie-deficient diet. In both adults and
children with protein-calorie malnutrition a decrease in GFR
and renal plasma flow has been described [53]. Klahr and
Alleyne [54] found decreased values for GFR and renal plasma
flow in ten adults with protein malnutrition. Both GFR and
renal plasma flow increased significantly after protein repletion
[54].
These observations indicate that in humans a high intake of
protein will increase renal blood flow and GFR, thus producing
hyperperfusion and hyperfiltration, findings which are similar
to those obtained in experimental animals.
Role of phosphorus intake on the progression of renal disease
Several publications suggest a deleterious effect of high
phosphate intake on renal function [55—581. Haut et al [59]
confirmed these earlier reports and also found that, as renal
mass is reduced, renal damage is intensified and less phosphate
intake is required to induce renal injury. Normal rats fed a 2%
phosphate diet had no change in renal function, whereas
uninephrectomized and partially nephrectomized animals fed a
similar diet had a marked deterioration in renal function. In
general, it has been assumed that the pathogenesis of tissue
injury in hyperphosphatemia results from calcium-phosphate
deposition which leads to an inflammatory and fibrotic response
in a variety of tissues [60, 61]. A number of results, however,
suggest that there may be other mechanisms by which a high
phosphate intake can cause renal injury. First, the histologic
appearance of the calcium-phosphate deposits suggest they
582 Klahr et a!

Table 2. Blood pressure and blood levels (mg/dl) of urea, creatinine, calcium, magnesium, and phosphorus in five-sixths nephrectomized rats
fed a normal or decreased phosphorus dieta
BP
Diet mm Hg BUN Creatinine Ca Mg Pi

Normal Pi 119 8 54.3 6.8 2.19 0.25 9.3 0.28 1.88 0.9 8.21 0.5
Decreased Pi 129 8 62.7 12 1.96 0.29 10.6 0.25 2.34 0.15 6.93 2.0
P NS NS NS <0.01 <0.05 NS
Abbreviations: BP, blood pressure; Pi, phosphorus.
a These values represent the mean and SEM of six rats in each group. The animals were pair-fed.

result from intrarenal mechanisms [56]. Second, the kidney um-phosphate deposition in the kidney, other factors may also
appears to calcify early during the course of renal failure before explain the amelioration of renal deterioration in this particular
plasma phosphorus concentrations are elevated, whereas other model.
organs in the uremic patient calcify in the terminal phase of Purkerson and Klahr (unpublished observations) have exam-
renal insufficiency when there are markedly increased concen- ined the effects of reducing phosphate intake in five-sixths
trations of serum phosphorus [62, 63]. Thus, it has been nephrectomized rats. After being nephrectomized, the rats
suggested that phosphorus-induced renal injury is mediated were fed a diet containing either 12 or 63 mg of phosphorus per
through calcium-phosphate deposition in the kidney resulting day for 4 weeks. This latter intake of phosphate does not
presumably from increased phosphate excretion per nephron require an increased phosphaturia per nephron to maintain
[64]. phosphate balance in these rats. Table 2 shows data for blood
Gimenez et a! [65] found that male rats with a 70% reduction pressure, and blood levels of urea, creatinine, calcium, magne-
of renal mass fed a diet containing 2.2% phosphate had a sium, and phosphate in the two groups of rats. Only the levels
progressive increase in serum creatinine to values, at 2 weeks of serum calcium and magnesium were significantly higher in
after surgery, fourfold higher than the mean values in compara- the rats fed a phosphorus-restricted diet as compared to rats
bly partially nephrectomized animals fed a diet of normal ingesting a normal diet. Renal function as assessed by serum
phosphate content. This deterioration in renal function was levels of creatinine and BUN were not significantly different
associated with extensive nephrocalcinosis, cellular necrosis, between the two groups of rats. On the other hand, as shown in
and marked interstitial inflammation. The administration of 3- Table 3, there was a significant increase in the calcium and
phosphocitric acid, a compound which prevents calcium-phos- phosphate content of the viable portion of the remnant kidney
phate crystal growth and in vivo nephrocalcinosis, prevented in rats fed a normal phosphate diet when compared to rats fed a
the decrease in renal function, the increase in renal calcium phosphate-restricted diet. Thus, dietary phosphate restriction
content, and the histological changes observed in animals fed a prevents calcification of the viable portion of the remnant
high phosphate diet. kidney. We have not, as yet, examined the long-term effects (18
The finding that increased phosphate intake may induce renal to 24 weeks) of preventing renal calcification on function to
damage raised the possibility that decreased phosphate intake determine whether or not it contributes to the progression of
in animals or humans with renal insufficiency may be protec- renal disease in this model at later stages.
tive. In 1978 Ibels et al [661 reported that dietary restriction of Recently, Laouari et a! [68] have re-examined the effect of a
phosphate prevented proteinuria, renal calcification, histologic low phosphorus diet in rats with seven-eighths nephrectomy.
changes, and functional deterioration and death from uremia in They found that rats fed a diet markedly deficient in phosphorus
rats with one and three-fourths nephrectomy. Animals fed a diet had marked anorexia, growth arrest, severe hypophosphatemia
of normal calcium and phosphate content showed renal deposi- and rickets, and renal function stabilized, probably as a conse-
tion of calcium and phosphorus in cortical tubular cells, base- quence of decreased total food intake. On the other hand, a
ment membrane, and interstitium. Phosphate restriction mark- phosphate-restricted diet, such as to prevent the increased
edly decreased the amount of calcium and, phosphate deposited phosphaturia and hyperparathyroidism of renal failure without
in the kidney. In this study rats fed a phosphate-restricted diet causing anorexia or other side effects had little or no beneficial
had a mean serum phosphorus of 3.4 0.3 mgldl, whereas, rats effect on the deterioration of renal function. Thus, preservation
fed a normal phosphorus diet had a serum phosphorus of 11.2 of renal function in seven-eighths nephrectomized rats fed a low
1.1 mgldl. Thus, uremic rats fed a phosphate-restricted diet and phosphorus diet is mainly mediated by reduced ingestion of
aluminum hydroxide were severely hypophosphatemic since some other component of the diet and not by phosphorus
serum phosphate levels in normal rats usually exceed 6 mg/di restriction per se.
and uremic rats have even higher values (8 to 12 mg!dl). Severe Karlinsky et al [69] also examined the effects of phosphorus
hypophosphatemia may: (1) blunt tissue hypertrophy of the restriction in rats with nephrotoxic serum nephritis. Phosphate
remnant kidney and prevent the development of hyperfiltration; restriction initiated 30 days after the administration of nephro-
(2) prevent the development of secondary hyperparathyroidism toxic serum, when the rats had a well established autologous
and the lipid abnormalities that occur in this experimental phase proteinuria, prevented renal calcification, histologic dam-
model; and (3) decrease cardiac output [67] and ameliorate the age, and functional deterioration but had no apparent effect on
hypertension which develops in rats with renal insufficiency. proteinuria [69]. To determine whether the protective effect of
Therefore, although phosphate restriction may prevent the phosphate restriction in this model was due to suppression of
progression of renal insufficiency through a decrease in calci- parathyroid hormone secretion, thyroparathyroidectomy
 Dietary factors in chronic renal disease 583

Table 3. Weight and mineral content of the viable portion of the remnant kidney in five-sixths nephrectomized rats fed a normal or decreased
phosphorus intakes
Kidney weight, giwet wt Dry tissue weight (viable portion) mg/g
Viable
Diet Total portion Infarcted Ca Mg Pi
Normal Pi 0.99 0.08 0.53 0.04 0.46 0.05 4.02 1.42 1.13 0.12 25.07 3.53
Decreased Pi 0.83 0.02 0.58 0.03 0.25 0.02 0.75 0.28 0.99 0.04 14.22 0.32
P <0.05 NS <0.05 <0.05 NS <0.02
Abbreviations: BP, blood pressure; Pi, phosphorus.
These values represent the mean and SEM of six rats in each group. The animals were pair-fed.

(TPTX) was performed before and after the induction of neph- mon in glomerulonephritis; and crescent formation, in which
rotoxic serum nephritis [70]. TPTX prevented functional deteri- macrophage proliferation has been implicated, could also result
oration, proteinuria, renal calcification, and histologic change. from lipoprotein stimulation. Moorhead et al [73] cited clinical
Selective parathyroidectomy had no protective effect on renal examples in humans and animals in which abnormalities in
function, proteinuria, or histologic damage. Thyroidectomy lipids may be involved in the progression of renal disease. In
alone was as protective as TPTX in this model. Rats given humans the rare syndrome of familial lecithin:cholesterol acyl-
thyroid replacement after TPTX had histological changes and transferase (LCAT) deficiency is characterized by an abnormal
progression of renal failure comparable to that seen in control serum LDL fraction and kidney disease which progresses to
animals. This suggests that thyroid hormone plays a role in the renal failure. However, Gjone, Blomhoff, and Skarbovik [78]
progression of disease in this model. It should be stressed that described a patient with familial LCAT deficiency and normal
thyroid hormone is indispensable for renal growth and hyper- kidney function in whom the LDL level was also unexpectedly
trophy [71, 72]. Thus, similar to hypophosphatemia, thyroid normal, and they inferred a link between abnormal LDL levels
deficiency may prevent hyperfiltration and hemodynamic and renal disease in other patients with this familial LCAT
changes which may occur in this model of nephrotoxic serum deficiency. The syndrome of partial lipodystrophy in humans is
nephritis. also associated with glomerular changes which lead to renal
failure. However, no causal relationship has been established
Role of lipids in the progression of chronic renal disease between the glomerular pathology and the abnormalities of lipid
In a recent editorial, Moorhead et al [73] suggested a potential metabolism. In four patients with the nephrotic syndrome as a
role for plasma lipids in the progression of chronic renal complication of massive obesity, Weisinger et al [79] found that
disease. It is known that levels of total cholesterol, triglycer- dietary restriction was accompanied by weight loss and simulta-
ides, and phospholipids are increased in the nephrotic syn- neous remission in proteinuria and the nephrotic syndrome.
drome, and more so at lower albumin concentrations. The The serum cholesterol fell with dietary restriction, and when
mechanisms of hyperlipidemia in the nephrotic syndrome are the patients were given isocaloric high protein (120 to 180 g/day)
not completely clear but may relate to increased synthesis of diets, no exacerbations of proteinuria were found. Edwards [80]
lipoproteins by the liver and loss of lipoprotein lipase activator,noted a significant inverse correlation between fasting serum
such as apoprotein C2, in the urine [74]. It is of interest that triglycerides and mean GFR in patients with analgesic nephrop-
apoproteins, which function as carriers for lipids, have specific athy. He also observed that renal transplant function was worse
receptors on the surface of various cells including fibroblasts, in hypertriglyceridemic patients than in normolipernic controls.
smooth muscle cells, and lymphocytes [75]. Cells with recep-
tors for apoproteins B and E are able to ingest the lipoprotein Effects of manipulation of dietary lipids on the progression of
after which the protein moiety is broken down to amino acids renal disease
while the liberated cholesterol is involved in intracellular cho- Several reports suggest a role of dietary lipids in the progres-
lesterol metabolism. At physiological pH and ionic strength sion of renal disease. Glomerular sclerosis was shown to develop
some lipoproteins (VLDL and LDL) can bind with polyanionic in guinea pigs fed a 1% cholesterol diet [81]. Hurd et al [82]
glycosaminoglycans [76] which are major constituents of the examined the effects of diets rich or deficient in essential fatty
glomerular basement membrane. Potentially, therefore, lipo- acids on the progression of lupus nephritis in NZB/NZW hybrid
proteins may alter the permeability of the glomerular barrier by mice [83, 84]. These mice develop several immunologic abnor-
binding with charges in the membrane. An increase in basement malities, as well as circulating immune complexes and immuno-
membrane total lipids of up to 75% has been noted in glomerulo- globulin deposition in the renal glomerulus. The severity of the
nephritis; a twofold increase in basement membrane lipids with glomerulonephritis peaks at 9 months of age and causes death of
a fivefold increase in cholesterol has been observed in trans- most animals by 12 months of age [83—85]. In Hurd's study a
planted kidneys [77]. Moorhead et al [73] postulated that if in group of mice was fed safflower oil which contains 78% linoleic
the nephrotic syndrome lipoproteins are filtered in excessive acid. Linoleic acid is a precursor of both eicosa-8,ll ,15-trienoic
amounts and if mesangial cells possess receptors for apopro- (dihomo-y-linolenic) and eicosa-5 ,8, 11, lS-tetraenoic (arachi-
teins these cells will be able to ingest lipids. This may lead to donic) acids which can be converted to prostaglandins, throm-
proliferation of mesangial cells and deposition of excess base- boxanes, prostacyclins, or leukotrienes. A second group of
ment membrane material. Mesangial cell proliferation is corn- animals was fed a normal chow diet. The third group of animals
584 Klahr et a!

was fed the chow diet and was injected with PGE1. The fourth 6%) have shown that increased amounts of linoleic acid were
group was fed a diet deficient in essential fatty acids (< 1% associated with decreased susceptibility of platelets to throm-
linoleic acid). Animals fed this latter diet had markedly pro- bin-induced aggregation and prolongation of the clotting time of
longed life, reduced severity of glomerulonephritis, and lower platelet rich plasma [90]. These studies in rats confirm and
levels of ANA and anti-DNA antibodies. Safflower oil had no extend previous work showing that dietary saturated and poly-
apparent beneficial effect on the severity of glomerulonephritis unsaturated fatty acids had opposite effects on platelet func-
or survival. POE1 treatment caused prolonged survival but was tions in humans. Similar results have been reported in rabbits.
less effective than an essential fatty acid deficient-diet in Linoleic acid intake may also influence the progression of
reducing or preventing autoantibody production or the develop- diabetic retinopathy [91]. In a prospective study, half of 102
ment of glomerulonephritis. Although these studies did not patients with newly discovered diabetes mellitus received a
directly address the biochemical basis for the beneficial effects linoleic acid-enriched diet (20 g of linoleic acids per 1000 kcal)
of the essential fatty acid deficient diets on this model of lupus, and the other haff a saturated fat diet (5 g of linoleic acid per
it is possible that one or more metabolites of arachidonic acid 1000 kcal). After 5 years significantly less retinopathy and
may play a role in the pathogenesis of this disease. Products of radiographic abnormalities were observed in the group on the
the lipooxygenase pathway (12-hydroxy-eicosatetraenoic acid, linoleic acid rich diet. No significant changes in body weight
1 2-hydroperoxy-eicosatetraenoic acid, leukotrienes, and so occurred in either group as a consequence of dietary
forth) or cyclooxygenase pathway (prostacyclins, thrombox- manipulations.
anes, prostaglandins, and so forth) could be involved in mediat- The studies described above indicate that changes in dietary
ing murine lupus by virtue of their biological activity in chemo- lipids may influence the progression of a variety of renal
taxis, vascular permeability, and other factors involved in diseases as well as the retinopathy of patients with diabetes, an
inflammation [86, 871. Along similar lines, Prickett, Robinson, abnormality which is closely associated with diabetic glomeru-
and Steinberg [88] demonstrated that enrichment of the diet lar sclerosis. The mechanisms by which changes in dietary
with a polyunsaturated acid, eicosapentanoic acid, prevented lipids may produce their beneficial effects is not clear. In
proteinuria and prolonged survival in NZB/NZW F1 mice. experimental lupus nephritis it appears that decreased produc-
Dietary eicosapentanoic acid (EPA, C20:5), a fatty acid analog tion of one or more metabolites of arachidonic acid has a
of arachidonic acid (C20:4), has been shown to impair platelet beneficial effect on the disease. This effect may be related to the
aggregation in humans apparently through inhibition of the action of prostaglandins in immunological and/or inflammatory
synthesis of prostaglandins and thromboxanes from arachidonic processes. By contrast in the other entities increased synthesis
acid. Animals from 4 weeks of age were fed diets containing of arachidonic acid metabolites seem to play a beneficial role.
25% lipid supplied either as beef tallow or menhaden oil with Whether or not changes in the synthesis of vasodilatory prosta-
fatty acid analysis of less than 0.05 and 14.4% eicosapentanoic glandins is responsible is not known. Of interest, however, is
acid, respectively. By 13 months of age mice on the beef tallow the fact that exogenous administration of prostaglandins may
diet had all developed proteinuria and the majority (six of nine) affect the course of renal disease in several animal models [92—
had died with renal histologic examination revealing severe 94]. Changes in dietary lipids may affect the physiology of
glomerulonephritis. In contrast, none of ten mice fed menhaden platelets, and if thrombosis is involved in the progression of
oil had developed proteinuria or died at this time. In a second certain forms of renal disease, they may prevent the progres-
sion of the disease by impairing the ability of platelets to
experiment using 50 mice of each dietary group, 56% of the beef
tallow group versus none of the menhaden oil group had aggregate [95].
developed proteinuria at 9 months of age. These results demon- Regarding a potential role of prostaglandins in the progres-
strate that a diet high in eicosapentanoic acid prevents the sion of chronic renal disease, it is of interest that two groups
development of glomerulonephritis in NZBINZW F1 mice. have reported an increased excretion of urinary prostaglandins
Different results were obtained by Barcelli, Weiss, and Pollak of theE2 series in patients with chronic renal disease. Suzuki et
[89] who examined the effects of administering diets with a high al [96] found that urinary excretion of POE2 averaged 337 63
or normal linoleic acid content to three-fourths nephrectomized ng/24 hr in 25 female renal patients, a value significantly higher
and sham-operated rats. Nephrectomized rats fed the normal than values obtained in 38 normal females (166 17 ng/24 hr).
linoleic acid diet had progressive deterioration of renal function Blum et al [97] found increased excretion of prostaglandins in
with serum creatinine levels rising to 5.55 mg/dl by week 20. By the urine of 13 males and 7 females with chronic glomerulone-
contrast, nephrectomized rats fed the high linoleic acid diet phritis or chronic interstitial nephritis. Kirschenbaum and Ser-
maintained stable renal function (mean serum creatinine 0.97 ros [981 studied the effects of prostaglandin inhibition of GFR in
mg/dl at week 20). Urinary protein excretion was significantly rabbits with reduced renal mass. Administration of cyclooxy-
lower and glomerular sclerosis was prevented in the rats fed the genase inhibitors to normal rabbits reduced urinary prostaglan-
high linoleic acid diet. No changes were observed in the levels din excretion by 53% without a change in creatinine clearance,
of blood pressure, serum cholesterol, or serum triglycerides as In contrast, administration of cyclooxygenase inhibitors to
an effect of the diet. Increased POE2 production in the renal uremic animals decreased urine prostaglandin excretion by 71%
cortex of the rats fed the high linoleic acid diet may have had, and creatinine clearance by 50%. In these rabbits, urine prosta-
according to the authors, a protective effect on renal function in glandin excretion was twice that seen in normal rabbits and
this model of renal disease. Platelets and coagulation may play a when factored by either GFR or remaining renal mass, mean
role in the progression of the renal disease in three-fourths values were nine times and four times, respectively, those seen
nephrectomized rats [40, 491. It is of interest that studies in rats in normal animals. These findings suggest that intact renal
fed different concentrations of dietary linoleic acid (from 0 to prostaglandin biosynthesis is necessary for the maintenance of
 Dietary factors in chronic renal disease
GFR in animals with decreased renal mass. Similarly, Kimberly
et al [99] reported reduced renal blood flow and GFR in seven
patients with systemic lupus erythematosus associated with the
administration of aspirin. All of these patients had elevated
urine prostaglandin excretion prior to aspirin treatment suggest-
ing that prostaglandins were important in maintaining GFR in
the face of renal disease. These studies raise the question as to
the potential adverse effects that administration of nonsteroidal
anti-inflammatory agents may have in the progression of chron-
ic renal disease independent of their effects as analgesic nephro-
toxins [100].
In summary, although the observations reported are provoca-
tive and suggest a potential role for lipids in the progression of
renal disease, the evidence obtained is only circumstantial. A
cause-effect relationship has not been clearly established and
substantial additional work will be required to unravel the
potential mechanisms by which lipids may participate in the
progression of chronic renal disease.
Conclusions
The available evidence indicates a pronounced effect of
protein intake on the deterioration of renal function in several
widely differing experimental models of renal disease in rats and
mice. The evidence that similar effects occur in humans is
suggestive but tenuous. Although the "hyperfiltration theory"
provides a logical explanation for a link between dietary protein
intake and the progressive loss of renal function, the mecha-
nisms by which decreases in protein intake may attenuate the
progression of renal disease have not been unequivocally
established. Decreases in protein intake may modify immuno-
logical events, decrease hypertrophy and hyperfiltration in
remaining nephrons, affect lipid metabolism, prevent abnormal-
ities in coagulation, alter hormonal secretion and/or effects. All
of these factors alone or in combination may play a role in the
progression of renal disease. In addition, studies are required to
determine "safe" limits for protein restriction so as to avoid
prolonged negative nitrogen balance and malnutrition. The
evidence for a role of dietary phosphate in the progression of
renal disease is not compelling. The potential role of lipids,
although suggestive, is not conclusive. It is possible that each
one, protein, phosphate and lipid content of the diet, plays a
role in the progression of renal disease. The relative importance
of these dietary components may vary depending on the patho-
genesis, stage, and mechanisms of progression of any given
renal disease. The implications that dietary manipulations may
halt or delay the progression of renal disease are enormous. The
time is ripe for adequately controlled prospective studies in
humans to test the validity of some of the hypotheses proposed.
Such studies should carefully consider not only the criteria
needed to evaluate the effect of dietary manipulations on the
course of renal disease but also the nutritional requirements and
current intakes of protein, phosphate, and fatty acids in
humans.
SAULO KLAHR
JOHN BUERKERT
MABEL L. PURKERSON
St. Louis, Missouri
Acknowledgments
The work from our laboratory in this review was supported in part by
United States Public Health Service NIADDK grant AM-09976. The
585
authors thank Dr. B. Brenner, Renal Division, Peter Bent Brigham
Hospital, Boston, Massachusetts, for making available to us reports
from his laboratory which, at the time, were unpublished; the reports
have since been published in Kidney tnt 23:647—655, 1983 (see [8]).
Reprint requests to Dr. S. Klahr, Renal Division, Box 8126, Depart-
ment of Medicine, Washington University School of Medicine, 4550
Scott Avenue, St. Louis, Missouri 63110, USA
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