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Primary Versus Secondary Prevention of Chronic Kidney Disease: The Case of Dietary Protein

      Related Articles, p. 235 and p. 245
      The proclamation that “the greatest medicine of all is to teach people how not to need it” (Hippocrates. 460-370 BC, Greece) is the basic principle of primary disease prevention, which aims to prevent disease before it ever occurs. Preventing exposures to hazards that cause disease, such as altering unhealthy behaviors, is one example of primary disease prevention. Secondary or tertiary disease prevention, however, refers to reducing the impact of a disease that has already occurred, or limiting the impact of an ongoing illness that has lasting effects, respectively. Salutary diets or lifestyles for primary versus secondary/tertiary disease prevention may not necessarily align.
      In patients with manifest chronic kidney disease (CKD), a low-protein diet remains the first line of nutrition therapy for secondary prevention of CKD.
      • Kopple J.D.
      • Fouque D.
      Pro: the rationale for dietary therapy for patients with advanced chronic kidney disease.
      • Woodrow G.
      Con: the role of diet for people with advanced Stage 5 CKD.
      Potential effects of low-protein diets are the preservation of residual renal function, better control of uremia, reduced kidney stone formation, hyperphosphatemia, or gut-derived uremic toxins.
      • Kovesdy C.P.
      Traditional and novel dietary interventions for preventing progression of chronic kidney disease.
      • Black A.P.
      • Anjos J.S.
      • Cardozo L.
      • et al.
      Does low-protein diet influence the uremic toxin serum levels from the gut microbiota in nondialysis chronic kidney disease patients?.
      However, there remains conflicting data on the benefits of low-protein diets in retarding the progression to end-stage kidney disease
      • Klahr S.
      • Levey A.S.
      • Beck G.J.
      • et al.
      The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group.
      or lowering the risk of mortality,
      • Fouque D.
      • Laville M.
      • Boissel J.
      Low protein diets for chronic kidney disease in non diabetic adults.
      and the potential to promote undernutrition in the elderly.
      • Woodrow G.
      Con: the role of diet for people with advanced Stage 5 CKD.
      It is possible that conflicting evidence is explained by patient-centered experiences following this restrictive dietary approach.
      • Kelly J.T.
      • Campbell K.L.
      • Hoffmann T.
      • Reidlinger D.P.
      Patient experiences of dietary management in chronic kidney disease: a focus group study.
      In fact, compliance to a low-protein diet is commonly between 14% and 50% in CKD trials,
      • Woodrow G.
      Con: the role of diet for people with advanced Stage 5 CKD.
      and approximately, 70% of nephrologists report hesitation in prescribing it.
      • Kalantar-Zadeh K.
      • Moore L.W.
      • Tortorici A.R.
      • et al.
      North American experience with low protein diet for non-dialysis-dependent chronic kidney disease.
      In contrast to the low-protein diet advice in CKD, a high protein, low carbohydrate diet has been touted as a quick fix solution to today's epidemics of obesity and type 2 diabetes. Commentary has followed related to its safety, with several reports, and lay media raising concern that such diets in the general population may be detrimental to the healthy kidney.
      • Marckmann P.
      • Osther P.
      • Pedersen A.N.
      • Jespersen B.
      High-protein diets and renal health.
      • Delimaris I.
      Adverse effects associated with protein intake above the recommended dietary allowance for adults.
      • Manninen A.H.
      High-protein diets are not hazardous for the healthy kidneys.
      • Luyckx V.A.
      • Mardigan T.A.
      High protein diets may be hazardous for the kidneys.
      Yet, the current state of the evidence is uncertain, with little to no evidence to support these claims. To date, randomized controlled trials of a high-protein diet in individuals free from CKD have generally observed no adverse effect on renal function decline (Table 1). Existing studies are nonetheless too short in duration to meaningfully detect estimated glomerular filtration rate (eGFR) changes (<2 years), often include younger participants, and choose creatinine-based eGFR as a study outcome, which may be compromised when intervening on protein intake.
      • Inker L.A.
      • Schmid C.H.
      • Tighiouart H.
      • et al.
      Estimating glomerular filtration rate from serum creatinine and cystatin C.
      Similar conclusions were reached in a recent meta-analysis of randomized controlled trials that showed that a high-protein diet in populations free from CKD stimulated the renal reserve causing increases in eGFR, but no evidence of renal damage or eGFR decline was found.
      • Schwingshackl L.
      • Hoffmann G.
      Comparison of high vs. normal/low protein diets on renal function in subjects without chronic kidney disease: a systematic review and meta-analysis.
      Observational evidence also points to a lack of a clear association between a high-protein diet and renal function in the general population (Table 2). Finally, real-world examples support this contention, within the body-building community
      • Manninen A.H.
      High-protein diets are not hazardous for the healthy kidneys.
      and in historical accounts of extreme protein intakes (e.g., men in the famous Lewis and Clark expedition across America in 1804 reportedly ate as much as nine pounds of buffalo meat (>600 g protein) each day with no ill effects
      • Anderson S.
      • Brenner B.M.
      The aging kidney: structure, function, mechanisms, and therapeutic implications.
      ).
      Table 1Results of Studies Examining High Protein Intake and Renal Outcomes in Randomized Controlled Trials Conducted in Populations Free From CKD With Study Durations Greater Than 3 Months
      Study CitationPopulationDurationProtein ExposureHigh Protein Intake and Change in Renal Function
      Randomized controlled trials
       Campos-Nonato et al. 2017
      • Campos-Nonato I.
      • Hernandez L.
      • Barquera S.
      Effect of a high-protein diet versus standard-protein diet on weight loss and biomarkers of metabolic syndrome: a randomized clinical trial.
      Mexican adults; 20-60 y; BMI 25-45 kg/m2; metabolic syndrome; n = 1186 moHigh protein: 1.3 g/kg

      Low protein: 0.8 g/kg
      No significant change in renal function
       Freidman et al. 2012
      • Friedman A.N.
      • Ogden L.G.
      • Foster G.D.
      • et al.
      Comparative effects of low-carbohydrate high-protein versus low-fat diets on the kidney.
      Adults; 18-65 y; BMI 27-40 kg/m2; n = 30724 moHigh protein: >15%

      Low protein: 15%
      No significant change in renal function
       Krebs et al. 2012
      • Krebs J.
      • Elley C.
      • Parry-Strong A.
      • et al.
      The Diabetes Excess Weight Loss (DEWL) Trial: a randomised controlled trial of high-protein versus high-carbohydrate diets over 2 years in type 2 diabetes.
      Adults; 30-75 y; type 2 diabetes; BMI >27 kg/m2; n = 41924 moHigh protein: 30%

      Low protein: 15%
      No significant change in renal function
       Larsen et al. 2011
      • Larsen R.N.
      • Mann N.J.
      • Maclean E.
      • Shaw J.
      The effect of high-protein, low-carbohydrate diets in the treatment of type 2 diabetes: a 12 month randomised controlled trial.
      Adults; type 2 diabetes; BMI 27-40 kg/m2; n = 9912 moHigh protein: 30%

      Low protein: 15%
      No significant change in renal function
       Li et al. 2010
      • Li Z.
      • Treyzon L.
      • Chen S.
      • Yan E.
      • Thames G.
      • Carpenter C.L.
      Protein-enriched meal replacements do not adversely affect liver, kidney or bone density: an outpatient randomized controlled trial.
      Adults; >30 y; BMI 27-40 kg/m2; n = 10012 moHigh protein: 30%; 2.2 g/kg

      Low protein: 15%; 1.1 g/kg
      No significant change in renal function
       Noakes et al. 2005
      • Noakes M.
      • Keogh J.B.
      • Foster P.R.
      • Clifton P.M.
      Effect of an energy-restricted, high-protein, low-fat diet relative to a conventional high-carbohydrate, low-fat diet on weight loss, body composition, nutritional status, and markers of cardiovascular health in obese women.
      Adults; 20-65 y; BMI 27-40 kg/m2; n = 1003 moHigh protein: 37%

      Low protein: 17%
      No significant change in renal function
       Skov et al. 1999
      • Skov A.R.
      • Toubro S.
      • Bulow J.
      • Krabbe K.
      • Parving H.H.
      • Astrup A.
      Changes in renal function during weight loss induced by high vs low-protein low-fat diets in overweight subjects.
      Adults; BMI 25-34 kg/m2; n = 656 moHigh protein: 25%

      Low protein: 12%
      Increase in GFR of 5 mL/min

      No adverse renal effects reported
       Tay et al. 2015
      • Tay J.
      • Thompson C.H.
      • Luscombe-Marsh N.D.
      • et al.
      Long-term effects of a very low carbohydrate compared with a high carbohydrate diet on renal function in individuals with type 2 diabetes: a randomized trial.
      Adults; type 2 diabetes; n = 11512 moHigh protein: 28%

      Low protein: 17%
      No significant change in renal function
       Tirosh et al. 2013
      • Tirosh A.
      • Golan R.
      • Harman-Boehm I.
      • et al.
      Renal function following three distinct weight loss dietary strategies during 2 years of a randomized controlled trial.
      Adults; 40–65 y; BMI >27 kg/m2; n = 31824 moHigh protein: 22%

      Low protein: 19%
      High protein increased eGFR by 5%

      Albuminuria decreased in the low protein intervention.

      No adverse renal effects reported
       Wycherley et al. 2012
      • Wycherley T.
      • Brinkworth G.
      • Clifton P.
      • Noakes M.
      Comparison of the effects of 52 weeks weight loss with either a high-protein or high-carbohydrate diet on body composition and cardiometabolic risk factors in overweight and obese males.
      Adults; 20-65 y; BMI 27-40 kg/m2; n = 6812 monthsHigh protein: 35%; 1.2 g/kg

      Low protein: 17%; 0.8 g/kg
      No significant change in renal function
      BMI, body mass index; CKD, chronic kidney disease.
      Table 2Results of Studies Examining High Protein Intake and Renal Outcomes in Observational Studies Conducted in Populations Free From CKD
      Study CitationPopulationDurationProtein ExposureHigh Protein Intake and Change in Renal Function
      Dunkler et al. 2013
      • Dunkler D.
      • Dehghan M.
      • Teo K.K.
      • et al.
      Diet and kidney disease in high-risk individuals with type 2 diabetes mellitus.
      ONTARGET cohort; n = 6,1235.5 yProtein intake analyzed across tertiles

      High protein: 1 g/kg

      Low protein: 0.4 g/kg
      Lowest tertile of total and animal protein intake had an increased risk of CKD compared with participants in the highest tertile
      Halbesma et al. 2009
      • Halbesma N.
      • Bakker S.J.
      • Jansen D.F.
      • et al.
      High protein intake associates with cardiovascular events but not with loss of renal function.
      PREVEND cohort; n = 8,4616.4 yProtein intake analyzed across quintiles.

      High protein quintile = 3.3 g/kg
      No significant change observed in renal function
      Haring et al.
      • Haring B.
      • Selvin E.
      • Liang M.
      • et al.
      Dietary protein sources and risk for incident chronic kidney disease: results from the Atherosclerosis Risk in Communities (ARIC) Study.
      ARIC cohort; n = 11,95223 yProtein intake analyzed across quintiles.

      High protein quintile: 110 g/d
      No significant change observed in renal for total protein intake

      Red and processed meat consumption associated with risk of CKD

      Protective associations from plant, egg, and fish protein sources
      Knight et al. 2003
      • Knight E.L.
      • Stampfer M.J.
      • Hankinson S.E.
      • Spiegelman D.
      • Curhan G.C.
      The impact of protein intake on renal function decline in women with normal renal function or mild renal insufficiency.
      Nurses' Health Study cohort; n = 1,62411 yProtein intake analyzed across quintiles.

      High protein quintile: 93 g/d
      No significant change observed in renal function in non-CKD

      Significant association to renal function decline in those with established CKD
      Lew et al. 2016
      • Lew Q.-L.J.
      • Jafar T.H.
      • Koh H.W.L.
      • et al.
      Red meat intake and risk of ESRD.
      Singapore Chinese Health Study cohort; n = 63,25715.5 yProtein intake analyzed across quartiles of animal, poultry, fish, and plant sources

      High protein quintile: 64 g/d

      Low protein quintile: 53 g/d
      Red meat consumption associated with risk of ESRD

      Protective associations from plant, egg, and fish protein sources
      Cirillo et al. 2018
      • Cirillo M.
      • Cavallo P.
      • Bilancio G.
      • Lombardi C.
      • Vagnarelli O.T.
      • Laurenzi M.
      Low protein intake in the population: low risk of kidney function decline but high risk of mortality.
      Gubbio study cohort; n = 4,67915.9 yLowest protein: 20% of the sample's UUN distributionNo significant change observed in renal function in non-CKD

      Significant association to renal function decline in those with established CKD
      Malhotra et al. 2018
      • Malhotra R.
      • Lipworth L.
      • Cavanaugh K.L.
      • et al.
      Protein intake and long-term change in glomerular filtration rate in the Jackson Heart study.
      Jackson Heart study cohort; n = 3,1658 yProtein intake analyzed across quartiles

      High protein quintile: 19%; 1 g/kg

      Low protein quintile: 10%; 0.6 g/kg
      No significant change observed in renal function in non-CKD

      Significant association to renal function decline in those with uncontrolled diabetes
      CKD, chronic kidney disease; ARIC, Atherosclerosis Risk in Communities; ONTARGET, The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; PREVEND, Prevention of Renal and Vascular End-Stage Disease; ESRD, end-stage renal disease; UUN, urine urea nitrogen.
      In this issue of JREN, we are presented with two studies examining the effects of dietary protein on the healthy kidney. Cirillo et al.
      • Cirillo M.
      • Cavallo P.
      • Bilancio G.
      • Lombardi C.
      • Vagnarelli O.T.
      • Laurenzi M.
      Low protein intake in the population: low risk of kidney function decline but high risk of mortality.
      present a post hoc analysis of the Gubbio study, an Italian population-based study of 4,679 adults. Dietary protein intake was measured from overnight urine urea nitrogen (UUN), with low protein intake defined as the lowest quartile of UUN distribution. CKD progression was defined as an eGFR reduction of less than or equal to 1 standard deviation from baseline. Over 16 years of follow-up, they found no association between low UUN and the odds of eGFR decline. Interestingly, when the analysis was restricted for those participants with reduced renal function at baseline (defined as eGFR decline from equal to or below a Z-score of -1 baseline eGFR), a low protein intake was significantly associated with lower odds of eGFR decline (odds ratio: 0.44 [95% confidence interval 0.22, 0.85]). Also in this issue, Malhotra et al.
      • Malhotra R.
      • Lipworth L.
      • Cavanaugh K.L.
      • et al.
      Protein intake and long-term change in glomerular filtration rate in the Jackson Heart study.
      present another observational analysis based on 3,165 participants from the Jackson Heart study. The sample included African–American adults who were mostly female (65%) and had dietary protein intake ascertained at baseline from food frequency questionnaires. Change in GFR was calculated as the final visit GFR minus the baseline GFR, using the CKD Epidemiology Collaboration equation. The primary finding of this study was a lack of significant association between protein intake and GFR decline over 8 years of observation. However, when the analysis was stratified by diabetes status, participants with diabetes had a higher incidence of eGFR decline across the lowest (−20.0 ± 1.7 mL/min/1.73 m2) and highest (−15.9 ± 2.8 mL/min/1.73 m2) quintiles of protein intake, as compared to those with middle quintile (−12 ± 1.6 mL/min/1.73 m2).
      These 2 studies add to the body of evidence that restricting protein intake may not be beneficial in the primary prevention of CKD. Nonetheless, they also suggest that a lower protein intake may be beneficial in some high-risk populations, including those with some mild degree of renal impairment or diabetes. This agrees with preceding observational reports, such as the Nurses' Health study, where an association of low protein intake with less rapid decline of kidney function over time was only observed in the subgroup of 489 participants with established mild renal impairment.
      • Knight E.L.
      • Stampfer M.J.
      • Hankinson S.E.
      • Spiegelman D.
      • Curhan G.C.
      The impact of protein intake on renal function decline in women with normal renal function or mild renal insufficiency.
      There is also the suggestion that quality of the ingested protein (animal vs. plant-based) within an overall healthy dietary pattern, may be more important than the total protein ingested.
      • Kelly J.T.
      • Carrero J.J.
      Dietary sources of protein and chronic kidney disease progression: the proof may be in the pattern.
      Indeed, acute laboratory studies suggest that animal protein stimulates the renal reserve more so than plant-based proteins.
      • Hostetter T.H.
      • Troy J.L.
      • Brenner B.M.
      Glomerular hemodynamics in experimental diabetes mellitus.
      As recently shown in JREN,
      • Haring B.
      • Selvin E.
      • Liang M.
      • et al.
      Dietary protein sources and risk for incident chronic kidney disease: results from the Atherosclerosis Risk in Communities (ARIC) Study.
      people consuming the highest quartile of vegetable protein had a 24% reduced risk of incident CKD over a 23-year follow-up period, but the analysis of overall protein intake yielded no association. When the analysis targeted individual food items, there was an increased CKD risk for those who consumed more protein from red and processed meats (HR 1.23; P < .01), and a reduced CKD risk for those who consumed more protein from dairy products, nuts, and legumes. While an important limitation of all these studies is their observational nature because of the lack of adequately powered and well-designed intervention trials. Such evidence forms the basis for many nutrition guidelines in primary and secondary prevention.
      The Science of Nutrition is a science of “virtue in moderation”, where any excess nutrient intake or deficit is a risk for more harm than good. Concerns relating to a high-protein diet are likely because of harmful effects other than kidney damage. Some of the adverse effects attributed to excessive protein intake include disorders of bone and calcium homeostasis, renal stone formation, possible increased risk of cancer, disorders of liver function, hypertension, and coronary artery disease.
      • Delimaris I.
      Adverse effects associated with protein intake above the recommended dietary allowance for adults.
      • Golzarand M.
      • Bahadoran Z.
      • Mirmiran P.
      • Azizi F.
      Protein foods group and 3-year incidence of hypertension: a prospective study from Tehran Lipid and Glucose study.
      It is interesting, in this sense, that Malhotra et al.
      • Malhotra R.
      • Lipworth L.
      • Cavanaugh K.L.
      • et al.
      Protein intake and long-term change in glomerular filtration rate in the Jackson Heart study.
      observed a U-shape association between protein intake and mortality. Neither too little nor too much protein intake may be good for health, as it was similarly shown in other population-based studies.
      • Halbesma N.
      • Bakker S.J.
      • Jansen D.F.
      • et al.
      High protein intake associates with cardiovascular events but not with loss of renal function.
      • Knight E.L.
      • Stampfer M.J.
      • Hankinson S.E.
      • Spiegelman D.
      • Curhan G.C.
      The impact of protein intake on renal function decline in women with normal renal function or mild renal insufficiency.
      These two interesting studies leave us with two conclusions. First, they align with current evidence, which does not support the assertion that a high-protein diet leads to incident CKD in the community, at least in those with normal renal function. Interestingly however, is a call for caution about prescribing high-protein diets in populations at high risk of CKD, such as those with minimal renal impairment or diabetes. There is a need to better understand lifestyle advice for the primary prevention of CKD separately from secondary prevention, preferably in randomized controlled trials.
      Second, these studies make us realize that although a healthy diet is likely to be effective for primary CKD prevention,
      • Kelly J.T.
      • Palmer S.C.
      • Wai S.N.
      • et al.
      Healthy dietary patterns and risk of mortality and ESRD in CKD: a meta-analysis of cohort studies.
      the characteristics of such a diet are, to date, poorly defined.
      • Campbell K.L.
      • Carrero J.J.
      Diet for the management of patients with chronic kidney disease; it is not the quantity, but the quality that matters.
      The case of dietary protein and CKD illustrated in these 2 studies is an excellent example that primary and secondary prevention strategies are not always aligned. There is still much to be learned in the case of dietary protein, and more improvement is needed for effective strategies to minimize the burden of CKD in the community. After all, CKD afflicts 1 in 10 adults and causes as many deaths as diabetes.
      Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      • Thomas B.
      • Matsushita K.
      • Abate K.H.
      • et al.
      Global cardiovascular and renal outcomes of reduced GFR.

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