Dietary satisfaction and quality of life in chronic kidney disease patients on low-protein diets: a multicentre study with long-term outcome data (TOrino-Pisa study)

Abstract

Background

Concerns about adherence and quality of life (QoL) limit the diffusion of low-protein diets (LPDs) as a way to slow chronic kidney disease (CKD) progression and postpone dialysis. The aim of this multicentre study is to assess dietary satisfaction in stable CKD patients.

Methods

This was a multicentre cross-sectional study with long-term follow-up data. Prevalent patients on LPD for at least 6 months were selected in four Italian centres. QoL was assessed using the World Health Organization Quality of Life questionnaire, and diet satisfaction with the Modification of Diet in Renal Disease satisfaction questionnaire. Comorbidity was assessed by Charlson Comorbidity Index, estimated glomerular filtration rate (eGFR) was calculated by the CKD Epidemiology Collaboration equation and protein intake by Maroni–Mitch formula. Survival was analysed with Kaplan–Meier curves and Cox Proportional Hazard Model.

Results

Four hundred and twenty-two CKD Stages 3–5 patients were enrolled. Over 95% were on moderately restricted diets (0.6 g/kg/day). Compliance was good (protein intake: 0.59 g/kg/day at baseline, 0.72 at the end of follow-up). Median dietary satisfaction was 4 on a 1–5 scale. QoL was not affected by the type of diet, but was influenced by age, comorbidity and setting of care. Two years later, at the end of follow-up, 66.6% of the patients were still on a diet; the main causes of discontinuation were dialysis and death. The dropout rate was low (5.5%); in Cox analysis, patient and renal survival were influenced by age and eGFR, but not by QoL, setting of care or type of diet.

Conclusions

LPDs are compatible with high dietary satisfaction and minimal dropout, at least in patients who are able to follow such a diet for at least 6 months.

chronic renal insufficiency, CKD, nutrition, quality of life, survival analysis

INTRODUCTION

Chronic kidney disease (CKD) is a growing concern throughout the world [1, 2]. In highly resourced countries, the increase in CKD patients occurred along with the increase in life expectancy, and the prevalence of CKD, in all its stages, reaches 30% above the age of 70 years; costs have increased exponentially across CKD stages [1–3]. While the prevalence of glomerulonephritis, polycystic kidney disease and interstitial nephropathies as a cause of end-stage kidney disease has been stable over recent decades, the most common, and still increasing, causes of end-stage kidney disease are those related to hypertension, diabetes and diffuse vascular disease, alone or in combination [4–6]. In many settings in poorly resourced countries, the balance between competitive mortality and development of CKD has not yet been reached, and the need for renal replacement therapy is rapidly increasing, posing complex ethical and clinical challenges [1, 2, 4].

In both settings, there are many reasons to try to slow the progression of CKD: CKD is associated with an increased risk of death from all causes and from cardiovascular diseases [7–9]. The risk increases commensurately with reduction in kidney function [3]. Renal replacement therapy, in both its forms of dialysis and transplantation, is expensive, and while long-term survival is possible, mortality is still much higher than that of the overall population in the same age groups [10–13]. Furthermore, slowing the progression of CKD is associated with improved quality of life (QoL) in settings where dialysis is available, and is still synonymous with prolonging life in about two-thirds of the world, where dialysis is not available or access is limited [10–13].

CKD is a heterogeneous disease in terms of pathogenesis, clinical presentation, progression rate and complications; whatever the cause, it is generally held that when at least 50–70% of the kidney parenchyma is damaged, the disease progresses independently from the initial cause, albeit with different individual trajectories, hence the interest in ‘nephroprotection’ or ‘renoprotection’, terms that include all measures aimed at stabilizing the kidney function or slowing the progression of kidney damage [14–16].

Among these measures, a healthy lifestyle, control of hypertension, physical activity, good nutritional status and control of comorbid conditions are all important, but none is specific to CKD as they are all suggested for patients with cardiovascular diseases, diabetes and obesity [17]. Conversely, protein restriction and, in a broader sense, nutritional management, is associated with a significant improvement in the dialysis-free interval [18–21]. However, low-protein diets (LPDs) are more often described than prescribed, and the major concerns are feasibility and compliance, reflecting the intrusiveness of dietary manipulations in daily life [22–30].

As recently pointed out in a revised version of the well-known Cochrane review on LPDs, few studies have attempted to assess dietary satisfaction in patients on LPDs, in other words, there has been little research on ‘whether quality of life is impacted by difficulties in adhering to protein restriction’ [31]. Such studies are needed if we wish to widely recommend these dietary approaches [31].

The aim of this multicentre study, the largest recent study including stable patients on different protein-restricted diets, is to assess QoL and dietary satisfaction in a large cohort of CKD patients being followed in four Italian centres, all of which offer several options of protein-restricted diets. Long-term follow-up data are also analysed to assess the rate of dropouts and search for correlations between dietary satisfaction and risk of mortality and dialysis start.

MATERIALS AND METHODS

Settings of study

The study was conducted in four Italian centres, each of which had long-term experience in prescribing LPDs, but each different in terms of organization, reflecting the heterogeneity of the settings of nephrology care in Italy. There were two large and two small centres; two were hospital centres and two were university centres; Torino is situated in Northern Italy, Pisa in central Italy, Solofra in southern Italy and Cagliari in one of the islands. Torino is a small university centre with three senior nephrologists and one in training, plus one part-time dietician with a university fellowship; there is no hospitalization ward, but its day hospital has over 2500 day hospitalizations per year. Pisa is a large university centre with hospitalization, transplantation and a network of day hospital and outpatient units. Cagliari is a large hospital centre with hospitalization, transplantation and a network of day-hospital and outpatient units. Counselling with a dietician is requested in particular cases, while dietary counselling is a part of the nephrology consultation. Solofra is small hospital centre, without hospitalization beds, and where the senior nephrologist, who is experienced in the prescription of LPDs and very-LPDs (vLPDs), directly follows the cohort of patients with advanced CKD.

Diets offered and general policies

All centres offered at least two dietary options, and some offered three or four choices. These are summarized in Table 1 and presented in greater detail in the consensus papers of the Italian study group on the conservative management of CKD, and in the group’s previous publications [32–35].

Table 1

The different LPDs offered in the different centres and employed in this study

Type of diet	Protein intake (g/kg/day)	Main features	Notes	TO	PI	CA	SO
LPD with protein-free food	0.6 g/kg/day; mixed proteins	Protein-free pasta, bread and other carbohydrates replace standard bread, pasta and rice	Carbohydrates are the basis of Mediterranean cuisine and replacing them makes it possible to restrict protein intake to 0.6 g/kg/BW	+	+	+	+
Vegan supplemented (moderate restriction)	0.6 g/kg/day; vegetable proteins, supplemented with amino- and keto-acids (Alfa-kappa or ketosteril)	Based on forbidden (animal origin) and allowed (plant-based) food. Supplementation with Alfa-kappa or ketosteril is tailored to nutritional status and clinical situation (1:8–1: 10 kg BW)	Amino- and keto-acid supplements ensure adequate intake of proteins without the need to rely on plant-derived food;1–3 unrestricted meals per week in TO	+	−	−	+
Very low-protein supplemented vegan diet	0.3 g/kg/day; vegetable proteins only with protein-free food, supplemented with Alfa-kappa or ketosteril	This diet is vegan and supplementation with Alfa-kappa or ketosteril pills is higher (1:5 kg BW). Carbohydrates are mainly or exclusively protein-free	This diet merges vegan supplemented and protein-free food. It is demanding and requires taking a large number of pills. It is not prescribed as a ‘first-line’ diet	+	+	−	+
Tailored solutions	Usually 0.6 g/kg/day; vegetable or mixed	These solutions employ different combinations of protein-free and vegan foods plus supplements	The main reason for prescribing these diets is to take the patient’s needs into account: example vegan and protein-free food at different meals	+	+	+	−
‘Traditional’	0.6–0.8 g/kg/day; mixed proteins (animal and plant derived)	Modulated on quantity of usual food; mainly based on traditional Italian regional dishes	Often corresponds to what elderly patients already eat, in particular if they cook their own food	+	+	+	−
Vegan non-supplemented	0.6–0.8 g/kg/day; vegetable proteins	Average protein intake in unrestricted vegan diets is 0.7–0.9 g/kg/day; due to the different bioavailability, a 0.7 diet roughly corresponds to a 0.6 mixed protein diet	This diet is based on the integration of cereals and legumes at each meal, thus ensuring complementarity in amino acids	+	+	−	−

BW: body weight; TO: Torino; PI: Pisa; CA: Cagliari; SO: Solofra. The last three diets were included under the heading ‘other diets’. Vegan diets: diets without any animal-derived food (except in the unrestricted meals).

The common policy consisted of offering a moderately protein-restricted diet (LPD, 0.6 g/kg/day) to all patients with rapidly progressive CKD Stage 3, or those in Stages 4 and 5 who were not on dialysis, in the absence of signs of protein energy wasting, alimentary disorders or very short life expectancy. Diet is usually continued on once-weekly incremental dialysis. A few patients with severe proteinuria, non-responsive to conventional therapies are also included. Vegan diets are defined as diets without any animal-derived food (except during the unrestricted meals). vLPDs (0.3 g/kg/day of proteins, vegan supplemented with amino acids and ketoacids: one tablet of ketosteril per each 5 kg of body weight per day) are offered in selected cases where good compliance suggests a potential advantage from further lowering of protein intake to retard dialysis start or to maintain a patient waiting for kidney transplantation. At least one unrestricted meal is allowed per week to improve compliance and facilitate social life.

LPDs and vLPDs are occasionally employed as a rescue treatment for patients with severe proteinuria who prove unresponsive to conventional management with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or other specific treatments.

Conversely, normalization of protein intake (0.8 g/kg/day) is occasionally offered to patients with a very high-protein intake or with a slow progression of kidney disease and advanced age; for the sake of this study, these cases are considered together with ‘traditional’ diets.

Protein intake is usually assessed per kilogram of real body weight, but an average between real and ideal body weight is used for patients whose body mass index (BMI) is >40 kg/m².

Energy intake was tailored to 3–35 kcal/kg of body weight per day; however, 25 kcal/day is considered acceptable for very old (>80 years) or for obese patients. The management of sodium, potassium and phosphate intake followed the usual rules of good clinical practice.

Dialysis start was decided within an ‘intent to delay’ policy based on the usual clinical and biochemical markers of blood pressure control, fluid overload, hyperparathyroidism or any clinical element suggesting uraemic toxicity.

Study design, selection criteria and long-term follow-up

The study was performed in two phases: the first phase of the study consisted of a cross-sectional evaluation of the population, combining clinical and biochemical data with two validated questionnaires: the World Health Organization’s quality of life (WHOQOL) and the dietary-satisfaction questionnaire (DSQ), developed as part the Modification of Diet in Renal Disease (MDRD) study. The second part of the study analyses survival, dialysis start and dropout rates according to the results of the initial cross-sectional evaluation.

In each setting, participation in the study was offered to all adults (age >18 years), prevalent patients on an LPD for at least 6 months, who wished to participate and who were able to answer the questionnaires. The baseline analysis took place from July to December 2014.

The follow-up analysis took place in 2017, gathering data at the last follow-up in all centres, except the one in Torino, where, following directives from the general management and the senior nephrologist’s transfer to another hospital, the outpatient unit dedicated to advance CKD was progressively closed, starting in February 2016.

Assessment of QoL

Two questionnaires, WHOQOL-BREF and DSQ (modified from MDRD), were administered to participating patients, who could choose between completing them at home or filling them in while waiting for their clinical visit, in selected cases with the help of another person, usually a medical student or a nurse (not the usual caregiver). Both questionnaires were validated in CKD patients.

In DSQ-MDRD, each item was rated on a visual analogue scale from 1 (dislike extremely) to 5 (like very much) [36]. The mean of each domain was calculated for each patient. Only cases with ≥80% answers were considered as recommended by the scoring system. Due to the low number of cases with low to very low satisfaction, scores 1 and 2 were considered together. Likewise, the ‘high satisfaction’ scores (4 and 5) were considered together [36].

The WHOQOL-BREF, which comprises 26 items, measuring four different domains (physical health, psychological health, social relationship and environment) was analysed per question and per domain. The analysis complied with the standard indications for the questionnaire; scores 1 and 2 (low scores) and scores 4 and 5 (highest scores) were likewise analysed together [37].

Data gathered

The following data were gathered: demographic (gender, age, country of origin, level of education, occupation and marital status); type of kidney disease and whether or not the patient was on dialysis; current treatments; type of diet (previous diets, at cross-sectional analysis and at last follow-up).

Comorbidity was assessed using the Charlson Comorbidity Index (CCI) [38].

Clinical data included height, weight, BMI, blood pressure; laboratory data including urea, creatinine, electrolytes, albumin, total proteins, haemoglobin, parathyroid hormone. Data not shown in tables are available in the database, on demand. Compliance with the diet was assessed using the Maroni–Mitch formula on 24-h urine collection; estimated glomerular filtration rate (eGFR) was assessed using the MDRD short and the CKD Epidemiology Collaboration (CKD-EPI) formulas [39, 40].

Statistical analysis

Analysis was performed using SPSS Statistics version 14 (IBM Corp., Armonk, NY, USA). Descriptive analysis was conducted as appropriate; the Shapiro–Wilk test was used to verify the normality distribution of the data. Median (min–max) was used for non-parametric data and mean and standard deviation for normal distribution.

Statistical significance was assessed using analysis of variance for parametric data and Kruskal–Wallis for non-parametric data in compliance with standard indications for continuous variables. Dichotomous data are presented as risks, rates and proportions; in this case, the significance of the differences was analysed using the Chi-square test.

The significance of pre/post differences was assessed using the t-test for normally distributed variables and the Wilcoxon signed rank test for variables that were not normally distributed.

Survival analysis: Kaplan–Meier analysis was conducted for the following events: death, dialysis start (or pre-emptive kidney transplantation) and diet discontinuation (or discontinuation of follow-up). Survival analysis was stratified by age group, gender, eGFR, CCI, type of diet, QoL and dietary satisfaction; comparison between stratifications was made using the log-rank test. Statistically and clinically significant stratifications were entered in the Cox multiple hazard method. Patients on once weekly dialysis (10 subjects) were excluded from survival analysis. Significance was a two-tailed α-level of <0.05.

Ethical issues

The study was conducted in accordance with the Declaration of Helsinki.

The study was initially named TOPI, from TOrino-PIsa as it initially merged these two cohorts (from Torino and Pisa), and later TOPI di CASA, with the participation of Cagliari (CA) and Solofra (SA); the shorter acronym is used in the paper (TOPI). In Pisa, the items analysed were included in a comprehensive prospective observational study on patients on protein-restricted diets (ethical approval: 6/11/2014, Prot. no. 66006); in Torino, the study was registered with the name PROTERENE (ridurre le PROTEine per PROTEggere il RENE: reducing protein for protecting the kidney; ethics committee approval, delibera 282, 28 January 2015) and in this version, it was shared with Cagliari (PROTERENE, delibera 232, 19 February 2015) and Solofra (PROTERENE, extension of the Delibera 282, 28 January 2015).

Informed consent was obtained for anonymous management of clinical data from each patient at the start of follow-up in each centre. Further consent for publication was not needed, as this study deals with overall data, not individual cases.

RESULTS

Baseline data

Table 2 reports the main clinical characteristics of the population according to centre of care; the four centres contributed almost equally to the study. The male–female ratio is not significantly different between centres, while age is significantly higher in Solofra, where almost half of the patients are >80 years. Accordingly, CCI, which integrates age, was the highest in Solofra and lowest in Pisa, where age was the lowest.

Table 2

Baseline characteristics of the population, according to the centre of care

Diet at study	Torino	Pisa	Cagliari	Solofra	P among groups
N	128	101	106	87
Males, n (%) Females, n (%)	80 (62.5)	71 (70.3)	66 (62.3)	46 (52.9)	0.119*
	48 (37.5)	30 (29.7)	40 (37.7)	41 (47.1)
Age (years), median (min–max)	73.5 (20–90)	70 (34-84)	70.5 (19–91)	79 (18–97)	<0.001
BMI (kg/m2), median (min–max)	25.4 (17.3–39.5)	27.8 (15.6–40.8)	26 (17.3–39.6)	28.2 (15.6–42.4)	<0.001
CCI, median (min–max)	6 (2–11)	5 (2–9)	6 (2–14)	7 (3–11)	<0.001
Diabetes, n (%)	46 (35.9)	30 (29.7)	25 (23.6)	32 (36.8)	0.137*
sCreatinine (mg/dL), median (min–max)	3.04 (0.66–15.59)	2.10 (1.00–-8.00)	3.01 (1.49–14.68)	2.25 (1.00–4.78)	<0.001
eGFR-EPI (mL/min), median (min–max)a	17.7 (2.5–72.9)	28.6 (6.8–83.3)	19.1 (2.9–41)	22 (10.1–82.6)	<0.001
eGFR <15 mL/min at study, n (%)	53 (41.4)	14 (13.9)	33 (31.1)	12 (13.8)	<0.001*
Proteinuria (g/day), median (min–max)	0.92 (0.01–9.65)	0.20 (0.01–4.24)	1.09 (0.01–13.8)	0.24 (0.01–6.9)	<0.001
Proteinuria ≥3 g/day, n (%)	13 (10.2)	2 (2)	19 (17.9)	5 (5.7)	<0.001*
Protein intake (g/kg/day), median (min–max)	0.50 (0.31–1.03)	0.80 (0.47–1.84)	0.53 (0.32–0.94)	0.75 (0.42–1.85)	<0.001
Glomerulonephritis-systemic disease, n (%)	14 (10.9)	11 (10.9)	31 (29.2)	9 (10.3)	<0.001*
Vegan supplemented (0.6 g/kg/day), n (%)	59 (46.1)	0	0	19 (21.8)	<0.001*
With protein-free food (0.6 g/kg/day), n (%)	50 (39.1)	45 (44.6)	36 (34)	60 (69)
vLPD (0.3 g/kg/day), n (%)	7 (5.5)	0	0	8 (9.2)
Other diets, n (%)	12 (9.4)	56 (55.4)	70 (66)	0

eGFR-EPI, GFR according to the CKD-EPI equation; sCreatinine, serum creatinine. The Chi-squared test was used when ‘*’ is specified for all qualitative data. All series were non-parametric, consequently the Kruskal–Wallis test was used for quantitative data. To take into account the multiple comparison error, Bonferroni correction was applied: P = 0.0125 and bold P-values were significantly different.

a

CKD stages: Stages 1 and 2 (prescription of protein restriction in the context of heavy proteinuria: 14 cases (9 males, 5 females, CCI 4, median age 55 years); Stage 3: 91 cases (67 males, 24 females, CCI 6, median age 70 years); Stage 4: 213 cases (123 males, 90 females, CCI 7, median age 75 years); Stage 5: 104 cases (64 males, 40 females, CCI 7, median age 71 years; 10 patients on diet plus once weekly dialysis were not considered in survival analysis).

While median kidney impairment is CKD Stage 4, about 40% of the patients in the Torino had an eGFR of <15 mL/min at the time of observation, versus 13% in Pisa and Solofra. Patients in Torino and Cagliari displayed the highest proteinuria, possibly reflecting a high prevalence of diabetes and glomerulonephritis.

Table 3 reports the main baseline characteristics according to diet choice. Diets were not evenly distributed: almost half of the patients were on a moderately restricted diet that employed protein-free food; conversely, vLPDs were chosen by a minority of cases in Torino and Solofra. Patients who chose protein-free food were generally older than those who preferred plant-based or other diets; however, comorbidity was homogeneously distributed across diets and kidney function differed only, as expected, in the subset on vLPDs. Protein intake at baseline was 0.3–0.4 g/kg/day in 36 cases. The policy of increasing protein intake, when below prescription, is probably the main reason for the small increase in protein intake over time in patients still on follow-up (from 0.59 to 0.70 g/kg/day: P < 0.001; Supplementary data, Figure S1). At the last update, after a mean of 1.75 years, creatinine significantly increased (from 2.30 to 2.42 mg/dL; P = 0.004) while proteinuria remained stable (0.55 g/24 h; P = 0.423).

Table 3

Baseline characteristics of the population according to the diet followed at time of study

Diet at study	With protein-free food (0.6)	Vegan supplemented (0.6)	vLPD (0.3)	Other diet (0.6)	All cases	P among diets
N	191	78	15	138	422
Males, n (%)	116 (61)	45 (58)	13 (87)	89 (64)	263 (62)	0.173*
Females, n (%)	75 (39)	33 (42)	2 (13)	49 (36)	159 (38)
Age (years), median (min–max)	76 (18–92)	69 (20–97)	75 (53–91)	72 (19–91)	73 (18–97)	<0.001
Age ≥65 years, n (%)	141 (74)	44 (56)	9 (60)	84 (61)	278 (66)	0.500*
Age ≥80 years, n (%)	61 (32)	12 (15)	3 (20)	23 (17)	99 (24)	0.240*
BMI (kg/m2), median (min–max)	26.6 (15.6–42.4)	25.8 (15.6–36.2)	27.4 (19.6–42.1)	26.9 (17.3–40.8)	26.5 (15.6–42.4)	0.277
CCI, median (min–max)	6 (2–12)	6 (2–10)	6 (5–11)	6 (2–14)	6 (2–14)	0.065
CCI ≥7, n (%)	94 (49)	32 (41)	7 (47)	53 (38)	186 (44)	0.243*
CCI ≥10, n (%)	20 (10)	4 (5)	3 (20)	9 (7)	36 (9)	0.150*
Diabetes, n (%)	70 (37)	23 (29)	6 (40)	34 (25)	133 (32)	0.750*
Neoplasia, n (%)	21 (11)	6 (8)	1 (7)	21 (15)	49 (12)	0.340*
sCreatinine (mg/dL), median (min–max)	2.70 (0.85–14.68)	2.78 (0.66–15.59)	4.70 (3.49–10.1)	2.29 (1–13.91)	2.53 (0.66–15.59)	<0.001
eGFR-EPI (mL/min), median (min–max)	20 (4–83)	20 (2–64)	12 (5–16)	26 (3-83)	21 (2–83)	<0.001
eGFR <15 mL/min at study, n (%)	50 (26)	27 (35)	13 (87)	21 (15)	111 (26)	<0.001*
Proteinuria (g/day), median (min–max)	0.67 (0.01–6.9)	0.68 (0.01–9.65)	0.57 (0.24–6.06)	0.77 (0.01–13.8)	0.71 (0.01–13.8)	0.340
Proteinuria ≥1 g/day, n (%)/N data	52 (40)/130	28 (39.4)/71	4 (30.7)/13	36 (41.3)/87	120 (40)/301	0.446*
Proteinuria ≥3 g/day, n (%)/N data	16 (12.3)/130	10 (14.1)/71	1 (7.7)/13	12 (13.8)/87	39 (12.9)/301	0.676*
Protein intake (g/kg/day), median (min–max)	0.62 (0.32–1.84)	0.54 (0.35–1.86)	0.49 (0.31–1.03)	0.60 (0.31–1.41)	0.59 (0.31–1.86)	0.0115
Glomerulonephritis, n (%)	20 (30.8)	13 (20)	1 (1.5)	31 (47.7)	65 (10.5)	0.020*
Nephroangiosclerosis, n (%)	37 (37)	14 (14)	0	49 (49)	100 (23.7)	<0.001*
ADPKD, n (%)	8 (4.1)	4 (5.1)	1 (6.6)	9 (6.5)	22 (5.2)	0.813*
Torino, n (%)	50 (26)	59 (76)	7 (47)	12 (9)	128	<0.001*
Pisa, n (%)	45 (24)	0	0	56 (40)	101
Cagliari, n (%)	36 (19)	0	0	70 (51)	106
Solofra, n (%)	60 (31)	19 (24)	8 (53)	0	87

eGFR-EPI, GFR according to the CKD-EPI equation; ADPKD, autosomal dominant polycystic kidney disease; sCreatinine, serum creatinine. Chi-squared test was used when ‘*’ is specified for all qualitative data. All series were non-parametric, consequently the Kruskal–Wallis test was used for quantitative data. To take into account the multiple comparison error, Bonferroni correction was applied: P = 0.0125; significantly different P-values are in bold.

Dietary satisfaction and QoL

Overall, the DSQ-MDRD questionnaire was good to very good, with <3% of the patients reporting low satisfaction with their diet (Table 4). Even in the context of similar median data, the distribution of the answers is different for different diets (Figure 1). The highest satisfaction was recorded in patients with ‘other’ diets, which are the most adapted to individual needs, while the vLPDs were considered more difficult to follow. An important centre effect is also present, and the hospital in Solofra registered lower satisfaction, probably at least partly explained by higher age and comorbidity.

FIGURE 1

Distribution of dietary satisfaction scores according to diet (score 1 not satisfied, score 5 highly satisfied). Prot. free food, diet at 0.6 g/kg/day of proteins, with protein-free food; Other, other diets at 0.6 g/kg/day of proteins; Veg. Supp 0.3, vegan supplemented vLPDs at 0.3 g/kg/day of proteins; Veg. Supp 0.6, vegan supplemented LPDs at 0.6 g/kg/day of proteins

Table 4

Distribution of DSQ-MDRD according to different parameters

	Low (scores 1–2)	Average (score 3)	High (scores 4–5)	P-values
	n (Row %)	n (Row %)	n (Row %)
All patients	11 (2.7)	94 (23.4)	297 (73.9)
Initial diet				0.0001
With protein free-food (0.6)	6 (3.2)	61 (32.4)	121 (64.4)
Vegan supplemented (0.6)	3 (3.9)	17 (22.4)	56 (73.7)
vLPD (0.3)	1 (6.7)	8 (53.3)	6 (40.0
Other diet (0.6)	1 (0.8)	8 (6.5)	114 (92.7)
Setting of the study				<0.0001
Pisa	1 (1.1)	8 (8.4)	86 (90.5)
Torino	0	18 (14.2)	109 (85.8)
Cagliari	1 (1.1)	14 (14.9)	79 (84.0)
Solofra	9 (10.5)	54 (62.8)	23 (26.7)
eGFR (mL/min/1.73 m2)				0.9793
≥15	8 (2.7)	68 (23.2)	218 (74.1)
<15	3 (2.8)	26 (24.1)	79 (73.1)
Gender				0.1442
Males	5 (2.0)	53 (21.0)	194 (77.0)
Females	6 (4.0)	41 (27.3)	103 (68.7)
Age (years)				0.0824
≥70	7 (3.0)	64 (27.2)	164 (69.8)
<70	4 (2.4)	30 (18.0)	133 (79.6)
CCI				0.0001
<7	3 (1.3)	36 (15.9)	188 (82.8)
≥7	8 (4.6)	58 (33.1)	109 (82.8)

eGFR-EPI, GFR according to the CKD-EPI equation. ‘0.6’ and ‘0.3’ indicate the prescribed protein intake in grams per kilogram per day. Statistically significant differences in bold.

According to the WHOQOL questionnaire, whose results are summarized in Table 5, QoL is deeply affected by age and comorbidity and is correlated with gender. An important centre effect is also present. Conversely, no difference is observed between the different diets or according to the severity of eGFR reduction. The effect of comorbidity and age is higher in the domain of physical and psychological health; patients equally rate their physical and psychological health (poor physical health 35.5%, poor psychological health 32.3%). The distribution of each answer is available in Supplementary data, Figure S2.

Table 5

Distribution of QoL by domain

	Domain 1: Physical health				Domain 2: Psychological health
	Poor,	Average,	Good,	P-value	Poor,	Average,	Good,	P-value
	n (Row %)	n (Row %)	n (Row %)		n (Row %)	n (Row %)	n (Row %)
All patients	149 (35.5)	219 (52.3)	51 (12.2)	–	136 (32.3)	253 (60.1)	32 (7.6)	–
Initial diet
With protein free-food (0.6)	78 (41.1)	96 (50.5)	16 (8.4)	0.1400	75 (39.3)	106 (55.5)	10 (5.2)	0.0073
Vegan supplemented (0.6)	25 (32.1)	41 (52.6)	12 (15.3)	–	23 (29.5)	47 (60.3)	8 (10.2)	–
vLPD (0.3)	7 (46.7)	7 (46.7)	1 (6.6)	–	7 (46.7)	5 (33.3)	3 (20.0)	–
Other diet (0.6)	39 (28.7)	75 (55.1)	22 (16.2)	–	31 (22.6)	95 (69.3)	11 (8.1)	–
Setting of the study
Pisa	21 (21.4)	58 (59.2)	19 (19.4)	<0.0001	16 (16.0)	78 (78.0)	6 (6.0)	<0.0001
Torino	34 (26.6)	80 (62.5)	14 (10.9)	–	40 (31.2)	78 (60.9)	10 (7.9)	–
Cagliari	42 (39.6)	47 (44.4)	17 (16.0)	–	33 (31.1)	63 (59.5)	10 (9.4)	–
Solofra	52 (59.8)	34 (39.1)	1 (1.1)	–	47 (54.0)	34 (39.1)	6 (6.9)	–
eGFR (mL/min/1.73 m2)
≥15	108 (35.1)	156 (50.6)	44 (14.3)	0.0850	104 (33.5)	183 (59.0	23 (7.5)	0.6585
<15	41 (36.9)	63 (56.8)	7 (6.3)	–	32 (28.8)	70 (63.1)	9 (8.1)	–
Gender
Males	78 (29.9)	147 (56.3)	36 (13.8)	0.0069	73 (27.9)	167 (63.7)	22 (8.4)	0.0418
Females	71 (44.9)	72 (45.6)	15 (9.5)	–	63 (39.6)	86 (54.1)	10 (6.3)	–
Age (years)
≥70	110 (45.3)	116 (47.7	17 (7.0)	<0.0001	94 (38.4)	138 (56.3)	13 (5.3)	0.0023
<70	39 (22.2)	103 (58.5)	34 (19.3)		42 (23.9)	115 (65.3)	19 (10.8)	–
CCI
<7	49 (20.9)	144 (61.2)	42 (17.9)	<0.0001	53 (22.5)	158 (66.9)	25 (10.6)	<0.0001
≥7	100 (54.3)	75 (40.8)	9 (4.9)	–	83 (44.9)	95 (51.3)	7 (3.8)	–

	Domain 3: Social relationships				Domain 4: Environment
All patients	86		141 (33.5)		62 (14.7)	224 (53.2)	135 (32.1)
Initial diet
With protein free-food (0.6)	40 (20.9)	96 (50.3)	55 (28.8)	0.0850	36 (18.8)	100 (52.4)	55 (28.8)	0.0415
Vegan supplemented (0.6)	19 (24.4)	28 (35.9)	31 (39.7)		10 (12.8)	38 (48.7)	30 (38.5)
vLPD (0.3)	1 (6.7)	11 (73.3)	3 (20.0)		1 (6.7)	13 (86.6)	1 (6.7)
Other diet (0.6)	26 (19.0)	59 (43.0)	52 (38.0)		15 (10.9)	73 (53.3)	49 (35.8)
Setting of the study
Pisa	13 (13.0)	45 (45.0)	42 (42.0)	0.0002	3 (3.0)	59 (59.0)	38 (38.0)	<0.0001
Torino	21 (16.4)	60 (46.9)	47 (36.7)		9 (4.7)	72 (56.2)	50 (39.1)
Cagliari	13 (17.9)	51 (48.1)	36 (34.0)		13 (12.3)	54 (50.9)	39 (36.8)
Solofra	33 (37.9)	38 (43.7)	16 (18.4)		40 (46.0)	39 (44.8)	8 (9.2)
eGFR (mL/min/1.73 m2)
≥15	64 (20.7)	139 (45.0)	106 (34.3)	0.7489	54 (17.5)	158 (51.1)	97 (31.4)	0.0293
<15	22 (19.6)	55 (49.1)	35 (31.3)		8 (7.2)	66 (58.9)	38 (33.9)
Gender
Males	50 (19.0)	122 (46.6)	90 (34.4)	0.6699	28 (10.7)	141 (53.8)	93 (35.5)	0.0059
Females	36 (22.6)	72 (45.3)	51 (32.1)		34 (21.4)	83 (52.2)	42 (26.4)
Age (years)
≥70	56 (22.9)	116 (47.3)	73 (29.8)	0.1172	43 (17.6)	125 (51.0)	77 (31.4)	0.1515
<70	30 (17.1)	78 (44.3)	68 (38.6)		19 (10.8)	99 (56.2)	58 (33.0)
CCI
<7	33 (14.0)	108 (45.8)	95 (40.2)	0.0001	23 (9.7)	126 (53.4)	87 (36.9)	0.0016
≥7	53 (28.6)	86 (46.5)	46 (24.9)		39 (21.1)	98 (53.0)	48 (25.9)

eGFR-EPI, GFR according to the CKD-EPI equation. ‘0.6’ and ‘0.3’ indicate the protein intake in grams per kilogram per day.

Analysis according to WHOQOL-BREF, Introduction, administration, scoring and generic version of the assessment, Field Trial Version. Programme on Mental Health, CH-1211 Geneva 27, Switzerland. In accordance with the multiple comparison recommendations.

The odds for having a low dietary satisfaction are strongly associated with comorbidity, and low QoL for the physical, social and environment domains, and are weakly associated with gender; they are independent from age, GFR and QoL in the psychological domain. Likewise, the odds for a poor QoL are weakly associated with age (for domains 1 and 2), with gender (for domains 1, 2 and 4) and significantly associated with comorbidity (for domains 1, 2 and 3). Adjustment for centre does not affect the results (Figures 2 and 3; Supplementary data, Figures S3 and S4).

FIGURE 2

Multivariate regression analysis: odds ratios of having a poor dietary satisfaction, according to age, gender, kidney function and CCI, and to different domains of quality of health. eGFR, GFR according to the CKD-EPI equation.

FIGURE 3

Multivariate regression analysis: odds ratios of having a poor quality of life in each QoL domain, according to age, gender, kidney function, CCI and dietary satisfaction. eGFR, GFR according to the CKD-EPI equation; Sat, satisfaction.

Follow-up analysis: survival analysis and Cox analysis

Figure 4 shows Kaplan–Meier analysis of the outcomes survival, start of renal replacement therapy and diet discontinuation in patients sorted according to the diet followed at the moment of the cross-sectional analysis.

FIGURE 4

Survival analysis according to Kaplan–Meier for the outcomes: patient survival, dialysis start and diet discontinuation. The patients are sorted according to the first diet. Prot. free food, diet at 0.6 g/kg/day of proteins, with protein-free food; Other, other diets at 0.6 g/kg/day of proteins; Veg. Supp 0.3, vegan supplemented vLPDs at 0.3 g/kg/day of proteins; Veg. Supp 0.6, vegan supplemented LPDs at 0.6 g/kg/day of proteins; short-term dropouts (within the first 6 months) were excluded from the analysis.

Over 60% of the patients were still on diet at the end of follow-up; death and dialysis were the main recorded events, while diet discontinuation was minimal without differences across diets (Table 6 andFigure 4). Indeed, only 23 (5.5%) patients discontinued the diet or were lost to follow-up after the first 6 months of follow-up.

Table 6

Long-term outcomes: distribution according to patient’s first diet, comorbidity and eGFR

	Long-term outcomes
	Continued,	Discontinueda,	On dialysis,	Died,	Overall follow-up,	P-values
	n (Row %)	n (Row %)	n (Row %)	n (Row %)	years
All patients	281 (66.6)	23 (5.5)	80 (19.0)	38 (9.0)	646.9	–
Initial diet
With protein free-food (0.6)	47 (60.3)	4 (5.1)	22 (28.2)	5 (6.4)	116.5	0.0036
Vegan supplemented (0.6)	125 (65.4)	13 (6.8)	32 (16.8)	21 (11.0)	296.4	0.0754b
vLPD (0.3)	5 (33.3)	0	8 (53.3)	2 (13.3)	19.7	–
Other diet (0.6)	104 (65.4)	6 (4.3)	32 (16.8)	21 (11.0)	214.3	–
eGFR (mL/min/1.73 m2)
≥15	249 (80.1)	19 (6.1)	19 (6.1)	24 (7.7)	527.4	<0.0001
<15	32 (28.8)	4 (3.6)	61 (55.0)	14 (12.6)	119.5
CCI
<7	161 (68.2)	13 (5.5)	49 (20.8)	13 (5.5)	360.2	0.0383
≥7	120 (64.5)	10 (5.4)	31 (16.7)	25 (13.4)	286.7	–

a

Discontinued and lost to follow-up.

b

Without vLPD (0.3).

eGFR, GFR according to the CKD-EPI equation. ‘0.6’ and ‘0.3’ indicate the protein intake in grams per kilogram per day. Survival analysis performed on 412 patients (the 10 patients on infrequent dialysis and diet were excluded).

In the univariate analysis, patient survival was affected by age, CCI and eGFR; risk of dialysis start differed significantly according to age and GFR, while gender, QoL and dietary satisfaction were non-relevant (Supplementary data, Figures S5 and S6). In the multivariate cox regression model analysis, only age and low eGFR were retained (Figures 5 and 6).

FIGURE 5

Cox analysis: risk of death over follow-up. OR: odds ratio; CI: confidence intervals. eGFR, GFR according to the CKD-EPI equation. Graph: Red markers are significant variables with alpha error at <0.05, resulting from the last step of Cox regression model including significant variables only.

FIGURE 6

Cox analysis: risk of renal replacement therapy start. OR: odds ratio; CI: confidence intervals. eGFR, GFR according to the CKD-EPI equation. Graph: Red markers are significant variables with alpha error at <0.05, resulting from the last step of Cox regression model including significant variables only.

DISCUSSION

The recent Cochrane review on the efficacy of LPDs in retarding the need for renal replacement therapy concludes by raising concerns about the impact of changes in dietary habits on CKD patients’ QoL, and emphasizes that very few studies have actually addressed this important issue [31].

This study may help answer this question by reporting data on QoL obtained in a large multicentre cohort of CKD patients managed with moderately protein-restricted diets: 422 patients who, at the time of the study, were clinically stable on a protein-restricted diet for at least 6 months. The first part of the study consists in a cross-sectional evaluation of this cohort by two validated questionnaires: the World Health Organization’s widely used questionnaire (WHOQOL) and the DSQ-MDRD questionnaire, developed as part the MDRD study, the only one available for this topic in nephrology [36, 37]. The second part of the study analyses survival, dialysis start and dropout rates according to the initial cross-sectional evaluation.

Dietary habits and, as a consequence, satisfaction with dietary changes, are closely related to setting of the study [23, 32, 33, 41–45]. Our results have to be contextualized in a setting in which dietary interventions are adapted as much as possible to individual patients. This is the ‘Italian way’ of prescribing LPDs, and each of the centres offered at least two dietary options (Table 1) [32–35].

The study population is in line with the current population with advanced CKD observed in Europe: relatively old (median: 73 years) and with high comorbidity (median CCI 6); one patient out of three was diabetic. According to the most frequent current indications of protein restriction, the median eGFR was low (21 mL/min). A small number of cases (14 patients) with Stages 1–2 CKD and severe proteinuria were also part of the cohort, as were 10 patients managed with once-weekly dialysis and moderate protein restriction (the latter were not considered in the survival analysis) (Table 2). The four participating centres contributed almost evenly to the study; the baseline differences, reported in Table 2, presumably reflect different settings (rural versus urban, large versus small centre). As for diet distribution, the three main options of moderate protein restriction (aimed at a 0.6 g/kg/day) are almost evenly represented (Table 3). As reported in previous studies, different kinds of patients tend to choose different diets: substitution of bread and pasta with protein-free food and ‘other diets’ that encompass tailored solutions are the choice preferred by older patients. vLPDs were chosen by a small number of patients (15 cases), in keeping with previous Italian experiences [32–35].

All diets were well followed, and median protein intake was on target in all LPDs, and slightly above target in the small group of patients on vLPDs; good compliance with dietary prescriptions was maintained over 2 years of follow-up (Supplementary data, Figure S1).

The results of the analysis of dietary satisfaction are remarkably good: <3% of the patients rated their diet as unsatisfactory, while 74% gave their diet a median score of 4–5; as expected, vLPDs are felt to be more difficult to follow (Table 4).

Interestingly, in a context in which the search for an ‘ideal’ standardized treatment is increasingly at odds with personalized approaches, the highest satisfaction was recorded for tailored solutions (‘other diets’). This should be borne in mind when designing randomized controlled trials (RCTs) on dietary interventions in CKD: in fact, in RCTs, efforts are made to standardize the diets prescribed, and this lack of adaptation to individual needs may be one of the reasons why RCTs either enrol a small percentage of the screened population, as occurred in the Garneata and in the Brunori trials, or are affected by a high degree of non-compliance, as occurred in the MDRD trial in which the conclusions differ if the study is analysed based on protocol or in terms of intention to treat [46–48].

Comorbidity is closely associated with dietary satisfaction, suggesting that baseline clinical status affects not only QoL, but also the perception of quality of diet (Table 4). A centre effect may, however, be present and should be kept in mind in future studies (Figures 2 and 3; Supplementary data, Figures S3 and S4). If LPD is positively perceived, then QoL is not rated uniformly well: about one out of three patients felt that their physical health (36%) or their psychological health (32%) was poor, an interesting finding in an aged, high-comorbidity population, in which attention is often focussed on clinical rather than psychological issues (Table 5). Probably as a reflection of the Italian social structure, in which elderly patients are usually cared for by their families, the domains of social relationships and environment present better scores. These latter data may indicate that the LPDs do not significantly interfere with patients’ social life, an important issue often raised in discussions about diet options.

Overall, the data on QoL are comparable to those of the non-CKD population with high comorbidity in similar age groups, and are generally in the higher range compared with other populations with advanced CKD [49–52]. In the context of good adherence to LPDs, dropout from diets was rare, and the most common reasons for discontinuation were start of dialysis and death (Figure 4).

None of the outcomes tested (dropout from diet, mortality and dialysis start) was associated with QoL or dietary satisfaction, while mortality and dialysis start were closely related to age, comorbidity and kidney function impairment.

Indeed, in this study, we did not analyse the cases who did not choose following a diet, nor those who dropped out early. According to previous studies of our group, the patients who did not choose or were not prescribed a low-protein diet are characterized by higher morbidity and shorter life expectancy; this reflects the fact that the indications for protein restriction are not evident in patients with low life expectancy [35, 53]. Conversely, in the same studies, patients who dropped out early were not easily distinguished from those who continued the diet [53]. On these bases, we defined our policy to offer a diet trial to all patients who could benefit from a reduction of protein intake. While information on early dropout may be of relevance in assessing the obstacles to LPDs, it would require a different, longitudinal study design, which will be planned in the future. This statistical weakness partly reflects the clinical strength of the centres in which the vast majority of patients are enrolled in a nutritional programme. Furthermore, due to the fact that in Italy, protein restriction is so deeply integrated in the nutritional management of advanced CKD to be considered an indirect marker of quality of care, the inclusion of further centres not offering protein-restricted diets would have introduced different biases [32, 33].

This study is not an RCT; indeed, its aim was not to assess efficacy, but to test whether our patients felt imprisoned by a coercive diet, and learnt whether at least those who followed their diet for at least 6 months did not report a negative impact on their QoL.

The fact of living in Italy, where the Mediterranean diet is still the standard, in particular in elderly patients, has probably facilitated adherence to the LPDs. The substitution of usual bread and pasta with protein-free food allows a 30% reduction of protein intake, and in vegan diets the avoidance of animal-derived food may be rather easily compensated by a higher intake of pasta, legumes and fruits, in which the Mediterranean diet is rich [32, 33]. Interestingly, one of the authors recently reported on the implementation of a similar ‘diet system’ in an elderly population in France, a country in which the clinical use of LPDs is limited to few reference centres [54].

The finding of high dietary satisfaction, in the context of a QoL in line with similar elderly populations, is an important point in support of a wider use of LPDs in CKD. Furthermore, we consider that our results indirectly support an individualized approach, in agreement with what is increasingly being suggested in many chronic diseases and in dialysis [55, 56].

CONCLUSION

Stable patients with advanced CKD who follow moderately restricted LPDs are generally satisfied with them, and their rating for their QoL is comparable to that of populations of similar age with a similar degree of comorbidity. This positive finding, described in the context of a multiple option diet system, making wide use of tailored dietary interventions, coexists with good dietary compliance and with a very rare loss to follow-up in the long term. In this context, diets with similar protein intake allow similar results in terms of compliance, renal and patient survival.

SUPPLEMENTARY DATA

Supplementary data are available at ndt online.

ACKNOWLEDGEMENTS

Thanks to Susan Finnel for her careful language review of this article.

AUTHORS’ CONTRIBUTIONS

Initial idea was conceived by A.Cupisti and G.B.P.; A.Cupisti, G.B.P., B.R.D.I. and G.C. contributed to study design; G.B.P., B.R.D.I., C.A., M.N., I.C., F.N.V., A.F., S.M. and G.C. were involved in questionnaires and data gathering; C.A., I.C., F.N.V. and B.R.D.I. contributed to dietary management; B.R.D.I., S.M., A.F., F.N.V. and M.N. contributed to the database; A.Chatrenet, P.S. and G.B.P. contributed to statistical analysis; and G.B.P., A.Chatrenet, G.C. and B.R.D.I. contributed to drafting of the manuscript. All authors have read and approved the current version of the article.

CONFLICT OF INTEREST STATEMENT

G.B.P. and A.Cupisti received travel reimbursement and consultation fees from Fresenius Kabi, and travel fees from Mevalia. A.Cupisti received consultation fees from Aproten and travel fees from Mevalia. No other author reports further potential conflicts of interest.

(See related article by Combe et al. Dietary protein restriction in chronic kidney disease: one size does not fit all. Nephrol Dial Transplant 2020; 35: 731--732)

Author notes

*

Giorgina Barbara Piccoli and Biagio Raffaele Di Iorio contributed equally to the study.