Keto acid-supplemented low-protein diet for treatment of adult patients with hepatitis B virus infection and chronic glomerulonephritis

Abstract

Objectives

An open-label, randomized, controlled, single-centre clinical trial to evaluate the effects of low-protein intake, with or without keto acid supplementation, on nutritional status and proteinuria, in patients with hepatitis B virus (HBV) and early stage chronic glomerulonephritis.

Methods

Patients with chronic glomerulonephritis and HBV infection were randomized to receive a low-protein diet (0.6–0.8 g/kg ideal body weight [IBW] per day) either without (LP group) or with (sLP group) keto acid supplementation (0.1 g/kg IBW per day), for 12 months. Nutritional, clinical and safety parameters were recorded.

Results

The study included 17 patients (LP group n = 9; sLP group n = 8). Proteinuria and microalbuminuria were significantly lower in the sLP group at 6 and 12 months compared with baseline, and at 12 months compared with the LP group. There were no significant differences in serum creatinine level or estimated glomerular filtration rate. Nutritional parameters (serum albumin and prealbumin) were significantly improved at 12 months, compared with baseline, in the sLP group.

Conclusions

Restriction of dietary protein intake to 0.6–0.8 g/kg IBW per day appears to have an acceptable safety profile. Supplementation with keto acids is associated with decreased urine protein excretion.

Keywords

Chronic glomerulonephritis chronic hepatitis B virus infection keto acids low-protein diet

Introduction

The effect of changes in dietary protein on renal function and disease were recognized more than 50 years ago.¹ Restriction of dietary protein slows the progression of renal disease in experimental animal models,² but the consequences of dietary protein restriction on outcome in patients with chronic kidney disease (CKD) are less well understood.³ Supplementation of a low-protein diet with a mixture of keto acids and amino acids resulted in a slower decline in glomerular filtration rate (GFR) than a low-protein diet alone, in patients with end-stage renal disease.^4,5 Most urea is derived from dietary protein intake (DPI), and it has been suggested that a lower DPI can retard the progression of advanced renal disease and proteinuria.^6,7 A low-protein diet is recommended for patients with CKD before the start of dialysis in order to preserve residual renal function.⁸ These diets are supplemented with keto acids, for nutritional reasons and because of their independent effect on maintaining renal function.⁹ To our knowledge, however, there are no studies regarding keto acid supplementation in the early stages of renal disease.

Epidemiological studies have shown that chronic hepatitis B virus (HBV) carrier status may lead to nephrotic syndrome in some individuals.¹⁰ The prevalence of the HBV carrier state varies widely, from 0.3–1% in North America to 10% in China.¹¹ About 30% of adults with HBV-related glomerulopathy can progress to renal failure, with as many as 10% requiring dialysis or kidney transplant.¹² Patients with CKD who acquire HBV have higher morbidity and mortality rates and, among CKD patients, managing these infections with antiviral agents is associated with high rates of adverse effects.¹³ The optimal management of HBV in patients with CKD is poorly defined because of insufficient data from clinical trials. In particular, there are no randomized prospective studies evaluating the impact of a low-protein diet (with or without keto acids) on nutritional status and proteinuria in the early stages of chronic glomerulonephritis, in patients with HBV.

The current study observed the therapeutic effects of restricted protein intake, supplemented with keto acids, on proteinuria and nutritional status in patients with persistent HBV infection and chronic glomerulonephritis, randomized to receive a low-protein diet (0.6–0.8 g/kg ideal body weight [IBW] per day), either with or without keto acids (0.1 g/kg IBW per day).

Patients and methods

Study Population

This open-label, randomized, controlled, single-centre clinical trial was conducted between January 2008 and December 2009, at the Renal Divison of Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Patients aged ≥18 years with chronic glomerulonephritis and HBV infection were enrolled. Inclusion criteria were: (i) compensative chronic hepatitis B virus infection; (ii) alanine transaminase more than two-fold the normal value; (iii) CKD stage I–II;¹⁴ (iv) 24-h total proteinuria ≥1 g; (v) hypercalcaemia (serum calcium >2.5 mmol/l). Each patient underwent renal biopsy.

Patients with moderate to severe hepatitis, decompensated hepatitis, concurrent wasting disease (e.g. cancer), evidence of infection or inflammation, current hormone or antiviral drug treatment, hypertension (blood pressure ≥160/90 mmHg despite antihypertensive treatment), pregnancy, autoimmune disease, phenylketonuria or acute kidney injury were excluded from the study.

The study was approved by the Scientific and Ethics Committee of Renji Hospital, Shanghai Jiao Tong University School of Medicine. Patients were informed of the potential risks associated with treatment, and provided written informed consent prior to enrolment.

Study Design

Patients were allocated to one of two groups at study entry, using a computer-generated randomization schedule. Patients were randomized to receive a low-protein diet (0.6–0.8 g/kg IBW per day), either without (LP group) or with (sLP group) keto acid supplementation (0.1 g/kg IBW per day Ketosteril®; Fresenius-Kabi, Beijing, China). Meals containing a net DPI of 0.6–0.8 g/kg IBW per day were provided to patients throughout a 1-month wash-in period, with ∼66% of protein provided by animal products. The total energy intake (TEI) was 35 kcal/kg IBW per day in both groups. DPI and TEI were calculated based on actual food consumption, using the Keto Acids Diet Calculator, version 2.0 (Fresenius-Kabi). During the wash-in period, experienced dietitians instructed patients repeatedly on how to prepare their food and record their actual consumption. Throughout the remainder of the study period, the patients prepared their own meals according to menus provided by the dietitians. Baseline data were collected at the end of the wash-in period.

Patients were followed-up at 1, 3, 6 and 12 months. Examinations included: 24-h total proteinuria and microalbuminuria (Dimension®, Siemens, Erlangen, Germany); serum creatinine (Scr), glucose, albumin and prealbumin (Modular Analytics, Roche, Basel, Switzerland); serum calcium, phosphorus, intact parathyroid hormone (iPTH) and high sensitivity C-reactive protein (hs CRP)(BN™ II; Siemens); and serum total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)(DDP Modular System Chemistry Analyzer, Roche). All laboratory analyses were carried out at the Biochemistry Laboratory of Renji Hospital Shanghai Jiao Tong University School of Medicine. GFR was estimated with the four-variable Modification of Diet in Renal Disease (MDRD) Study equation: GFR = 186 × (Scr/88.4)^−1.154× age^−0.203 ( × 0.742 [if female]).¹⁵

Safety parameters were assessed at each follow-up visit, including HBV DNA copy number (via real-time fluorescent quantitative polymerase chain reaction; ABI 7900, Applied Biosystems, Foster City, CA, USA); serum ammonia, alanine transaminase, aspartate transaminase, lactate dehydrogenase and bilirubin (DDP Modular System Chemistry Analyzer); and coagulation parameters (ACL TOP® 700, Beckman Coulter, Brea, CA, USA). A subjective global assessment of nutrition (SGA) was performed (A, no malnutrition; B, moderate malnutrition; C, severe malnutrition),¹⁶ and body mass index (BMI) was calculated as body weight (kg)/height²(m²).

All patients received angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers to control hypertension, with a target blood pressure of 130/80 mmHg. Amino acids and other nutritional supplements were expressly forbidden.

Outcome Variables and Definitions

Primary outcome variables were cumulative numbers of patients with complete or partial remission. Complete remission was defined as proteinuria ≤0.3 g/day, and partial remission as proteinuria >0.3–<3.5 g/day or ≥50% decrease in protein. Secondary outcome variables included serum creatinine concentration, proteinuria and adverse effects.

Statistical Analyses

Data were presented as mean ± SD. Differences between groups were assessed by Student’s t-test. Differences across groups were assessed by Wilcoxon signed–rank test and the χ²-test. All analyses were carried out with SPSS® software, version 13.0 (SPSS Inc., Chicago, IL, USA) for Windows®. A P-value < 0.05 was considered statistically significant.

Results

The study included 17 patients (LP group n = 9, five males/four females, mean age 47.8 ± 14.1 years; sLP group n = 8, eight males/three females, mean age 42.1 ± 12.0 years). There were no significant between-group differences in baseline demographic and clinical characteristics (Table 1). All patients completed ≥12 months’ therapy and were included in efficacy analyses. Renal biopsy findings were: LP group, three patients with mild lesions, three with mesangioproliferative glomerulonephritis, two with membranous nephropathy and one with diabetic nephropathy; sLP group, two patients with IgA nephropathy, two with mild lesions, two with membranous nephropathy, one with mesangioproliferative glomerulonephritis and one with diabetic nephropathy.

Table 1.

Demographic and clinical characteristics of patients with persistent hepatitis B virus infection and early stage chronic glomerulonephritis, randomized to received a low-protein diet (LP; 0.6–0.8 g protein/kg body weight per day; n = 9) or a low-protein diet supplemented with keto acids (sLP; 0.1 g keto acids/kg body weight per day; n = 8), at baseline and after 1, 3, 6 and 12 months of treatment.

Parameter	Baseline	1 month	3 months	6 months	12 months
BMI, kg/m²
LP	21.1 ± 3.3	21.1 ± 3.2	21.1 ± 3.3	21.1 ± 3.2	21.1 ± 3.2
sLP	23.5 ± 3.7	23.5 ± 3.8	23.4 ± 3.7	23.4 ± 3.7	23.5 ± 3.5
Dietary protein intake, g/kg per day
LP	0.76 ± 0.03	0.77 ± 0.01	0.76 ± 0.03	0.76 ± 0.02	0.77 ± 0.02
sLP	0.76 ± 0.03	0.76 ± 0.01	0.77 ± 0.02	0.76 ± 0.02	0.77 ± 0.02
Total energy intake, kcal/day
LP	2007 ± 413	2028 ± 410	2004 ± 428	2033 ± 430	1987 ± 414
sLP	2279 ± 349	2304 ± 365	2272 ± 334	2274 ± 337	2266 ± 387
SGA, A/B/C
LP	3/6/0	3/5/1	2/6/1	1/4/4	1/4/4
sLP	3/4/1	3/5/0	4/4/0	5/3/0^a	5/3/0^a
Mean arterial pressure, mmHg
LP	97.2 ± 9.2	96.7 ± 9.4	97.1 ± 8.7	97.0 ± 8.8	97.6 ± 7.9
sLP	98.9 ± 9.8	98.3 ± 10.1	98.5 ± 9.7	97.9 ± 9.2	98.1 ± 9.6
hsCRP, mg/l
LP	1.15 ± 1.09	0.96 ± 0.92	1.08 ± 0.51	0.77 ± 0.38	0.83 ± 0.52
sLP	1.43 ± 1.34	1.28 ± 0.95	1.09 ± 0.82	1.39 ± 1.23	1.37 ± 1.12
Serum calcium, mmol/l
LP	2.10 ± 0.15	2.02 ± 0.15	2.06 ± 0.13	2.00 ± 0.13	2.05 ± 0.12
sLP	2.21 ± 0.12	2.22 ± 0.13^b	2.20 ± 0.1^b	2.22 ± 0.16^b	2.23 ± 0.14^b
Serum phosphorus, mmol/l
LP	1.33 ± 0.29	1.35 ± 0.17	1.40 ± 0.24	1.3 ± 0.29	1.38 ± 0.21
sLP	1.39 ± 0.38	1.36 ± 0.3	1.25 ± 0.25	1.23 ± 0.17	1.27 ± 0.21
iPTH, pg/ml
LP	71.5 ± 65.1	72.2 ± 68.7	81.5 ± 78.5	76.8 ± 74.8	78.7 ± 72.3
sLP	51.7 ± 45.4	48.2 ± 39.2	45.4 ± 32.4	43.7 ± 32.7	43.4 ± 34.9
Serum prealbumin, g/l
LP	225.9 ± 42.2	230.6 ± 41.1	233.5 ± 52.3	229.7 ± 35.0	236.2 ± 38.3
sLP	251.3 ± 53.1	270.2 ± 35.0	281.0 ± 54.6	288.6 ± 27.8^b	314.0 ± 30.7^a,b
Serum albumin, g/l
LP	28.6 ± 10.8	28.3 ± 8.8	28.1 ± 7.3	27.1 ± 6.8	28.7 ± 6.4
sLP	30.9 ± 8.4	33.9 ± 9.8	36.2 ± 8.6	36.4 ± 9.4^b	38.5 ± 8.6^a,b
Serum creatinine, µmol/l
LP	89.3 ± 28.0	85.2 ± 33.2	86.9 ± 32.4	88.3 ± 33.5	89.5 ± 30.6
sLP	110.9 ± 49.5	106.1 ± 42.0	102.6 ± 42.3	101.4 ± 38.1	101.1 ± 38.5
Microalbuminuria, mg/l
LP	2503 ± 1260	3329 ± 2273	3681 ± 2656	2778 ± 1524	2778 ± 1458
sLP	3070 ± 1377	2685 ± 1359	2370 ± 1342	2061 ± 1241^a	1220 ± 831^a,b
24-h total proteinuria, g/24 h
LP	4.2 ± 2.6	4.3 ± 2.6	4.8 ± 3.3	5.0 ± 3.4	4.4 ± 2.7
sLP	4.5 ± 2.8	4.5 ± 2.8	4.2 ± 2.7	3.1 ± 2.6^a	2.0 ± 1.8^a,b
Total cholesterol, mmol/l
LP	7.5 ± 0.9	6.5 ± 0.8	6.9 ± 0.8	6.7 ± 0.7	6.1 ± 1.5
sLP	7.5 ± 1.8	6.4 ± 1.4	6.1 ± 1.4	5.5 ± 0.9	5.2 ± 1.9
Triglyceride, mmol/l
LP	2.1 ± 0.3	1.7 ± 0.2	2.3 ± 0.6	2.3 ± 0.6	2.1 ± 1.4
sLP	2.3 ± 0.6	2.7 ± 0.7	2.7 ± 0.7	2.0 ± 0.3	1.9 ± 0.9
HDL-C, mmol/l
LP	1.7 ± 0.2	1.7 ± 0.2	1.7 ± 0.2	1.7 ± 0.2	1.7 ± 0.5
sLP	1.5 ± 0.2	1.3 ± 0.1	1.3 ± 0.1	1.5 ± 0.1^a	1.8 ± 0.5^a
LDL-C, mmol/l
LP	4.8 ± 0.9	4.1 ± 0.6	4.2 ± 0.5	4.0 ± 0.5	4.1 ± 1.5
sLP	4.2 ± 0.9	3.9 ± 1.0	3.8 ± 1.0	3.7 ± 0.7	3.6 ± 1.9
eGFR, ml/min per 1.73 m²
LP	83.7 ± 32.3	93.3 ± 40.4	88.6 ± 35.4	87.3 ± 35.3	84.3 ± 33.0
sLP	70.1 ± 23.5	71.4 ± 22.2	75.8 ± 26.3	74.9 ± 23.4	75.0 ± 22.6

Data presented as mean ± SD or n of patients.

BMI: body mass index; SGA: subjective global assessment of nutrition;¹⁶ hsCRP: high sensitivity C-reactive protein; iPTH: intact parathyroid hormone; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; eGFR: estimated glomerular filtration rate.¹⁵

P < 0.05 versus baseline, ^bP < 0.05 versus LP; Student’s t-test.

Table 1 shows the demographic and clinical characteristics at baseline and after 1, 3, 6 and 12 months of treatment. There were no between-group or between-timepoint changes in DPI, total energy intake, mean arterial pressure, hsCRP, total cholesterol, triglycerides, HDL-C, LDL-C or BMI. Keto acid supplementation (sLP group) was associated with significantly improved SGA at 6 and 12 months compared with baseline (P < 0.05 for both comparisons; Table 1). The mean daily dose of keto acids was 6.05 ± 1.17 g throughout the study period.

Serum calcium was significantly higher in the sLP group than the LP group at 1, 3, 6 and 12 months (P < 0.05; Table 1), but concentrations remained within the normal range.¹⁷ There were no significant differences in serum phosphorus or iPTH in either group at any timepoint.

Partial remission was achieved by five patients in the sLP group, and none in the LP group (P = 0.005). No patient achieved complete remission in either group. Serum albumin and prealbumin were significantly higher in the sLP group than the LP group at 6 and 12 months (P < 0.05; Table 1).

In the sLP group, microalbuminuria and 24-h total proteinuria were significantly lower than baseline at both 6 and 12 months, and significantly lower in the sLP group than the LP group at 12 months (P < 0.05 for all comparisons; Table 1). There were no statistically significant between-timepoint or between-group differences in estimated GFR or serum creatinine.

Data regarding safety parameters at baseline and 12 months are shown in Table 2. There were no significant between-group or between-timepoint differences in any safety parameter.

Table 2.

Safety parameters in patients with persistent hepatitis B virus infection and early stage chronic glomerulonephritis, randomized to received a low-protein diet (LP; 0.6–0.8 g protein/kg body weight per day) or a low-protein diet supplemented with keto acids (sLP; 0.1 g keto acids/kg body weight per day), at baseline and after 12 months of treatment.

Parameter	Timepoint	LP n = 9	sLP n = 8
Alanine transaminase, IU/l	Baseline	34.8 ± 7.7	18.6 ± 2.1
	12 months	20.8 ± 3.0	22.1 ± 2.5
Aspartate transaminase, U/l	Baseline	37.6 ± 7.9	21.4 ± 2.0
	12 months	22.7 ± 2.2	22.4 ± 1.0
Lactate dehydrogenase, U/l	Baseline	218.6 ± 29.1	185.3 ± 14.2
	12 months	216.6 ± 20.6	178.3 ± 10.3
Direct bilirubin, µmol/l	Baseline	2.1 ± 0.5	3.0 ± 0.8
	12 months	2.3 ± 0.5	2.4 ± 0.6
Total bilirubin, µmol/l	Baseline	8.5 ± 2.1	12.0 ± 3.0
	12 months	7.6 ± 1.7	7.6 ± 1.7
Prothrombin time, s	Baseline	12.8 ± 2.1	12.0 ± 0.8
	12 months	10.7 ± 0.3	13.2 ± 1.1
Fibrinogen, g/l	Baseline	4.5 ± 0.5	4.4 ± 0.7
	12 months	3.7 ± 0.2	4.1 ± 0.3
Ammonia, IU/ml	Baseline	27.1 ± 4.6	24.4 ± 3.9
	12 months	25.2 ± 4.2	35.0 ± 8.7
Hepatitis B virus DNA, copies/ml	Baseline	7.8 ± 1.2	5.9 ± 0.9
	12 months	6.6 ± 0.7	5.9 ± 0.6

Data presented as mean ± SD or n of patients.

No statistically significant differences (P ≥ 0.05; Student’s t-test).

A single patient in the LP group experienced adverse effects during the treatment period: this patient was admitted to hospital with an upper respiratory tract infection, and made a complete recovery after antibiotic treatment.

Discussion

Protein-restricted diets supplemented with keto acids are considered an integral part of the basic management of patients with chronic kidney disease.¹⁸ Keto acid-supplemented restricted protein diets have been shown to decrease uraemic toxins, reduce proteinuria, improve calcium–phosphate metabolism and hyperparathyroidism, improve the lipid profile and slow the progression of CKD in predialysis or end-stage kidney disease.⁹

To our knowledge, the current study is the first prospective, randomized trial of low-protein diets in patients with stage I–II CKD, and suggests that a low-protein diet supplemented with keto acids can be useful in patients with chronic glomerulonephritis and HBV infection. Others have shown beneficial effects of keto acid/amino acid supplementation in patients with hepatic disease,¹⁹ and this may be partially responsible for the findings of the current study.

A DPI of 0.6–0.8 g/kg per day (66% of the currently recommended level)²⁰ was associated with a neutral nitrogen balance in patients without significant malnutrition or inflammation, in the present study. Keto acid supplementation resulted in better preservation of proteinuria, with five of eight (62.5%) patients achieving partial remission after 12 months of treatment.

The majority of patients with persistent HBV infection and chronic glomerulonephritis in the present study presented with nephrotic syndrome (24-h total proteinuria >3.5 g, serum albumin <30 g/l and elevated serum cholesterol). It is not clear whether such patients should be treated with antiviral drugs or immunosuppressive agents.²¹ Antiviral therapy has been recommended for chronic glomerulonephritis with HBV infection, since it can effectively inhibit HBV replication and attenuate proteinuria.²² Findings of the current study demonstrated that supplementation of a low-protein diet with keto acids significantly improved proteinuria and malnutrition, compared with a nonsupplemented low-protein diet.

A low-protein diet was found to result in a negative nitrogen balance in haemodialysis patients.²³ Others found no benefit of a keto/amino acid supplemented very low-protein diet (0.28 g/kg per day) in slowing the rate of eGFR decrease, although a DPI of 0.58 g/kg per day over 2–3 years was found to have a good safety profile.²⁴ It is possible that the protein intake of previous trials is too low for patients with CKD. A keto acid-supplemented low-protein diet was both nutritionally safe and associated with improvements in malnutrition, in the present study. Keto acid supplementation also resulted in significant improvements in serum albumin and prealbumin compared with a nonsupplemented diet in the present study, but there were no between-group differences in serum creatinine concentrations or the eGFR. This may be due to the limited duration of the study.

Keto acid supplementation resulted in a significant reduction in urinary protein excretion and microalbuminuria in the present study, possibly mediated by decreased levels of fibrotic factors such as transforming growth factor-β.²⁵ A low-protein diet reduced uremic waste (including urea and phosphate) in predialysis patients,²⁶ and keto acid supplementation ameliorated the kidney and oxidative stress injury induced by a low-protein diet in nephrectomized rats.²⁷

The increased serum calcium concentrations observed in the sLP group in the present study may be the result of an iatrogenic effect, as each keto acid tablet contained 50 mg of calcium, resulting in a total daily calcium supplementation of 0.01 g/kg IBW. Keto acid treatment has been shown to suppress iPTH secretion directly,²⁸ and care must therefore be taken to limit the risk of adynamic bone disease in patients with early stage renal disease. Studies have found that a mixture of keto acids is very effective in lowering increased serum phosphate and iPTH levels.²⁹

Hyperphosphataemia is a common symptom of early stage renal disease that can be treated using calcium carbonate. As keto acids provide less calcium than calcium carbonate, they could represent a less dangerous alternative. Serum phosphorus concentrations were unchanged throughout the treatment period in both groups, in the present study.

The present study has several limitations. First, the small sample size and relatively short duration of follow-up limited the power of the study. Secondly, DPI was assessed via food diaries, and some patients may have mis-stated their intake, although all patients had been educated in how to manage their diet within the prescribed ranges.

In conclusion, the findings of this prospective randomized trial indicate that dietary protein restriction does not present safety concerns in patients with persistent hepatitis B virus infection and early stage chronic glomerulonephritis, who are free from significant malnutrition and inflammation. When combined with keto acid supplementation, a low-protein diet is associated with decreased urine protein excretion in these patients.

Footnotes

Declaration of Conflicting Interest

The authors declare that there are no conflicts of interest.

Funding

The Project was sponsored in part by National Basic Research Program of China 973 Program No. 2012CB517600 (No. 2012CB517602) and National Key Technology Research and Development (R&D) Program of the Ministry of Science and Technology of China (No.2011BAI10B04). The Project was also sponsored by Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry and National Natural Science Foundation of China (81102700), the Science and Technology Commission of Shanghai Municipality China (09dZ1973600 and 10JC1410100), and Shanghai Healthy Bureau (2010L063A).

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