In this meta-analysis of 39 RCTs, which is an update on this topic, the effects of HP and SP/LP diets on the renal function parameters in general population without CKD were compared. The evidences suggested that HP diets probably led to a significantly increased GFR and an increased concentration of serum urea, uric acid, and creatinine in obese subjects. However, the results in T2D patients and healthy participants did not show a notable detrimental effect on the renal outcomes. When the participants were sub grouped according to the duration of intervention, an increase in GRF was only presented in the obese subjects following a long-term intervention. As for albuminuria, no significant difference was observed in those individuals after an HP diet, except for healthy participants which was reported by only one study.
Increased protein consumption has been considered as a potential regulator of renal function as a result of increasing renal plasma flow and GFR . In a mouse model, a 4-week HP diet led to a significant increase in the GFR by 33.6%, renal blood flow by 38.0%, and kidney weight by 25.7% compared with an LP diet . A randomized study had demonstrated that a high dietary protein intake over six months in overweight subjects induced an increase in GFR by approximately 10%, and similar changes were observed in renal size . In this study, a significant difference in GFR was found in obese adults between the HP diet and SP/LP diet groups after a follow-up over six months, but no elevated GRF was detected following a short-term HP intervention. Increased glomerular pressure and hyperfiltration occurs as a rise in GFR, which may result in the loss of kidney function over a long term. In addition, a meta-analysis including 17 studies showed that HP diets were associated with increased all-cause mortality . However, some researchers recognize that a rise in GFR may probably be a normal adaptation for kidney due to an elevated urea filtration following an ingestion of HP diets .
In healthy individuals, an increase in protein intake up to a maximum of 3.32 g/kg/d over 4 months had no adverse effects on the marks of kidney function . The present study resulted in the same finding in healthy and T2D subjects independent of the intervention duration, which was also consistent with findings from several RCTs among T2D individuals [8, 17]. In a 2-year investigation of 115 adults with T2D, comparison of the HP (28% total energy) diet with LP (17% total energy) diets showed that both diets achieved no adverse renal effects, including estimated GFR or albuminuria . Similarly, a short-term trial by Luger et al. showed that a 5-week HP diet did not increase creatinine clearance among T2D subjects .
UAE is another marker for kidney damage and a predictor of end-stage renal disease in the general population and in individuals with diabetes mellitus . Increased UAE has recently been reported to be associated with increased mortality and morbidity of cardiovascular risk in healthy adults and patients with diabetes [50, 51]. Although HP diet has been demonstrated to increase urinary albumin creatinine ratio in animal models  and short-term clinical trials , this meta-analysis showed that HP diet did not alter UAE in subjects without CKD. Additionally, a clinical intervention study reported no difference between plant and animal protein meals on the urine albumin in T2D subjects without microalbuminuria .
Protein-enriched meals can also result in the proportional elevation in urea and the generation of other nitrogenous waste products which due to increased protein metabolism. An experimental study has shown that high serum urea concentration, namely azotemia, is a common indicator for uremia, which may lead to oxidative stress, inflammation, endothelial dysfunction, and cardiovascular disease by increasing protein carbamylation and generating reactive oxygen species . In the present meta-analysis, a rise in serum urea concentration was found in obese and healthy adults following an HP diet. Other nitrogenous waste product, such as creatinine, also increased in T2D and obesity subjects after an HP diet intervention. Of note, no difference was found between two groups when the T2D subjects were divided into subgroups according to the HP intervention duration. Increased serum urea and GFR among subjects without CKD was only an adaptation to a high protein load, because nitrogenous waste products may result in osmotic diuresis, and no indication of kidney damage was found .
A recent meta-analysis conducted by Schwingshackl et al. in 2014  showed that HP diets were associated with increased GFR, serum urea, serum uric acid, and urinary calcium excretion in healthy individuals or individuals with T2D and obesity. Moreover, the study enrolled participants with normal and microalbuminuria, and subgroup analysis was not performed. Considering that most of the RCTs included in the previous meta-analysis recruited obese individuals, the authors infer that HP diets will increase the risk of kidney dysfunction for this population and this inference was consistent with this update study.
Several study limitations exist in this meta-analysis. First, the main outcome parameter GFR was evaluated by creatinine-based method. Clearance of endogenous creatinine, a previously widely used method to measure GFR, overestimates GFR by probably 10% because of the reabsorption and secretion of creatinine in renal tubules. In addition, HP intake, body size, and muscle mass are important sources of error in creatinine-based GFR , especially in those undergoing remarkable weight loss. Thus, a conservative attitude should be considered toward the GFR results reported in this meta-analysis. A randomized crossover trial by Juraschek et al. showed that the GFR changes during the HP diet measured using a cystatin C-based method differed from that using a creatinine-based method . Second, compliance with HP diet intervention reported poor and higher dropout rates in most long-term trials, and enough protein are difficult to take to maintain the inclusion criteria for participants, especially to those with HP diet intervention. Third, several outcomes presented high heterogeneity even if subgroup analysis based on the intervention duration and participants have been performed. Some reasons for the significant heterogeneity may include different study designs (RCTs and crossover studies), study populations (age, sex, and race), and definition of HP and SP/LP diets. Fortunately, the outcomes were all laboratory test results, that is, the data were quantitative, not qualitative.