Recent dietary trends for those with T2 Diabetes (T2D) include ‘keto’ and low carbohydrate diets (LCD) which may lead to a potentially increased protein intake
. As a result, the safety of habitually consuming dietary protein in excess of recommended intakes has been questioned. In particular, there is concern that high protein intake may promote renal damage by chronically increasing glomerular pressure and hyperfiltration [1,2] . This paper reviews some of the available evidence and looks at relevant real-world data from primary care. [2,3] Box 1:
no caption available
First hinted at by Wilhelm Griesinger in 1859
, chronic kidney disease (CKD) is now a recognised microvascular complication of diabetes mellitus and in this context it is called diabetic kidney disease (DKD) or diabetic nephropathy  . Diagnosis requires an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m  2 body surface area, and/or microalbuminuria > 3 mg/g, or an albumin-to-creatinine ratio (ACR) ≥ 3 mg/mmol in a patient with a diagnosis of type 1 diabetes (T1D) or T2D . Development of DKD is associated with longer duration of diabetes and is often preceded by diabetic retinopathy  . Metabolic changes associated with diabetes drive glomerular hypertrophy, tubulointerstitial inflammation, and glomerulosclerosis, and underlie the progression of DKD. Concomitant essential hypertension is also likely to contribute to the pathophysiology. Signs of progression in DKD include worsening albuminuria, decreasing eGFR, increasing serum creatinine, and hypertension  . 
A LCD can be an effective option in the management of many metabolic conditions
including T2D  and has been recently endorsed by the American Diabetes Association  . Despite having no formally accepted definition, LCDs are generally considered to contain < 130 g of carbohydrate per day, by reducing simple sugars and starchy carbohydrate foods such as; rice, potatoes, bread, pasta and other grain-based products [11▪▪] . In their 2018 policy statement  , the British Dietetic Association concluded that LCDs can be effective for managing weight, improving glycaemic control and cardiovascular risk in people with T2D but raised concerns about long-term adherence (over 12 months) and potential negative effects on heart health. People following a LCD may well replace dietary carbohydrate with relative increases in dietary fat and/or protein. Increasing dietary fat has historically been attributed to cardiovascular disease (CVD) risk  . Increasing dietary protein may aid satiety and weight loss  but protein can modulate renal function and some studies suggest intakes in excess of recommended daily allowances may increase the risk of developing CKD  . 
Brenner, Meyer and Hostetter's 1982 highly cited review on this topic concluded that regular overconsumption of protein negatively impacts kidney function via a sustained increase in glomerular pressure and renal hyperfiltration
. Most of the evidence from this review was from animal studies and it did not answer whether the primary driver was relatively high dietary protein per se or the unrelenting, ‘ad libitum’ nature of modern eating patterns. Two recent, large-scale cohort studies based on food frequency questionnaires reported an association between higher dietary protein intake and decline in renal function  . On the other hand, evidence from several randomised controlled trials (RCTs) up to 2 years in length suggest higher-protein, lower-carbohydrate diets do not worsen renal function in people with normal renal function at baseline, even for those with T2D [16,17] . Yet, there remains a paucity of scientific literature about the impact on renal function of advising LCDs to people with T2D, with and without DKD, particularly in ‘real world’ settings. [18–21]
Against this background, the Norwood Surgery, a National Health Service (NHS) general practice in the north of England, has been offering a LCD approach to its patients with T2D since 2013
. Given the concerns and uncertainties surrounding the risks of LCDs on CKD and CVD, and also the lack of longer-term, real-world primary care data on using this approach, this paper reviews the evidence and presents clinical data from our latest service evaluation. We aim to address the following question: for patients choosing a LCD to help manage their T2D, how might their renal risk factors such as: serum creatinine, eGFR, urinary albumin/creatinine ratio, body weight, glycaemic control (as represented by HbA1c), blood pressure and lipid profiles be affected over time? [22,23▪] METHODS
We present a retrospective analysis of routine clinical data from a single suburban GP practice with approximately 9,700 patients in the north of England. Advice on following a LCD was offered routinely by specifically trained GPs and practice nurses to the 485 patients in the practice who had a diagnosis of T2D (collated on the practice's diabetes register). The doctor/practice nurse protocol for this approach is shown in the supplementary file, item 1,
. Data were collected for the seven years between the end of March 2013 and March 2020. https://links.lww.com/COE/A23
After an introduction to LCDs and how they may improve glycaemic control, patients were asked if they were interested in pursuing this treatment option under medical supervision with regular blood tests and weight measurement (approximately 3 times per year). LCDs were introduced as an option alongside clear and simplified explanations of key physiological principles including: how glucose and insulin levels change in response to different foods; the composition of starchy carbohydrates as many glucose molecules; and, the concept that foods can have either a low or high glycaemic index (GI) and glycaemic load (supplementary file, items 2,3&4,
The LCD sheet we offered to people with T2D (
Fig. 1.) is based on GI and glycaemic load data derived from the index. It is designed with the aim of encouraging a reduction in the intake of sugary and starchy foods by replacing them with, for example, green leafy vegetables, full fat dairy, eggs, meat, fish, berries and nuts. FIGURE 1:
The Norwood Diet sheet.
This work is subject to ongoing audit of service provision. Practice patients who have T2D and choose the LCD are coded as such within the practice electronic health record. The relevant records can then be easily retrieved and interrogated to produce the data which are presented as ‘baseline’ (i.e., before time of coding) and ‘latest follow up’. The metrics measured are part of the routine care for this group of patients at the Norwood GP practice: weight, creatinine, eGFR, urinary ACR, BP, lipid profile, HbA1c. Exclusion criteria were severe mental illness, terminal illness and eating disorders.
Baseline measurements of weight and BP were done at the surgery and the blood tests by our local NHS phlebotomy clinic. By the end of March 2020, we had 143 patients who had both persisted with the diet and for whom we had data. A note on the ethical considerations of this work is to be found in the supplementary file, item 5,
. https://links.lww.com/COE/A23 Statistical analysis of cohort results
Statistical analyses were performed with R version 4.0.2. In all cases a
p value < 0.05 was considered statistically significant. Comparisons between continuous variables have been made using the Wilcoxon signed rank test for paired samples. Baseline and follow up distributions of patient data are presented visually using box and whisker charts, the red dot indicates the mean value and the upper and lower whiskers indicate either, the minimum/maximum value, or 1.5 times the inter-quartile range, Cohort results
Of the 143 patients with T2D, 91 (64%) were male and the median (IQR) age of the group was 61
years. This represents 29% of the known Norwood practice T2D population. They were recorded as on a LCD for a significant mean (SD) duration of 30  months. At baseline they had had T2D for a mean duration of 5 years and 3 months. 
Table 1 shows descriptive statistics for renal and cardiometabolic variables at baseline and at follow-up for the 143 participants. There was a statistically significant reduction in all variables of interest other than a statistically significant increase in eGFR and HDL cholesterol.
Table 1 -
Results; renal and cardiometabolic variables at baseline and at follow-up for the 143 participants
Cohort of 143 T2D participants. Mean (SD)duration of diet, 30 (22) months
Baseline measure median (IQR)
Latest follow up median (IQR)
Matched pairs n (%)
Difference between before and after Mean (SD)
2) 85.5 (18.3)
Urine ACR (mg/mmol)
Serum cholesterol (mmol/L)
HDL cholesterol (mmol/L)
Calculated LDL cholesterol (mmol/L)
Systolic BP (mmHg)
Diastolic BP (mmHg)
ACR, albumin-to-creatinine ratio; eGFR, estimated glomerular filtration rate; T2D, T2 Diabetes.
There were significant improvements in all three measures of renal function; serum creatinine, eGFR and urine ACR. The most statistically significant improvement, and with the most complete data set, occurred in serum creatinine, this reduced by a mean (SD) of 4.7 (14.9) μmol/L (
P = 0.0000054). Out of 132 patients, 88 (67%) showed an improvement in creatinine as shown in Fig. 2. In Fig. 3 we present regression analyses plotting improvements in creatinine as the outcome against changes in four other metrics: weight, HbA1c, systolic BP and diastolic BP. The low values for R 2 (all < 0.006) and large P values (all > 0.4) indicate very little relationship between improvements in creatinine and improvements in these metrics. FIGURE 2:
Box and whisker and pie graph of serum creatinine for 132 people with T2D on a
low carbohydrate diet for an average of 32 months. T2D, T2 Diabetes. FIGURE 3:
Regression analyses plotting improvements in creatinine against improvements in weight, HbA1c, systolic BP and diastolic BP.
Weight and glycaemic control
Weight dropped significantly from a median (IQR) of 97.3 (23.8) kg to 88.0 (21.0) kg,
P < 0.001 ( Table 1). The average participant lost nearly 10% of their body weight (9.6%).
Of the 143 participants 3 weight measurements were missing and 134 lost weight (94%). For the cohort as a whole HbA1c improved from a median (IQR) of 65.0 (25.5) mmol/mol to 47.0 (10.5) mmol/mol,
P < 0.001 ( Table 1, Fig. 4). This mean improvement in glycaemic control (21.5 mmol/mol) was observed in all patients despite a net ‘deprescribing’ of 35 medications for diabetes as detailed in Table 2. Cases of note include 6 patients who were able to come off insulin altogether and a further 9 who had their insulin dosage reduced significantly. Using Taylor et al. s definition of T2D remission , of 143 patients who chose the LCD approach, 68 were off all drugs for diabetes and had an HbA1c < 48 mmol/mol, which equates to a T2D remission rate of 48%. Updated remission rates for this cohort between 2017 and 2021 are shown in the supplementary file, item 6,  ; they have increased from 31% to 52% over 4 years. The drug-free remission rate for the practice overall (using the total number of patients with T2D on our practice register as a denominator) is now (March 2021) 20%. https://links.lww.com/COE/A23 FIGURE 4:
Diabetic control as shown by HbA1c for 143 people with T2D before and after a
low carbohydrate diet for an average of 30 months (Box and whisker and Pie graph). T2D, T2 Diabetes.
Table 2 -
Variation in medication use by 143 participants (both for T2D drugs and drugs for cardiovascular disease) after an average of 30 months on a LCD
CVD, cardiovascular disease; LCD,
low carbohydrate diet; T2D, T2 Diabetes. Lipid profiles
Table 1 shows a statistically significant reduction in total cholesterol and triglycerides with a significant increase in HDL cholesterol and a corresponding significant decrease in calculated LDL cholesterol, this is despite a net total of 5 patients coming off atorvastatin ( Table 2). Blood pressure
SD improvements in BP were observed. The mean reduction in systolic and diastolic BP were 11.7
mmHg and 5.7 (9.9) mmHg, respectively (  Table 1). This was despite 18 patients being taken off antihypertensive medication ( Table 2). DISCUSSION
The UK Prospective Diabetes Study
showed that over a median of 15 years from T2D diagnosis nearly 40% of patients developed albuminuria and nearly 30% developed renal impairment (DKD). Having advised a LCD to a cohort of 143 people with T2D we observed, over a mean duration of 30 months, significant improvements in a range of variables relevant to renal and cardiometabolic health: serum creatinine, eGFR, urine ACR, HbA1c, BP and weight. This is remarkable when considering this cohort had an average age of 61 years and an average duration of T2D at baseline of 5 years and 3 months. Typically, a general pattern of deterioration in these parameters over such a time period would be anticipated  . Our results also contradict the literature on renal ageing, which is considered by many to be part of the normal ageing process of cellular and organ senescence  . This phenomenon describes how progressive, physiological nephron loss in adults leads to a reduction of eGFR at a rate of approximately 1 ml/min/1.73m [27,28] 2 body surface area per year . In the context of T2D and DKD anticipating an even greater rate of decline in eGFR would not be considered unreasonable. This makes the mean improvement in eGFR of 2.4/min/1.73m [27,28] 2 body surface area over this 30-month service evaluation period all the more remarkable. To our knowledge, this is the first primary care service evaluation data published that suggests management of T2D with a LCD may also improve biomarkers of DKD.
In this review we consider three major factors in DKD: chronic hyperglycaemia, body weight and hypertension. We also explore the possible role of dietary macronutrients, particularly protein and carbohydrates, on renal function in T2D.
Hyperglycaemia in diabetic kidney disease
Many of the underlying mechanisms for DKD can be attributed to chronic hyperglycaemia playing a central part in a cascade of damaging effects
as represented in  Fig. 5. Hyperglycaemia, via its osmotic effect, leads to increased renal filtration and increased glomerular pressure, which in turn leads to glomerular hyperfiltration. A high local production of angiotensin II at the efferent arteriole produces vasoconstriction worsening this situation .  FIGURE 5:
The role of hyperglycaemia in the development of diabetic kidney disease.
Associated with this are the negative effects of advanced glycation end products (AGEs). The result of irreversible glycation of proteins occurring in the presence of intracellular hyperglycaemia
, AGEs impair the function of both intracellular and extracellular proteins and lead to inflammation and cell damage  . The average weight of our cohort was 97.3 kg (15.3 stone) so many were overweight. Hyperglycaemia in the setting of obesity, may also impair the process of autophagy, which involves intracellular degradation of cytotoxic proteins and organelles by lysosomes whenever a cell is experiencing oxidative stress. Impaired autophagy can lead to renal tubular cell damage  . 
One major cohort study investigating primary and secondary prevention of DKD demonstrated that a reduction in HbA1c via a combination of antidiabetic medications and lifestyle modifications has favourable effects on the development of DKD
. However intensive glycaemic control with certain medications is associated with an increased risk of hypoglycaemia  . Our LCD service was associated with mean improvements in HbA1c of 21.5 mmol/mol (  Table 1 and Fig. 4) and nearly half of these patients (48%) achieved drug-free T2D remission thus minimising their risk of iatrogenic hypoglycaemia. 
As per the various mechanisms described above, we hypothesize that a reduction in chronic hyperglycaemia (as our results demonstrate) decreases the osmotic diuretic effects thus reducing glomerular hyperfiltration and many of the other factors contributing to DKD as shown in
The UK Prospective Diabetes Study concluded: ‘
Mortality rates for those with nephropathy are high, increasing from 1.4% per annum (normoalbuminuria) to 4.6% per annum (clinical grade proteinuria), and to 19.2% per annum for those with renal impairment. More intensive blood glucose control resulted in both a 33% reduction in relative risk of development of microalbuminuria or clinical grade proteinuria at 12 years, and a significant reduction in the proportion doubling their plasma creatinine’ . This seems to justify a closer look at methods for improving hyperglycaemia in a clinical context to preserve renal function in at-risk groups. Reducing dietary sugar and refined carbohydrates is arguably a logical first step to achieve this. The significant improvements in HbA1c in our cohort, in whom 97% reduced their HbA1c despite the deprescribing of 35 antidiabetes medications (  Fig. 4), appears to support this approach. Body weight and hypertension in diabetic kidney disease
The significant mean weight loss of 9.5 kg observed in this cohort may itself have improved eGFR, however the relationship between weight loss and improved renal function is not consistent or straightforward
. In randomised trials, weight loss via diet or bariatric surgery reduces the urinary ACR, but the effects on estimated glomerular filtration rate (eGFR) are inconsistent  . Indeed, as shown in [37–41] Fig. 3, we found no link between weight loss and improved creatinine in our cohort ( R 2 = 0.0003 P = 0.855). Another potential explanation for our results may be via the effect of the improved BP. Hypertension is an important factor in the development of DKD . In patients with DKD stages 3 to 5  each 10 mmHg increase in mean systolic BP has been associated with a 15% increase in the hazard ratio for development of both micro and macroalbuminuria and impaired kidney function (defined as eGFR < 60 ml/min/1.73m  2 body surface area or doubling of creatinine level) . Thus, the mean improvements in systolic BP of 11.7mmHg amongst our cohort could partly underlie the significant improvements observed in renal function. 
The relationship between dietary carbohydrates and BP has been considered in an earlier report from this cohort
. Suffice it to say, there is good evidence that one of the effects of insulin in patients with T2D is renal sodium retention and raised BP [44▪] . This physiology goes into reverse in a LCD, helping to explain the 17 patients coming off antihypertensive medication shown in  Table 2. Mechanistically, it follows that reversal of renal sodium retention leads to increased sodium and water excretion that manifests as a marked diuresis. This may explain why 3 patients were able to safely come off furosemide (a potent diuretic). Despite this, Fig. 3 again shows the relationship between changes in BP and creatinine was surprisingly weak (systolic BP R 2 = 0.0048, P = 0.461; diastolic BP R 2 = 0.0054, P = 0.431). Dietary carbohydrate and protein in renal function
Our results align with those of a meta-analysis carried out in mostly healthy individuals that found that a high-protein diet (defined as either 1.5 g protein per kg bodyweight, or 20% of total kcal from protein, or 100 g of total protein per day) did not significantly affect eGFR
. However, only 4 of the 28 included studies had participants with T2D, and 3 of these focused on lean and plant-based sources of protein. A year-long RCT that used a diet of similar composition to the one we advised, but with measured macronutrient intakes (14% energy as carbohydrate [CHO < 50 g/day], 28% protein, 58% fat), concluded that ‘c  ompared with a traditional high carbohydrate, weight loss diet, consumption of a low carbohydrate, high protein diet does not adversely affect clinical markers of renal function in obese adults with T2D . Another RCT found no adverse effect of a low carb approach on renal health but greater optimization of T2D management over a 2-year period  . It is important to remember our real-world T2D cohort from primary care had a baseline median (IQR) eGFR of 85.5 (18.3) mL/min/1.73m  2 body surface area representing quite good renal function, so our results may not be as relevant to those with existing renal disease. A recent Cochrane review looking at adults with CKD found much of the relevant evidence to be weak; it concluded “  diet changes may lower blood pressure and cholesterol, but the longer-term impact of these effects on well being is not proven. This means we still need large and good-quality research studies to help understand the impact of diet on the health of people with kidney disease”. Since then, an observational study looking at the effect of a very low-calorie ketogenic diet (<50 g/day carbohydrate) in people with mild CKD reported normalisation of eGFR in 27.7% of participants despite the dietary intervention having a protein content of approximately 1–1.4 gr/kg of ideal body weight/day . [50▪▪]
Returning to the possible underlying aetiology of our improved results for renal function. As already mentioned, it was unexpected that our regression analysis (
Fig. 3) returned no evidence that the magnitude of weight loss, improvements in BP and diabetic control (HbA1c) correlated significantly with improvements in renal function. This could point to there being other, more important factors at play here. Another possible mechanism by which LCDs might mediate an improvement in renal function is via nitric oxide (NO), which has an important function in the maintenance of microvascular endothelial function. It has been known for some time that insulin's effect on vascular endothelium is mediated through its own receptor and insulin signalling pathways, resulting in the increased release of NO , a process that is disrupted in the state of systemic insulin resistance. This was investigated recently by an RCT of a 6-week LCD, which improved microvascular endothelial function via increasing bioavailability of NO in women with obesity  . [52▪]
Whatever the underlying reasons for the significant improvements in renal function that our audit revealed, there seems to be a good physiological argument for putting improved blood glucose central to the care of people with T2D, hypertension and DKD. It is likely that reducing hyperglycaemia improves T2D control in addition to hypertension and renal function in this vulnerable group. Our cohort results suggest that, for those interested in safely improving blood glucose to achieve these potential benefits, our method of advising and supporting a reduction in dietary sugar and starchy carbohydrate is a sensible approach. After 8 years of experience in providing this service we find this approach to be clinically effective, patient-friendly and sustainable.
Practical considerations: medication and deprescribing
In our clinic many patients had their antihypertensive medications and antidiabetic medications reduced whilst enrolled in the LCD service (
Table 2). This has probably contributed to the Norwood practice spending over £55,000 per year less than the local practice average on drugs for diabetes (supplementary file, item 7, ). Careful deprescribing and vigilance with BP and glucose monitoring are essential to avoid complications such as hypotension, hypoglycaemia or hyperglycaemia. The British Journal of General Practice recently published a relevant open access paper on safe deprescribing as part of a low carb approach https://links.lww.com/COE/A23 . A multidisciplinary approach with a team experienced in LCDs is particularly important for patients already taking prescribed medications. [53▪▪] Limitations of our cohort data
When analysing real-world data from lifestyle interventions in clinical practice there are common problems. First, both randomisation and blinding are not possible, or ethical, outside a formal clinical trial setting. There can be no real placebo arm to compare dietary changes to. Interventions can be hard to define clearly and verification of adherence to specific dietary parameters is difficult; even food questionnaires and diaries are imperfect
. More on this is to be found in the supplementary file, item 8,  . https://links.lww.com/COE/A23
In view of these limitations, we suggest future research should investigate: the exact dietary pattern and macronutrient composition followed by these patients in primary care, mechanisms by which a LCD may influence renal function, elucidating the key factors that are important for maintaining drug-free T2D remission and the improvements in the biomarkers of renal and cardiovascular health observed in our audit.
Given the central role of hyperglycaemia in the pathogenesis of DKD it seems logical to suggest a LCD approach, which by its very nature reduces blood glucose, may be beneficial in the management of risk factors impacting on DKD. This review suggests for people with T2D and normal renal function or mild DKD this may well be the case. Our real-world results seem to agree, showing that in addition to a T2D drug-free remission rate for the patients enrolled of 48%, a LCD approach was associated with significant improvements in serum creatinine, eGFR, urine ACR, BP, body weight, and lipid profiles. On balance this review contradicts the notion that LCDs, despite being likely to include higher dietary protein and fat intakes may be harmful to renal health. There is however more uncertainty around using the approach for people with moderate/severe DKD. At least for those with normal renal function or mild DKD this review offers healthcare professionals using a LCD intervention some reassurance that this dietary approach may improve multiple aspects of cardiometabolic health whilst posing little risk to renal function for people with T2D.
The authors would like to thank all of the patients involved in this work, also the staff of The Norwood Surgery, particularly the senior partner and diabetic lead; Dr Simon Tobin. Financial support and sponsorship
The cohort work was part of the ordinary NHS care offered to the patients at the Norwood Surgery. There was no other financial support. Conflicts of interest
There are no conflicts of interest. REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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