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D iabetes mellitus (DM) is a metabolic disease characterized by chronically elevated blood glucose levels. The DM constitutes a global health concern that has attained epidemic levels in the Kingdom of Saudi Arabia (KSA), with a prevalence of 11.20% among the adult population. , The elevated prevalence of DM in KSA presents a considerable public health challenge, resulting in heightened risks of various consequences, such as cardiovascular illnesses, neuropathy, and chronic kidney disease (CKD). , The CKD is defined as the presence of structural or functional abnormalities that persist for at least 3 months, with a negative impact on health. It is classified based on the glomerular filtration rate (GFR) categories (≥90, 60-89, 45-59, 30-44, 14-29, and <15 l/min/1.73 m²) and persistent albuminuria categories (<30, 30–300, and >300 mg/g). Among patients with DM, CKD is diagnosed based on the presence of albuminuria and/or decreased estimated glomerular filtration rate (eGFR) in the absence of signs or symptoms of other primary causes of kidney damage.

Diabetic kidney disease (DKD) affects approximately 40% of patients with type 2 DM (T2DM) and 30% of those with type 1 DM. The DKD pathogenesis involves complex mechanisms initiated by hyperglycemia, including metabolic alterations, protein kinase C modifications, and hexosamine and polyol pathway changes; these processes trigger oxidative stress and inflammation, resulting in progressive kidney damage. - The DKD is considered the predominant cause of end-stage kidney disease (ESKD) and significantly elevates the risk of developing numerous comorbid conditions, substantially reducing life expectancy among affected individuals. The DKD pathogenesis involves changes in renal hemodynamics, glomerular hypertension, hypoxia, ischemia, oxidative stress, and upregulation of the renin-aldosterone system. , Micro-proteinuria (microalbuminuria) was previously regarded as the clinical onset of DKD, with kidney function decline considered to begin only with the onset of overt proteinuria (macroalbuminuria). However, recent evidence has suggested that proteinuria does not always precede renal function loss in DM. The understanding of DKD has significantly evolved over time, with non-proteinuric DKD now recognized as a distinct phenotype, particularly among patients with T2DM.

The high prevalence of DM in KSA has resulted in a corresponding increase in CKD risk, presenting a significant healthcare burden that warrants urgent attention. The CKD affects approximately 8.2% of the population within the Middle Eastern region—slightly below the global average of 9.5%—with considerable geographic variation, ranging from 4.9% in Yemen to 12.2% in Lebanon. A previous Saudi study reported a CKD prevalence of 5.7, warranting immediate public health interventions to improve lifestyle practices, enhance early DM detection and management, and promote renal protective strategies to alleviate the long-term effects of this chronic condition. Therefore, the increased prevalence of DKD requires the conduct of comprehensive guidelines for appropriate disease management and treatment.

The recent years have seen substantial progress in CKD and DM management. – Established recommendations, such as those from the Kidney Disease: Improving Global Outcomes (KDIGO) effort and the Kidney Disease Outcomes Quality (KDOQI) effort, have been revised to incorporate the most recent evidence-based approaches. , These guidelines emphasize the importance of early identification, comprehensive care, and the utilization of novel therapeutic agents. Essential recommendations encompass strict blood pressure regulation, optimal glycemic control, and the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 (GLP-1) receptor agonists to mitigate renal disease progression and cardiovascular incidents. , We aimed to establish a systematic framework for patients with DKD through the Saudi DKD Guidelines. These guidelines are grounded in comprehensive literature evaluations, expert insights, and consensus-building processes, aiming to standardize therapy and improve patient outcomes and quality of life (QoL) by integrating the latest research and best practices.

These Saudi national guidelines provide evidence-based recommendations for managing DKD in patients with T2DM. The guidelines were developed to address the significant healthcare burden posed by the high DM prevalence in KSA and its associated increased CKD risk. Recent advancements in clinical research and therapeutic strategies were incorporated in these guidelines to provide comprehensive guidance for DKD monitoring and treatment.

The goals of these guidelines are to establish a systematic framework for the management of patients with DKD in KSA across various clinical contexts, and to optimize patient care by integrating the latest research findings and best clinical practices to deliver the most beneficial care for the target populations. These guidelines aim to address the unique characteristics and needs of the Saudi healthcare system and patient demographic, with the overarching objective of improving patient outcomes by equipping healthcare providers with clear, practical recommendations for DKD management. Additionally, they seek to serve as a national reference for healthcare professionals, enabling the selection of the most suitable interventions and promoting cost-saving measures wherever possible.

The scope of these guidelines encompasses several key areas of clinical importance. Specifically, they address recommendations for monitoring kidney function and disease progression in adults with DKD in Saudi Arabia. They also outline evidence-based approaches to the pharmacological management of DKD, including glucose-lowering therapies, blood pressure control, lipid management, and strategies for cardiovascular risk reduction. In addition, the guidelines provide recommendations on the role of non-pharmacological interventions, such as lifestyle modifications, dietary adjustments, physical activity, and smoking cessation, in managing DKD. Finally, they cover guidance on risk assessment, appropriate evaluation methods, comorbidity management, and the timing and indications for initiating renal replacement therapies.

These Saudi national guidelines were primarily developed for managing DKD in adult patients with T2DM. This guideline is intended to support various healthcare providers involved in the management of DKD across KSA.

The end-users of these guidelines are nephrologists, endocrinologists, primary care and family medicine physicians, and clinical pharmacists in KSA. These guidelines provide valuable insights into DKD management, serving as a crucial resource for policymakers, researchers, and guideline developers.

The Ministry of Health of KSA aims to provide clinicians and their patients with guidance for managing DKD in adults. When reviewing guidelines created using the Grading Recommendations, Assessment, Development, and Evaluation (GRADE) approach, it is essential to recognize that no guideline can fully address every aspect of an individual patient’s case. Each recommendation includes supporting statements that consider essential factors such as underlying ethical principles and patient preferences, resource requirements, practical implementation, equity considerations, patient tolerance, and other pertinent elements. These accompanying statements are vital for the accurate interpretation of the recommendations. Additionally, we emphasize that these guidelines should complement, rather than substitute for, clinical expertise in routine practice. Healthcare providers must assess each patient’s unique needs and circumstances when selecting optimal management approaches for diabetic kidney disease. This involves weighing impacts on clinical outcomes and evaluating the risk-benefit profile of diagnostic and treatment modalities while accounting for any relevant comorbidities or complications during guideline implementation in clinical settings.

The Ministry of Health, KSA, initiated the guideline development process through the establishment of a multidisciplinary expert panel. The panel comprised 2 methodologists and 10 clinical experts with extensive clinical and academic experience in DKD. The panel members were selected based on their demonstrated expertise as nephrologists, endocrinologists, clinical pharmacists, and methodologists, ensuring comprehensive coverage of aspects related to DKD management. Among the panel members, 5 were nephrologists, 4 were pharmacists, one was an endocrinologist, and 2 were methodologists. There were 10 members from Riyadh (central region), one from Taif (western region), and one from Tabuk (northwest region). The average years of experience, publications, and treated patients per year were 16.8 years, 59 manuscripts, and 763 patients, respectively.

The guideline development process adhered to the GRADE methodology, facilitating systematic consensus-building and evidence synthesis. This methodological framework encompassed structured panel deliberations, systematic evidence evaluation, and transparent decision-making processes. The GRADE approach enabled the systematic evaluation of evidence certainty while minimizing potential bias through its structured assessment criteria and explicit consideration of factors influencing the strength of recommendations. All panel participants regularly participated in meetings and openly communicated to summarize the evidence, assess its reliability, and formulate recommendations.

The guideline panel reviewed recent guidelines to identify key research questions for improving clinical management of DKD in KSA. Additionally, the panel utilized an iterative process to formulate new PICO questions in the Saudi Arabian healthcare context. After systematic deliberation, they prioritized and ratified 40 clinical questions.

The study methodologists conducted a literature search to update the evidence supporting the previously published guidelines. Three medical databases (PubMed, EMBASE, and Scopus) were comprehensively searched. The search terms are available in Supplementary File 1. The time frame for the selected studies included those published between 2014 and 2024. However, we included articles published before 2014 in cases where there was insufficient evidence. Two independent reviewers systematically screened the selected studies and evaluated titles and abstracts against predetermined inclusion criteria specific to each PICO question. Next, full-text assessments of potentially eligible articles were performed by the same reviewers to determine final study inclusion. If relevant systematic reviews were unavailable, we included RCTs or observational studies addressing our research questions (). We used “the Cochrane risk of bias tool” to assess potential sources of bias in RCTs and evaluate their quality, whereas we assessed the quality of cohort observational studies using the Newcastle–Ottawa scale.

Evidence tables were systematically generated using the GRADEpro Guideline Development Tool (GDT) for each PICO question, incorporating critical outcomes. These profiles encompassed documentation of absolute and relative effect estimates alongside structured certainty assessments. After assessing different GRADE domains (including “study design, risk of bias, publication bias, consistency in findings, indirectness of evidence, and imprecision of the estimate”), we categorized the certainty into “very low,” “low,” “moderate,” and “high”. The classification of evidence certainty was defined as follows. High certainty evidence denotes substantial confidence that the actual effect lies near the effect estimate. Moderate certainty suggests moderate confidence, although the actual effect likely approximates the estimated effect. Low certainty evidence suggests limited confidence in the effect, with the possibility that the actual effect may substantially deviate from the forecast. Very low certainty evidence reflects minimal confidence in the effect estimate, with a high probability that the actual effect markedly differs from the estimated effect, warranting further research to reduce uncertainty.

Recommendations were formulated through systematic evaluation of the benefit-risk ratio, available evidence quality, and collective clinical expertise of panel members. The draft recommendations underwent iterative refinement through structured virtual consultative sessions. Four structured consultative sessions, involving all panel members, were conducted via online meetings with a predefined structured agenda, enabling focused discussions, expert feedback, and continuous refinement to ensure the clarity, clinical relevance, and accuracy of the recommendations. The final recommendations were subjected to voting via the GRADEpro system. Since there is no specific criterion for consensus in the literature, with suggestions ranging from 51% to 80%, we adopted a predetermined threshold of 70% for agreement. , The recommendations either favored the intervention or advised against it. Recommendation strength was systematically classified into 2 distinct categories: strong and conditional. Differentiating recommendation strength is critical for clinical decision-making processes and implementation strategies ().

For adults with T2DM and DKD, we suggest undertaking either moderate-intensity physical activity or a level compatible with their cardiovascular and physical tolerance (Conditional recommendation, moderate certainty evidence).

An RCT evaluated the effects of “moderate-intensity physical activity in adults with T2DM and DKD”. , “Physical activity” resulted in reduced body weight (Mean difference [MD] 0.64 kg/m , [-3.68 to 2.39]; low certainty, Table S2) and hemoglobin A1C (HbA1c) (MD 0.44%,[-1.235 to 0.355]; low certainty, Table S2) and increased fasting insulin (MD 3.95 pmol/L,[-9.27 to 1.37]; low certainty, Table S2). Regarding lipid profiles, reductions in LDL (MD 0.46 mmol/L [-0.69 to -0.22]; moderate certainty, Table S2), triglycerides (MD 0.35 mmol/L, [-0.52 to -0.18]; moderate certainty, Table S2), and total cholesterol (MD 0.22 mmol/L, [-0.439 to -0.001]; moderate certainty, Table S2) were observed. In another meta-analysis, the impact of “physical activity” on eGFR at a follow-up of 52 weeks assessed using the CKD Epidemiology Collaboration (CKD-EPI) creatinine-based equation revealed improvements (MD -1.76, [-7.5 to 3.99]; very low certainty, Table S2). Similarly, improvements were reported in the “CKD-EPI cystatin C-based equation” (MD -0.16, [-0.76 to 0.44]; very low certainty, Table S2). Moreover, physical activity resulted in decreased serum cystatin C at a follow-up of 52 weeks (MD -0.12 mg/L, [-0.39 to 0.15]; very low certainty, Table S2.

A pilot study demonstrated the feasibility and potential clinical benefits of exercise training programs in patients with obesity, DM, and CKD, demonstrating possible clinical effects on various kidney function tests, 24-hour protein excretion, hemoglobin, and lipid profiles.

Population-level evidence consistently demonstrates that body mass index (BMI) serves as a reliable indicator of adiposity, with clinical significance extending beyond simple weight classification. Research has established that adults maintaining a BMI >25 kg/m² (categorized as overweight or obese) face substantially elevated risks of developing multiple chronic conditions, including hypertension, cardiovascular disease (CVD), and CKD. The relationship with CKD appears dose-dependent, with higher BMI values correlating with progressively increasing kidney disease risk through multiple pathophysiological mechanisms, including glomerular hyperfiltration, systemic inflammation, oxidative stress, and metabolic dysregulation of the renin-angiotensin-aldosterone system (RAAS). The guideline panel suggests that adults with T2DM and DKD engage in moderate-intensity physical activity tailored to their cardiovascular and physical tolerance. This approach helps manage blood glucose levels, reduce cardiovascular risk factors, and enhance overall well-being. However, customizing the exercise intensity to each individual’s health status is crucial to ensure safety and effectiveness. This recommendation is similar to that issued by the KDIGO guidelines. It emphasizes the importance of providing guidance to patients with CKD using BMI while incorporating additional information such as dietary habits, comorbidity assessment, and laboratory value changes.

For adults with T2DM and DKD, we suggest maintaining a protein intake of 0.8 g/kg over an intake of less than 0.8 g/kg body weight (Conditional recommendation, moderate certainty evidence).

Protein restriction may offer renal protection in CKD. Research suggests that lowering protein consumption below the known dietary recommendation of “0.8 g/kg/day” may potentially decrease glomerular hyperfiltration and slow disease progression. However, patients with DM are already advised to limit carbohydrates and fat, and further protein restriction may significantly reduce overall caloric intake, resulting in considerable weight loss and adversely impacting QoL. The risk of malnutrition due to protein and calorie deficiency becomes concerning in populations or individuals with already low protein consumption. Importantly, adequate protein intake is crucial in DM management to prevent hypoglycemia, and excessive restriction increases the risk of these dangerous episodes.

A meta-analysis of RCTs with moderate certainty evaluated the effects of a lower protein diet compared to “standard protein intake (0.8 g/kg)” in patients with diabetic nephropathy. Regarding kidney function parameters, no difference was observed between “low-protein diet” and “standard protein intake” for GFR (weighted MD (WMD) -0.13 mL/min, [-2.63 to 2.38]; low certainty, Table S3), albuminuria (WMD -20.57 mg/24h, [-45.4 to 4.26]; very low certainty, Table S3), and serum creatinine level (WMD 0.01 mg/dL, [-0.08 to 0.1]; moderate certainty, Table S3). Regarding metabolic parameters, low protein intake reduced HbA1c (WMD -0.2%, [-0.39 to -0.01]; moderate certainty, Table S3), whereas no significant effects were observed in blood glucose levels (WMD 2.15 mg/dL, [-5.62 to 9.91]; low certainty, Table S3). No significant difference was observed in total cholesterol (WMD -2.29 mg/dL, [-17.04 to 12.47]; very low certainty, Table S3), LDL-C (WMD -1.26 mg/dL, [-12.16 to 9.63]; low certainty, Table S3), or triglyceride levels (WMD 3.73 mg/dL, [-11.84 to 19.3]; very low certainty, Table S3).

However, a recent study found that high protein restriction may result in malnutrition and other adverse health effects, particularly in patients with already compromised nutritional status. This study, alongside recent clinical investigations, has emphasized individualizing protein intake for patients undergoing hemodialysis through comprehensive risk-benefit assessments rather than standardized recommendations. This approach recognizes the variations in optimal protein requirements based on disease stage, residual kidney function, dialysis parameters, nutritional status, and comorbidities. While protein restriction may benefit earlier CKD stages, patients undergoing hemodialysis experience protein losses during treatment and increased catabolism, often requiring higher protein intake to prevent malnutrition. Therefore, protein requirements must be dynamically adjusted throughout treatment, particularly during illness or following surgical interventions.

A moderate protein intake aids in preventing malnutrition risk in patients with CKD, particularly in populations with traditionally low protein consumption. A previous RCT on traditional protein intake (0.8g/kg), which included 60 patients, demonstrated that a protein-restricted diet may result in improved renal function in patients with T2DM and macroalbuminuria. The study offers evidence supporting the role of dietary protein modification in managing DKD complications. Based on the WHO recommendation of “a protein intake of 0.8 g/kg” for the general population and the risk of low-protein diets in adults with DKD, the guideline panel estimated that “protein intake of 0.8 g/kg body weight” is generally suggested to delay disease progression in such patients. This approach contributes to reducing the workload on the kidneys, potentially slowing the deterioration in kidney function and delaying ESKD onset. Moreover, the panel indicated that individual dietary needs should be carefully assessed as overly restrictive diets may not be suitable for all patients, particularly those having different nutritional backgrounds or CKD stages.