Chronic renal failure (CRF) represents the terminal stage of progression for various chronic kidney diseases (CKD), characterized by a clinical syndrome involving the retention of metabolic waste products, imbalances in water, electrolytes, and acid-base regulation, as well as systemic manifestations.

Definition and Staging

Chronic kidney disease (CKD) refers to structural or functional abnormalities in the kidney persisting for ≥3 months. This includes the presence of markers of kidney damage (such as albuminuria, abnormal urine sediment, tubular disorders, histological abnormalities, imaging abnormalities, or a history of kidney transplantation) with or without a reduction in glomerular filtration rate (GFR). Alternatively, CKD can be defined by a GFR reduction to <60 ml/(min·1.73m²) of unknown cause for ≥3 months. Clinically, estimated GFR (eGFR) is commonly calculated using serum creatinine and/or cystatin C levels.

Table 1 K/DOQI classification and recommendations for chronic kidney disease

The internationally recognized CKD staging system, as defined in the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, divides CKD into five stages based on GFR. While a mild reduction in GFR (60–89 ml/min) without markers of kidney damage is not classified as CKD, GFR <60 ml/(min·1.73m²) is categorized as CKD stage 3 or higher. Additionally, the Kidney Disease Improving Global Outcomes (KDIGO) organization recommends further evaluation using cystatin C-derived eGFR for individuals with creatinine-based eGFR of 45–59 ml/(min·1.73m²) who lack markers of kidney damage to confirm CKD.

Chronic renal failure (CRF) is a concept predating CKD and refers to a syndrome characterized by GFR reduction and associated metabolic disturbances and clinical symptoms caused by chronic kidney diseases. It corresponds to the decompensatory stages of CKD and is generally equated with CKD stages 4–5. CRF lacks a specific diagnostic standard.

Prevalence and Etiology

Chronic kidney disease represents a significant global public health issue. In 2017, there were 697.5 million individuals worldwide with CKD, accounting for approximately 9.1% of the global population.

The primary causes of CKD include diabetic nephropathy, hypertensive nephrosclerosis, primary and secondary glomerulonephritis, and tubulointerstitial diseases (such as chronic interstitial nephritis, chronic pyelonephritis, hyperuricemic nephropathy, and obstructive nephropathy). Other causes include renal vascular diseases and hereditary kidney disorders (such as polycystic kidney disease and hereditary nephritis). In developed countries, diabetic nephropathy and hypertensive nephrosclerosis are the leading causes of CKD. In contrast, primary glomerulonephritis remains the most common cause in developing countries, although the prevalence of CKD due to diabetic nephropathy has risen significantly and may become the leading cause in the future.

Risk Factors for CKD Progression

CKD typically progresses slowly but can deteriorate rapidly over a short period in the presence of certain triggers. Clinically, it is critical to manage risk factors for progressive CKD to delay disease progression while identifying and addressing reversible factors that may lead to acute exacerbations.

Risk Factors for Progressive CKD

Progression of CKD is associated with factors such as hyperglycemia, hypertension, proteinuria (including microalbuminuria), hypoalbuminemia, and smoking. Other contributors include anemia, hyperlipidemia, hyperhomocysteinemia, advanced age, malnutrition, and the accumulation of uremic toxins (e.g., methylguanidine, parathyroid hormone, phenols). These factors play a role in the long-term progression of CKD.

Risk Factors for Acute Exacerbations or Deterioration

Factors contributing to acute deterioration of CKD include:

Worsening or recurrence of underlying kidney-related diseases, such as primary or secondary glomerulonephritis, hypertension, diabetes, or ischemic nephropathy.
Reduction in effective blood volume, resulting from conditions like hypotension, dehydration, significant hemorrhage, or shock.
Sudden reduction in renal blood flow, often seen in patients with renal artery stenosis using ACE inhibitors or ARBs.
Severe uncontrolled hypertension.
Use of nephrotoxic medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycoside antibiotics, contrast agents, and herbal remedies containing aristolochic acid.
Urinary tract obstructions.
Other factors, including severe infections, hypercalcemia, liver failure, or heart failure.

Among these, reduced effective blood volume or acute declines in renal perfusion and filtration in residual nephron units represent major causes of acute deterioration. Improper use of nephrotoxic drugs is another common cause of renal function decline.

Acute deterioration of kidney function during the course of CKD may be partially reversible if timely and appropriate interventions are undertaken. However, delayed diagnosis or treatment, or severe acute deterioration, can result in irreversible progression of the disease.

Pathogenesis

The mechanisms underlying the progression of CKD have not been fully elucidated, but several factors are believed to contribute.

Hyperperfusion and Hyperfiltration of Nephrons

In CKD, residual nephrons experience a state of hyperperfusion and hyperfiltration, leading to glomerular sclerosis and further loss of functional nephrons. Hyperperfusion and hyperfiltration promote mesangial cell proliferation and matrix deposition, endothelial cell injury, and increased platelet aggregation. These processes are accompanied by inflammatory cell infiltration and increased mesangial cell apoptosis, accelerating glomerular sclerosis and progressive nephron loss.

Hypermetabolism of Nephrons

Residual nephrons in CKD exhibit a hypermetabolic state, which is a key factor contributing to tubular atrophy, interstitial fibrosis, and progressive nephron damage.

Epithelial-Mesenchymal Transition of Renal Tissue Cells

Under the influence of specific growth factors (e.g., TGF-β₁) or inflammatory factors, renal tubular epithelial cells, glomerular epithelial cells (including Bowman’s capsule epithelial cells and podocytes), and renal interstitial fibroblasts may transform into myofibroblasts, playing a critical role in renal interstitial fibrosis and glomerular sclerosis.

Extracellular Matrix Proliferation

In the kidneys of CKD patients, certain cytokines and growth factors (such as TGF-β₁, interleukin-1, angiotensin II, and endothelin-1) are overexpressed, while matrix metalloproteinase levels are downregulated. The expression of tissue inhibitors of metalloproteinases and plasminogen activator inhibitors is upregulated, thereby promoting the proliferation of extracellular matrix.

Other Mechanisms

Multiple animal models of chronic kidney disease suggest that increased apoptosis of intrinsic renal cells is closely associated with glomerular sclerosis and interstitial fibrosis. Additionally, elevated levels of aldosterone contribute to the processes of glomerular sclerosis and interstitial fibrosis.

Mechanisms of Uremic Symptoms

The symptoms of uremia and damage to various organ systems are primarily caused by the following factors:

Decline in Renal Excretory and Metabolic Functions

This decline results in disturbances in water, electrolyte, and acid-base balance, leading to conditions such as water and sodium retention, hypertension, and metabolic acidosis.

Toxic Effects of Uremic Toxins

Uremic toxins are substances that accumulate in the body due to reduced functional nephron mass, resulting in impaired excretion of metabolic waste products or incomplete degradation of certain hormones and peptides. These toxins cause various symptoms and signs and can be categorized into three types:

Small-molecule toxins (molecular weight <500 Da): These include potassium, phosphate, hydrogen ions, amino acids, and nitrogenous waste products, with urea being the most abundant. Other examples include guanidine compounds (e.g., methylguanidine, succinylguanidine), amines, and phenols, which can accumulate and contribute to clinical symptoms.
Middle-molecule toxins (molecular weight 500–5,000 Da): These include peptides and protein-like substances. The accumulation of these toxins is associated with long-term complications of CKD such as uremic encephalopathy, endocrine disorders, and weakened cellular immunity. Parathyroid hormone (PTH) is the most common middle-molecule toxin and can induce renal osteodystrophy and soft tissue calcification.
Large-molecule toxins (molecular weight >5,000 Da): Examples include ribonuclease, β2-microglobulin, and vitamin A, which also exhibit certain toxic effects. Advanced glycation end products, oxidized protein end products, carbamylated proteins, and carbamylated amino acids are additional potential uremic toxins.

Disruption of Renal Endocrine Functions

Decreased secretion of erythropoietin (EPO) leads to renal anemia, while reduced production of calcitriol [1,25-(OH)₂D₃] results in renal osteodystrophy. Additionally, a persistent inflammatory state and deficiencies in nutrients (such as essential amino acids, water-soluble vitamins, and trace elements) may either provoke or exacerbate uremic symptoms.

Clinical Manifestations

The clinical manifestations of CKD vary depending on its stages. Patients in CKD stages 1 to 3 may remain asymptomatic or experience only mild discomfort, such as fatigue, lower back soreness, increased nighttime urination, and reduced appetite. As the disease progresses to stages 3b to 4, these symptoms become more pronounced. By stage 5, patients may develop acute left heart failure, severe hyperkalemia, gastrointestinal bleeding, central nervous system dysfunction, and other conditions, some of which may become life-threatening.

Water and Electrolyte Metabolism Disorders

Various electrolyte imbalances and acid-base disturbances are common in CKD, with metabolic acidosis and water-sodium balance disruptions being the most frequent.

Metabolic Acidosis

In patients with mild to moderate CKD [GFR >25 ml/(min·1.73m²) or serum creatinine <350 μmol/L], metabolic acidosis with a normal anion gap, known as renal tubular acidosis, may result from impaired hydrogen ion secretion or decreased bicarbonate resorption in the renal tubules. When GFR decreases to <25 ml/(min·1.73m²) or serum creatinine exceeds 350 μmol/L, acidic metabolic products such as phosphates and sulfates accumulate due to impaired excretion, leading to high anion gap metabolic acidosis referred to as "uremic acidosis."

Most patients tolerate mild chronic acidosis, but symptoms such as poor appetite, vomiting, weakness, and deep, labored breathing become evident when arterial blood bicarbonate levels fall below 15 mmol/L. These symptoms are linked to the inhibition of key enzyme activities in the body during acidosis.

Water and Sodium Metabolism Disorders

Water and sodium retention often lead to dilutional hyponatremia, manifesting as varying degrees of subcutaneous edema and/or fluid accumulation in body cavities, commonly accompanied by elevated blood pressure. Severe cases may result in complications such as left heart failure or cerebral edema. However, a small number of patients, particularly those on long-term low-sodium diets, with poor food intake, or frequent vomiting, may develop hyponatremia and hypovolemia. Differential diagnosis is clinically important in these cases.

Potassium Metabolism Disorders

Potassium excretion declines when GFR falls to 20–25 ml/(min·1.73m²) or lower, predisposing patients to hyperkalemia. This risk becomes particularly pronounced under conditions such as excessive potassium intake, acidosis, infections, trauma, hemolysis, bleeding, or blood transfusions.

Certain medications, such as ACE inhibitors (ACEI), angiotensin receptor blockers (ARB), and potassium-sparing diuretics, can also induce hyperkalemia, necessitating careful use in patients with impaired renal function. Conversely, hypokalemia may occur due to insufficient potassium intake, excessive gastrointestinal losses, or the use of potassium-wasting diuretics.

Calcium-Phosphorus Metabolism Disorders

Blood calcium and phosphorus levels are typically maintained within the normal range during the early stages of CKD and generally do not cause clinical symptoms. As the disease progresses and GFR further declines, reduced urinary phosphorus excretion results in elevated serum phosphorus concentrations. Hypocalcemia is primarily associated with inadequate calcium intake, deficiency of active vitamin D, hyperphosphatemia, and metabolic acidosis. These imbalances exacerbate secondary hyperparathyroidism through increased parathyroid hormone (PTH) secretion, and in some cases, parathyroid adenomas may develop.

Magnesium Metabolism Disorders

When GFR falls below 20 ml/(min·1.73m²), diminished renal magnesium excretion can lead to mild hypermagnesemia. Although generally asymptomatic, the use of magnesium-containing medications, such as certain antacids and laxatives, should be avoided. Hypomagnesemia may occasionally occur due to inadequate magnesium intake or the overuse of diuretics.

Disorders of Protein, Carbohydrate, Lipid, and Vitamin Metabolism

Protein Metabolism Disorders

These are typically characterized by the accumulation of protein metabolism byproducts (e.g., azotemia) and reductions in serum albumin or essential amino acids. Such metabolic abnormalities are related to increased protein catabolism, decreased protein synthesis, negative nitrogen balance, and impaired renal excretion.

Carbohydrate Metabolism Abnormalities

Two main patterns are observed: impaired glucose tolerance and hypoglycemia, with the former being more common. Impaired glucose tolerance is associated with elevated glucagon levels and insulin receptor dysfunction and may manifest as increased fasting or postprandial blood glucose levels. However, overt symptoms are typically uncommon.

Lipid Metabolism Disorders

Hyperlipidemia is a frequent finding in CKD, with most cases presenting as mild to moderate hypertriglyceridemia. In a smaller proportion of patients, mild hypercholesterolemia or a combination of both is observed. Elevated plasma levels of very low-density lipoproteins (VLDL) and lipoprotein(a) [Lp(a)], along with reduced high-density lipoprotein (HDL) levels, are also detected in some individuals.

Vitamin Metabolism Disorders

These abnormalities are also common in CKD. For example, serum vitamin A levels may be elevated, while deficiencies of vitamins B₆ and folic acid are commonly observed. These changes are usually linked to insufficient dietary intake and impaired enzyme activity related to CKD.

Cardiovascular Manifestations

Cardiovascular complications are common in patients with chronic kidney disease (CKD) and constitute the leading cause of death. In end-stage renal disease (ESRD), the incidence of cardiovascular events and atherosclerotic cardiovascular disease is 15 to 20 times higher than in the general population, with mortality rates increasing further (accounting for 45% to 60% of uremia-related deaths).

Hypertension and Left Ventricular Hypertrophy

Most patients exhibit varying degrees of hypertension, often caused by water and sodium retention, elevated renin-angiotensin levels, and/or insufficient production of certain vasodilatory factors. Hypertension contributes to arterial sclerosis, left ventricular hypertrophy, and heart failure. Anemia and the use of arteriovenous fistulas for hemodialysis lead to a high cardiac output state, further increasing the burden on and hypertrophy of the left ventricle.

Heart Failure

The prevalence of heart failure rises significantly as renal function deteriorates, reaching 65% to 70% in the uremic stage. Contributing factors include water and sodium retention, hypertension, and uremic cardiomyopathy. Acute left heart failure may cause symptoms such as shortness of breath, inability to lie flat, and pulmonary edema, typically without severe cyanosis.

Uremic Cardiomyopathy

This condition may be related to the retention of metabolic waste products and anemia. It is sometimes accompanied by coronary atherosclerotic heart disease. Various types of arrhythmias frequently occur, associated with myocardial injury, hypoxia, electrolyte imbalances, and the accumulation of uremic toxins.

Pericardial Disorders

Pericardial effusion is common in CKD patients and is often associated with uremic toxins, hypoalbuminemia, and heart failure. Less commonly, it may also be linked to infection or bleeding. Mild cases may be asymptomatic, while severe cases may present with muffled or distant heart sounds and, occasionally, cardiac tamponade. Pericarditis can be classified as uremic or dialysis-related; the former has become rare, while the latter presents with symptoms similar to general pericarditis, and the pericardial effusion is often hemorrhagic.

Vascular Calcification and Atherosclerosis

Vascular calcification plays a critical role in CKD-related cardiovascular complications and is induced by hyperphosphatemia, abnormal calcium distribution, and a deficiency of vascular protective proteins (e.g., fetuin-A). Atherosclerosis progresses rapidly, and hemodialysis patients exhibit more severe vascular changes compared to non-dialyzed patients. In addition to coronary arteries, cerebral and peripheral arteries throughout the body may also develop atherosclerosis and calcification.

Respiratory Symptoms

Fluid overload or acidosis may cause shortness of breath or rapid breathing. Severe acidosis results in deep and labored breathing (Kussmaul respiration). Fluid overload and cardiac insufficiency may lead to pulmonary edema or pleural effusion. Increased permeability of alveolar capillaries caused by uremic toxins, as well as pulmonary congestion, can result in "uremic pulmonary edema," which may exhibit a "butterfly wing" pattern on chest X-ray.

Gastrointestinal Symptoms

Digestive system symptoms are often the earliest manifestations of CKD progression to uremia. These include loss of appetite, nausea, vomiting, and uremic breath odor. Gastrointestinal bleeding is also relatively common and occurs at a significantly higher rate than in the general population, primarily due to gastric mucosal erosion or peptic ulcers.

Hematologic Manifestations

These primarily include renal anemia, bleeding tendencies, and a predisposition to thrombosis. Most patients exhibit mild to moderate anemia caused by reduced erythropoietin (EPO) secretion by the kidneys, referred to as renal anemia. Contributing factors include iron deficiency, malnutrition, shortened red blood cell lifespan, chronic gastrointestinal bleeding, and inflammation. Advanced CKD patients have a tendency to bleed, often due to reduced platelet function, and some exhibit decreased activity of coagulation factors. Mild bleeding tendencies may manifest as subcutaneous or mucosal petechiae and ecchymoses, while severe cases may present with gastrointestinal or cerebral hemorrhage. Thrombosis is common in dialysis patients due to vascular access occlusion by thrombi, potentially related to reduced antithrombin III activity, inadequate fibrinolysis, and vascular endothelial injury.

Neuromuscular Symptoms

Early symptoms include fatigue, insomnia, and difficulty concentrating. Later stages may involve personality changes, depression, memory loss, and impaired judgment. Severe uremia often leads to mental dullness, delirium, seizures, hallucinations, and coma, collectively referred to as uremic encephalopathy. Peripheral neuropathy is also common and primarily affects sensory nerves, manifesting as glove-and-stocking sensory loss. Other symptoms include limb numbness, burning sensations, pain, reduced or absent deep tendon reflexes, increased neuromuscular excitability (e.g., muscle tremors, spasms, restless leg syndrome), as well as muscle atrophy and weakness. Dialysis disequilibrium syndrome may occur in first-time dialysis patients, presenting with nausea, vomiting, headache, and, in severe cases, seizures.

Endocrine Dysfunction

Renal Endocrine Dysfunction

This includes deficiencies of 1,25-(OH)₂D₃, reduced EPO production, and excess intrarenal renin-angiotensin II.

Abnormal Glucose Tolerance and Insulin Resistance

These are associated with reduced glucose uptake by skeletal muscle and other peripheral organs, acidosis, and decreased renal degradation of small molecules.

Hypothalamic-Pituitary Dysfunction

Levels of hormones such as prolactin, melanocyte-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and adrenocorticotropic hormone are elevated.

Peripheral Endocrine Gland Dysfunction

Secondary hyperparathyroidism (elevated PTH levels) occurs in most patients, while mild hypothyroidism affects approximately one-quarter of patients. Gonadal dysfunction is also fairly common.

Skeletal Abnormalities

CKD patients frequently exhibit disturbances in calcium-phosphorus metabolism and endocrine function (e.g., elevated PTH, deficiency of 1,25-(OH)₂D₃), resulting in mineral and bone disorders, vascular calcification, and soft tissue calcification collectively referred to as CKD-mineral and bone disorder (CKD-MBD). Bone mineralization and metabolic abnormalities in CKD, termed renal osteodystrophy, include high-turnover bone disease, low-turnover bone disease, and mixed bone disease, with high-turnover bone disease being the most common. In non-dialyzed patients, approximately 35% show skeletal abnormalities on X-ray, but symptoms such as bone pain, difficulty walking, and spontaneous fractures are relatively rare (less than 10%). However, bone biopsies reveal abnormalities in about 90% of cases, underscoring the importance of early diagnosis through biopsy.

High-Turnover Bone Disease

High-turnover bone disease is primarily caused by excessively elevated parathyroid hormone (PTH) levels, resulting in overactive osteoclasts that lead to bone mineral dissolution, increased bone resorption, and destruction of collagenous bone matrix, which is replaced by fibrous tissue. This condition can develop into fibrous-cystic osteitis and is associated with an increased risk of rib fractures. The minerals mobilized into the bloodstream deposit in other soft tissues, forming metastatic calcifications. X-ray examinations may reveal findings such as metastatic calcifications, cystic bone lesions (e.g., in phalanges and ribs), and osteoporosis (e.g., in the spine, pelvis, and femur).

Low-Turnover Bone Disease

This type primarily includes osteomalacia and adynamic bone disease.

Osteomalacia is mainly caused by deficiencies in calcitriol or aluminum toxicity, which impair bone tissue calcification and result in excessive accumulation of unmineralized bone tissue. In adults, early and prominent manifestations are primarily observed in the spine and pelvis, sometimes accompanied by skeletal deformities.

Adynamic Bone Disease is mainly associated with relatively low serum PTH levels and insufficient osteogenic factors, which fail to sustain normal bone remodeling. In dialysis patients, prolonged overuse of active vitamin D, calcium supplements, or high-calcium dialysis solutions may lead to relatively low serum PTH concentrations.

Mixed Bone Disease

This category involves a combination of factors underlying both high-turnover and low-turnover bone diseases. Histological features include characteristics of both fibrous-cystic osteitis and osteomalacia.

Dialysis-Related Amyloid Bone Disease (DRA)

This condition occurs only after many years of dialysis and is likely caused by the deposition of β₂-microglobulin amyloid in bone tissue. X-ray imaging may show cystic changes in the carpal bones and femoral head, and spontaneous femoral neck fractures may occur.

Diagnosis

Diagnosing CKD is generally not difficult and is primarily based on the patient’s medical history, renal function tests, and related clinical manifestations. However, the clinical presentation of CKD is complex, and symptoms from various systems can emerge as the initial signs. Therefore, it is essential for clinicians to be highly familiar with the characteristics of CKD’s clinical history, conduct a thorough inquiry into the patient’s medical history and physical examination, and focus on renal function assessments to establish a diagnosis early and reduce the likelihood of misdiagnosis. For patients with unclear previous medical history or suspected recent acute exacerbating factors, differentiation from acute kidney injury (AKI) is necessary. Indicators such as anemia, hypocalcemia, hyperphosphatemia, elevated PTH levels, and kidney atrophy can assist in distinguishing CKD from AKI. Patients meeting the criteria for kidney biopsy can undergo the procedure to confirm the pathological type, identify reversible factors contributing to renal function decline, and slow CKD progression toward end-stage renal disease.

Differential Diagnosis

Distinguishing CKD from prerenal azotemia is not challenging. In patients with prerenal azotemia, renal function typically recovers within 48 to 72 hours after effective blood volume replenishment, whereas renal function in CKD does not exhibit such recovery.

Differentiating CKD from AKI is also usually straightforward and can often be accomplished based on the medical history. When the patient’s medical history is incomplete, imaging studies (e.g., ultrasound, CT) or renography can aid in the assessment. Bilateral kidney atrophy (notable exceptions include diseases such as diabetic nephropathy, renal amyloidosis, polycystic kidney disease, and multiple renal cysts, where kidneys may not shrink) or findings suggesting chronic renal changes on renography support the diagnosis of CKD.

Acute exacerbations or concurrent acute kidney injury can occur in CKD. If the severity of CKD is significant and the worsening does not exhibit features characteristic of acute kidney injury, the condition is referred to as "acute progression of chronic renal failure (CRF)." Alternatively, if CKD is relatively mild but acute kidney injury predominates and develops in a manner consistent with the course of AKI, this condition is termed "acute kidney injury on CKD (AKI on CKD)." The treatment approach for the latter mirrors the principles applied in managing acute kidney injury.

Prevention and Treatment

Early Prevention Strategies and Measures

Early diagnosis, active and effective treatment of primary diseases, and avoidance or correction of risk factors that lead to the progression of renal function decline form the foundation of CKD prevention and treatment. These measures are critical for preserving kidney function and slowing the progression of CKD.

CKD prevention and treatment require a systemic, comprehensive, and individualized approach. Long-term follow-up and management of CKD patients are essential, with targeted treatment to slow disease progression. Awareness about CKD must be heightened, and emphasis placed on detailed medical history collection, physical examinations, and renal function assessments. Even among healthy individuals, annual screening is recommended to facilitate early diagnosis. For pre-existing kidney diseases or conditions that may cause renal damage (e.g., diabetes, hypertension), effective and timely treatment is necessary, with regular testing (e.g., urinalysis and renal function assessments) at least twice a year to detect CKD at an early stage.

For patients diagnosed with CKD, a range of measures should be implemented to delay progression to end-stage renal disease (ESRD). The fundamental strategies include:

Adhering to treatment for underlying causes, such as proper long-term management of hypertension, diabetic nephropathy, or glomerulonephritis.
Avoiding and eliminating risk factors for acute deterioration of renal function.
Blocking or suppressing the progressive damage of nephron units to protect the remaining functional nephron units. Blood pressure, blood glucose, urine protein levels, the rise in serum creatinine, and the decline in GFR should all be maintained within "optimal ranges."

Table 2 Treatment goals for CKD-CRF patients

Effective and Timely Control of Hypertension

Controlling hypertension plays a critical role in protecting target organs. The blood pressure target for CKD patients is currently set below 130/80 mmHg. However, individualized treatment is necessary to avoid the adverse effects of excessive blood pressure reduction. The 2021 KDIGO guidelines suggest lowering blood pressure to below 120/80 mmHg for CKD patients with hypertension, though evidence supporting intensified blood pressure reduction in Chinese CKD patients remains limited.

Use of Renin-Angiotensin-Aldosterone System Inhibitors

ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) not only effectively reduce blood pressure but also decrease glomerular hyperfiltration and reduce proteinuria, primarily by dilating the efferent arterioles. Additionally, these medications help reduce cardiac remodeling and lower the risk of cardiovascular events. However, their use should be approached cautiously in cases of bilateral renal artery stenosis, serum creatinine levels exceeding 256 μmol/L, or significant hypovolemia. The newer nonsteroidal mineralocorticoid receptor antagonist finerenone has shown significant benefits in slowing CKD progression and reducing cardiovascular risks in patients with diabetes-related CKD.

Strict Glycemic Control

Strict control of blood glucose levels, targeting fasting plasma glucose between 5.0 and 7.2 mmol/L (6.1–8.3 mmol/L at bedtime), and glycated hemoglobin (HbA1c) below 6.5%–8.0%, can delay CKD progression in diabetic patients.

Proteinuria Control

Reducing proteinuria to below 0.5 g/24 hours or significantly alleviating microalbuminuria improves long-term outcomes, including slowing disease progression and increasing survival rates.

Application of Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2is)

SGLT2 inhibitors inhibit glucose reabsorption in the proximal renal tubules and have been shown to provide strong glucose-lowering effects. Independent of the presence of diabetes, these agents significantly slow CKD progression.

Application of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs)

GLP-1 receptor agonists are a new class of anti-diabetic drugs. Evidence suggests they reduce cardiovascular events in diabetic patients with CKD and improve renal outcomes.

Additional Measures

Correcting anemia, using statins, and smoking cessation may also provide some degree of renal protection.

Nutritional Therapy

Protein restriction is an important aspect of CKD management as it reduces the production of nitrogen-containing metabolic waste, alleviates symptoms and complications, and may even slow disease progression.

For CKD stages 1–2, whether or not diabetes is present, a protein intake of 0.8–1.0 g/(kg·d) is recommended.

Starting from CKD stage 3 until dialysis initiation, a protein intake of 0.6–0.8 g/(kg·d) is suggested.

For hemodialysis and peritoneal dialysis patients, the recommended intake is 1.0–1.2 g/(kg·d).

For low-protein diets, approximately 50% of protein intake should come from high biological value proteins, such as eggs, lean meat, fish, and milk. If feasible, patients on a 0.6 g/(kg·d) low-protein diet may also receive α-keto acid supplementation at a dose of 0.075–0.12 g/(kg·d).

Regardless of the dietary regimen, sufficient calorie intake of 30–35 kcal/(kg·d) is essential. Patients also need adequate supplementation of vitamins, folic acid, and other nutrients, while intake of potassium, phosphorus, and other elements should be carefully controlled. Phosphorus intake should generally be kept below 800 mg/d.

Pharmacological Treatment of CKD and Its Complications

Correction of Acidosis and Fluid/Electrolyte Imbalances

Correction of Metabolic Acidosis

Oral sodium bicarbonate is the primary treatment. Mild cases require 1.5–3.0 g/day, while moderate to severe cases require 3–15 g/day, with intravenous administration reserved for necessary situations. The total bicarbonate dosage should be divided into 3–6 doses daily to correct acidosis over 48–72 hours or longer. For patients with significant heart failure, precautions against volume overload should be taken, and sodium bicarbonate infusion should proceed slowly to avoid exacerbating cardiac workload.

Management of Water and Sodium Imbalances

Sodium intake should be appropriately restricted to prevent water and sodium retention. Guidelines recommend a sodium intake of no more than 2 g/day (sodium chloride intake no more than 5 g/day). Loop diuretics (e.g., furosemide, bumetanide) may be used as needed, while thiazide diuretics and potassium-sparing diuretics are generally avoided in moderate to severe CKD due to limited efficacy and potential risks of hyperkalemia, hyperuricemia, and drug accumulation. Severe cases, such as pulmonary edema or acute left heart failure, may require timely hemodialysis or continuous renal replacement therapy (CRRT) to avoid delayed treatment.

Mild to moderate hyponatremia typically does not need aggressive management; instead, the underlying cause should be identified. Sodium supplementation should be cautiously provided only if true sodium deficiency is confirmed. For severe hyponatremia resulting from significant sodium loss (e.g., "salt-losing nephritis"), active replenishment of sodium is necessary, though such conditions are rare.

Prevention and Management of Hyperkalemia

Preventing the occurrence of hyperkalemia is a key priority. CKD patients at stage 3 or higher are recommended to limit potassium intake appropriately. For those with GFR <10 ml/(min·1.73 m²) or serum potassium levels exceeding 5.5 mmol/L, stricter potassium intake restrictions are necessary.

For patients who already have hyperkalemia, it is important to address all possible underlying causes (e.g., medications such as ACEIs or ARBs) and take more proactive measures, including the following:

Correcting acidosis actively, which may involve oral sodium bicarbonate; intravenous sodium bicarbonate can be administered if serum potassium levels exceed 6 mmol/L. Additional doses may be given every 4–6 hours as needed, depending on the patient’s condition.
Administering loop diuretics, such as intravenous or intramuscular injections of furosemide (40–80 mg, or 2–4 mg of bumetanide). If necessary, the dosage can be increased to 100–200 mg per administration intravenously.
Providing glucose-insulin infusion therapy, generally with a glucose-to-insulin ratio of 4–6:1 (in grams and units, respectively).
Administering oral potassium-binding resins, such as polystyrene sulfonate, typically dosed at 5–20 g per administration, three times daily. Calcium polystyrene sulfonate is the preferred option as it releases calcium rather than sodium during ion exchange, avoiding excessive sodium load.
Recommending hemodialysis treatment for severe hyperkalemia (serum potassium >6.5 mmol/L) that cannot be corrected with medical therapy.

Management of Hypertension

Timely and appropriate treatment of hypertension is crucial, not only to alleviate symptoms but also to protect target organs such as the heart, kidneys, and brain. Blood pressure targets for non-dialysis patients are generally <130/80 mmHg, while for dialysis patients, blood pressure should be maintained below 140/90 mmHg. Commonly used antihypertensive drugs include ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers, loop diuretics, β-blockers, and vasodilators, with ACEIs, ARBs, and calcium channel blockers being more widely used.

Studies have shown that ACEIs and ARBs significantly reduce the incidence of kidney failure, and ACEIs also lower all-cause mortality. However, ACEIs and ARBs may increase serum potassium levels and cause transient rises in serum creatinine. Close monitoring of serum potassium and creatinine levels is necessary, especially among patients with severe renal impairment. Due to these potential risks, current international guidelines do not recommend combined use of ACEIs and ARBs.

Management of Anemia

For dialysis patients with hemoglobin levels <100 g/L, recombinant human erythropoietin (rHuEPO) therapy is considered if other causes such as bleeding or deficiencies in hematopoietic nutrients are excluded. Initiation of rHuEPO treatment aims to prevent hemoglobin levels from dropping below 90 g/L. For non-dialysis patients with hemoglobin <100 g/L, individualized decisions on initiating rHuEPO treatment can be made after evaluating the rate of hemoglobin decline and associated risks.

The typical starting dose for rHuEPO is 80–120 U/kg per week, divided into 2–3 doses (or 2,000–3,000 U per injection, given 2–3 times per week) via subcutaneous or intravenous injection. Dosages are adjusted based on hemoglobin levels and the rate of hemoglobin increase. Subcutaneous injection is more efficient, achieving similar efficacy with a 25–33% reduction in dosage. For non-dialysis patients, a low-dose regimen of rHuEPO (2,000–3,000 U, once or twice per week) is trending, offering good efficacy with minimal side effects. Hemoglobin levels of 110–120 g/L are considered optimal, and maintaining levels >130 g/L is not recommended. Monthly dose adjustments are made to reduce rHuEPO use while maintaining target levels.

For dialysis patients with poor response to rHuEPO therapy, potential causes should be analyzed, and the treatment plan should be adjusted accordingly. A novel option for correcting anemia is roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, which provides an alternative treatment for renal anemia.

Iron deficiency is a critical factor limiting the efficacy of rHuEPO therapy. Iron status is assessed based on measures such as iron storage and utilization, categorized as absolute or functional iron deficiency. Concurrent monitoring of serum ferritin and transferrin saturation is necessary during rHuEPO therapy, with appropriate supplementation of iron. Oral iron preparations, such as ferrous fumarate or ferrous sulfate, are available, although their absorption is often poor in some dialysis patients. Intravenous iron supplementation, such as iron sucrose, is thus commonly required. Emerging studies indicate that even non-dialysis patients with CKD stages 3–5 may benefit from intravenous iron supplementation.

Transfusion of red blood cells is generally not recommended for CKD patients with anemia unless complications requiring rapid anemia correction (e.g., acute bleeding or acute coronary syndrome) are present. Transfusions pose risks, including potential sensitization, which may adversely affect kidney transplantation outcomes.

Treatment of Hypocalcemia, Hyperphosphatemia, and Renal Osteodystrophy

For patients with significant hypocalcemia, oral administration of 1,25-(OH)₂D₃ (calcitriol) can be used at a dose of 0.25 μg/day for 2–4 weeks. If blood calcium levels and symptoms show no improvement, the dosage may be increased to 0.5 μg/day. After achieving correction of hypocalcemia, routine use of calcitriol in non-dialysis patients is not recommended. Patients taking oral calcitriol require monitoring of serum calcium, phosphorus, and parathyroid hormone (PTH) levels. For maintenance dialysis patients, intact parathyroid hormone (iPTH) levels should generally be maintained within 150–300 pg/ml.

In cases of significantly elevated iPTH levels (e.g., >500 pg/ml), calcitriol pulse therapy may be considered when hyperphosphatemia and hypercalcemia are absent. The novel calcimimetic agent cinacalcet has shown efficacy in treating secondary hyperparathyroidism and can be considered for patients with concurrent hyperphosphatemia and hypercalcemia. Extremely high iPTH levels (>1,000 pg/ml) raise the possibility of parathyroid adenomas, which may require confirmation through diagnostic tools such as ultrasound or SPECT imaging, with surgical removal performed if necessary.

When GFR drops below 30 ml/(min·1.73 m²), in addition to phosphorus dietary restrictions, oral phosphate binders such as calcium carbonate (40% calcium content), calcium acetate (25% calcium content), sevelamer, or lanthanum carbonate may be used. These agents are most effective when taken with meals. The use of calcium-containing phosphate binders should be limited as much as possible, particularly for patients with severe hyperphosphatemia (>2.26 mmol/L) or high serum calcium levels, where calcium supplementation should be halted to reduce the risk of metastatic calcification. New calcium-free phosphate binders such as sevelamer and lanthanum carbonate effectively lower serum phosphorus without increasing calcium levels.

Prevention and Management of Infections

Infections represent the second leading cause of death among CKD patients. The prevention of infections caused by various pathogens is critical. The principles for the selection and use of antibiotics in CKD patients are similar to those for the general population, with adjustments required for dosage based on GFR levels. Among drugs with comparable efficacy, those with the least nephrotoxicity are preferable.

Treatment of Hyperlipidemia

For non-dialysis patients, the principles of hyperlipidemia management align with standard treatment approaches, with active intervention being recommended while remaining cautious about side effects from lipid-lowering therapies. For non-dialysis CKD patients over 50 years old, statin therapy can be considered for the prevention of cardiovascular disease, even when blood lipid levels are normal. For maintenance dialysis patients, less stringent lipid targets are appropriate, with total serum cholesterol levels maintained between 6.5–7.8 mmol/L (250–300 mg/dL) and triglycerides between 1.7–2.3 mmol/L (150–200 mg/dL). Preventive use of statins for dialysis patients is generally not advised.

Oral Adsorption and Purgation Therapy

Oral administration of agents such as oxidized starch, activated charcoal, or rhubarb preparations may enhance the removal of uremic toxins through the gastrointestinal tract. These therapies are primarily used in non-dialysis patients to provide auxiliary support in alleviating azotemia. However, they should not be relied upon as primary treatment options. Attention must be given to the potential risk of malnutrition, as well as electrolyte and acid-base imbalances that may arise as side effects.

Additional Measures

In diabetic patients with renal failure, insulin dosage adjustments may become necessary as GFR declines due to reduced insulin degradation. Downward adjustments are generally required.

For hyperuricemia accompanied by gout, relevant guidelines may be referenced. Studies suggest that allopurinol treatment for hyperuricemia may slow the progression of renal dysfunction and reduce cardiovascular risk, although large-scale evidence is needed for confirmation.

For pruritus, oral antihistamines, management of hyperphosphatemia, and intensified dialysis can offer relief for some patients.

Renal Replacement Therapy

For patients with CKD stage 4 or higher, or those expected to require dialysis within six months, preparation for renal replacement therapy is recommended. The timing of initiating renal replacement therapy remains uncertain. Generally, for patients with non-diabetic kidney diseases, renal replacement therapy becomes necessary when GFR falls below 10 ml/(min·1.73m²) with evident uremic symptoms and signs. For diabetic kidney disease patients, therapy initiation may be advanced to when GFR drops below 15 ml/(min·1.73m²).

Renal replacement therapy includes hemodialysis, peritoneal dialysis, and kidney transplantation. Hemodialysis and peritoneal dialysis offer comparable efficacy, each with strengths and weaknesses, and can be used complementarily in clinical practice. However, dialysis can only partially replace the excretory functions of the kidney (removal of small molecules is equivalent to only about 10–15% of normal kidney function) and does not replace the endocrine and metabolic functions of the kidneys. Patients on dialysis should continue active management of renal hypertension, renal anemia, and other complications.

Kidney transplantation remains the optimal renal replacement therapy. Successful transplantation can restore normal kidney function, including both endocrine and metabolic roles.