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Chronic Kidney Disease: Etiology, Symptoms, and Treatment
Definition of Chronic Kidney Disease
Chronic kidney disease (CKD) is defined as a persistent reduction in glomerular filtration rate (GFR) or evidence of persistent kidney damage (KDIGO 2024). Abbreviations and synonyms include CKD, chronic renal failure, and end-stage renal disease. The KDIGO guidelines specify two criteria; either one is sufficient for the diagnosis:
- GFR <60 ml/min/1.73 m2 for more than 3 months, with or without kidney damage
- Abnormalities of kidney structure or function that persist for more than 3 months and have implications for health. Examples include albuminuria, abnormalities in urine sediment, electrolyte and other abnormalities caused by tubular disorders, histologically demonstrated abnormalities, structural abnormalities detected by imaging, or a history of kidney transplantation
GFR categories in CKD
The reduction in GFR is classified into six categories according to the KDIGO guidelines:
| Category | GFR | Description |
|---|---|---|
| G1 | ≥90 | Normal or high |
| G2 | 60–89 | Mildly decreased |
| G3a | 45–59 | Mildly to moderately decreased |
| G3b | 30–44 | Moderately to severely decreased |
| G4 | 15–29 | Severely decreased |
| G5 | <15 | Kidney failure |
Albuminuria categories in CKD
Albuminuria is classified into three categories, A1–A3, and is used for further risk assessment:
| Category | AER [mg/24 h] | ACR [mg/g] |
|---|---|---|
| A1 | <30 | <30 |
| A2 | 30–300 | 30–300 |
| A3 | >300 | >300 |
Prognosis and risk assessment
GFR and albuminuria help assess the clinical significance and prognosis of CKD.
| Category | A1 | A2 | A3 | Prevalence |
|---|---|---|---|---|
| G1 | 55.6% | 1.9% | 0.4% | 57.9% |
| G2 | 32.9% | 2.2% | 0.3% | 35.4% |
| G3a | 3.6% | 0.8% | 0.2% | 4.6% |
| G3b | 1.0% | 0.4% | 0.2% | 1.6% |
| G4 | 0.2% | 0.1% | 0.1% | 0.4% |
| G5 | 0% | 0% | 0.1% | 0.1% |
| Prevalence | 93.2% | 5.4% | 1.3% |
Epidemiology of Chronic Kidney Disease
Prevalence of CKD in the United States
See the table above.
Prevalence of end-stage kidney disease
Europe: 92 per 100,000; United States: 208 per 100,000. Prevalence is increasing because of improved treatment outcomes.
Incidence of end-stage kidney disease
Europe: 13 per 100,000; United States: 35 per 100,000 (Heaf et al., 2017). Incidence is decreasing because of improved treatment options in the early stages of CKD.
Etiology: Causes of CKD
The most common causes of end-stage kidney disease in the United States in 2008 were diabetic nephropathy (44%), vascular disease, including peripheral artery disease and hypertension (27%), glomerulopathies (7%), polycystic kidney disease (3%), and unknown or mixed causes (19%).
Prerenal causes
Hypovolemia, sepsis, shock, renal artery stenosis, hepatorenal syndrome, and congestive heart failure (cardiorenal syndrome).
Glomerulonephritis
Primary glomerulonephritis, IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, lupus nephritis, ANCA-associated vasculitis, and other immune-mediated diseases.
Interstitial nephritis
Nephrolithiasis, hydronephrosis, vesicoureteral reflux, gout, nephrocalcinosis, drug-induced (allergic) nephritis, analgesic nephropathy, and Balkan endemic nephropathy caused by aristolochic acid.
Cystic kidney diseases
Tuberous sclerosis, ADPKD, ARPKD, medullary sponge kidney, juvenile nephronophthisis, medullary cystic kidney disease, and congenital nephrotic syndrome.
Systemic diseases
Diabetes mellitus, hypertension, autoimmune diseases and vasculitis (Goodpasture syndrome, granulomatosis with polyangiitis, polyarteritis nodosa, SLE, IgA vasculitis, and thrombotic thrombocytopenic purpura), and amyloidosis.
Microangiopathies
Hemolytic-uremic syndrome, disseminated intravascular coagulation, malignant hypertension, and antiphospholipid antibodies.
Postrenal causes
Bladder outlet obstruction (posterior urethral valves, BPH), vesicoureteral reflux, Prune-Belly syndrome, and ureteral stones. See also the section on BPH.
Pathophysiology
Glomerular adaptation to nephron loss
The remaining nephrons hypertrophy and increase single-nephron GFR. After nephrectomy, the initial postoperative GFR rises from 50% to 80% of baseline within a few months.
Mechanisms that increase GFR include increased glomerular blood flow and plasma flow, increased glomerular hydrostatic pressure, and increased filtration area due to glomerular hypertrophy.
Glomerulotubular balance
Tubular function reflects glomerular function. A hypertrophied glomerulus is associated with a hypertrophied tubule, whereas an atrophic glomerulus induces tubular atrophy and obliteration.
Intact nephron theory
Progressive CKD usually reflects progressive nephron loss. The remaining nephrons hypertrophy and perform more work than an individual nephron in a healthy kidney.
When hyperfunction exceeds a certain level, the remaining nephrons sustain chronic damage because their regenerative capacity is exceeded. This causes CKD to progress to kidney failure. Glomerulosclerosis is the histologic sign of chronic nephron damage; clinically, proteinuria develops.
Impaired excretory function
Reduced urine output causes the accumulation of endogenous metabolic products and exogenous substances, including medications. Increased concentrations of these substances in the primary urine initially compensate for reduced kidney function and maintain comparable excretion (the stage of compensated retention).
Substances that undergo glomerular filtration only, without tubular secretion or reabsorption, such as creatinine, have plasma concentrations that depend directly on GFR. Halving GFR doubles the serum creatinine concentration. A 75% reduction in GFR results in a fourfold increase in plasma creatinine. Even small further reductions in GFR then cause marked increases in creatinine concentration.
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Substances that are also subject to tubular reabsorption or secretion may have normal plasma concentrations despite a severely reduced GFR because tubular mechanisms compensate for reduced filtration. Examples include phosphate, urate, potassium, sodium, and water.
Urea excretion is the first clinical problem caused by retention; impaired water and electrolyte homeostasis develops later. Increased protein intake or a transient decline in kidney function further increases urea levels. Removal of urea during the first dialysis treatment can cause a sudden decrease in urine output.
Electrolyte disturbances
A GFR above 5 ml/min is sufficient for marginal compensation of water and electrolyte balance. Urine osmolality in a severely damaged kidney approaches that of plasma (isosthenuria); the kidney cannot produce concentrated or highly dilute urine. Osmotic urea diuresis increases sodium loss and may cause sodium depletion, which can further reduce GFR.
Life-threatening hyperkalemia is uncommon in end-stage kidney disease because potassium secretion in the distal tubule remains intact. Risk factors include excessive potassium intake, acidosis, oliguria, sodium depletion, potassium-sparing diuretics, and hypoaldosteronism.
Reduced acid excretion causes metabolic acidosis.
Endocrine dysfunction
- Renal anemia develops because of reduced erythropoietin secretion
- Renal osteopathy: Impaired renal hydroxylation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D causes hypocalcemia and impaired bone mineralization. Secondary hyperparathyroidism also contributes to osteopathy
- Secondary hyperparathyroidism: As GFR declines, phosphate excretion decreases. The resulting increase in serum phosphate can cause hyperparathyroidism
Uremic organ dysfunction
Uremia affects almost every organ system, particularly the cardiovascular system, and explains the high mortality among patients receiving dialysis. Uremic toxins originate primarily from protein metabolism. In addition to urea, they include guanidines, urates, creatinine, tryptophan, tyrosine, nucleic acid metabolites, polyamines, and phenols.
The kidney also inactivates endogenous signaling substances, including parathyroid hormone, glucagon, insulin, LH, and prolactin. Reduced kidney mass impairs this function.
Molecular mechanisms of uremia
Impaired Na-K-ATPase function changes electromechanical properties, resting membrane potential, and cell volume. Reduced Na-K-ATPase activity also contributes to hypothermia and a reduced basal metabolic rate.
Protein metabolism
Uremia causes protein-energy wasting and a catabolic metabolic state. Weight loss may be masked by water and sodium retention.
Carbohydrate metabolism
Mild glucose intolerance may occur and does not, by itself, require treatment (azotemic pseudodiabetes). Causes include peripheral insulin resistance and activation of glucagon and catecholamines.
Lipid metabolism
Hypertriglyceridemia and reduced HDL cholesterol contribute to atherosclerosis.
Kidneys
Unclear cystogenic and mutagenic substances in uremia may cause acquired cystic kidney disease and kidney tumors.
Signs and Symptoms of Chronic Kidney Disease
Early stages of CKD are often asymptomatic; symptoms usually develop only in advanced CKD.
Electrolyte disturbances
Volume expansion, hypernatremia or hyponatremia, hyperkalemia, metabolic acidosis, hyperphosphatemia, and hypocalcemia.
Hormonal symptoms
Osteomalacia, glucose intolerance, impotence, decreased libido, amenorrhea, and hypothermia.
Nervous system
Fatigue, headache, memory impairment, muscle spasms, restless legs syndrome, peripheral neuropathy, paralysis, cramps, and impaired alertness.
Cardiovascular system
Hypertension, pulmonary edema, dyspnea, pericarditis, myocardial ischemia due to accelerated atherosclerosis, and cardiac arrhythmias.
Skin
Pallor, hyperpigmentation, pruritus, and bleeding.
Gastrointestinal tract
Weight loss, nausea and vomiting, uremic fetor, diarrhea, stress ulcers, gastrointestinal bleeding, ascites, and peritonitis.
Renal symptoms
Cysts or kidney tumors may rarely cause local symptoms. Other symptoms depend on the underlying kidney disease.
Hematologic system
Normocytic, normochromic anemia, lymphocytopenia, bleeding tendency, increased susceptibility to infection, and splenomegaly.
Diagnosis of Chronic Kidney Disease
Physical examination
Assess blood pressure, vascular status, and clinical signs of uremia.
Urine tests
Urine sediment and urine culture. Measure albumin excretion using either a 24-hour urine collection or the albumin-to-creatinine ratio in a spot urine sample.
Laboratory tests
Complete blood count, creatinine, cystatin C if indicated, electrolytes including calcium and phosphate, total protein and electrophoresis, blood gas analysis, liver enzymes, blood glucose, parathyroid hormone, alkaline phosphatase, 25-hydroxyvitamin D, and HbA1C.
Ultrasound
Assess the kidneys for size, cysts, tumors, and hydronephrosis, and the bladder for postvoid residual urine.
Kidney biopsy
Indicated for unexplained kidney failure, nephrotic or nephritic syndrome, and allograft dysfunction.
Treatment of CKD: Preventing Disease Progression
Treatment aims to address the cause and prevent further kidney damage, slow disease progression, reduce cardiovascular risk, treat CKD complications, and prepare in a timely manner for dialysis or kidney transplantation.
Lifestyle
Smoking cessation, avoidance of overweight, and regular physical activity.
Protein intake
A moderate protein intake (0.8 g/kg body weight) is indicated when GFR is below 60 ml/min.
Sodium intake
Reduce sodium intake to less than 2 g/day (equivalent to 5 g of table salt) when GFR is below 60 ml/min, or in patients with hypertension or edema.
Hypertension
Reliable blood pressure control slows CKD progression. A systolic blood pressure below 120 mmHg is recommended if tolerated. Less intensive targets may be appropriate for patients at increased risk of falls or with limited life expectancy. ACE inhibitors and angiotensin II receptor blockers are particularly nephroprotective and are first-line agents.
SGLT2 inhibitors
SGLT2 inhibitors are an important component of modern CKD treatment to reduce cardiovascular complications. Initiate treatment as early as possible (GFR ≥20 ml/min) in patients with type 2 diabetes, albuminuria, or heart failure.
Finerenone
Finerenone selectively blocks the mineralocorticoid receptor and reduces aldosterone-mediated inflammation and fibrosis in the kidneys and heart. It is an option for patients with type 2 diabetes and albuminuric CKD, GFR ≥25 ml/min, and normal serum potassium.
Lipid metabolism
Because mortality from cardiovascular disease is markedly increased, aggressive dietary and pharmacologic reduction of LDL cholesterol is recommended.
Antiplatelet therapy
Aspirin or other antiplatelet agents are used for secondary prevention in patients with established atherosclerotic disease.
Medication use
Carefully assess indications and account for altered pharmacokinetics when prescribing renally eliminated drugs to patients with CKD. Avoid nephrotoxic agents such as aminoglycosides, nonsteroidal anti-inflammatory drugs, and radiographic contrast agents.
Fluid intake
Increased fluid intake does not slow CKD progression. In advanced CKD, the kidneys cannot compensate for changes in fluid intake. Weigh patients daily and, if necessary, monitor urine output and fluid losses. Treat edema with fluid and salt restriction and, when appropriate, loop diuretics.
Electrolyte intake
Recommend a low-potassium and low-phosphate diet. Identify and treat contributing factors in hyperkalemia. See the section on acute hyperkalemia for treatment of life-threatening episodes.
Renal osteopathy
Prevention of secondary hyperparathyroidism includes a low-phosphate diet, avoidance of unnecessary phosphate intake, treatment of vitamin D deficiency, and phosphate binders for hyperphosphatemia.
If hyperparathyroidism develops despite these measures, cinacalcet, a modulator of the calcium-sensing receptor, can inhibit parathyroid hormone release. Alternatively, or as a last resort, surgical removal of the parathyroid glands may be required.
Renal anemia
The target hemoglobin concentration is above 10 g/dl. Monitor ferritin and transferrin saturation to guide oral or intravenous iron supplementation. Use erythropoietin for symptomatic anemia.
Renal Replacement Therapy
Dialysis
See the section on dialysis.
Kidney transplantation
See the section on kidney transplantation.
Prognosis
The prognosis of CKD is determined primarily by cardiovascular disease, albuminuria, eGFR decline, diabetes mellitus, age, frailty, the underlying disease, and complications. Cardiovascular risk increases substantially as eGFR declines and albuminuria increases.
| Acute renal failure treatment | Index | Dialysis |
Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
References
Heaf J. Current trends in European renal epidemiology. Clinical Kidney Journal. 2017;10(2):149–153. doi:10.1093/ckj/sfw150.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024 Apr;105(4S):S117-S314. doi: 10.1016/j.kint.2023.10.018.
Ruggenenti P, Schieppati A, Remuzzi G. Progression, remission, regression of chronic renal diseases. The Lancet. 2001;357(9268):1601–1608.
Deutsche Version: Chronische Niereninsuffizienz: Definition, Ursachen und Epidemiologie. und Chronische Niereninsuffizienz: Diagnose und Therapie.
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