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End-stage renal disease (ESRD) is the final stage of chronic kidney disease (CKD), defined by a glomerular filtration rate (GFR) of less than 15 mL/min/1.73 m², often necessitating renal replacement therapy such as dialysis or kidney transplantation. The condition results from progressive loss of kidney function and is most commonly caused by diabetes mellitus, hypertension, and glomerular diseases. Patients with ESRD experience significant morbidity, reduced quality of life, and increased mortality. The Kidney Disease: Improving Global Outcomes guidelines provide a framework for staging CKD and guiding management based on GFR and albuminuria levels. Despite available guidelines, many patients initiate dialysis without prior nephrology referral, permanent access placement, or education about treatment options, which contributes to poor short-term outcomes and missed opportunities for timely intervention. This educational activity enhances clinical competence by improving the learner’s ability to identify, evaluate, and manage ESRD using current evidence and guideline-based strategies. Emphasis is placed on the early recognition of disease progression, the appropriate use of pharmacological therapies, and timely referral for renal replacement therapy. Participants gain insight into monitoring complications such as anemia, mineral and bone disorders, and electrolyte imbalances. Collaborative care with nephrologists, dietitians, pharmacists, and nursing professionals is emphasized as crucial for optimizing treatment outcomes, enhancing patient education, and ensuring continuity of care throughout the transition to dialysis or transplantation. Objectives: Identify clinical and laboratory criteria that define end-stage renal disease, including glomerular filtration rate thresholds and associated signs of kidney function decline. Apply current evidence to determine eligibility for renal replacement therapies, including hemodialysis, peritoneal dialysis, and kidney transplantation, based on patient-specific factors. Implement guideline-based interventions, including pharmacological therapies such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, to manage proteinuria and delay the progression of end-stage renal disease.

Apply current evidence to determine eligibility for renal replacement therapies, including hemodialysis, peritoneal dialysis, and kidney transplantation, based on patient-specific factors. Implement guideline-based interventions, including pharmacological therapies such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, to manage proteinuria and delay the progression of end-stage renal disease. Collaborate with an interprofessional team to develop strategies for improving care coordination and communication to ensure improvement and best outcomes in end-stage renal disease. Access free multiple choice questions on this topic.

More than 500,000 people in the United States (US) live with end-stage renal disease (ESRD). The development of chronic kidney disease (CKD) and its progression to ESRD remains a significant cause of reduced quality of life and premature mortality.[1] CKD is a debilitating disease, and standards of medical care involve aggressive monitoring for signs of disease progression and early referral to specialists for dialysis or possible renal transplant. The Kidney Disease Improving Global Outcomes (KDIGO) foundation guidelines define CKD using kidney damage markers, specifically those that determine proteinuria and glomerular filtration rate (GFR). By definition, the presence of both factors (GFR <60 mL/min and albumin >30 mg/g of creatinine) along with abnormalities of kidney structure or function for greater than three months signifies chronic kidney disease. ESRD is defined as a GFR of less than 15 mL/min.[2][3] According to KDIGO 2012 clinical practice guideline, CKD is classified into the following 6 stages based on the GFR level: Stage 1: Kidney damage with normal GFR (>90 mL/min) but other abnormalities in urine production Stage 2: Mild reduction in GFR (60-89 mL/min) Stage 3a: Moderate reduction in GFR (45-59 mL/min) Stage 3b: Moderate reduction in GFR (30-44 mL/min) Stage 4: Severe reduction in GFR (15-29 mL/min) Stage 5: Renal failure (GFR <15 mL/min)[4] In the US, in 2008, over 100,000 patients were initiated on dialysis; of those, 44% had received no predialysis care, which may have contributed to the observed high mortality within the first 3 months of dialysis initiation.[5] Most patients in the US are treated with in-center dialysis. They are not offered alternative forms of renal replacement, such as home dialysis, peritoneal dialysis, or pre-emptive kidney transplant. Providing education on alternative forms of renal replacement is crucial, as it enables the establishment of permanent access to the dialysis method of choice.[6] Study results indicate a low rate of renal replacement therapy, excluding in-center dialysis, despite no contraindications, primarily due to a lack of patient education and preparation.

Many chronic diseases can cause end-stage renal disease. In many developed and developing countries, diabetes mellitus is the leading cause.[7] Other causes include the following: Vascular diseases Renal artery stenosis Cytoplasmic pattern antineutrophil cytoplasmic antibody–positive and perinuclear pattern antineutrophil cytoplasmic antibody (P-ANCA)–positive vasculitides ANCA-negative vasculitides Atheroemboli Hypertensive nephrosclerosis Renal vein thrombosis [8][9][10] Primary glomerular diseases Membranous nephropathy Alport syndrome Immunoglobulin A nephropathy Focal and segmental glomerulosclerosis Minimal change disease Membranoproliferative glomerulonephritis Complement-related diseases (atypical hemolytic-uremic syndrome [HUS], C3 glomerulopathy, dense deposit disease) Rapidly progressive (crescentic) glomerulonephritis [8][9][11][12] Causes of tubulointerstitial disease Drugs (eg, sulfonamides, allopurinol) [13] Infection (viral, bacterial, parasitic) Sjögren syndrome Tubulointerstitial nephritis and uveitis syndrome Chronic hypokalemia Chronic hypercalcemia Sarcoidosis Multiple myeloma cast nephropathy Heavy metals Radiation nephritis Polycystic kidneys Cystinosis and other inherited diseases [14][15] Mesoamerican Nephropathy (aka Chronic Interstitial Nephritis in Agricultural Communities) [8][9][16] Urinary tract obstruction Benign prostatic hypertrophy Urolithiasis (kidney stones) Urethral stricture Tumors Neurogenic bladder Congenital (birth) defects of the kidney or bladder Retroperitoneal fibrosis [17] Reflux nephropathy Systemic causes of glomerular disease Diabetes mellitus Systemic lupus erythematosus Rheumatoid arthritis Mixed connective tissue disease Scleroderma Mixed cryoglobulinemia Endocarditis Hepatitis B and C Syphilis Human immunodeficiency virus infection Parasitic infection Heroin use Gold (largely historical) Penicillamine Amyloidosis Light-chain deposition disease Neoplasia Thrombotic thrombocytopenic purpura Shiga-toxin or Streptococcus pneumoniae–related HUS IgA vasculitis (Henoch-Schönlein purpura) [8][9][18][19][20][21] Please see StatPearls' companion references for each of the above conditions.

According to the US Renal Data System annual report, the number of incident ESRD cases increased by 31.3% between 2002 and 2022 (https://usrds-adr.niddk.nih.gov/2024/end-stage-renal-disease/1-incidence-prevalence-patient-characteristics-and-treatment-modalities), reflecting an increasing burden of kidney failure. The prevalence of the disease has been increasing at a steady rate of approximately 20,000 cases per year.[22][23] The likely reasons for this are the increasing access to kidney replacement therapies and improved survival in ESRD.[24] Kidney disease is the ninth leading cause of death in the United States. Race/Ethnicity The degree of kidney failure varies widely by race in the US. As an example, the lifetime risk of development of end-stage renal disease was 3.4 times higher in Black patients and 1.3 times higher in Hispanic patients when compared to White patients.[25] In 2015, the rate of ESRD was 3 times higher in Black patients compared to White patients (393.5 versus 139.9 per million population). That same year, the ESRD prevalence was about 10 times higher in American Indians or Alaska Natives and twice as high in Native Hawaiians or Pacific Islanders; prevalence rates were 1.3 times higher in Asian Americans, as well. Notably, incidence rates in the African American population have decreased annually since 2006, resulting in a 21% overall decline. This reduction has been even more pronounced in Indigenous Americans.[26] Age The prevalence of CKD increases with age, with the most rapid growth in people aged 60 years or older. For example, the prevalence is 6.0% among people aged 18 to 44 and 38.1% among people aged 65 or older. Sex The cumulative incidence of end-stage renal disease is around 50% higher in males than in females.[27]

ESRD usually develops as a progression of long-standing chronic kidney disease, but could also develop relatively earlier following an acute kidney injury that fails to recover over at least 3 months. The natural history of renal failure depends on the etiology of the disease, but ultimately involves early homeostatic mechanisms involving hyperfiltration of the nephrons. The kidney maintains GFR, despite the progressive destruction of nephrons, because the remaining normal nephrons develop hyperfiltration and compensatory hypertrophy. As a result, the patient with mild renal impairment can show normal creatinine values, and the disease can go undetected for some time.[28] This nephron adaptability allows for continued normal clearance of plasma solutes. This adaptive mechanism will run its course and eventually cause damage to the glomeruli of the remaining nephrons, leading to proteinuria. At this point, antihypertensives such as angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) may be beneficial in slowing the progression of the disease and preserving renal function. Plasma levels of substances such as urea and creatinine start to show measurable increases only after total GFR has decreased by 50%. For example, a rise in plasma creatinine from 0.6 mg/dL to 1.2 mg/dL in a patient, although within the normal range, actually represents a loss of more than 50% of functioning nephron mass. Although hyperfiltration and hypertrophy of residual nephrons are beneficial for maintaining GFR, they ultimately lead to progressive renal dysfunction.[29] The increased glomerular capillary pressure may damage the capillaries, leading to focal and segmental glomerulosclerosis and eventually to global glomerulosclerosis. Factors that may worsen renal injury include the following: Nephrotoxins (nonsteroidal anti-inflammatory drugs) Contrast dye exposure Systemic hypertension Proteinuria Dehydration Smoking [30] Hyperlipidemia Uncontrolled diabetes Hyperphosphatemia Complications and Clinical Manifestations of ESRD Hyperkalemia

This nephron adaptability allows for continued normal clearance of plasma solutes. This adaptive mechanism will run its course and eventually cause damage to the glomeruli of the remaining nephrons, leading to proteinuria. At this point, antihypertensives such as angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) may be beneficial in slowing the progression of the disease and preserving renal function. Plasma levels of substances such as urea and creatinine start to show measurable increases only after total GFR has decreased by 50%. For example, a rise in plasma creatinine from 0.6 mg/dL to 1.2 mg/dL in a patient, although within the normal range, actually represents a loss of more than 50% of functioning nephron mass. Although hyperfiltration and hypertrophy of residual nephrons are beneficial for maintaining GFR, they ultimately lead to progressive renal dysfunction.[29] The increased glomerular capillary pressure may damage the capillaries, leading to focal and segmental glomerulosclerosis and eventually to global glomerulosclerosis. Factors that may worsen renal injury include the following: Nephrotoxins (nonsteroidal anti-inflammatory drugs) Contrast dye exposure Systemic hypertension Proteinuria Dehydration Smoking [30] Hyperlipidemia Uncontrolled diabetes Hyperphosphatemia Complications and Clinical Manifestations of ESRD Hyperkalemia Only 2% of potassium resides extracellularly, while 98% remains intracellularly. In normal physiology, approximately 10% of potassium is excreted through the gastrointestinal tract, while 90% is excreted renally.[31] Potassium excretion at near-normal levels is generally maintained in CKD as long as aldosterone secretion and distal flow are maintained. Hyperkalemia develops when GFR falls to less than 20 to 25 mL/min/1.73 m²; at this point, the kidneys have decreased ability to excrete potassium.[32] Patients with CKD develop adaptive responses to secrete potassium, while those with acute kidney injury are much more prone to complications at the same potassium levels. Hyperkalemia is considered to be levels greater than 5.0 mEq/L and is compounded by renal failure, diabetes, and heart failure; this can be worsened by medications like ACEI/ARB and potassium-sparing diuretics.[31] Metabolic acidosis

Only 2% of potassium resides extracellularly, while 98% remains intracellularly. In normal physiology, approximately 10% of potassium is excreted through the gastrointestinal tract, while 90% is excreted renally.[31] Potassium excretion at near-normal levels is generally maintained in CKD as long as aldosterone secretion and distal flow are maintained. Hyperkalemia develops when GFR falls to less than 20 to 25 mL/min/1.73 m²; at this point, the kidneys have decreased ability to excrete potassium.[32] Patients with CKD develop adaptive responses to secrete potassium, while those with acute kidney injury are much more prone to complications at the same potassium levels. Hyperkalemia is considered to be levels greater than 5.0 mEq/L and is compounded by renal failure, diabetes, and heart failure; this can be worsened by medications like ACEI/ARB and potassium-sparing diuretics.[31] Metabolic acidosis Metabolic acidosis is common with CKD and leads to bone demineralization, muscle mass loss, and worsening of renal function. The kidneys regulate bicarbonate through both reabsorption and distal nephron excretion of hydrogen ions.[33] This is considered high anion gap metabolic acidosis, but with the anion gap generally not higher than 20 mEq/L. In stage 5 CKD, the accumulation of phosphates, sulfates, and other organic anions is the cause of the increase in the anion gap.[34] Healthy kidneys can filter 4500 mEq of bicarbonate daily, and approximately 80% of the bicarbonate filtered through the glomerulus is reabsorbed in the proximal tubule. The kidney can excrete titratable acids until the estimated GFR is less than about 15 mL/min/m²; however, the primary mechanisms of acid-base balance involve the excretion of ammonium, which is the main bicarbonate production mechanism. Metabolic acidosis has deleterious effects on protein balance, leading to the following: Induces net negative nitrogen and protein balance and triggers chronic inflammation, which can promote protein catabolism Inhibits osteoblast and osteoclast stimulation Likely worsens hyperparathyroidism Interferes with vitamin D metabolism and worsens hyperkalemia [35][36] Salt and water handling abnormalities

Metabolic acidosis has deleterious effects on protein balance, leading to the following: Induces net negative nitrogen and protein balance and triggers chronic inflammation, which can promote protein catabolism Inhibits osteoblast and osteoclast stimulation Likely worsens hyperparathyroidism Interferes with vitamin D metabolism and worsens hyperkalemia [35][36] Salt and water handling abnormalities Salt and water handling by the kidney is affected in CKD and ESRD. Volume overload results from the failure of sodium and free-water excretion, occurring when the GFR falls to less than 10 to 15 mL/min/1.73 m². This leads to peripheral edema, pulmonary edema, and hypertension. Tubulointerstitial renal diseases often cause fluid loss rather than overload. Thus, despite severe reductions in GFR, tubulointerstitial renal diseases may manifest as polyuria and volume depletion, with the inability to concentrate the urine.[37] Patients with oliguria/anuria tend to fare worse than those who can still produce urine. Anemia Commonly found iron indices in anemia of CKD include normal or total iron-binding capacity, with low transferrin saturation and increased ferritin levels. Causes of anemia in ESRD are multi-factorial and include the following: Decreased erythropoietin production Decreased iron metabolism and stored Chronic blood loss from dialysis (uremia-induced platelet dysfunction enhances a bleeding tendency) Increased hepcidin levels, which decrease iron absorption Generalized inflammation Nutritional deficiency Please refer to StatPearls' comprehensive review of "Anemia of Chronic Disease" for further information on this complicated topic. Bone disease In 2005, Moe et al coined the term chronic kidney disease–mineral and bone disorder to describe a complex clinical syndrome encompassing disorders of calcium, phosphate, parathyroid hormone (PTH), vitamin D, and fibroblast growth factor-23 (FGF23) metabolism. These disruptions lead to alterations in bone morphology (renal osteodystrophy), vascular calcification, and cardiovascular death in patients with CKD. Different types of bone disease occur with CKD, as follows: High-turnover bone disease from high PTH levels Low-turnover bone disease (adynamic bone disease) [38] Defective mineralization (osteomalacia) Mixed disease Beta–2–microglobulin–associated bone disease (also known as dialysis-related amyloidosis) [39] Some of the key players are listed below:

Different types of bone disease occur with CKD, as follows: High-turnover bone disease from high PTH levels Low-turnover bone disease (adynamic bone disease) [38] Defective mineralization (osteomalacia) Mixed disease Beta–2–microglobulin–associated bone disease (also known as dialysis-related amyloidosis) [39] Some of the key players are listed below: Phosphate retention: Serum hyperphosphatemia can stimulate PTH secretion through various mechanisms. Typically, this occurs either by directly increasing PTH messenger ribonucleic acid levels or indirectly by reducing calcium and calcitriol levels, leading to an elevation in PTH levels.[40][41] Calcium: Calcium plays a crucial role in regulating PTH levels through the calcium-sensing receptor. A decrease in serum calcium levels triggers the parathyroid glands to secrete PTH, highlighting the established relationship between calcium and PTH levels. Calcitriol: The role of calcitriol is crucial in maintaining serum calcium levels and regulating PTH secretion. Calcitriol and PTH work together to increase serum calcium levels. When calcitriol levels decrease, secondary hyperparathyroidism can develop due to reduced calcium absorption in the intestine, leading to a reflex increase in PTH secretion. Additionally, calcitriol is necessary to suppress PTH secretion by the parathyroid glands. FGF23: This hormone decreases phosphate levels in the body. In CKD, the first biochemical abnormality noted is decreased α-Klotho (referred to as Klotho), a transmembrane receptor primarily found in the proximal and distal renal tubules. Klotho is a cofactor for FGF23, and reduced levels lead to increased FGF23 due to the lack of negative feedback. This increase in FGF23 results in decreased renal phosphorus reabsorption by downregulating the sodium-phosphate cotransporter type II in the proximal tubule. Additionally, FGF23 downregulates the 1-α-hydroxylase enzyme, which decreases activated vitamin D.[42][43] Hyperphosphatemia develops when the kidneys are unable to excrete excess phosphate. Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to calcitriol. Increased phosphate concentration also affects PTH concentration by directly affecting the parathyroid glands (posttranscriptional effect). Hypocalcemia results from decreased intestinal calcium absorption because of low plasma calcitriol levels.

Hyperphosphatemia develops when the kidneys are unable to excrete excess phosphate. Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to calcitriol. Increased phosphate concentration also affects PTH concentration by directly affecting the parathyroid glands (posttranscriptional effect). Hypocalcemia results from decreased intestinal calcium absorption because of low plasma calcitriol levels. Hypocalcemia, hyperphosphatemia, and low serum calcitriol levels stimulate PTH synthesis and secretion. With persistent stimulation in advanced CKD, parathyroid glands become hypertrophic and then hyperplastic, which can sometimes lead to tertiary hyperparathyroidism. Please see StatPearls' comprehensive review, "Chronic Kidney Disease-Metabolic bone disorder."

End-stage renal disease can present with a constellation of signs and symptoms. Some include volume overload refractory to diuretics, hypertension poorly responsive to medication, anemia, mineral and bone disorders, and metabolic derangements including hyperkalemia, hyponatremia, metabolic acidosis, hypo/hypercalcemia, and hyperphosphatemia.[44] Metabolic acidosis in stage 5 CKD presents protein-energy malnutrition, muscle weakness, and loss of lean body mass. Salt and water retention can cause peripheral edema, pulmonary edema, and hypertension. Anemia manifests as fatigue, impaired cognitive function, and reduced quality of life. Anemia can also lead to heart failure. Other manifestations of uremia in end-stage renal disease include the following: Pericarditis Heart failure [45][46] Pleural effusion [47] Encephalopathy Peripheral neuropathy Restless leg syndrome Anorexia, nausea, vomiting, diarrhea Dry skin, pruritus, ecchymosis Malnutrition Erectile dysfunction, decreased libido, amenorrhea Bleeding diathesis Most of the above causes are an indication of urgent dialysis.[48] Uremic symptoms generally appear in stages 4 and 5 when the GFR is less than 30 mL/min. Some patients with nephrotic syndrome and cystic renal disease may present earlier owing to symptoms specific to these diseases. Depression is ubiquitous in patients with ESRD and should be screened for on presentation.[49]

Chronic kidney disease is diagnosed when there is evidence of kidney damage for at least 3 months or in any patient with a GFR of less than 60 mL/min for that same amount of time.[50][51] To calculate estimated GFR (eGFR), 3 equations have been commonly used (the Modification of Diet in Renal Disease Study, CKD-Epidemiology Collaboration [CKD-EPI], and Cockcroft-Gault formula). Until recently, the CKD-EPI equation was commonly used to calculate eGFR from serum creatinine, age, and race in the majority of health systems. In 2021, a joint American Society of Nephrology(ASN) and the National Kidney Foundation (NKF) task force recommended using a new CKD-EPI 2021 equation that does not include the race coefficient, which is now the current standard of care.[52] However, the equation tends to underestimate actual GFR when the GFR is greater than 60 mL/min/1.73 m².[53] The ASN/NKF task force also recommended the use of cystatin C in calculating eGFR. Cystatin C is a protein secreted by all nucleated cells, is freely filtered by the kidneys, and has a near-complete absorption; hence, its levels are less affected by muscle mass, diet, or nutritional status.[54] The newer eGFR equation, which incorporates serum creatinine and cystatin C, is considered more accurate and has fewer differences between Black and non-Black populations.[55] Further evaluation of kidney disease can include a renal ultrasound, complete blood count, basic metabolic panel, urinalysis, and/or kidney biopsy. Complete Blood Count Anemia is common in patients with ESRD, and it is unusual for these patients to have normal hemoglobin levels. Anemia is associated with decreased quality of life and increased mortality. The landmark Normal Hematocrit Trial, along with several other trials, actually showed higher rates of heart failure and thrombotic complications when hemoglobin was corrected to greater than 11.0 mg/dL.[56][57] Basic Metabolic Panel

Anemia is common in patients with ESRD, and it is unusual for these patients to have normal hemoglobin levels. Anemia is associated with decreased quality of life and increased mortality. The landmark Normal Hematocrit Trial, along with several other trials, actually showed higher rates of heart failure and thrombotic complications when hemoglobin was corrected to greater than 11.0 mg/dL.[56][57] Basic Metabolic Panel The blood urea nitrogen and serum creatinine levels are elevated. Hyperkalemia and low bicarbonate levels are usually present before dialysis (whose goal is to normalize electrolytes). Serum albumin levels are low due to urinary protein loss or malnutrition. Serum phosphate, 25-hydroxyvitamin D, alkaline phosphatase, and intact PTH levels are obtained to look for evidence of renal bone disease.[58] A lipid profile should be obtained because of the risk of cardiovascular disease. Urinalysis A spot urine protein/creatinine ratio can be used to quantify albuminuria. A value higher than 30 mg of albumin per gram of creatinine is considered 'moderately increased albuminuria', while values greater than 300 mg/g are considered 'severely increased albuminuria'. Additionally, a 24-hour urine protein test can also be performed; a value greater than 3.5 g is concerning for nephrotic-range proteinuria. Renal Ultrasonography Renal ultrasonography should be performed to look for hydronephrosis or involvement of the retroperitoneum with fibrosis, tumor, or diffuse adenopathy. Small, echogenic kidneys are observed in advanced renal failure. Structural abnormalities, such as polycystic kidneys, may also be observed on ultrasonograms. An ultrasound can provide data estimating size, obstructions, stones, echogenicity, and cortical thinning.[59] Radiology Plain abdominal radiography can detect radio-opaque stones or nephrocalcinosis, while a voiding cystourethrogram is diagnostic for vesicoureteral reflux.[60] Computed tomography scanning can help better describe renal masses and cysts and is also sensitive for identifying renal stones. Magnetic resonance angiography can accurately diagnose renal artery stenosis. A renal radionuclide scan with captopril administration can help diagnose renal artery stenosis and quantify the differential renal contribution to the total GFR. Renal Biopsy

Plain abdominal radiography can detect radio-opaque stones or nephrocalcinosis, while a voiding cystourethrogram is diagnostic for vesicoureteral reflux.[60] Computed tomography scanning can help better describe renal masses and cysts and is also sensitive for identifying renal stones. Magnetic resonance angiography can accurately diagnose renal artery stenosis. A renal radionuclide scan with captopril administration can help diagnose renal artery stenosis and quantify the differential renal contribution to the total GFR. Renal Biopsy Percutaneous ultrasound-guided renal biopsy is indicated when the diagnosis is unclear after an appropriate workup.[61] Specific Tests Serum and urine protein electrophoresis for multiple myeloma Antinuclear antibodies (ANA), double-stranded deoxy ribonucleic acid antibody levels for systemic lupus erythematosus Serum complement levels Cytoplasmic and perinuclear pattern antineutrophil cytoplasmic antibody levels for granulomatosis with polyangiitis (Wegener granulomatosis) and microscopic polyangiitis Anti–glomerular basement membrane antibodies for Goodpasture syndrome Hepatitis B and C, human immunodeficiency virus, and venereal disease research laboratory serology

Treatment of CKD or ESRD involves correcting parameters at the level of the patient's presentation.[62] Interventions aimed at slowing the rate of kidney disease should be initiated and can include: The baseline treatment involves addressing the underlying cause and managing blood pressure and proteinuria. Blood pressure should be targeted to a systolic blood pressure of less than 130 mm Hg and a diastolic blood pressure of less than 80 mm Hg in adults with or without diabetes mellitus whose urine albumin excretion exceeds 30 mg for 24 hours. For diabetic individuals with proteinuria, an ACEI or ARB should be started in cases where urine albumin values range between 30 and 300 mg in 24 hours and greater than 300 mg in 24 hours. These drugs slow disease progression, particularly when initiated before the GFR decreases to less than 60 mL/min or before the plasma creatinine concentration exceeds 1.2 mg/dL in women and 1.5 mg/dL in men.[63] Other targets in preventive care and monitoring should include achieving tight glycemic control, reducing cardiovascular risk, controlling hypertension, and implementing general lifestyle recommendations such as smoking cessation and dietary restriction of salt. Glycemic control and lipid control are critical. A glycated hemoglobin A1C of less than 7% is generally recommended to prevent or delay microvascular complications in this population. Management with sodium-glucose transporter 2 inhibitors may reduce the disease burden in those with type 2 diabetes mellitus.[64] Treatment for Specific Indications Hyperkalemia

Other targets in preventive care and monitoring should include achieving tight glycemic control, reducing cardiovascular risk, controlling hypertension, and implementing general lifestyle recommendations such as smoking cessation and dietary restriction of salt. Glycemic control and lipid control are critical. A glycated hemoglobin A1C of less than 7% is generally recommended to prevent or delay microvascular complications in this population. Management with sodium-glucose transporter 2 inhibitors may reduce the disease burden in those with type 2 diabetes mellitus.[64] Treatment for Specific Indications Hyperkalemia Many advances have been made regarding the treatment of hyperkalemia. In general, avoiding triggers for hyperkalemia is recommended. Reducing potassium-containing foods has long been recommended; however, recent evidence suggests that this approach may have limited effects and could lead to nutrient deficiencies in already malnourished patients.[31][65] Many patients with CKD/ESRD have concomitant heart disease requiring potassium-raising drugs such as ACEIs, ARBs, neprilysin inhibitors, mineralocorticoid antagonists, and other necessary drugs that cannot be discontinued. Notably, treating metabolic acidosis is also an essential component of managing hyperkalemia, as potassium shifts from the intracellular to the extracellular space. For short-term, immediate management of hyperkalemia, please see StatPearls' companion reference, "Hyperkalemia." The long-term treatments of choice for hyperkalemia include the following: Sodium polystyrene sulfonate has traditionally been used; however, this is often poorly tolerated by patients and has many gastrointestinal (GI) adverse events. Rarely has it been associated with serious or fatal adverse events such as colonic necrosis.[31][65][66] Newer potassium binders have started to replace the above. These drugs exchange potassium for other drugs in the GI tract and tend to be better tolerated than sodium polystyrene sulfonate. Sodium zirconium cyclosilicate exchanges potassium for sodium and hydrogen ions. The most common adverse event is edema. Patiromer acts similarly except that it exchanges potassium for calcium ions. The most common adverse events are GI: constipation, diarrhea, nausea, abdominal discomfort, and flatulence.[31][65][67] Metabolic acidosis

Newer potassium binders have started to replace the above. These drugs exchange potassium for other drugs in the GI tract and tend to be better tolerated than sodium polystyrene sulfonate. Sodium zirconium cyclosilicate exchanges potassium for sodium and hydrogen ions. The most common adverse event is edema. Patiromer acts similarly except that it exchanges potassium for calcium ions. The most common adverse events are GI: constipation, diarrhea, nausea, abdominal discomfort, and flatulence.[31][65][67] Metabolic acidosis Protein metabolism creates an acid load, while fruits and vegetables contain alkaline compounds, which neutralize the acid. Decreased ammoniagenesis is associated with reduced glutamine uptake in the proximal tubule, particularly in patients with high protein intake and low consumption of fruits and vegetables.[36] Several studies have shown a slowing of GFR decline with the use of bicarbonate, citrate, and a diet rich in fruits and vegetables. Therefore, all patients with a sodium bicarbonate level of less than 22 mEq/L be treated for acidemia.[68][69][70] One study found that treatment of acidemia with fruits and vegetables for 1 year improved parameters without causing hyperkalemia.[70][71] Fluid titration Fluid status is closely monitored in all patients on renal replacement therapy. This is achieved through regular weight checks and clinical assessments. Patients on peritoneal dialysis and home hemodialysis are especially encouraged to check daily weights. If a patient on hemodialysis is very fluid-overloaded, ultrafiltration can be done for fluid removal alone. Anemia

Fluid status is closely monitored in all patients on renal replacement therapy. This is achieved through regular weight checks and clinical assessments. Patients on peritoneal dialysis and home hemodialysis are especially encouraged to check daily weights. If a patient on hemodialysis is very fluid-overloaded, ultrafiltration can be done for fluid removal alone. Anemia As noted above, management of anemia in patients with ESRD is very complex. Please refer to StatPearls' comprehensive review of "Anemia of Chronic Disease," for further information on this complicated topic. Briefly, as per KDIGO Guidelines, erythropoiesis-stimulating agents (ESAs) are typically considered for patients with CKD when hemoglobin levels drop below 10 g/dL. However, ESA treatment is individualized based on factors such as anemia symptoms, transfusion requirements, the rate of hemoglobin decline, and response to iron therapy. Erythropoietin (50-100 units/kg) is usually administered intravenously or subcutaneously every 1 to 2 weeks, while darbepoetin alfa is dosed every 2 to 4 weeks. For patients on dialysis, erythropoietin is administered with each dialysis session (3 times a week), whereas darbepoetin alfa is administered once a week. The biosimilar epoetin alfa-epbx was also approved for use in the US in 2018. Continuous erythropoiesis receptor activator is a newer, longer-acting ESA that may be preferred over other ESAs due to its lower administration frequency. A crucial treatment component is that patients must be iron replete for the above medications to be effective. KDIGO recommends a target transferrin saturation between 20% and 30% and ferritin levels between 100 to 500 ng/mL in patients with CKD and anemia. The European Renal Best Practice Guidelines (2013) propose a ceiling for TSAT at 30% and ferritin at 500 ng/mL. Additionally, dialysis centers often have their own specific goals and protocols.[72] Guidelines from the National Institute for Healthcare and Excellence (2015) and the Renal Association (2017) suggest using a ferritin ceiling of 800 ng/mL.[73] Bone disease As noted above, please see StatPearls' comprehensive review, "Chronic Kidney Disease-Metabolic bone disorder," for a review of this very complex topic. Patients on dialysis have the following recommended targets of therapy:

A crucial treatment component is that patients must be iron replete for the above medications to be effective. KDIGO recommends a target transferrin saturation between 20% and 30% and ferritin levels between 100 to 500 ng/mL in patients with CKD and anemia. The European Renal Best Practice Guidelines (2013) propose a ceiling for TSAT at 30% and ferritin at 500 ng/mL. Additionally, dialysis centers often have their own specific goals and protocols.[72] Guidelines from the National Institute for Healthcare and Excellence (2015) and the Renal Association (2017) suggest using a ferritin ceiling of 800 ng/mL.[73] Bone disease As noted above, please see StatPearls' comprehensive review, "Chronic Kidney Disease-Metabolic bone disorder," for a review of this very complex topic. Patients on dialysis have the following recommended targets of therapy: Phosphate levels are typically targeted to be between 3.5 and 5.5 mg/dL (1.13-1.78 mmol/L) in patients on dialysis. Serum calcium levels are ideally maintained below 9.5 mg/dL (less than 2.37 mmol/L); cincalcet is often required for this. PTH levels should be maintained at less than 2 to 9 times the upper limit for the assay.[74] Vitamin D is often replaced with calcitriol or vitamin D analogs. Once hyperphosphatemia is under control, PTH management is based on trends rather than isolated laboratory values. Notably, it is not advisable to suppress PTH to less than twice the upper limit, as this may lead to adynamic bone disease.[75] Phosphate binders used include calcium phosphate, calcium acetate, sevelamer, and lanthanum. Planning for Long-term Renal Replacement Therapy

Once hyperphosphatemia is under control, PTH management is based on trends rather than isolated laboratory values. Notably, it is not advisable to suppress PTH to less than twice the upper limit, as this may lead to adynamic bone disease.[75] Phosphate binders used include calcium phosphate, calcium acetate, sevelamer, and lanthanum. Planning for Long-term Renal Replacement Therapy Early patient education should be initiated regarding the natural progression of the disease, various modalities for dialysis, and renal transplantation. For patients in whom transplantation is not imminent, a primary arteriovenous fistula should be created in advance of the anticipated date of dialysis.[76] The optimal timing of dialysis initiation (early vs late) in patients with CKD is unknown. [77] Every patient with end-stage renal disease should be timely referred for renal transplantation. Referral for kidney transplantation evaluation is generally done when the eGFR falls to less than 20 ml/min/1.73m2.[78] As noted above, early planning leads to improved outcomes. Patients should be educated about the options of in-center hemodialysis, peritoneal dialysis, home hemodialysis, and preemptive kidney transplant. Over 80% of patients in the US are initiated on dialysis via a central venous catheter, which is associated with significantly higher infection rates than permanent access. Permanent access requires preparations (usually once GFR is less than 20 mL/min/1.73m2), as the mean time for arteriovenous fistula maturation is 3 months, and many fistulas do not mature for dialysis use initially. Arteriovenous grafts can usually be used sooner than fistulas, at around 2 to 3 weeks post-placement; however, they usually last only 2 to 3 years and require more frequent interventions to maintain patency.[5] All potential modalities should be discussed with patients in an interdisciplinary team setting, and patients should be closely monitored once they reach stage 4 CKD.

The clinical features of ESRD mimic many other disorders, and many diseases lead to end-stage renal disease.[79][80] Therefore, the following differentials should be considered whenever assessing a patient with end-stage renal disease. Chronic glomerulonephritis Chronic pyelonephritis Rapidly progressive glomerulonephritis Nephropathy of pregnancy/pregnancy toxemia Unclassifiable nephritis Polycystic kidney disease Nephrosclerosis Malignant hypertension Diabetic nephropathy Systemic lupus erythematosus nephritis Amyloidal kidney Gouty kidney Renal failure due to a congenital abnormality of metabolism Renal/urinary tract tuberculosis, calculus, or tumor Obstructive urinary tract disease Myeloma Renal hypoplasia

ESRD is a progressive disorder, and timely renal replacement therapy is necessary to prevent death. The disorder is associated with hospitalizations, increased healthcare costs, and metabolic changes. The mortality rates for patients with ESRD are significantly higher than those without the disease. Even with timely dialysis, the death rates vary from 20% to 50% over 24 months. The most common cause of death in ESRD is cardiovascular disease, followed by infections.[81] Mortality rates are higher for men than women; similarly, Black patients are more prone to death due to ESRD than White patients. The highest mortality rate is within the first 6 months of starting dialysis. The 5-year survival rate for a patient undergoing long-term dialysis in the US is approximately 35% and about 25% in patients with diabetes.

Complications of end-stage renal disease are divided into 2 groups—complications due to ESRD and complications due to vascular access or dialysis. Complications due to ESRD Coronary heart disease This is a significant complication of chronic kidney disease and is the most common cause of death in this population. Patients on dialysis have a 10 to 30 times higher cardiovascular mortality risk than the general population.[82] Peripheral vascular disease [83] Hypertension Mineral and bone disorders (secondary to hyperparathyroidism, vitamin D deficiency) Hyperuricemia Metabolic acidosis Hyperphosphatemia Hypoalbuminemia Anemia Decreased libido, erectile dysfunction Complications due to Vascular Access/Dialysis Bleeding Local or disseminated intravascular infection Graft occlusion Electrolyte abnormalities after dialysis Dialysis dementia Dialysis disequilibrium syndrome

Managing end-stage renal disease requires a dedicated interprofessional healthcare team comprised of the following: Nephrologist Primary care clinician Intensivist Renal transplant surgeon Nurse educator Pharmacist Nutritionist

The US Preventive Services Task Force (USPTF) does not recommend screening asymptomatic individuals for CKD.[84] However, for those at higher risk for the disease, such as those with diabetes or hypertension, USPSTF recommends ongoing screening for CKD with proteinuria testing. However, it is essential to note that screening for proteinuria is not necessary for patients who are already on ACEI or ARB therapy. Patients with end-stage renal disease should be educated about the following: Avoidance of nephrotoxic drugs like non-steroidal anti-inflammatory drugs Advanced counseling for renal replacement modalities, including peritoneal dialysis, hemodialysis, and transplantation Timely placement of vascular access for hemodialysis Pregnancy could be fatal in ESRD Avoid phosphate-rich foods [85] Potassium restriction in the diet Sodium and water restriction to avoid volume overload Protein restriction to delay the onset of uremic symptoms (0.6-0.8 g/kg) [86] Reduction in salt intake may slow the progression of diabetic CKD Some studies support a vegetarian diet to slow GFR decline [5]

Pearls and other issues to consider include the following: ESRD is a terminal illness with a glomerular filtration rate of less than 15 mL/min. The most common cause of ESRD in the US is diabetic nephropathy, followed by hypertension. Other etiologies can include glomerulonephritis, CKD, recurrent kidney infections, and chronic obstruction. The disease can present with nausea, vomiting, metabolic, hematologic, and electrolyte derangements, seizures, coma, bleeding diathesis, refractory fluid overload, hypertension unresponsive to pharmacotherapy, and uremic pericarditis. Vigilant monitoring of GFR and proteinuria in diabetics and non-diabetics is essential for managing disease progression in patients with chronic kidney disease. Early referral to specialists is necessary for timely dialysis or renal transplant planning.

Once a patient has been diagnosed with ESRD, a significant number of patients will require dialysis, and a few may be eligible for a renal transplant. Unfortunately, end-stage renal failure significantly increases morbidity and mortality; it also leads to enormous costs to the healthcare system. Thus, the disorder is best managed by an interprofessional team dedicated to adequate disease control and improving outcomes for these patients. An interdisciplinary team and close follow-up are particularly important because planning for renal replacement should begin months in advance of the need for renal replacement. A dedicated interprofessional healthcare team should comprise a nurse educator, a specialized pharmacist, a nutritionist, a social worker, and clinical providers, including a primary care clinician and a trained nephrologist. The specialized nurse educator plays a crucial role in counseling patients on lifestyle modifications to help prevent the progression of CKD. In advanced CKD, the nurse also plays an essential role in preserving an arm for potential arteriovenous fistula placement. During hospitalizations, the clinical nurse should place limb restrictions on that arm to ensure venipunctures and blood pressure readings are not taken on that arm. The pharmacist should identify patients with a diagnosis of CKD and provide specialized instructions to these patients, particularly regarding the avoidance of nephrotoxic agents and medications. In addition, the pharmacist plays a crucial role in communicating and guiding the providers about the patient's medications to limit those that can adversely affect the kidneys. A trained nutritionist should also be involved in the care of these patients to guide an appropriate diet plan specific to their needs.[87] A social worker should be involved in the care to ensure that the patient has a support system and financial resources to continue therapy. To improve outcomes, each interprofessional team member should maintain accurate and up-to-date patient records, communicate effectively with other team members, and collaborate to ensure that patients receive optimal care, resulting in the best possible outcomes.