Etiology
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Chronisch nierlijden (multidisciplinaire aanpak)Published by: WORELLast published: 2017GPC pluridisciplinaire sur la néphropathie chronique (IRC)Published by: Groupe de travail Développement de recommandations de première ligneLast published: 2017Creatinine is an amino acid breakdown product of creatine and phosphocreatine. It is generated almost exclusively in skeletal muscle (90%) at a fairly constant rate, and is freely filtered through the glomerulus. In addition, 5% to 10% of creatinine is secreted by the proximal tubules.
Factors influencing the generation of creatinine
Elevated serum creatinine is commonly associated with reduced glomerular filtration rate (GFR), but levels can also be elevated due to several other factors.
Muscle mass
The amount of creatinine the body produces each day depends on the person's muscle mass: a young, muscular man produces more creatinine than a petite, older woman. Failure to consider variations in creatinine production due to differences in muscle mass between individuals may lead to misinterpretation of serum creatinine levels. For example, a serum creatinine value in the reference range in a young, healthy person reflects a different GFR value than an identical serum creatinine value in an older person.
Low serum creatinine in certain muscle-wasting conditions, malnutrition, and amputation does not exclude an underlying kidney dysfunction.
In obesity, excess mass is fat and does not contribute to increased creatinine generation.
Because muscle mass normally changes very little, creatinine is usually produced at about the same rate every day in each person.
Age and sex
Women and older people usually have less muscle mass and, consequently, lower production of creatinine and lower serum creatinine than men and younger people. These age and sex differences are taken into account by most equations that estimate GFR.
The likelihood of chronic kidney disease (CKD) in older people and in women, and the risk of adverse outcomes, is inflated by equations that use patient demographics to estimate creatinine generation. In one study, the use of equations that used age to estimate creatinine generation were associated with a higher likelihood of CKD in older patients, and equations that used sex were associated with a higher likelihood of CKD in women.[1]
It is important to note that elevation of serum creatinine is not a normal feature of aging, and is a pathologic finding that needs further attention.
Race
The effect of race on serum creatinine levels is not clear. Even though serum creatinine concentrations are significantly higher in black than in non-black patients, these differences are not readily explained by differences in nutritional status or body composition.[2]
Nutrition
The creatine content of raw meat is 4 to 5 g/kg. Cooking meat converts creatine to creatinine, which is readily absorbed from the gastrointestinal tract into the circulation. The transient increase in serum creatinine can be the source of up to 30% of excreted creatinine.[3]
A vegetarian diet is associated with decreased generation of creatinine.
Creatine is often taken as a supplement to boost muscle mass and increase athletic performance. Typically, 20 to 30 g/day of creatine is given for 5 to 7 days in the loading phase, followed by 2 to 5 g/day in the maintenance phase.
Creatine supplementation increases phosphocreatine levels in the muscles (up to 20%), but only minimally affects serum creatinine concentrations and renal function in young healthy adults. Prolonged intake of creatine supplementation of >10 g/day may increase serum creatinine concentrations, but is unlikely to affect estimates of creatinine clearance.[4][5] Upon discontinuation of supplemental creatine, muscle creatine concentrations and urinary creatinine excretions return to baseline values in 3 to 4 weeks.
Intra- and interpatient variability
Plasma creatinine levels vary substantially (coefficient of variability: 8% to 27%), mostly due to the effects of diet and of intra- and interpatient variability in the production, tubular secretion, and renal and extrarenal excretion and degradation of creatinine.
Concurrent use of medications that inhibit tubular secretion or cause hemodynamic changes to renal perfusion
Trimethoprim, cimetidine, and ranitidine can inhibit tubular secretion of creatinine.[6]
Calcineurin inhibitors such as tacrolimus cause dose-dependent vasoconstriction of the afferent arterioles.[7]
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit kidney prostaglandin production, which reduces kidney perfusion.[8]
Artifactual increases
Can occur because of interfering substances or the choice of measurement assay.
Prerenal causes of elevated creatinine
A reduction in kidney perfusion will lead to a decreased GFR, and a resulting rise in levels of serum creatinine. Factors contributing to a reduction in kidney perfusion are as follows.
Hypotension
Any cause of hypovolemic, redistributive, cardiogenic, or obstructive shock can produce a decrease in kidney perfusion.
Volume depletion
Causes include diabetic ketoacidosis, gastrointestinal loss, burn injury, and excessive insensible fluid loss.
Renal artery stenosis
Usually due to atherosclerosis of the renal artery, leading to decreased kidney perfusion. Consequences include ischemic nephropathy and renovascular hypertension.
Renal artery thrombosis
A hypercoagulable state or preexisting renal artery stenosis leads to thrombosis of the renal artery. In patients with normal kidney function, the thrombosis usually manifests with a modest increase in serum creatinine and blood pressure. If there is preexisting renal impairment, renal artery thrombosis can precipitate acute kidney injury (AKI), heart failure, and marked hypertension.
Renal vein thrombosis
A hypercoagulable state leads to thrombosis of the renal vein. The most common underlying cause is nephrotic syndrome. Chronic thrombosis is usually covert, but acute thrombosis presents with flank pain and severe hematuria.
Traumatic kidney infarction
Traumatic kidney infarction occurs in 1% to 2% of all nonpenetrating abdominal trauma. Likelihood is increased in the presence of lumbar vertebral injury.[9]
Multiple cholesterol emboli syndrome
Characterized by elevated serum creatinine days or weeks following arterial manipulation, vascular surgery, stent placement, or cardiac catheterization. It produces a stepwise acute or subacute progressive rise in serum creatinine, and includes multiorgan involvement (cutaneous lesions, "thrash toes, blue toes," pancreatitis, stroke, ischemic bowel, angina).
Chronic heart failure (CHF)
CHF leads to inadequate kidney perfusion and an inappropriate activation of the sympathetic and renin-angiotensin systems.
Hepatorenal syndrome
Cirrhosis leads to decreased kidney blood flow. The mechanism is poorly understood, but is believed to involve vasoconstriction of the kidney circulation as a result of increased portal venous system pressure, suppression of vasodilators, and activation of vasoconstrictors affecting the kidney circulation.[10]
Drugs
ACE inhibitors and angiotensin receptor blockers can increase serum creatinine levels by 20% to 30%; the increase is maximized when an ACE inhibitor and angiotensin receptor blocker are used concomitantly.[11] The mechanism is related to a blunted ability of the pre-glomerular circulation to vasodilate following normalization of blood pressure, leading to hypoperfusion.
Calcineurin inhibitors such as tacrolimus cause dose-dependent vasoconstriction of the afferent arterioles.[7]
NSAIDs inhibit kidney prostaglandin production, which reduces kidney perfusion.[8]
Cardiac surgery
Clamping of the main arteries during cardiac surgery leads to diminished kidney perfusion, and blood loss during surgery leads to hypovolemia.
Renal causes of elevated creatinine
Renal causes of elevated creatinine are due to kidney damage, which leads to a decrease in GFR and serum creatinine filtration. Tubulointerstitial diseases also interfere with tubular creatinine secretion.
Primary glomerular disease
Primary glomerular diseases may present with edema, hypertension, proteinuria, hematuria, elevated creatinine, and other signs and symptoms. A kidney biopsy is usually required to diagnose these entities.
Primary glomerular diseases include:
minimal change disease
focal segmental glomerulosclerosis
membranoproliferative (mesangiocapillary) glomerulonephritis
membranous glomerulonephritis
immunoglobulin A (IgA) nephropathy
antiglomerular basement membrane glomerulonephritis (Goodpasture syndrome)
idiopathic crescentic glomerulonephritis
rapidly progressive glomerulonephritis
Secondary glomerular disease
Associated with comorbid conditions such as diabetes mellitus, hypertension, systemic lupus erythematosus, and others. Presenting symptoms may be the same as for primary glomerular diseases.
Diabetic nephropathy: hyperglycemia triggers inflammation, endothelial dysfunction, and oxidative stress, leading to kidney damage.
Hypertension: systemic hypertension produces high intraglomerular pressure, leading to glomerular damage and a decrease in GFR.
Preeclampsia: produces hypertension and proteinuria. Kidney blood flow and GFR are decreased, and creatinine elevation may be seen in the later stages. Elevated serum creatinine during pregnancy may also imply pregnancy-related AKI or the progression of undetected or known CKD.
Lupus nephritis: kidney involvement is present in approximately 50% to 70% of patients with systemic lupus erythematosus.[12] Lupus nephritis is more common in Hispanic and black patients and those with more severe disease in other organ systems. Those with antibodies to double-stranded DNA are more likely to develop glomerulonephritis. Most patients are asymptomatic. Other presentations include hypertension, nephrotic syndrome, or kidney failure.
Other vasculitides: a range of vasculitides can produce glomerular damage, leading to a decreased GFR. IgA vasculitis (formerly known as Henoch-Schonlein purpura) is a small-vessel vasculitis affecting the skin, lower extremity, and intestine, and is associated with mesangial IgA depositions in the kidneys. Granulomatosis with polyangiitis is a vasculitic disease affecting the upper respiratory tract, lungs, and kidneys, often leading to fulminant kidney failure. Microscopic polyangiitis is a pauci-immune, necrotizing, small-vessel vasculitis without necrotizing granulomatous inflammation.
Postinfectious glomerulonephritis can be caused by group A beta hemolytic Streptococcus, respiratory and gastrointestinal infections, hepatitis B and C, endocarditis, HIV, toxemia, syphilis, schistosomiasis, malaria, and leprosy.
Cryoglobulinemia: cryoglobulins (immunoglobulins that precipitate at cold temperatures) are associated with infectious diseases (hepatitis C), lymphoproliferative disorders (multiple myeloma, Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and B-cell non-Hodgkin lymphomas) and a range of autoimmune diseases. Kidney damage is produced by immune complex deposition.
Thrombotic microangiopathies: syndromes of microangiopathic hemolytic anemia, thrombocytopenia, and variable signs of organ impairment due to platelet aggregation in the microcirculation. Kidney damage leads to a decrease in the GFR.
Paraproteinemias: a group of multisystem disorders characterized by neoplastic proliferation of a single clone of immunoglobulin-producing plasma cells (multiple myeloma, monoclonal gammopathy of undetermined significance, amyloidosis, Waldenstrom macroglobulinemia). Protein deposition in the kidney leads to kidney damage, producing a decrease in GFR.
Drugs: penicillamine, gold sodium thiomalate, nonsteroidal anti-inflammatory drugs (NSAIDs), captopril, mitomycin C, and cyclosporine can cause glomerulonephritis. Glomerulonephritis may also be caused by the use of heroin.
Hereditary disorders: Fabry disease, Alport syndrome, thin basement membrane disease, and nail-patella syndrome can cause glomerulonephritis.
Tubulointerstitial disease
Acute interstitial nephritis: a hypersensitivity reaction usually triggered by an offending medication that resolves when the triggering medication is stopped. Medications commonly implicated include antibiotics (beta lactams, penicillins, cephalosporins, sulfonamides, rifampicin, quinolones), diuretics, NSAIDs, proton pump inhibitors, cimetidine, ranitidine, allopurinol, phenindione, phenytoin, sulfadiazine, mesalamine, and warfarin. Uncommon causes include sarcoidosis, Sjogren syndrome, or systemic lupus erythematosus. In some patients, there is no discernible cause.
Acute tubular necrosis: a condition characterized by an abrupt decline in kidney function. The pathogenesis is poorly understood. Causes include local or systemic ischemia from any cause, exogenous nephrotoxins (aminoglycosides, amphotericin-B, poisons [e.g., ethylene glycol], chemotherapeutic agents [e.g., cisplatin], NSAIDs, radiocontrast media, or bacterial toxins), and endogenous nephrotoxins (heme, uric acid, or increased light chain proteins).
Competitive inhibition of creatinine secretion: organic cations tend to compete for common secretory mechanisms. As a result, several drugs are competitive inhibitors of creatinine secretion and increase serum creatinine without affecting GFR. These include cimetidine, gentamicin, fibric acid derivatives other than gemfibrozil, and trimethoprim.
Kidney transplantation: increased serum creatinine following kidney transplantation may indicate transplant rejection, toxicity due to immunosuppressive drugs, or urologic complications, and requires urgent assessment.
Physiologic adaptation
Kidney donation or unilateral or partial nephrectomy: after an initial rise, serum creatinine decreases due to hyperfiltration by the remaining nephrons and reaches a new steady state. In the long term, serum creatinine remains at 1.6 to 1.8 mg/dL in patients who have a normal contralateral kidney. Any sustained rise in serum creatinine above the normal range requires further investigation.
Postrenal causes of elevated creatinine
Obstructive uropathy develops when blockage or a narrowing of some part of the urinary tract obstructs urine flow and results in back-pressure on the kidney. This leads to decreased kidney blood flow, decreased GFR, and up-regulation of the renin-angiotensin system. This in turn causes atrophy and apoptosis of the renal tubules as well as interstitial fibrosis. The most common causes are:
bladder tumors
benign prostatic hyperplasia
nephrolithiasis
anatomic blockages (e.g. stricture, extrinsic compression of a ureter by a mass in a nearby structure)
iatrogenic ureter damage during surgery, and
retroperitoneal fibrosis.
Prognostic value of elevated creatinine
Mild increases in in-hospital serum creatinine have been associated with short-term mortality, progression to CKD, and accelerated progression to kidney failure. Mild serum creatinine increases present a higher long-term mortality risk, especially in those with partial kidney recovery.[13][14][15]
While findings from observational studies suggest that minimal and/or transient elevations in serum creatinine predict poor prognosis, one meta-analysis of placebo-controlled trials found no appreciable effect on CKD, or mortality, months after mild to moderate (often temporary) elevations in serum creatinine.[16]
Patients with chronically elevated serum creatinine (i.e., impaired baseline kidney function) have a higher risk for AKI during hospital stays and are more often dialysis-dependent at hospital discharge than those without.[13][14][15][17][18][19][20] Chronically elevated serum creatinine has been linked to progression of CKD, increased mortality, and postoperative complications following cardiac surgery. Elevated serum creatinine after endovascular aneurysm repair has been reported to be a significant and strong predictor of postoperative mortality and complications.[21]
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