Increased Blood Creatinine Concentration, Egfr and Renal Function Tests

Essentials

• The principal renal function tests are plasma creatinine concentration, estimated glomerular filtration rate (eGFR) calculated from the creatinine concentration result and urinalysis.
• Impaired filtration rate with or without proteinuria and/or haematuria is suggestive of renal disease.
• If eGFR is over 60 ml/minute, no further investigations or follow-up are needed, unless other signs suggestive of renal disease are present (haematuria, proteinuria, microalbuminuria in a diabetic patient).

Findings suggestive of renal disease

• If the function of the kidneys is impaired
  • glomerular filtration rate (GFR) decreases and/or
  • higher than normal levels of protein, red blood cells or other substances are excreted in the urine.
• These processes may develop independently from each other: large amounts of protein may be excreted in the urine even when the GFR remains normal (e.g. nephrotic syndrome) and, on the other hand, a patient with severe renal failure may have a fairly normal urinalysis result (e.g. age-related ischaemic nephropathy, cystic renal disease).
• Screening for renal diseases and the initial laboratory diagnosis require only simple and inexpensive methods (fasting plasma creatinine/eGFR and urinalysis Urinalysis and Bacterial Culture). Follow-up investigations are based on the results of these tests.
• See proteinuria Proteinuria and haematuria Haematuria.

Measurement of renal function

• The determination of fasting plasma creatinine concentration remains the principal investigation both for screening purposes and in the monitoring of a patient with renal disease.The result is used to estimate calculatory eGFR (calculator program Gfr Calculator). Nowadays many laboratories provide an automatic estimation of GFR when determining creatinine concentration. The calculator should not be used when estimating eGFR in children.
• It is possible to determine the accurate GFR by using iohexol or a Cr-EDTA molecule with a radioactive label, but these techniques are not suitable for routine clinical practice.
• Plasma urea
  • Should not be used for screening purposes or initial investigations. Urea production by the body is influenced by the amount of protein intake and the rate of tissue breakdown. The concentration of urea in the plasma can be raised by, for example, increased tissue catabolism (infection, injury) and glucocorticoid medication.
  • Used in the monitoring of chronic renal failure to evaluate the degree of uraemia and in patients undergoing dialysis to assess the efficacy of the treatment.
• Cystatin C
  • A small protein produced in the body at a steady rate by nucleated cells.
  • Filtered freely through the glomerulus, reabsorbed within the renal tubule and almost completely degraded.
  • A better indicator of GFR than creatinine concentration, particularly in mild renal failure, but not better than eGFR. However, the investigation is more expensive than the creatinine determination. Recommended to be determined together with creatinine if the patient's muscle mass clearly deviates from normal.
    • For example, if slightly elevated plasma creatinine level is found as an incidental finding (and hence eGFR is, respectively, slightly decreased) and if urinalysis and urine cell count are normal (i.e. there is nothing abnormal in the urine), a normal plasma cystatin C level in practice excludes a kidney disease.

Creatinine as an indicator of renal function

• In addition to renal function, the patient's muscle mass influences the creatinine concentration.
  • Creatinine concentration may be above the reference range in a muscular man, even in the presence of normal renal function (in this case, cystatin C concentration is normal).
• With advancing age, some of the functional units of the kidneys, nephrons, are destroyed resulting in a diminished amount of glomerular filtrate. Creatinine concentration, however, usually remains stable as advancing age leads to a simultaneous loss of muscle mass.
  • For example, the GFR may be markedly reduced in an elderly, small woman even when her creatinine concentration is still within the reference range.
• The effect of sex and age can be reduced by using creatinine clearance or calculated estimates of GFR (eGFR).
• Formulas based on creatinine levels yield a good estimate of GFR and the stage of renal disease without the need for a urine collection.
• It should be borne in mind that the formulas will only give an estimate of GFR. CKD-EPI formula is used in current calculators.
• The calculation of eGFR is particularly justified if the patient has diabetic nephropathy or some other manifestation of renal dysfunction (proteinuria, haematuria). Especially in elderly patients eGFR helps in correct dosing of drugs that are eliminated through the kidneys.

Classification of renal failure

• The calculated eGFR can be used to stage renal disease as presented in table T1.

• Renal disease is clinically significant when eGFR falls below 60 ml/minute (stages 3-5).
• If eGFR is over 60 ml/minute, no further investigations or follow-up are needed, unless other signs suggestive of renal disease are present (haematuria, proteinuria, increased albuminuria in a diabetic patient).
• GFR falls with advancing age, and eGFR in an elderly person, calculated with the above formulas, is often decreased. In elderly patients, eGFR may be quite low (30-45 ml/minute) without it signifying the existence of a progressive renal disease, unless the patient has concomitant proteinuria, diabetes or uncontrolled hypertension.

Investigations of elevated creatinine concentration

• Check the patient's history: are there any underlying causative conditions?
  • Previous renal disease (creatinine concentration, proteinuria, haematuria)
  • Hypertension and possible medication
  • Other relevant underlying conditions (diabetes, atherosclerosis, prostatic hypertrophy, rheumatic disease, vasculitis, myeloma, sarcoidosis)
  • An effect of a medicine or other toxic factor (inflammatory drugs, ACE inhibitors, angiotensin receptor blockers, trimethoprim, diuretics, contrast media, substances used as alcohol substitutes)
• Physical examination
  • General condition (dehydration and fever indicate an acute illness)
  • Blood pressure (often elevated in renal disease, may be decreased if the patient is dehydrated)
  • Palpation and auscultation of the arteries (vascular disease)
  • Palpation of the abdomen (cystic kidneys, urinary retention)
  • Rectal examination (enlarged prostate, measurement of residual urine if indicated) Determining the Volume of Residual Urine by Ultrasonography
  • Oedema (nephrosis, low albumin)
• Other investigations indicated
  • Urinalysis, i.e. urine dipstick test, and, if indicated, an examination of urinary sediment and urine culture (other signs of renal disease)
  • Urinary albumin/creatinine ratio, and if it is abnormal, overnight collection for urinary albumin especially in diabetic patients or 24-hour urinary protein excretion
  • Basic blood count (anaemia, thrombocytopenia), CRP, ESR
  • Serum albumin (if severe proteinuria; > 3 g/24 hours)
  • Electrolytes (potassium, calcium, phosphate; the patient may have hyperkalaemia, hypo- or hypercalcaemia or hyperphosphataemia)
  • Ultrasound examination of the kidneys (size of the kidneys, parenchymal changes, hydronephrosis, cysts)

When to consult a specialist

• The reason for consulting a specialist is both to obtain diagnosis and to optimise the treatment of existing renal disease. After these have been achieved the patient may often return to the care of his/her own doctor.
• Emergency referral
  • When, in addition to renal failure, the patient is found to demonstrate signs or symptoms of an acute illness (e.g. fever, symptoms affecting the upper or lower respiratory tract or the joints). The patient may be undergoing a rapid deterioration of renal failure, and a quick diagnosis and initiation of treatment is important Acute Kidney Injury.
• Non-urgent referral
  • The cause of renal dysfunction, even if only discovered as an incidental finding, should be identified, particularly if the condition is progressing (increasing creatinine/decreasing GFR) or if other signs of renal disease coexist (proteinuria).
• No referral needed in the following situations:
  • the patient has severe comorbidities, and renal disease is of no particular significance as far as prognosis is concerned
  • an elderly patient has decreased eGFR (even to as low as 30-45 ml/min) but the condition is not progressive (plasma creatinine concentration is stable, not increasing), blood pressure is under control with medication and the patient has no metabolic problems associated with a renal disease (e.g. anaemia, hyperphosphataemia, acidosis) or significant proteinuria (over 0.5-1.0 g/24h).
• In problematic cases, a telephone consultation with a nephrologist should always be considered.