Quick tip: 24 hour urine collections to quantify proteinuria have been replaced by use of either spot albumin:creatinine ratio or spot protein:creatinine ratio in almost all circumstances.
Detecting proteinuria is important in the management of many renal diseases, from referral criteria to thresholds for starting treatments. Higher levels of proteinuria are associated with higher risk of progression of chronic kidney disease and long-term cardiovascular mortality.
Detects albumin in urine (beware: will not detect rarer causes of significant proteinuria, such as immunoglobulin light chains or monoclonal globulin e.g. Bence Jones Protein)
Heavy proteinuria indicates pathological leak across the glomerulus, though at lower levels proteinuria can be from tubular injury
Will miss low level albuminuria, and results are only semi-quantative
Performing urinalysis in AKI is vital as presence of blood and protein can indicate glomerular injury and make the diagnosis of glomerulonephritis more likely
Monitoring urinalysis in multi-system diseases can pick up renal involvement before creatinine rises, and the development of proteinuria in a renal transplant may indicate rejection
Urinary albumin:creatinine ratio (uACR)
Measures the amount of albumin in the urine. Given level of albuminuria will be affected by how dilute the urine is from hour to hour, it is indexed against the amount of creatinine in the urine to correct for dilution. Patients with diabetes should undergo regular urinary ACR screening for renal disease.
Urinary protein:creatinine ratio (uPCR)
This test measures all the protein in the urine (ie. albumin plus other proteins), and therefore the uPCR is always higher than the uACR. Outside of using ACR in diabetes, there is no consensus on whether using uPCR or uACR is preferable.
Multiple myeloma, in which little albumin is excreted in urine but large amounts of immunoglobulin spill into the urine (Bence Jones proteins), will classically show a low ACR and high PCR pattern
There are many causes of low grade proteinuria:
Physiological: standing for a long time, exercise, high protein diet or training supplements, fever
Pathological: diabetes, hyperfiltration, pre-eclampsia, glomerulonephritis, interstitial nephritis, pyelonephritis, renal vein congestion
Reproducibility of ACR and PCR is very poor, and large changes (of 40-80%) are required to be confident the underlying disease has changed
Note that uACR and uPCR do not follow a linear conversion.
‘A2’ in KDIGO CKD staging. If patient has diabetes begin ACEi/ARB and target BP <130/80.
‘A3’ in KDIGO CKD staging. If patient is hypertensive then preference for ACEi/ARB.
Equal to 1g of protein lost over 24 hours
‘Nephrotic range’ proteinuria
There is strong evidence that benefit derived from ACEi in proteinuric kidney disease correlates with degree of proteinuria reduction, and nephrologists endeavour to maximise the ACEi dose if tolerated.
Second line therapies for proteinuria reduction are supported by a much weaker evidence base but include:
Addition of ARB to ACEi (specialist led)
There is strong evidence for the use of ACEi/ARBs and SGLT2-inhibitors in reducing levels of proteinuria and slowing progression of CKD [Heerspink et al.]
Non-dihydropyridine calcium-channel blocker (diltiazem or verapamil)
Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. PMID: 32970396. H.Heerspink et.al
Quick tip: being on an antiplatelet or anticoagulant is not an adequate explanation for haematuria
There is a broad differential for visible and non-visible haematuria including:
Visible (previously labelled ‘frank’) haematuria is frequently due to cancer. It requires severe cystitis to be due to infection, and is only rarely due to nephritis such as IgA nephropathy or post-infection glomerulonephritis.
NICE referral criteria:
Refer to Urology to rule out bladder/renal cancer if aged >45 and:
Visible haematuria when no UTI
Visible haematuria that persists/recurs after treatment of UTI
Also refer visible haematuria to Urology if aged <45, though as 'urgent' rather than under 2 week wait.
Visible haematuria also meets British Association of Urological Surgeons (BAUS) criteria for needing:
Definition: at least one + (not trace) of blood on dip AND
on TWO occasions within 6 weeks (and while without UTI) OR
if 2 out of 3 reagent strips are positive (NICE guidelines)
Trauma and menstruation should be excluded. Microscopy is not required to confirm positive result.
If aged >60 refer:
non-visible haematuria meeting definition under 2 week wait to Urology if ALSO have either i) high serum WCC, or ii) dysuria
recurrent UTI should be routinely referred to Urology for cancer rule out even if no dipstick haematuria
If age 40-59:
BAUS recommend non-urgent Urology referral for asymptomatic non-visible haematuria to rule out bladder cancer (0.8% of referrals aged 40-59 have bladder cancer, though likelihood higher if personal history of immunosuppression or cyclophosphamide exposure)
Refer asymptomatic non-visible haematuria to renal if ACR >30, hypertensive (>140/90) or meets eGFR criteria (differential diagnosis includes IgA nephropathy, Alport syndrome, thin basement membrane disease)
If there is persistent non-visible haematuria without proteinuria, after urological investigation NICE CKD guidelines recommend annual monitoring of blood pressure, eGFR and urinalysis for as long as the non-visible haematuria persists. This can be done in primary care.
Other causes of red urine include:
Quick tip: elevation in PTH in patients with CKD is a chronic problem from which the patient will come to no harm in the short term - management can be led by the renal team as an outpatient
PTH levels increase as CKD progresses, initially as an adaptive mechanism to increase phosphate loss in the urine, to compensate for decreased phosphate filtration. However, as PTH levels rise, so does the risk of CKD mineral bone disease (CKD-MBD).
Key facts regarding CKD-MBD:
Treatment is usually started in CKD stages 4 or 5, and is aimed at decreasing phosphate and PTH levels while keeping calcium within the normal range. This is achieved by:
See the app ‘Managing CKD Mineral Bone Disorder’ for more detail and for management algorithms for different biochemical parameters.
In the outpatient setting, patients with CKD may be prescribed oral sodium bicarbonate to counteract the associated metabolic acidosis. It is common practice to consider replacement when levels around <20mmol/L, and then to target the normal range. Patient are advised to decrease dietary acid load (eg. from animal protein) and to increase dietary base intake (eg. increase fruit and vegetable intake), though given dietary limitations on potassium intake this can be difficult.
Serum bicarbonate levels of <22mmol/L are associated with:
Sodium bicarbonate therapy:
Quick tip: have a low threshold to test for HIV, and hepatitis B and C in severe AKI. It is highly beneficial for resource planning of isolation rooms to have virology status confirmed prior to need for emergency haemodialysis.
The below hopes to outline the common blood tests requested to investigate AKI in specific situations, but does not represent a ‘screening panel’ that should always be sent in all patients with AKI.
ANCA autoantibodies = MPO & PR3 autoantibodies
Serum immunoglobulins, electrophoresis and serum free light chains
ANA, anti-double stranded DNA and related auto-antibodies
TTP is a medical emergency, if there is concern regarding a possible TMA you need to seek urgent haematology advice. An urgent blood sample for ADAMTS13 activity levels is the diagnostic test, though if TTP is suspected plasma exchange should be started as an emergency prior to the result being available.
Creatine kinase (CK)
ASOT (Antistreptolysin O titre)
Nephrotic syndrome = high urine PCR >300mg/mmol, peripheral oedema, low serum albumin <30g/L, hypertension (see separate section on nephrotic syndrome)
Quick tip: usual findings in long-standing CKD are small kidneys on ultrasound with a thin cortex, increased echogenicity and loss of corticomedullary differentiation
Quick tip: In the setting of abnormal kidney function, an USS is helpful to
Increased kidney size bilaterally, with normal kidney function and echogenicity
Asymptomatic, unilateral increase in kidney size
Symptomatic, unilateral increase in kidney size
Varying echogenicity is not a reliable way to distinguish different causes of AKI, but in conjunction with the clinical picture may make certain conditions more or less likely.
Normal or increased echogenicity with reduced kidney function
Decreased cortical echogenicity
Increased medullary echogenicity (normal cortex)
Quick tip: patients will usually take twice daily immunosuppressants at 10am and 10pm - this leaves time in the morning for trough levels to be taken before the dose.
Quick tip: it can take several days in some centres to get tacrolimus and ciclosporin results, so the patient should continue taking their usual dose while results are awaited
Renal transplant medications with commonly measured levels include tacrolimus, ciclosporin and sirolimus.
All levels must be taken as trough levels, before the morning dose.
Target ranges will be patient specific, factoring in:
As a rough rule of thumb, if used within a combination of immunosuppression and over one year since transplant, reasonable targets levels are:
However, clearly, one should always discuss target levels and clinical situation of specific patients with the transplant team who knows the patient.
There is no widely available laboratory test to measure mycophenolate levels.
‘Managing CKD Mineral Bone Disorder’ - recommended app