Buku Medicine

Proteinuria

Quick tip: 24 hour urine collections to quantify proteinuria have been replaced by use of either spot albumin:creatinine ratio or spot protein:creatinine ratio in almost all circumstances.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.

Urine dip

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

Test characteristics:

Reproducibility of ACR and PCR is very poor, and large changes (of 40-80%) are required to be confident the underlying disease has changed

Conversion:

Note that uACR and uPCR do not follow a linear conversion.

uACR (mg/mmol)	uPCR (mg/mmol)	Implication
>3	>15	‘A2’ in KDIGO CKD staging. If patient has diabetes begin ACEi/ARB and target BP <130/80.
30	50	‘A3’ in KDIGO CKD staging. If patient is hypertensive then preference for ACEi/ARB.
70	100	Equal to 1g of protein lost over 24 hours
250	300	‘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)
SGLT2-inhibitors
- 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.]
Spironolactone
Non-dihydropyridine calcium-channel blocker (diltiazem or verapamil)

References

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

Haematuria

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:

Transitional cell carcinoma
Renal cell cancer
Prostate cancer
UTI
Urethritis
Glomerulonephritis, including IgA nephropathy, Alport’s disease and thin basement membrane disease
Polycystic kidney disease
Kidney stones
Renal TB
Schistosomiasis

Visible haematuria

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:

rectal exam
PSA

Non-visible haematuria

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:

Haemoglobinuria secondary to rhabdomyolysis
Porphyria
Medications / foods / toxins – rifampicin, beets, lead poisoning

Parathyroid hormone

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:

Strongly associated with cardiovascular disease and mortality
Target level for PTH is between 2-9 times the upper limit of normal

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:

advising low phosphate dietary intake, with help from renal dietitian colleagues
phosphate binders, to decrease GI absorption
replacing inactive vitamin D orally (it is unclear whether this is beneficial, though it is often done and is not considered detrimental)
activated vitamin D products (reserved for severe and progressive hyperparathyroidism and dialysis dependant CKD)
calcimimetics such as cinacalcet lower PTH and serum calcium in tertiary hyperparathyroidism

See the app ‘Managing CKD Mineral Bone Disorder’ for more detail and for management algorithms for different biochemical parameters.

Bicarbonate level

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:

Increased risk of CKD progression
Bone demineralisation
Protein catabolism
Hyperkalaemia

Sodium bicarbonate therapy:

Starting oral dose of 500mg three times daily reasonable, with uptitration to 1g TDS if required and tolerated
Helps control hyperkalaemia
Side-effects include GI upset and increased pill burden
Unlike sodium chloride, it is not associated with hypertension, though levels above 26mmol/L are associated with increased heart failure and vascular calcification
If made NBM on admission to hospital is a non-urgent medication which can be safely omitted

"Renal screen" explained

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

Screen for granulomatosis with polyangiitis (GPA, previously Wegeners) and microscopic polyangiitis (MPA)
Often see progressive AKI associated with blood and protein on urinalysis
Usually have some extra-renal features present (eg. lethargy, malaise, haemoptysis, vasculitic rash, fever, mononeuritis, uveitis, ENT involvement, high inflammatory markers)
Relapsing and remitting conditions. Changing antibody titres over time correlate poorly with symptoms

Anti-GBM antibody

Progressive AKI, associated with blood and protein on urine dip
If renal and pulmonary involvement (haemorrhage) then known as Goodpasture’s syndrome
Renal prognosis poor if patient requires dialysis - need to test urgently and act quickly

Serum immunoglobulins, electrophoresis and serum free light chains

Myeloma can cause AKI without blood or protein seen on urine dip (remember that urinalysis detects albumin, not immunoglobulins)
Testing urine for Bence Jones protein is a less expensive alternative to testing serum free light chains but is less specific and therefore has been widely replaced by serum free light chain measurement
Maintain a low threshold for screening for myeloma in AKI, as smouldering myeloma can be unmasked by the oliguria of typical AKI insults

ANA, anti-double stranded DNA and related auto-antibodies

Screen for autoimmune disorders such as SLE, Sjogren’s syndrome and scleroderma which can be associated with AKI with blood and/or protein on urinalysis
Lupus nephritis often has extra-renal features such as rash, arthralgia, fatigue, and low C3 and C4
(In some labs these extended antibody panels will need to be requested individually; SCL-70, anti-centromere, Anti Ro/La under ENA (extractable nuclear antibody))

Complement studies

Usually C3 and C4 levels measured
High complement levels may indicate non-specific infection or inflammation and are not relevant clinically
Low levels seen in diseases in which complement proteins are consumed but also in malnutrition, severe sepsis and liver failure, and the sensitivity and specificity of the following is poor:
- Low C3, normal C4 consider bacterial endocarditis, C3 glomerulopathy, atypical HUS, post-infectious glomerulonephritis, cholesterol atheroemboli
- Low C4 consider SLE, cryoglobulinaemia
- Low C3 & C4 consider SLE

‘Haemolysis screen’

Send FBC, bilirubin, haptoglobin, LDH, direct antiglobulin test (DAT), reticulocyte count and an urgent blood film
Haemolysis can be associated with AKI when due to thrombotic microangiopathy (TMA), in which case fragmented red blood cells called shistocytes are observed on blood film. Usually see low Hb, low platelets, high LDH, low haptoglobin and high bilirubin due to haemolysis and TMA.
Causes of AKI with TMA include:
Haemolytic uraemic syndrome (HUS)
Thrombotic thrombocytopaenic purpura (TTP)
Atypical haemolytic uraemic syndrome (aHUS)
Infection, cancer, certain medications like tacrolimus and ciclosporin

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)

Marker of rhabdomyolysis, which can cause AKI
Commonly elevated after ‘long lie’ or strenuous exercise, but CK elevation can occur without muscle symptoms
Need to maintain high level of suspicion for rhabdomyolysis in COVID-19 and in the post-op patient (muscle breakdown due to positioning on operating table)
Levels have to be >5000 (usually >10,000) U/L to cause renal dysfunction

ASOT (Antistreptolysin O titre)

Occasionally can help diagnose post-infectious glomerulonephritis as cause of AKI, typically several weeks after a throat or skin infection
False negative result common
If positive, need to ensure patients have received a full course of anti-strep antibiotics to eradicate group A strep

Nephrotic syndrome = high urine PCR >300mg/mmol, peripheral oedema, low serum albumin <30g/L, hypertension (see separate section on nephrotic syndrome)

Consider requesting:

Cholesterol levels – nephrotic syndrome is also associated with hypercholesterolaemia
Coagulation and group & save – renal biopsy often required to make diagnosis
ANA and dsDNA – SLE can cause nephrotic (or nephritic) syndrome
Complement C3 and C4 levels
HIV, Hep B and Hep C
Blood glucose and HbA1c – diabetes is the most common cause of nephrotic syndrome, though nephrotic syndrome is a late feature of diabetes rather than a presenting complaint. Additionally, given steroid therapy is a common treatment in nephrotic syndromes it is useful to identify glucose intolerance prior to treatment.
Serum immunoglobulins, electrophoresis and serum free light chains – acts as screen for amyloidosis, though normal results will not rule out the diagnosis.
Anti-PLA2R – specialist autoantibody test to diagnose primary membranous nephropathy

Renal ultrasound findings

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

Exclude hydronephrosis
Measure kidney size
Confirm two kidneys present
Occasionally give the diagnosis e.g polycystic kidneys

Increased kidney size bilaterally, with normal kidney function and echogenicity

Obesity
Tall stature
Steroid use
Acromegaly
Diabetes
Leukaemia infiltrating kidneys (very rare)

Asymptomatic, unilateral increase in kidney size

Hypertrophy of one kidney due to decreased function of the other (eg. unilateral renal artery stenosis)
Leukaemia (though usually affects both kidneys)

Symptomatic, unilateral increase in kidney size

Unilateral obstruction
Pyelonephritis
Acute vascular insult eg. renal vein thrombosis

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

Glomerulonephritis
Acute interstitial nephritis
Amyloid
Multiple myeloma
HIV nephropathy
Pre-eclampsia

Decreased cortical echogenicity

Acute cortical necrosis
Oedema

Increased medullary echogenicity (normal cortex)

Nephrocalcinosis
Urate nephropathy
Sickle cell disease
Sjogren's syndrome
Medullary sponge kidney

Transplant meds levels

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:

rejection risk
infection and cancer risk
other immunosuppression taken
time since transplant
current clinical situation

As a rough rule of thumb, if used within a combination of immunosuppression and over one year since transplant, reasonable targets levels are:

Tacrolimus 3-7ng/L
Ciclosporin 100-150ng/L
Sirolimus 4-7ng/L

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.

References

https://renal.org/information-resources/the-uk-eckd-guide/proteinuria/

https://www.baus.org.uk/professionals/baus_business/publications/17/haematuria_guidelines/

‘Managing CKD Mineral Bone Disorder’ - recommended app

https://cjasn.asnjournals.org/content/9/2/382