The following laboratory tests may be indicated for differential
diagnoses, to identify serious complications or to help distinguish one form of
kidney injury or disease from another.
Proteinuria/Urine
dipstick testing: The early and accurate assessment of proteinuria is a
critical aspect in the detection and management of kidney disease in people
living with HIV.8 Urinary dipstick tests
yield qualitative results. “Usually, if there is more than 2g/day (~ 2+ on a
dipstick) of proteinuria, the kidney disease is glomerular. Anything less can
come from tubulointerstitial or glomerular disease” according the South African
Handbook of HIV Medicine.
However, as noted in the first HATIP in this series, urine
dipstick tests for proteinuria aren’t perfect. They primarily measure albumin
and their accuracy is somewhat affected by urine concentration, hydration and
other factors, but they are inexpensive and relatively easy to perform even at
the primary care clinic level.
Urine spot protein creatinine ratios are the
ratio of grams of protein to creatinine measured in a urine specimen. These
ratios are a more accurate and sensitive measurement of proteinuria, especially
people with low levels of abnormal proteinuria (0.3 to 0.99
gp/gc).9 This
investigation may also prove more useful in detecting proteinuria due to renal
proximal tubular disorders (such as that due to tenofovir).
Haematuria: There are also
dipstick tests to detect red blood cells in the urine, haematuria. Whenever
there is evidence of haematuria, urine should be sent off for microscopy
(including bilharzia ova) bacterial culture and sensitivity and, importantly,
TB culture.10
Urine
microscopy: should look for red blood cells, white blood cells, casts (dead
cells from damaged kidney tissue) and crystals (drug precipitates).
Albumin: Albuminuria,
in the urine may be a marker of glomerular kidney disease, (however, the
measurement is not specific since it may also be elevated as a result of fever,
malignant hypertension or even vigorous exercise.
Urinary volume: Asking about or monitoring changes
in urine output may prove both helpful for isolating the cause (or site) of
acute kidney injury, and for staging AKI (see previous HATIP) after excluding
for urinary tract infections. Although some people with serious kidney disease
may experience no change in urine output, urine output is often reduced
(oliguria) or virtually absent (anuria). Oliguria is defined as a urinary
output of less than 400/mL per day, and sometimes occurs as a result of a
reversible cause of acute tubular necrosis, such as septic shock or dehydration
due to diarrhoea. When oliguria occurs in the context of other types of kidney
injury, it suggests a poorer prognosis. Anuria is output of less than 50-100 mL
of urine per day. If the onset has been sudden, it is generally due to a
bilateral obstruction (check for a palpable bladder), but it could also be
associated with a rapidly progressive acute glomerulonephritis leading to loss
of kidney function.
Malaria smears for microscopy should also be done in endemic regions, as malaria
can cause AKI, and should also be considered in the differential diagnosis of
some symptoms.
Serum urea/blood urea nitrogen: Azotemia (high
levels of urea in the blood) is generally asymptomatic but very high levels
(eg, two times normal) generally indicate kidney injury and may help identify
uraemia.
Serum
electrolyte assessments of sodium (Na+),
potassium (K+), chloride (Cl-), and bicarbonate, reveal fluid and electrolyte
disturbances that are quite common in people living with HIV. Theses imbalances
are sometimes due to kidney damage, but may be due to other serious illness as
well. Regardless, electrolyte imbalances can have important clinical
consequences. These include hyponatraemia,
low concentrations of sodium can result in fluid overload, and if the onset is
severe or abrupt, it may be associated with symptoms including nausea,
vomiting, fatigue, seizures and coma. Hypokalemia, abnormally low
potassium levels, is usually asymptomatic, although severely low potassium
levels can cause cardiac complications. Hyperkalaemia, high serum
potassium, can alter the electrical responsiveness of cells, nerves and
membranes in a number of organ systems, and may be associated with symptoms
such as lethargy and muscle weakness. If potassium levels are above 6.5mEq/L,
urgent correction is needed since it can pose a high risk of life-threatening
fatal arrhythmias and sudden death. Bicarbonate helps moderate blood pH, and
high plasma bicarbonate levels > 15mmol/L indicate metabolic acidosis.
FeNa is the Fractional Excretion of Sodium (Na+), which can provide an indication of whether there is an altered
excretion of sodium (perhaps due to tubular dysfunction):
FeNa = (Urine sodium ÷Serum sodium) / (Urine Cr ÷
Serum Cr)
Serum calcium: High levels are generally asymptomatic, but severe cases of hypercalcaemia, can be life-threatening
and require urgent management, presenting with confusion, coma or cardiac
arrhythmias. Hypercalcaemia can have a number of causes, including hyperparathyroidism secondary
to renal failure, and is sometimes seen in severe CKD. It can also lead to
pre-renal kidney failure and kidney stones.
Serum phosphate: Hyperphosphataemia
is sometimes seen in severe CKD. Hypophosphataemia may be an indicator of
tenofovir-related renal proximal tubule dysfunction.11 Note,
dysregulation of calcium and phosphate levels have been associated with
alternations in bone metabolism.12
Fasting glucose
levels are useful for the diagnosis of diabetes, and a host of other
conditions
Full blood
count: Special attention should be given to haemoglobin levels. According
to the South African HIV Handbook, “A
normal haemoglobin (>11g/dl) points towards an acute kidney illness, while a low haemoglobin, in the setting of
HIV infection could be due to a number of causes including chronic renal
failure.”
Serum creatinine levels can be
used to estimate glomerular filtration
rates (GFR) in patients whose levels are in a steady state, and serve as
the best marker of kidney dysfunction, used both for staging CKD and
recognising AKI. As noted in the first HATIP in this series, none of the three
equations to calculate the estimated GFR have been adequately validated in
people living with HIV or in different sub-Saharan African populations — and in
the two studies, factors to adjust for African-American ethnicity did not
appear to be appropriate in Ghanian or South African populations.
The HMA-IDSA guidelines recommend the simplified MDRD equation for
monitoring people living with HIV. However, the Cockcroft-Gault equation was
what was used to determine whether medication dosage adjustments are necessary.
It is unclear, to this author at least, how reliable the recommended dose
adjustments are in sub-Saharan African populations, until the equation
determining renal impairment is validated here. If Cockcroft-Gault
over-estimates kidney impairment here, the recommendations could lead to
underdosing a potentially significant number of people.
The simplified MDRD GFR (mL/min/1.73m2) = 186 x [serum creatinine
(mg/dL)] x [age (yr) x [0.742 if female] (with the ethnicity factor omitted).
CrCl (ml/min) = [140 – Age (yr)] x weight (kg) [0.85 in female] / (72 x serum creatinine (mg/dL)
Serum
anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, complement levels,
hepatitis B and C virus antibodies, syphilis serology (if a biopsy is
contemplated) can be useful in identifying when kidney disease may be
auto-immune related or potentially due to HBV, HCV or syphilis.
Lactate: increased lactate levels may occur as a result
of nucleoside analogue-associated lactic acidosis. Levels five times the upper
limit of normal are life-threatening.
Ultrasound scans
can
show whether a kidney is normally sized (normal 10-12cm), large, or shrunken or
whether there are obstructions in the urinary track. According to the South
African Handbook, small kidneys (<9cm) may point towards CKD, “whilst with
normal or big kidneys it is difficult to be sure as many HIV related
nephropathies cause increased size initially.”
Renal biopsy: Thedefinitive diagnosis of some types of
kidney disease cannot be made on clinical grounds alone, but requires a biopsy.
The South African HIV Handbook suggests considering a biopsy when there is
heavy proteinuria or in cases of acute kidney failure where the cause is not
immediately apparent (such as ATN).
But what does a kidney biopsy really involve? It may be
interesting to refer to patient directed educational materials from the
industrialised world and try to picture how what they describe would play out
in resource limited settings.
According to materials published by the National Kidney Federation
in the United Kingdom [see here],
many doctors in the UK
are cautious about recommending a kidney biopsy because it is a somewhat
invasive procedure and there is a small risk of bleeding afterwards. This risk
may be minimised by telling the patient to discontinue any drugs — including
aspirin — that thin the blood a couple of days before the procedure, and then
by assessing whether the patient’s blood clots properly (which it doesn’t
always do in people living with HIV and some forms of kidney disease) before
the procedure is performed.
The procedure is done under local
anaesthetic and, when guided by ultrasound or CT imaging, should take less than
a half hour to perform. Afterwards the patient needs to rest in a bed at the
facility for at least six hours and have their blood pressure and pulse
monitored. Their urine should be repeatedly tested for blood and they should be
given pain killers when the anaesthesia wears off. If there is no bleeding,
they may be sent home that same day, or possibly the next day. They should also
be told not to exercise for the next couple of days and to contact the facility
if there is any blood in their urine or if they develop severe pain.
The educational materials state that after
the procedure, about one out of ten cases have visible bleeding that resolves
by itself. One out of 50 have bleeding that requires a blood transfusion.
Complications that lead to surgery to stop the bleeding or in removal of the
kidney only occur in one out of 1500, and one out of 3000 respectively. The
risk of death is small.
Its not clear that these safety statistics would be matched in
many resource-limited settings outside of a good kidney unit, such as at Groote Schuur
Hospital in Cape Town — which incidentally performs
baseline biopsies on all of its patients with ESKD. But elsewhere, getting a
kidney biopsy may be easier said than done — even at tertiary hospitals in Africa. Even in South Africa, doctors on our
advisory panel told HATIP that kidney biopsies can be a bit difficult to
arrange within the public health system. Therefore, there needs to be a
compelling reason to believe that the biopsy findings will truly affect the course
of treatment and affect a patient’s clinical outcome. For many of the
conditions below, that does not appear to always be the case.