# 21.3 Clinical presentation of renal disease 4764 R

# 21.3 Clinical presentation of renal disease 4764 Richard E. Fielding and Ken Farrington

ESSENTIALS
Renal disease may present in many ways, including (1) the screening 
of asymptomatic individuals; (2)  with symptoms and signs re-
sulting from renal dysfunction; and (3) with symptoms and signs of 
an underlying disease, often systemic, which has resulted in renal 
dysfunction.
History and clinical signs—​in many cases these are nonspecific or 
not apparent, and detection of renal disease relies on a combination 
of clinical suspicion and simple investigations, including urinalysis 
(by dipstick for proteinuria and haematuria, with quantification 
of proteinuria most conveniently performed by estimation of the 
albumin:creatinine ratio, ACR, or protein:creatinine ratio, PCR) and 
estimation of renal function (by measurement of serum creatinine, 
expressed as estimated glomerular filtration rate, eGFR).
Asymptomatic renal disease—​this is common and most often de-
tected as chronic depression of eGFR (known as chronic kidney dis-
ease, CKD), proteinuria, or haematuria, either as isolated features or 
in combination.
Symptomatic renal disease—​may present in many ways, including 
(1)  with features of severe chronic depression of GFR—​‘uraemia’, 
manifesting with some or all of anorexia, nausea, vomiting, fatigue, 
weakness, pruritus, breathlessness, bleeding tendency, apathy and 
loss of mental concentration, and muscle twitching and cramps; 
(2) acute kidney injury (AKI); (3) with urinary symptoms—​frequency, 
polyuria, nocturia, oliguria, anuria, and visible (macroscopic) haema-
turia; and (4) loin pain.
Specific renal syndromes—​these include (1) nephrotic syndrome—​
comprising oedema, proteinuria, and hypoalbuminaemia—​caused 
by primary or secondary glomerular disease; and (2) rapidly progres-
sive glomerulonephritis with AKI.
Other conditions—​renal disease may be associated with and 
present in the context of many underlying conditions, including 
(1)  diabetes mellitus; (2)  renovascular disease; (3)  myeloma and 
other malignancies; (4) infectious diseases, either as a nonspecific 
manifestation of the sepsis syndrome or as a specific complica-
tion of the particular infection (e.g. haemolytic uraemic syndrome, 
poststreptococcal glomerulonephritis, hantavirus infection, lepto-
spirosis, and HIV nephropathy); (5) systemic inflammatory diseases 
(e.g. systemic vasculitides, rheumatological disorders, sarcoidosis, 
and amyloidosis); (6) drug-​induced renal disease; and (7) pregnancy.
Introduction
Renal disease may present in a multitude of ways. In practice, it is 
usually detected as a result of:
	•	screening of asymptomatic individuals
	•	symptoms and signs resulting from renal dysfunction
	•	symptoms and signs of an underlying disease, often systemic, 
which has resulted in renal dysfunction
Symptoms and signs of renal pathology are often absent or subtle, 
even in the presence of significant disease, hence the detection of 
renal problems requires careful evaluation of the history and clin-
ical findings to assess the potential risk of underlying renal disease. 
This evaluation should focus on features of systemic and inflamma-
tory disease as well as those relating directly to the renal tract, and 
similarly a drug and obstetric history may help elucidate the cause 
of renal disease. However, in many cases the history and clinical 
signs are nonspecific or not apparent, with detection of renal disease 
relying on a combination of clinical suspicion and simple investiga-
tions, including urinalysis and estimation of renal function.
Presentation of asymptomatic renal disease
Asymptomatic renal disease is common and may often remain stable 
and undetected. However, some patients with asymptomatic disease 
are at increased risk of developing renal failure with the passage of 
time or in the event of intercurrent illnesses. Active screening for 
subclinical disease is thus carried out in certain subpopulations with 
the result that patients may be identified with abnormal renal func-
tion or with abnormalities on urinalysis that may indicate significant 
renal pathology. Examples of such screening include:
	•	screening patients in primary care—​general population screening 
via eGFR reporting (see ‘Asymptomatic renal dysfunction and 
21.3
Clinical presentation of renal disease
Richard E. Fielding and Ken Farrington


21.3  Clinical presentation of renal disease
4765
screening for chronic kidney disease’); monitoring of patients at 
‘high risk’ of developing renal disease (e.g. hypertension, diabetes, 
or multisystem disease); and occupational and insurance medicals
	•	screening patients admitted to hospital with acute illnesses—​as an 
incidental finding, and as part of renal and electrolyte surveillance 
in patients at risk (e.g. in the presence of sepsis, hypovolaemia, and 
usage of nephrotoxic drugs)
	•	incidental finding on abdominal imaging—​stones, cysts and tu-
mours, or reduced renal size
	•	screening of the family members of patients with inherited renal 
disease
Asymptomatic renal dysfunction and screening 
for chronic kidney disease
Traditionally, the main means of assessing renal function has been 
estimation of serum creatinine, and this can be used—​with or 
without estimation of urinary creatinine excretion—​to estimate 
the GFR, as described in Chapter 21.4. The Cockcroft–​Gault equa-
tion, which estimates creatinine clearance from serum creatinine, 
weight, age, and sex, has largely given way as a screening tool to the 
Modification of Diet in Renal Disease (MDRD) formula, which in 
its simplest form generates an eGFR normalized to body surface area 
from serum creatinine, age, sex, and race. Using this method, popu-
lation studies have estimated the global prevalence CKD as around 
15%, with that of moderate to severe kidney failure (eGFR <60 ml/​
min per 1.73 m2 body surface area—​stage 3 to 5 CKD) as around 8% 
(Fig. 21.3.1). Over 90% of these subjects have CKD stage 3 (eGFR 
30–​59 ml/​min/​1.73m2), most of whom are elderly, and it is notable 
that very few progress to require treatment for endstage kidney dis-
ease (ESKD). Over a five-​year period, only around 1 to 3% of people 
with CKD stage 3 progress, compared with about 20% of those with 
CKD stage 4, but it is increasingly recognized that CKD is an im-
portant risk factor for cardiovascular mortality. People with CKD 
are around 10 times more likely to die than to progress to ESKD, 
with cardiovascular disease being the commonest cause of death.
Population and ‘risk group’ screening 
for renal dysfunction
Population data suggest that most renal disease identified by 
screening is not progressive, but there are subpopulations in which 
progressive renal disease is more likely and in whom early inter-
vention and optimal management may delay or prevent the need 
for dialysis. Hence in the United States of America and the United 
Kingdom, guidelines have been drafted in which ‘risk groups’ are 
screened for renal dysfunction/​CKD (Box 21.3.1). It is not yet 
known whether screening for renal dysfunction has any effect on 
outcome, but in the United Kingdom, data on the prevalence of CKD 
and associated information such as blood pressure measurement, its 
control, and the use of angiotensin-​converting enzyme (ACE) in-
hibitors in the CKD population, were incorporated into the Primary 
Care Quality and Outcomes Framework, which linked funding to 
the achievement of targets. As a consequence, there has been a sub-
stantial rise in the number of patients identified with asymptom-
atic renal dysfunction, and an increased rate of referral to secondary 
care, especially of elderly patients. There is still considerable doubt 
about the validity and value of labelling many very elderly people as 
having moderate to severe renal failure, especially since in many pa-
tients an eGFR in this range seems to confer a very much higher risk 
of cardiovascular demise than of ESKD.
Stage 3
(7.6%)
Stage 2
(3.9%)
Stage 1
(3.5%)
Stage 4
(0.4%)
Stage 5
(0.1%)
Fig. 21.3.1  Global prevalence of chronic kidney disease (CKD stages 
1–​5) in the general population. Overall global prevalence of CKD (stages 
1–​5) has been reported as over 15%.
Box 21.3.1  Summary of United Kingdom guidelines for serum 
creatinine measurement and estimation of GFR
Serum creatinine concentration should be measured at initial assess-
ment and then at least annually in all adult patients with the following 
conditions:
	•	 Previously diagnosed CKD:
	
—​	 Persistent proteinuria
	
—​	 Unexplained haematuria
	
—​	 Identified renal pathology
	•	 Conditions associated with a high risk of developing obstructive 
kidney disease:
	
—​	 Bladder voiding dysfunction (outflow obstruction, neurogenic 
bladder)
	
—​	 Urinary diversion surgery
	
—​	 Urinary stones
	•	 Conditions associated with a high risk of silent development of paren-
chymal kidney disease:
	
—​	 Diabetes
	
—​	 Hypertension
	
—​	 Cardiovascular disease—​ischaemic heart disease, chronic heart 
failure, peripheral vascular disease, and cerebrovascular disease
	•	 Conditions requiring long-​term treatment with potentially nephro-
toxic drugs:
	
—​	 ACE inhibitors, angiotensin receptor blockers, NSAIDs, lithium, 
mesalazine, ciclosporin, and tacrolimus
	•	 Multisystem diseases that may involve the kidney:
	
—​	 Systemic lupus erythematosus
	
—​	 Systemic vasculitides
	
—​	 Myeloma
	
—​	 Rheumatoid arthritis
	
—​	 Individuals with a family history of stage 5 CKD or hereditary renal 
disease


section 21  Disorders of the kidney and urinary tract
4766
Employment or insurance health screening
As well as targeted screening of ‘at-​risk’ populations, asymptom-
atic renal disease may also be identified as a result of employment 
or insurance health screening. Common abnormalities identified 
are hypertension or abnormal urinalysis, such as proteinuria and 
nonvisible (microscopic) haematuria. Patients identified in this way 
will often be referred for subsequent investigation.
Screening for renal dysfunction in secondary care
In the secondary care setting, patients in specialist clinics who are 
at risk of renal disease, such as patients with diabetes, are periodic-
ally screened for the development of hypertension, proteinuria, and 
renal dysfunction. Renal disease also often presents in acute med-
ical and surgical patients, with up to 15% of patients admitted as 
emergencies to hospital suffering some acute deterioration of kidney 
function, mostly due to hypotension, sepsis, or the use of nephro-
toxic drugs (see Chapter 21.5). Monitoring renal function in such 
patients may help in the acute management of their illness and may 
also identify those with underlying chronic renal impairment who 
require long-​term management.
Screening for drug-​induced renal disease
Renal disease resulting from the use of nephrotoxic drugs is often 
asymptomatic, and CKD may develop as a result of long-​term use 
of agents such as nonsteroidal anti-​inflammatory drugs (NSAIDs), 
lithium, and calcineurin inhibitors. Often the only evidence for this 
is a progressive rise in serum creatinine and fall in eGFR, which may 
be progressive and—​if not detected by routine screening—​may pre-
sent with advanced renal failure. Other drugs such as ACE inhibitors 
may cause an acute deterioration in renal function, screening for 
which is required, especially in high-​risk groups.
Other incidental findings of renal disease
Subclinical renal disease may also present as an incidental finding 
on biochemical testing, for example, abnormalities of potassium 
and acid–​base homeostasis identified on a ‘routine’ sample may in-
dicate a renal tubular acidosis and prompt further investigation for 
an underlying cause.
Renal disease identified incidentally with imaging
Advances in imaging technology combined with their widespread 
use have increased the number of incidental renal abnormalities 
identified. Many of these are anatomical abnormalities which are of 
little consequence, such as duplex ureters and isolated renal cysts, 
but significant pathology is sometimes found incidentally, such as 
polycystic kidneys, renal tumours, and asymmetrical kidneys.
Family screening for renal disease
Patients with a family history of inherited renal disease may also 
be identified with early, asymptomatic renal disease as a result of 
screening. The most common example is autosomal dominant poly-
cystic kidney disease, which may be reliably identified by ultrason-
ography from the third decade onwards. The identification of disease 
genes for inherited renal diseases such as autosomal dominant poly-
cystic kidney disease, tuberous sclerosis, von Hippel–​Lindau dis-
ease, Alport’s syndrome, and congenital nephrotic syndrome raises 
the possibility of future antenatal screening and early detection of 
these diseases long before they become clinically manifest.
Proteinuria
Detection of proteinuria
The availability of reliable and cheap urine dipstick reagent strips has 
led to their widespread use to screen for and monitor renal disease in 
primary and secondary health care (Fig. 21.3.2).
Most multireagent strips are sensitive to 100 to 200 mg/​litre of pro-
tein, giving either a ‘trace’ or ‘+’, although some designed to screen 
for microalbuminuria are more sensitive. Within the general popu-
lation, up to 5% of apparently healthy adults and 16% of those aged 
over 80 years have either a ‘trace’ or ‘+’ of protein, but most of these 
do not have significant treatable disease, making routine population 
screening uneconomic and unnecessary. Reagent strips do not de-
tect low molecular weight proteins such as immunoglobulin light 
chains, and thus assay of light chains using urine immunoelectro-
phoresis is essential as part of the investigations for myeloma, pri-
mary amyloidosis, and light-​chain glomerulopathy.
The kidney normally excretes less than 150 mg of protein in 24 h, 
mainly due to failed tubular reabsorption of albumin. Urinary pro-
tein excretion also reduces overnight while recumbent, but increases 
during the day owing to posture and exercise. Urinary protein con-
centration also depends on urine flow rate. To overcome the di-
urnal variation, proteinuria has been traditionally evaluated from 
a 24-​h urine collection, but these have been largely superseded by 
measuring the ratio of albumin or protein to creatinine in the urine 
(albumin:creatinine ratio, ACR; protein:creatinine ratio, PCR). This 
method has been validated against 24-​h urinary collections and—​as 
a rule of thumb—​a urinary ACR of 70 mg/​mmol or PCR of 100 mg/​
mmol equates approximately to a 24-​h protein excretion of 1 g/​24 h.
Screening for proteinuria
Guidelines aimed at identifying subclinical renal disease recom-
mend screening for proteinuria only for patients with renal disease 
or at increased risk of renal disease. The guidelines recommend use 
of the urinary ACR rather than standard reagent sticks in this popu-
lation. Current United Kingdom guideline recommendations (2014) 
for screening in this population are summarized in Box 21.3.2.
Approach to patient with proteinuria
Proteinuria may be an early presentation of renal disease, but tran-
sient proteinuria is not associated with significant renal disease. 
A finding of proteinuria should lead the physician to take a his-
tory focusing on risk factors for renal disease (e.g. diabetes, drugs, 
Fig. 21.3.2  Multireagent test strips used to screen patients for 
proteinuria and nonvisible haematuria.


21.3  Clinical presentation of renal disease
4767
multisystem disease, and family history), to measure the blood pres-
sure, and examine for oedema (Box 21.3.3).
In the absence of risk factors or signs of renal disease, transient 
proteinuria is not likely to indicate underlying renal disorder, hence 
an initial finding of proteinuria on dipstick testing should be re-
peated a week or so later, and any positive result confirmed and 
quantitated by estimation of ACR (or PCR). If postural or ortho-
static proteinuria is suspected, an early-​morning urine specimen 
should be sent for ACR (or PCR). The diagnosis is substantiated by 
the finding of normal urinary protein excretion in this specimen.
Management of asymptomatic proteinuria
Persistent proteinuria (ACR >70 mg/​mmol, PCR >100 mg/​mmol) 
on two or more occasions requires further investigation with:
	•	renal function (eGFR)
	•	serum albumin, for diagnosis of nephrotic syndrome
	•	serum paraprotein electrophoresis and urinary Bence Jones pro-
tein for myeloma
	•	immunological screen (antinuclear antibodies, complement, 
antineutrophil cytoplasmic antibodies (ANCAs))
	•	renal ultrasonography
	•	consideration of renal biopsy
The presence of nonvisible haematuria in addition to proteinuria im-
plies a high likelihood of intrinsic renal disease. It may be the first sign 
of a severe glomerulonephritis, perhaps in relation to multisystem 
disease. Apparently asymptomatic patients with persistent protein-
uria and haematuria may describe subtle symptoms on close ques-
tioning (e.g. myalgia, arthralgia, ‘sinusitis’, rash, or fever) which may 
be clues to an underlying multisystem disorder. Nephrology referral 
for further investigation, including serum ANCAs, antiglomerular 
basement membrane (anti-​GBM) antibodies, antinuclear and anti-​
double-​stranded DNA antibodies, complement levels, and renal bi-
opsy, is indicated. Those with abnormal renal function, haematuria, 
and proteinuria require urgent referral.
Asymptomatic nonvisible haematuria
Nonvisible haematuria may potentially arise from anywhere in the 
urinary tract. As with renal dysfunction and proteinuria, isolated 
nonvisible haematuria, that is in the absence of other features of 
renal disease—​hypertension, renal impairment, proteinuria, sys-
temic disease, or a family history of renal disease—​is common. 
Population studies indicate a prevalence between 0.2 and 16%, with 
a higher prevalence of up to 18% in men aged over 50 years. Studies 
of male army recruits screened and followed up for 12 years showed 
that 39% had nonvisible haematuria on one occasion, and 16% had 
nonvisible haematuria on two or more occasions. Although isolated 
nonvisible haematuria may be associated with benign glomerular 
disease, in practice, the main concern is the possibility of urinary 
tract malignancy.
Urothelial and bladder carcinomas account for approximately 5% 
of nonvisible haematuria. This risk increases with age, particularly in 
men over the age of 65 years. In contrast, underlying malignancy in 
those younger than 40 years is very rare, particularly in the absence 
of risk factors such as smoking and exposure to azo dyes.
Causes of nonvisible haematuria
The causes of nonvisible haematuria are summarized in Box 21.3.4. 
The true prevalence of intrinsic renal disease is unknown because 
renal biopsies are not routinely performed in the absence of protein-
uria or abnormal renal function. However, small biopsy studies of 
patients with no other cause for haematuria identified a glomerular 
cause in 16 to 30%. Within this group, IgA nephropathy and thin 
basement membrane disease are most common.
Management strategy for nonvisible haematuria
The key to managing patients with asymptomatic nonvisible haema-
turia is identifying risk factors for malignancy. In routine practice, 
patients older than 50 years, smokers, or those with an occupational 
history of dye exposure should be investigated for malignancy and 
referred to a urologist for cystoscopy.
Numerous different approaches to the management of patients 
with nonvisible haematuria have been published, reflecting a lack 
of consensus and an insufficient evidence base. There are no in-
dications for screening for nonvisible haematuria as the positive 
Box 21.3.2  United Kingdom guidelines for screening 
for albuminuria in patients at risk of CKD
ACR estimation should be carried out in people with:
	•	 diabetes
	•	 hypertension
	•	 cardiovascular disease (ischaemic heart disease, chronic heart failure, 
peripheral vascular disease, or cerebral vascular disease)
	•	 structural renal tract disease identified on imaging
	•	 recurrent renal calculi or prostatic hypertrophy
	•	 multisystem diseases with potential kidney involvement—​for example, 
systemic lupus erythematosus, vasculitis, and myeloma
	•	 family history of ESKD (glomerular filtration rate <15 mL/​min per 1.73 m2) 
or hereditary kidney disease
	•	 opportunistically detected haematuria
	•	 following an episode of AKI if the GFR remains below 90 mL/​min 
per 1.73m2
Box 21.3.3  Approach to the patient 
with dipstick-​positive proteinuria
Key features to establish
	•	 Is there any evidence of urinary tract infection?
	•	 Is there any evidence of diabetes?
	•	 Are there any risk factors for, or signs of, renal disease?
	•	 Is proteinuria transient or persistent?
Transient proteinuria
Causes include:
	•	 urinary tract infection
	•	 fever
	•	 exercise
	•	 orthostatic proteinuria
Persistent proteinuria
	•	 Send urine for spot ACR (or PCR)
	•	 Evaluate risk factors for renal disease:
	
—​	 Diabetes, hypertension, systemic inflammatory disease, myeloma, 
and family history of renal disease
	
—​	 Are there any features of nephrotic syndrome (heavy proteinuria 
with oedema and low serum albumin)?


section 21  Disorders of the kidney and urinary tract
4768
predictive value for malignancy is as low as 5% in an elderly popu-
lation, and there is little evidence that early detection of disease im-
proves prognosis.
Following the detection, on urine dipstick, of nonvisible haema-
turia without proteinuria, a history of recent menstruation, exercise, 
or sexual activity should be elicited and the urine sent for micros-
copy and culture. Urinalysis should be repeated after 7 days. If still 
positive for blood, in the absence of urinary tract infection, further 
evaluation is required including measurement of blood pressure, 
urinary ACR or PCR, and serum creatinine/​eGFR.
Patients should be referred to urological services to exclude 
urinary tract malignancy and disease if they are over 40 years of 
age with:
	1.	 persistent asymptomatic haematuria (defined as two out of three 
positive dipsticks), or
	2.	 symptomatic nonvisible haematuria, or
	3.	 visible haematuria
Patients should be referred to a nephrologist if a urological cause has 
been excluded, or the criteria for urological assessment are not met, 
and the patient has:
	1.	 declining GFR, or
	2.	 CKD stage 4 or 5, or
	3.	 proteinuria with urinary PCR greater than 50 mg/​mmol or ACR 
greater than 30 mg/​mmol, or
	4.	 age less than 40 years and hypertension
Patients not meeting criteria for referral to urological or renal 
services, or who have had negative urological or nephrological in-
vestigations, need long-​term monitoring in primary care due to the 
uncertainty of the underlying diagnosis, with appropriate referral 
should they develop:
	1.	 voiding lower urinary tract symptoms, or
	2.	 visible haematuria, or
	3.	 significant or increasing proteinuria, or
	4.	 progressive renal impairment (falling eGFR), or
	5.	 hypertension
Symptomatic renal disease
Many patients with renal disease remain asymptomatic, but others 
develop symptoms that may be nonspecific (e.g. due to the gradual 
onset of uraemia in patients with progressive CKD), renal spe-
cific (e.g. loin pain or polyuria), or unrelated to the kidney and 
manifesting as isolated ‘nonrenal’ symptoms or as a constellation 
of symptoms suggestive of a particular systemic condition. Key 
features to establish are the duration of symptoms, the presence of 
nonspecific symptoms possibly related to uraemia, the presence of 
specific renal symptoms, and the presence of symptoms possibly in-
dicative of systemic disease.
Chronic kidney disease
The symptoms of CKD are attributed to the gradual onset of ur-
aemia, anaemia, and salt and water retention. Patients often develop 
these slowly and may not report them until renal function is severely 
impaired, perhaps even an eGFR as low as 10 ml/​min per 1.73 m2 or 
less. The number of symptoms and their severity tend to increase 
as renal function declines, forming a spectrum from asymptomatic 
to overtly symptomatic uraemia. Symptoms and the level of eGFR 
may not correlate well: some patients with an eGFR of 15 to 20 ml/​
min per 1.73 m2 may be symptomatic, whereas a few with an eGFR 
around 5 ml/​min per 1.73 m2 may be remarkably symptom free.
Most patients have some symptoms by the time that they start 
dialysis. Indeed, the presence of uraemic symptoms in the context 
of CKD stage 5 (eGFR <15 ml/​min per 1.73 m2) (Box 21.3.5) is 
now considered the indication to start dialysis. These include anor-
exia, nausea, and vomiting (in 76% of patients), fatigue and weak-
ness (72%), pruritus (40%), breathlessness and orthopnoea (26%), 
bleeding tendency (14%), apathy and loss of mental concentration 
(12%), and muscle twitching and cramps (11%).
Factors contributing to the development of ‘uraemia’ and other 
symptoms include retention of small-​molecular nitrogenous sub-
stances and other end products of protein metabolism, metabolic 
acidosis, salt and water retention, disturbances of mineral metab-
olism (e.g. phosphate retention), malnutrition, and anaemia.
Some of these symptoms may be improved by treatment with 
agents such as erythropoietin, diuretics, and oral sodium bicar-
bonate, and dietary advice to improve malnutrition and phosphate 
control. Others respond to the initiation of dialysis. Some symptoms 
may persist in spite of all these measures.
It is unfortunately not uncommon for patients to present for the 
first time very late in the course of progressive CKD, with profound 
and symptomatic uraemia. This is the initial mode of presentation in 
Box 21.3.4  Causes of nonvisible haematuria without proteinuria
Glomerular disease
	•	 IgA nephropathy
	•	 Thin basement membrane disease
	•	 Hereditary nephritis (Alport’s syndrome)
	•	 Other glomerulonephritides (mesangiocapillary glomerulonephritis, 
vasculitis, lupus, etc.)
Nonglomerular renal disorders
	•	 Nephrolithiasis
	•	 Pyelonephritis
	•	 Renal cell carcinoma
	•	 Cystic kidney disease (polycystic and medullary sponge)
	•	 Trauma
	•	 Papillary necrosis
	•	 Ureteric strictures
	•	 Hydronephrosis
	•	 Sickle cell disease
	•	 Renal infarcts and arteriovenous malformations
	•	 Renal tuberculosis
Lower urinary tract disorders
	•	 Cystitis, prostatitis
	•	 Bladder carcinoma
	•	 Benign bladder and ureteral tumours and polyps
	•	 Urethral strictures
Miscellaneous
	•	 Exercise
	•	 Over-​anticoagulation
	•	 Factitious


21.3  Clinical presentation of renal disease
4769
around 20% of patients entering dialysis programmes in the United 
Kingdom, who tend to be older, more dependent, and with greater 
comorbidities than those presenting earlier. Late presentation pre-
sents major problems: it is not possible to plan dialysis initiation, and 
patient choice of modality is limited, with haemodialysis being the 
default mode. Furthermore, it is often not possible to create defini-
tive vascular access, hence patients often need to begin dialysis with 
temporary or semi-​permanent central venous lines. These and other 
features increase morbidity and mortality after late presentation.
It can be difficult and sometimes impossible to distinguish patients 
presenting late with advanced CKD (‘crash-​landers’) from those 
with severe AKI with potentially reversible causes. Failure to be-
come dialysis independent by 90 days after dialysis initiation is often 
taken as proof that the acute presentation was with ESKD rather 
than AKI. Patients who ‘crash-​land’ are often extremely unwell and 
may be obtunded with uraemic encephalopathy. Fluid overload is 
common, with pulmonary and peripheral oedema. Metabolic acid-
osis is often present and if severe may cause Kussmaul’s respiration 
as well as cerebral and cardiac depression. Patients may also show 
signs of muscle twitching, which may be a sign of hyperkalaemia or 
hypocalcaemia. A pericardial friction rub indicates uraemic pericar-
ditis, which if unrecognized may lead to pericardial tamponade and 
occasionally to fatal pericardial haemorrhage.
See Chapter 21.6 for further discussion of CKD.
Acute kidney injury
Acute kidney injury is discussed in detail in Chapter 21.5, but, in 
brief, causes can be classified as being prerenal, renal (due to intrinsic 
renal disease), or postrenal (obstruction). In the general hospital set-
ting, most cases are prerenal and occur as the result of reduced renal 
perfusion due to volume depletion (30%), cardiac failure (12%), and 
sepsis (12%). Drug-​induced kidney injury accounts for 30%, urinary 
tract obstruction 10%, and acute glomerular disease and acute inter-
stitial nephritis cause 5 to 10%.
Key features to establish sequentially when managing a patient 
with AKI are as follows:
	1.	 How ill are they? The condition of patients with similar bio-
chemical abnormalities can range from the asymptomatic to the 
moribund: those with cardiorespiratory compromise need crit-
ical care support.
	2.	 Does the patient need emergency haemodialysis or haemo­
filtration? The major indications are severe hyperkalaemia, 
pulmonary oedema, profound acidosis, and severe uraemia—​the 
latter being defined more on clinical than biochemical grounds.
	3.	 Is there a prerenal element that may respond to volume reple-
tion or inotropic support? Clinical examination, perhaps supple-
mented by central venous pressure measurement, facilitates this 
decision.
	4.	 Is the patient obstructed? Clinical features can be helpful, and 
ultrasonography of the urinary tract is usually diagnostic.
	5.	 Is this AKI or chronic renal failure? Sometimes this is difficult or 
impossible to determine on clinical grounds, but small kidneys 
on ultrasonography signify chronic disease.
	6.	 Is this intrinsic renal disease? Clinical features of systemic dis-
ease and relevant immunological tests (including ANCAs and 
anti-​GBM antibody) must be pursued, and renal biopsy will usu-
ally be required to establish the diagnosis.
As with CKD, many of the symptoms and signs attributed to loss of 
renal function are nonspecific and occur with advanced AKI (GFR 
<15 ml/​min per 1.73 m2). However, in contrast to CKD, the acute 
metabolic changes are often less well tolerated. The greatest danger 
is hyperkalaemia, which may develop quickly and is almost always 
asymptomatic until the onset of cardiac arrhythmias and potentially 
cardiac arrest. Other potentially life-​threatening features include 
pulmonary oedema, metabolic acidosis, and uraemic pericarditis.
The clinical context and history are of overriding importance in 
establishing the likely aetiology of AKI. A patient developing AKI 
after surgery is likely to have prerenal and acute tubular injury due 
to a combination of hypovolaemia, sepsis, and analgesia with an 
NSAID. A patient presenting acutely after a prolonged period of un-
consciousness following a drug overdose is likely to have rhabdo-
myolysis. A patient with a past history of lupus presenting with a 
recent fever, myalgia, and rash is likely to have rapidly progressive 
lupus nephritis. A patient with a history of lower urinary tract symp-
toms or of urinary stones is likely to have obstruction.
It is always important to consider the possibility of urinary tract 
obstruction as it may be readily reversible. Complete anuria is highly 
suggestive of total obstruction, although it may also occur in pa-
tients with rapidly progressive glomerulonephritis (RPGN) and 
those with acute obstruction of the renal arterial supply. However, 
urinary output is generally a poor guide to the presence of urinary 
tract obstruction, and a normal or even increased output does not 
exclude the diagnosis. All patients with unexplained AKI should 
undergo ultrasound imaging of the kidneys and urinary tract. This 
permits the diagnosis or exclusion of obstruction in most cases, and 
also allows renal size to be assessed: small kidneys indicate chronic 
renal failure.
It is important to emphasize that, after stabilization, patients in 
whom the clinical features and initial investigations do not give suf-
ficient clues to allow a diagnosis to be established will require a renal 
biopsy to avoid missing potentially reversible intrinsic renal disease. 
Details of important and common presentations of acute renal dis-
ease are discussed later in this chapter and in Chapter 21.5.
Urinary symptoms
Micturition
Most symptoms related to micturition relate to problems arising in 
the lower urinary tract. Bladder outflow obstruction is commonly 
Box 21.3.5  Features of uraemia and an eGFR less than 15 ml/​min 
per 1.73 m2 body surface area
	•	 Anorexia and malnutrition
	•	 Nausea and vomiting
	•	 Tiredness
	•	 Fluid overload with oedema, breathlessness, and orthopnoea
	•	 Anaemia
	•	 Pruritus
	•	 Mental apathy and depression
	•	 Muscle twitching, restless legs, and cramps
	•	 Bleeding tendency—​haematemesis, epistaxis
	•	 Sexual dysfunction—​loss of libido and impotence
	•	 Cardiac—​pericarditis


section 21  Disorders of the kidney and urinary tract
4770
associated with symptoms such as urgency, hesitancy, poor urinary 
stream, nocturia, dysuria, and dribbling. Recognition of these symp-
toms is important as outflow obstruction may result in complete ob-
struction with AKI or chronic obstructive uropathy with CKD.
Patients may also describe discomfort or pain on micturition. 
This symptom of dysuria may also be associated with burning within 
the urethra or suprapubic pain during or after micturition. When as-
sociated with urinary frequency or fevers in young women, dysuria 
is likely to be caused by a urinary tract infection. However, dysuria 
occurring in isolation in men of any age suggests structural lesions 
within the prostate or bladder and warrants further investigation. 
Perineal or rectal pain associated with micturition suggests prostatic 
inflammation, such as prostatitis or malignancy.
Frequency
Patients may present with symptoms of increased frequency of mic-
turition. In this situation, it is important to distinguish between 
frequent voiding of small volumes of urine and an overall increase 
in urinary volume with more frequent emptying of a full bladder. 
Charting urinary frequency and voided volumes over a number of 
days can allow these to be distinguished. The frequent passage of 
small volumes of urine suggests bladder irritation (from inflam-
mation, stone, or tumour) or reduced volume from extrinsic com-
pression or contraction (e.g. following radiotherapy). Increased 
frequency of emptying a full bladder is suggestive of polyuria.
Polyuria
Polyuria (defined as a urinary output >3 litres/​24 h) may result from 
solute diuresis, water diuresis, or a combination of both. Solute di-
uresis occurs in conditions such as hyperglycaemia and salt-​losing 
states (e.g. overuse of diuretics and salt-​losing nephropathies). Water 
diuresis may result from primary polydipsia, failure to synthesize 
or secrete ADH normally (congenital and acquired cranial diabetes 
insipidus), or failure of cortical and medullary collecting ducts to 
respond to ADH (congenital and acquired nephrogenic diabetes 
insipidus).
There are numerous causes of acquired nephrogenic diabetes 
insipidus, including CKD (especially associated with ureteric ob-
struction, postobstructive states, and chronic interstitial nephritis), 
electrolyte abnormalities (hypercalcaemia and hypokalaemia), 
nephrotoxic drugs (such as lithium and amphotericin), and many 
other miscellaneous conditions including sickle cell disease, Sjögren’s 
syndrome, and sarcoidosis. Most patients with polyuria have asso-
ciated thirst, polydipsia, and nocturia. Polyuria needs confirmation 
by 24-​h urinary collection as most patients are unclear as to their 
true daily urine output. Once it is established that the patient is poly-
uric, common causes such as hyperglycaemia and excessive diuretic 
use need to be excluded, after which investigations should focus on 
excluding primary polydipsia and distinguishing between cranial 
and nephrogenic diabetes insipidus, as discussed in Chapter 21.2.1.
Nocturia
Nocturia is defined as the need to get up once or more times for noc-
turnal voids. It may have a considerable negative impact on quality of 
life and in older people predisposes to falls. Three types of nocturia 
have been identified: low voided volume, nocturnal polyuria, and 
mixed origin. Nocturia due to low voided volumes occurs in pa-
tients with bladder outflow obstruction and those with hyperactive 
bladders from any cause. Nocturnal polyuria occurs when there is a 
reversal of the normal circadian pattern of voiding such that there is 
an increased urine output overnight. These types of nocturia are dis-
tinguishable by the use of voiding diaries. Elderly patients who void 
in excess of 33% of their total 24-​h output between 11 p.m. and 7 a.m. 
are said to have nocturnal polyuria, the corresponding fraction in 
young adults being 20%. Factors predisposing to nocturnal poly-
uria include renal impairment, diabetes mellitus, congestive cardiac 
failure, sleep apnoea, and the mobilization of peripheral oedema due 
to any cause. In patients without predisposing causes, usually eld-
erly, low nocturnal levels of ADH have been described.
Oliguria and anuria
Oliguria is arbitrarily defined as a urinary output of less than 400 ml/​
24 h or 0.5 ml/​kg of body weight per hour. Oliguria is the normal 
renal physiological response to reduced renal perfusion from any 
cause and is common in hospital inpatients, particularly those with 
acute illnesses associated with hypotension and reduced effective 
circulating volume. Monitoring of fluid balance and urinary output 
in such patients allows its early detection and treatment, which may 
help prevent progression to established AKI. The recognition of oli-
guria should prompt an evaluation of the patient with attention to 
volume status, blood pressure, and the detection/​exclusion of sepsis, 
followed by appropriate management to optimize blood pressure 
and circulating volume.
Oliguria may also be a feature of intrinsic renal failure due to 
nephrotoxic drugs, acute glomerulonephritis, or interstitial neph-
ritis, but it is a poor marker of intrinsic renal disease as urinary 
output often remains normal despite significantly impaired renal 
function.
The development of anuria, meaning the total absence of urine, 
is strongly suggestive of urinary tract obstruction, which may occur 
at any level in the urinary tract. A careful history, examination for 
an enlarged bladder, and digital rectal examination for a prostatic 
or pelvic mass, should be followed by urgent ultrasonography of the 
kidneys and bladder. Very occasionally, anuria may be a manifest-
ation of severe intrinsic renal disease, such as a RPGN, cortical ne-
crosis, or renal infarction.
Urine appearance and visible haematuria
Visible haematuria is the most common abnormality of the urine 
noted by patients. As little as 5 ml of blood in a litre of urine will 
lead to a visible change in urinary colour. Haematuria may arise 
from anywhere within the urinary tract, but bright red haematuria 
(with or without clots) is suggestive of lower urinary tract bleeding, 
whereas dark, smoky brown–​black urine is more suggestive of renal 
pathology. Haematuria at the beginning of micturition, which then 
clears, suggests urethral pathology, whereas end-​stream haematuria 
is consistent with bladder pathology. Although the causes of haema-
turia are numerous (Box 21.3.6), infection, stones, and malignancy 
are the most common. Visible haematuria warrants investigation in 
all patients.
Frank haematuria is uncommon in glomerular disease, with the 
notable exception of IgA nephropathy in which visible haematuria 
classically occurs immediately following mucosal inflammation, 
typically an upper respiratory tract infection. In patients with poly-
cystic disease, cysts may haemorrhage to cause loin pain and haema-
turia. This may be associated with infection of the cysts and usually 


21.3  Clinical presentation of renal disease
4771
resolves with conservative management, with antibiotics if there are 
signs of infection.
Red–​brown–​black urine is occasionally caused by haemoglobin-
uria due to haemolysis or myoglobinuria precipitated by rhabdo-
myolysis. Beetroot and food colouring may turn the urine pink, 
whereas drugs such as rifampicin may discolour the urine orange–​
red. Rarely, urine is found to darken following exposure to light, sug-
gesting a diagnosis of porphyria or alkaptonuria. Turbid white urine 
suggests chyluria.
Loin pain
The presence of pain in the renal angle (loin pain) is consistent with 
inflammation, obstruction, or stretching of the renal capsule by a 
mass lesion. Pain arising from acute obstruction is common and typ-
ically colicky in nature, with radiation into the groin and scrotum. 
The pain may be exacerbated by oral fluids, which increase urinary 
volume and pressure within the renal pelvis. Acute pyelonephritis 
typically causes renal angle pain on the affected side and is often as-
sociated with pyrexia and leucocytes in the urine. Similarly, a renal 
abscess extending into the renal capsule may present with loin pain 
or with isolated symptoms of diaphragmatic irritation or involve-
ment of the psoas muscle, with pain on leg extension. Patients with 
polycystic kidneys may also develop loin pain as a result of infection 
or haemorrhage of single or multiple cysts.
Renal pain is an uncommon feature of glomerulonephritis and 
other intrinsic renal diseases: IgA nephropathy is very occasion-
ally associated with renal pain, but active necrotizing glomerulo-
nephritis and acute interstitial nephritis are almost invariably 
pain free.
Loin pain–​haematuria syndrome
Rarely, patients may present with recurrent intermittent loin pain, 
haematuria (nonvisible or visible), and normal renal function, with 
no relevant structural abnormality of the renal tract. The cause of 
this condition, termed the loin pain–​haematuria syndrome, is un-
known: it is a diagnosis of exclusion which is most often seen in 
young women.
The pain—​often described as ‘deep’, ‘burning’, or ‘throbbing’—​is 
usually felt in the loin, but can radiate in a typical renal pattern to 
the groin, genital area, and medial thigh. Some will describe a psy-
chologically traumatic event before the onset of pain. The pain can 
sometimes be induced or exacerbated by exercise and affected by 
posture (e.g. sitting for a prolonged length of time can be uncom-
fortable), and in some cases there is associated nausea and vomiting. 
Some patients report continuous pain that never goes away, whereas 
others describe episodic pain that lasts more or less continuously 
for days or (more typically) weeks, interspersed with periods of re-
mission. The pain is usually unilateral at presentation, but many pa-
tients eventually develop pain bilaterally. Many patients are taking 
large quantities of opioids and other analgesics (e.g. amitriptyline or 
gabapentin) by the time they are referred to specialist services.
Urological investigation is unremarkable, or shows incidental 
abnormalities only. If renal biopsy is performed, the appearances 
may be normal, but thinning or thickening of the GBM has been 
reported in about 60% of cases in some series, appearances of IgA 
nephropathy are sometimes seen, and deposition of complement 
component C3 in the renal arterioles has been described, but the 
relationship—​if any—​between these findings and symptomatology 
remains obscure.
Aside from loin pain, many patients will have other medically 
unexplained somatic symptoms, raising the possibility that this 
symptom is also a somatoform disorder. Patients may request neph-
rectomy and/​or renal autotransplantation, which the wise physician 
will not accede to, preferring to help the patient by sympathetic dis-
cussion and referral to pain management services.
Specific renal syndromes
Nephrotic syndrome
Definition
Nephrotic syndrome is the triad of oedema, proteinuria, and 
hypoalbuminaemia (see Box 21.3.7 for a case study). Proteinuria is 
usually greater than 3.5 g in 24 h, which equates approximately to 
an ACR of 250 mg/​mmol or PCR of 350 mg/​mmol. When patients 
have clinically apparent oedema, serum albumin is usually less than 
25 g/​litre (Fig. 21.3.3). However, in practice, the definition is some-
what arbitrary, and the correlation between the degree of protein-
uria, serum albumin, and presence of oedema is poor. Some patients 
(particularly older people) may develop oedema with proteinuria 
less than 3.5 g, whereas others remain free of oedema despite having 
a serum albumin considerably less than 25 g/​litre. Other patients 
may have heavy proteinuria but maintain a normal serum albumin 
and remain free of oedema.
Nephrotic syndrome indicates the presence of glomerular dis-
ease. Causes can usefully be divided into primary glomerular dis-
eases and those arising secondary to systemic disease (Box 21.3.8), 
Box 21.3.6  Causes of visible haematuria
	•	 Infections:
	
—​	 Cystitis and pyelonephritis
	
—​	 Prostatitis
	
—​	 Urethritis
	
—​	 Schistosomiasis
	•	 Urinary stones
	•	 Tumours:
	
—​	 Renal cell
	
—​	 Transitional cell
	
—​	 Prostatic
	
—​	 Urethral
	•	 Glomerular diseases:
	
—​	 IgA nephropathy
	
—​	 Alport’s syndrome
	
—​	 Crescentic glomerulonephritis
	•	 Interstitial and medullary renal diseases:
	
—​	 Polycystic kidneys
	
—​	 Interstitial nephritis
	
—​	 Papillary necrosis
	
—​	 Tuberculosis
	•	 Miscellaneous causes:
	
—​	 Release of urinary obstruction
	
—​	 Trauma
	
—​	 Loin pain–​haematuria syndrome
	
—​	 Arteriovenous malformations
	
—​	 Anticoagulation
	
—​	 Factitious


section 21  Disorders of the kidney and urinary tract
4772
with the geographical context important in determining the most 
likely cause in any particular case. The most common cause of neph-
rotic syndrome in Western countries is diabetes mellitus, whereas in 
developing countries it is most commonly associated with infection. 
Nephrotic syndrome due to malaria and hepatitis are particularly 
common in sub-​Saharan Africa, and poststreptococcal glomerulo-
nephritis is also an important cause.
Pathophysiology
The traditional explanation for oedema formation—​known as the 
‘underfill hypothesis’—​is that, via alterations in Starling forces, 
hypoalbuminaemia leads to intravascular volume depletion, 
stimulation of the renin–​angiotensin–​aldosterone system, and 
thereby to sodium retention. This is likely to be correct in chil-
dren with minimal change nephrotic syndrome, but the evidence 
is much less convincing in adults, in whom nephrotic syndrome 
is more likely caused by an intrinsic renal inability to excrete salt 
(‘overfill hypothesis’). The cause for this inability is uncertain, but 
it may be due to the activation of the epithelial sodium channel in 
the distal nephron by serine proteases in the glomerular filtrate of 
nephrotic patients.
Clinical features
One of the earliest symptoms patients may report is that of frothy 
urine. This often occurs before the onset of oedema and may be a 
useful indicator of the onset of heavy proteinuria. As proteinuria de-
velops and serum albumin falls, patients gradually develop oedema. 
This may be noticed first as periorbital swelling and ‘puffiness’ in 
the morning, or as ankle swelling in the evening due to the effects of 
gravity. Worsening leg oedema develops as salt and water retention 
Box 21.3.7  Case illustration—​proteinuria and oedema
A 54-​year-​old woman presents with worsening peripheral oedema. She 
had been diagnosed with type 2 diabetes 6 months earlier, but remained 
well until 4 weeks ago, when she suddenly noted frothy urine and mild 
peripheral oedema. Over the following weeks the oedema had worsened 
and she noted some abdominal distension. Her only regular medication 
is gliclazide.
Examination
	•	 Pitting oedema to her lumbar spine, with bilateral small pleural 
effusions
	•	 Jugular venous pressure not elevated and heart sounds normal
	•	 Mild erythema over right ankle and lower leg
Investigations
	•	 Urine dipstick test: protein 4+, no haematuria
	•	 ACR: 452 mg/​mmol
	•	 A 24-​h urinary collection: 6.8 g proteinuria
	•	 Serum albumin: 13 g/​litre
	•	 Serum creatinine: 82 µmol/​litre
	•	 Autoimmune and hepatitis serology: negative
	•	 Renal ultrasonography and venous Doppler: normal
	•	 Doppler ultrasonography of right leg: normal
	•	 Renal biopsy: membranous nephropathy with subepithelial spikes on 
silver stain
Diagnosis
	•	 Membranous nephropathy with nephrotic syndrome
Comment
Frothy urine, oedema, and hypoalbuminaemia indicate the onset of 
heavy proteinuria and nephrotic syndrome. The rapid onset of symp-
toms suggests a primary glomerular lesion rather than long-​standing 
diabetic nephropathy. The presence of leg erythema may be due to in-
fection or deep venous thrombosis, hence a Doppler ultrasound scan 
was requested. To make the diagnosis, a renal biopsy was performed, 
which showed membranous nephropathy. The patient was initially man-
aged conservatively with diuretics and low molecular weight heparin as 
thromboembolic prophylaxis.
Fig. 21.3.3  Severe peripheral oedema of the lower legs with pitting 
below the right knee (arrow).
Box 21.3.8  Causes of nephrotic syndrome
	•	 Primary glomerular diseases:
	
—​	 Minimal change
	
—​	 Focal segmental glomerulosclerosis (FSGS)
	
—​	 Membranous
	
—​	 Mesangiocapillary glomerulonephritis (MCGN)
	•	 Secondary glomerular diseases:
	
—​	 Diabetes
	
—​	 Amyloid
	•	 Drugs:
	
—​	 Gold, penicillamine, NSAIDs, captopril, heroin
	•	 Systemic disease:
	
—​	 Lupus
	•	 Infectious diseases:
	
—​	 Poststreptococcal glomerulonephritis
	
—​	 Hepatitis B and C
	
—​	 HIV
	
—​	 Malaria
	
—​	 Schistosomiasis
	
—​	 Filaria
	•	 Malignancy:
	
—​	 Minimal change
	
—​	 Membranous
	•	 Pre-​eclampsia
	•	 Hereditary:
	
—​	 Alport’s syndrome
	
—​	 Nail–​patella syndrome


21.3  Clinical presentation of renal disease
4773
increases, followed by abdominal distension from ascites. In men, 
scrotal oedema may be marked and very uncomfortable. Further 
fluid retention leads to pleural effusions, which are often bilateral 
but may be unilateral. Patients often feel lethargic, with a loss of ap-
petite and nausea due to associated gut oedema.
Clinical examination of the patient’s volume status may reveal a 
normal or low jugular venous pressure despite marked oedema. 
Although rare in untreated adult patients, it is important to identify 
intravascular volume depletion because the use of high-​dose diur-
etic therapy in this setting may provoke circulatory collapse from 
hypovolaemia, or less dramatically may further reduce renal perfu-
sion and exacerbate renal dysfunction. Conversely, a raised jugular 
venous pressure with a low blood pressure may suggest a significant 
pericardial effusion or underlying amyloid with cardiac involvement.
Patients may also present with complications associated with 
nephrotic syndrome. Thromboembolism may be difficult to de-
tect clinically. Patients with marked peripheral oedema often have 
swollen legs of unequal size and associated erythema due to an in-
creased susceptibility to cellulitis. These may mask the signs of deep 
venous thrombosis. Similarly, subtle symptoms of breathlessness, 
perhaps suggesting pulmonary embolism, or headache, perhaps 
suggesting cerebral venous sinus thrombosis, may be overlooked. In 
practice, a low threshold is required for investigation and treatment 
of suspected thromboembolism.
The combination of severe peripheral oedema and susceptibility 
to infection following skin breakdown often leads to cellulitis. Long-​
standing hypoalbuminaemia may lead to leuconychia. Severe hyper-
lipidaemia, which is a feature of nephrotic syndrome, may lead to 
cutaneous xanthomas.
Establishing a clinical diagnosis of nephrotic syndrome is often 
straightforward. The clinical history and examination may also pro-
vide clues to an underlying cause, which may be clear, such as in a 
patient with long-​standing diabetes and progressive diabetic neph-
ropathy. Alternatively, the immediate cause may only become ap-
parent after a detailed history revealing long-​standing use of drugs 
that may precipitate the condition (e.g. ACE inhibitors, NSAIDs, gold, 
or penicillamine). A history of chronic infections (such as hepatitis) 
may suggest an underlying membranous or mesangiocapillary glom-
erulonephritis, whereas a rash and arthralgia may lead to a diagnosis 
of an autoimmune condition such as systemic lupus erythematosus 
or cryoglobulinaemia. The presence of other long-​standing inflam-
matory conditions, such as rheumatoid arthritis, raises the possibility 
of systemic amyloidosis. In older patients, an associated malignancy 
remains a possibility and should be sought in the history and exam-
ination, but does not warrant further investigation apart from a chest 
radiograph in the absence of clinical clues (e.g. disturbance of bowel 
habit which would merit imaging of the colon). Very occasionally, a 
family history may reveal an inherited nephrotic syndrome such as 
familial focal segmental glomerulosclerosis.
Rapidly progressive glomerulonephritis with acute 
kidney injury
Around 5% of cases of AKI are caused by a RPGN. Recognizing this 
relatively small group of patients is important because many respond 
well to treatment, provided the diagnosis is made early and appro-
priate management started promptly. The key to making a diagnosis 
is having a high index of clinical suspicion such that important fea-
tures of the syndrome are identified (see Box 21.3.9 for a case study).
The hallmarks of a RPGN are rapidly declining renal function, 
haematuria and proteinuria on urine dipstick testing, dysmorphic 
red cells or red cell casts on urine microscopy, and crescentic and 
focal necrotizing glomerulonephritis on renal biopsy.
Clinical presentation
A RPGN may present either de novo in a previously well patient 
or as a complication in a patient known to have a systemic disease 
(Box 21.3.10). The clinical features may be diverse. Occasionally, 
Box 21.3.9  Case illustration—​ANCA-​associated vasculitis
An 80-​year-​old woman presents with a 2-​week history of increasing mal-
aise and lethargy. On close questioning she also reported arthralgia in 
the small joints of her hands, and numbness in her hands and feet in the 
last few months.
Examination
	•	 Subtle purpuric rash on both legs
	•	 Bibasal crepitations
	•	 Reduced pinprick sensation in a glove and stocking distribution
Investigations
	•	 Creatinine: 854 µmol/​litre (56 µmol/​litre 10 months before)
	•	 Urea: 45 mmol/​litre
	•	 Haemoglobin: 8.3 g/​dl
	•	 Urine dipstick test: blood 3+, protein 2+
	•	 Urine microscopy: red cell casts
	•	 Serological testing: perinuclear ANCA positive, with myeloperoxidase 
titre 78%
	•	 Renal biopsy: focal necrotizing glomerulonephritis
Diagnosis
	•	 AKI due to microscopic polyangiitis (an ANCA-​associated vasculitis) 
with associated peripheral neuropathy
Comment
The history is nonspecific, except that the onset of symptoms is recent 
and suggestive of a systemic disorder. The presence of a purpuric rash 
makes the diagnosis of vasculitis a possibility. Dipstick testing of the urine 
and checking the renal function are critical in making the diagnosis of AKI 
due to an inflammatory condition. Confirmation of a systemic vasculitis 
is made with a positive perinuclear ANCA and renal biopsy.
Box 21.3.10  Causes of a rapidly progressive glomerulonephritis
	•	 ANCA-​associated vasculitis:
	
—​	 Granulomatosis with polyangiitis
	
—​	 Microscopic polyangiitis
	
—​	 Eosinophilic granulomatosis with polyangiitis
	•	 Other primary systemic vasculitides (ANCA negative)
	•	 Other systemic disorders:
	
—​	 Systemic lupus erythematosus
	
—​	 Cryoglobulinaemia
	
—​	 Henoch–​Schönlein purpura
	•	 Infection-​related glomerulonephritis:
	
—​	 Postinfectious glomerulonephritis
	
—​	 Infective endocarditis
	•	 Anti-​GBM disease (Goodpasture’s syndrome)
	•	 Crescentic phase of a primary glomerulonephritis:
	
—​	 IgA nephropathy
	
—​	 Mesangiocapillary glomerulonephritis


section 21  Disorders of the kidney and urinary tract
4774
patients may present with very few symptoms and signs, except for 
proteinuria and haematuria with a recent decline in renal function, 
and at the other end of the spectrum, patients may present with se-
vere AKI associated with features of uraemia. Importantly, patients 
may also present with clinical features of systemic inflammation 
that indicate an underlying cause for glomerulonephritis. These 
range from the subtle, such as arthralgia or myalgia, to the florid, 
such as a purpuric rash (Fig. 21.3.4), haemoptysis, and peripheral 
neuropathy. Clinical features of specific inflammatory diseases asso-
ciated with a RPGN are detailed in Table 21.3.1.
In practice, specific features to elicit in patients presenting with 
an acute decline in renal function include arthralgia and arthritis, 
myalgia and muscle tenderness, rashes, eye symptoms (pain and 
redness), ear, nose, and throat symptoms (epistaxis, nasal crusting, 
and new deafness), haemoptysis (important, as it may indicate a 
life-​threatening pulmonary haemorrhage), and neuropathic symp-
toms and signs. Conversely, the clinician should have a high index 
of suspicion for a RPGN in patients presenting with any of these fea-
tures, and in this context suspicions are heightened by the presence 
of dysmorphic red cells and red cell casts on urinary microscopy 
(Fig. 21.3.5).
If a RPGN is suspected, investigations should include ANCAs, 
anti-​GBM antibodies, antinuclear and anti-​double-​stranded DNA 
antibodies, serum complement, antistreptolysin-​O titre, and im-
munoglobulins and serum electrophoresis (including tests for cryo-
globulins). It is almost certain that a patient with a RPGN will require 
a renal biopsy to confirm the diagnosis and to guide management. 
All patients with suspected RPGN should be referred urgently to a 
nephrologist.
Presentation of renal disease associated with  
other underlying diseases
Renal disease can present in many complex and diverse ways, and 
many renal problems arise as either direct or indirect complications 
of other diseases. Examples include AKI caused by sepsis, and pro-
gressive CKD due to diabetes (Box 21.3.11). This section illustrates 
some common and important presentations of renal disease.
Diabetic nephropathy
In the Western world, diabetes is the most common cause of 
renal disease, accounting for around 45% of new cases of ESKD 
in the United States of America and around 25% in the United 
Kingdom (Box 21.3.12). Diabetic nephropathy develops over 
the course of years and is preceded by a clinically silent phase of 
microalbuminuria, which is often detected as a result of diabetic 
screening programmes, enabling a targeted approach to manage-
ment in which tight glycaemic control and blood pressure control 
with the use of agents to block the renin–​angiotensin system aim 
to reduce the rate of progression of the nephropathy. As with other 
causes of progressive CKD, patients with diabetic nephropathy 
often only develop symptoms of kidney disease late in the course of 
their disease, but there is a tendency for those with this condition to 
become symptomatic, particularly in relation to anaemia and fluid 
retention, with lesser degrees of impairment of renal function than 
their nondiabetic counterparts. This leads to an earlier requirement 
for initiation of dialysis in patients with diabetic nephropathy.
Screening patients with diabetes for microalbuminuria and 
hypertension enables early diagnosis of complications and intensive 
management of glucose and blood pressure. As eGFR falls below 
30 ml/​min per 1.73 m2, patients should be referred to a nephrologist 
to plan for renal replacement therapy.
Patients with diabetes are also subject to develop other micro-
vascular and macrovascular complications, which may lead to 
superimposed renal atheroembolic disease and renal artery sten-
osis. These may present as an abrupt decline in renal function 
following the introduction of an ACE inhibitor or angiotensin re-
ceptor antagonist. Patients with diabetic nephropathy are also at in-
creased risk of AKI or chronic renal failure, with common causes 
Fig. 21.3.4  Purpuric rash affecting the lower legs, consistent with a 
systemic vasculitis.
Table 21.3.1  Key features of specific systemic inflammatory diseases causing a rapidly progressive glomerulonephritis
Feature
Type
Disease
Skin rashes
Purpuric
Lupoid
Any vasculitis
Lupus
Ear, nose, and throat symptoms
Nasal crusting
Deafness
Oral ulceration
Granulomatosis with polyangiitis
Granulomatosis with polyangiitis
Any vasculitis or lupus
Eye symptoms
Scleritis and episcleritis
Any vasculitis, lupus, rarely Behçet’s disease
Myalgia, arthralgia, and arthritis
Any vasculitis, Henoch–​Schönlein purpura, cryoglobulinaemia, lupus, 
rheumatoid arthritis, systemic sclerosis
Haemoptysis
Goodpasture’s disease, any vasculitis, lupus
Neuropathy
Any vasculitis, lupus, cryoglobulinaemia


21.3  Clinical presentation of renal disease
4775
for this including use of radiocontrast media for investigations such 
as coronary or peripheral angiography, surgery (especially cardiac 
surgery), and in the context of diabetic emergencies, particularly 
diabetic ketoacidosis.
See Chapter  21.10.1 for further discussion of diabetic renal 
disease.
Renovascular disease
Many patients with diffuse atherosclerosis have evidence of reno­
vascular disease. A  history of cerebrovascular, coronary, or per-
ipheral vascular disease makes a diagnosis of renovascular disease 
likely. Up to 24% of patients presenting with peripheral vascular 
(b)
(a)
Fig. 21.3.5  Phase contrast micrographs showing dysmorphic erythrocytes (a) and a red cell 
cast (b) within the urine.
Box 21.3.11  Important and common presentations 
of renal disease
	•	 Diabetic nephropathy with progressive CKD
	•	 Vascular disease:
	
—​	 Renal atheroemboli
	
—​	 Renal artery stenosis
	•	 Underlying malignancy:
	
—​	 Urinary tract obstruction
	
—​	 Membranous glomerulonephritis
	
—​	 Myeloma
	
—​	 Hypercalcaemia
	•	 Infection:
	
—​	 Acute presentation with renal failure:  (1) general syndromes—​
sepsis, rhabdomyolysis, HUS, postinfectious glomerulonephritis, 
tubulointerstitial nephritis; (2)  specific syndromes—​hantavirus, 
leptospirosis, malaria
	
—​	 Chronic infections associated with renal disease: hepatitis B, hepa-
titis C, filaria, schistosomiasis, HIV
	•	 Systemic inflammatory disease:
	
—​	 Systemic vasculitides
	
—​	 Systemic lupus erythematosus
	
—​	 Sarcoidosis
	•	 Drug-​induced renal disease
	•	 Pregnancy
Box 21.3.12  Case illustration—​progressive CKD due 
to diabetic nephropathy
A 66-​year-​old Asian man presents with nausea, anorexia, ankle swelling, 
and breathlessness. He has a 25-​year history of type 2 diabetes mellitus, 
a 14-​year history of hypertension, and had coronary artery bypass 
grafts 3 years ago. Insulin, furosemide, and ramipril are his only regular 
medications.
Examination
	•	 Cardiovascular—​blood pressure 167/​88 mmHg, jugular venous pres-
sure +3 cm, cardiomegaly, bibasal crepitations, and peripheral oedema 
to sacrum
	•	 Fundi—​treated diabetic retinopathy
	•	 Neurological—​reduced pinprick sensation in stocking distribution 
to knees, with absent ankle reflexes, proprioception, and vibration 
sensation
Investigations
	•	 Urine dipstick test: protein 4+, no haematuria
	•	 Urine ACR: 1720 mg/​mmol
	•	 Serum creatinine:  568 µmol/​litre (eGFR 9 ml/​min per 1.73 m2 body 
surface area)
	•	 Serum bicarbonate: 15 mmol/​litre
	•	 Full blood count: haemoglobin (Hb) 9.8 g/​dl
	•	 HbA1C: 10.2%
Further history
Five years previously, his blood pressure was 189/​92 mmHg with cre-
atinine of 154 µmol/​litre and protein+ on urine dipstick. At the time of 
his coronary surgery, blood pressure was 165/​86 mmHg with creatinine 
210 µmol/​litre. Over the last year he had felt well until the last 2 months, 
since when he had developed increasing lethargy, anorexia, and breath-
lessness on exertion, and noted increasing ankle swelling.
Comment
This man with long-​standing diabetes presents with nonspecific symp-
toms and oedema. He also has evidence of end-​organ damage, with 
cardiovascular disease, retinopathy, and neuropathy. Five years ago he 
had evidence of nephropathy with proteinuria and an eGFR of 43 ml/​
min (CKD stage 3). Since then his blood pressure and glycaemic control 
have been poor, which contributed to the progression of nephropathy to 
eGFR of 30 ml/​min (CKD stage 3/​4) 3 years ago, and now to CKD stage 5 
with symptoms of uraemia.


section 21  Disorders of the kidney and urinary tract
4776
disease have stenoses in both renal arteries, and up to 50% have 
more than 50% stenosis in at least one renal artery. The absence 
of peripheral pulses and the presence of a femoral bruit make the 
diagnosis of renovascular disease likely, although most of these pa-
tients remain asymptomatic from the renal point of view. Common 
presentations of renovascular disease are outlined in Box 21.3.13.
See Chapter  21.10.10 for further discussion of renovascular 
disease.
Myeloma and other malignancies
Myeloma can cause AKI in a number of ways. Features suggestive of 
underlying myeloma in a patient presenting with unexplained renal 
failure are older age, bone pain (often nonspecific), hypercalcaemia 
(sometimes mild, and sometimes ‘relative’ considering the degree of 
renal impairment), anaemia (often inappropriately severe for the de-
gree of renal impairment), an abrupt decline in renal function after 
a relatively minor prerenal ‘insult’, and unremarkable urine dipstick 
findings.
Up to 50% of patients presenting with myeloma have impaired 
renal function at the time of diagnosis. This may be reversible and 
due to hypercalcaemia, dehydration, hyperuricaemia, or infection. 
Cast nephropathy accounts for 10% of all renal dysfunction in pa-
tients with myeloma and is characterized by the formation of tubular 
casts of excreted light chains and Tamm–​Horsfall protein: these are 
thought to cause renal failure by obstructing the tubule and by direct 
tubular toxicity.
The key to the diagnosis is to maintain a high index of suspicion, 
particularly in elderly patients presenting with renal failure and 
hypercalcaemia. Serum electrophoresis and urinary Bence Jones 
proteins and serum free light chains are the required investigations, 
leading on to bone marrow examination.
Other malignancies may present with renal involvement through 
a number of mechanisms, including AKI due to urinary tract ob-
struction by pelvic or retroperitoneal tumour. Other possible causes 
are outlined in Box 21.3.14.
See Chapters 21.10.5 and 21.10.9 for further discussion.
Renal presentation of infectious diseases
A wide range of systemic infections can affect the kidney and result 
in either AKI or CKD. The presentation of infection-​related kidney 
disease varies worldwide, and in the developing world—​in contrast 
to the developed world—​infectious diseases are the leading cause of 
both AKI and CKD.
AKI may occur as part of a general systemic syndrome induced by 
infection, such as sepsis and septic shock, haemolytic uraemic syn-
drome (HUS), rhabdomyolysis, postinfectious glomerulonephritis, 
and acute tubulointerstitial nephritis. Alternatively, an infectious 
agent may cause specific nephrotoxicity, for example, hantavirus, 
leptospirosis, or malaria.
General systemic syndromes caused by infection
In Western countries, the most common infectious cause for renal 
disease is sepsis, which accounts for 10% of all hospital-​acquired 
renal failure and, if severe, may lead to AKI in the context of 
multiorgan failure.
Other general syndromes that may be induced by infection in-
clude HUS and rhabdomyolysis. For example, the verotoxin of 
Escherichia coli O157:H7 causes (D+) HUS, which is a thrombotic 
microangiopathy characterized by diarrhoea, AKI, and thrombo-
cytopenia. Patients with influenza, legionella, or streptococcal in-
fection may present with fever, severe myalgia, and dark urine in the 
context of AKI due to rhabdomyolysis.
Poststreptococcal glomerulonephritis is still one of the most 
common causes of AKI in the developing world, although now seen 
rarely in the United Kingdom and developed countries. Typical 
presentation is 10 days to a few weeks following a streptococcal in-
fection of the throat or skin with a ‘nephritic’ syndrome character-
ized by hypertension, oedema, haematuria, proteinuria, and AKI.
Specific nephrotoxicity caused by infection
Hantavirus and leptospirosis
Hantaviruses are endemic in specific rodent reservoirs and are trans-
mitted to humans by inhalation of infectious aerosols or rodent ex-
creta. In Europe, the main pattern of disease is haemorrhagic fever 
with renal syndrome. The disease presents in four stages: (1) an abrupt 
febrile stage characterized by fever, loin or abdominal pain, nausea, 
vomiting, and periorbital oedema, lasting for 3 to 7 days; (2) a hypo-
tensive phase associated with haemorrhages and ecchymoses, lasting 
hours to 2 days; (3) an oliguric phase for 3 to 14 days, with worsening 
AKI due to a tubulointerstitial nephritis and haemorrhage; and (4) a 
polyuric phase as renal function returns to normal.
Leptospirosis may present with similar features to hantavirus. 
However, leptospirosis is endemic worldwide and is typically asso-
ciated with jaundice and hepatomegaly. AKI occurs in 20 to 85% of 
patients due to acute tubulointerstitial nephritis.
Malaria
Severe infection with Plasmodium falciparum occurs in nonimmune 
adults. AKI may occur either in the acute phase of the disease or 
Box 21.3.13  Common presentations of renovascular disease
	•	 As part of the investigation for acute, severe, or refractory hypertension
	•	 An acute rise (>20%) in creatinine following introduction of an ACE 
inhibitor or angiotensin receptor antagonist
	•	 Incidental finding of asymmetric kidney size on renal ultrasonography
	•	 As part of the investigation for progressive CKD.
	•	 Symptomatically as acute (‘flash’) pulmonary oedema in the absence 
of cardiac failure or fluid overload
	•	 Postoperative AKI, especially following coronary artery bypass or aortic 
aneurysm surgery
Box 21.3.14  Renal presentations associated with malignancy
	•	 AKI:
	
—​	 Urinary tract obstruction
	
—​	 Hypercalcaemia
	
—​	 Tumour lysis with urate nephropathy
	
—​	 Chemotherapy (e.g. cisplatin, ifosfamide)
	
—​	 Leukaemic infiltration
	
—​	 Microangiopathy
	•	 Paraneoplastic glomerular disease:
	
—​	 Membranous
	
—​	 Amyloid
	
—​	 Mesangiocapillary glomerulonephritis


21.3  Clinical presentation of renal disease
4777
in the recovery phase. Sequestration of parasitized erythrocytes in 
the renal vasculature and proinflammatory cytokine release cause 
tubular cell ischaemia and injury. Rarely, patients with falciparum 
malaria present with ‘blackwater fever’ due to massive intravascular 
haemolysis, which often occurs following quinine administration in 
association with glucose-​6-​phosphate dehydrogenase deficiency.
Infections and CKD
In the developing world, CKD is commonly secondary to infectious 
disease, with the underlying infection often remaining subclin-
ical until the presentation with renal manifestations. Examples of 
CKD secondary to infective agents include hepatitis B, hepatitis C, 
P. malariae, filaria, schistosomiasis, and HIV.
Hepatitis B is classically associated with nephrotic syndrome due 
to membranous nephropathy, but occasionally it may result in a 
mesangiocapillary glomerulonephritis. Hepatitis B virus infection 
is also associated with the development of polyarteritis nodosa, al-
though the reported frequency of this appears to be falling. Patients 
who develop such complications usually have chronic hepatitis, 
having contracted the virus in childhood.
Hepatitis C is increasingly recognized as a common cause for 
cryoglobulinaemia. This remains asymptomatic in most patients, 
with only a few developing clinical evidence of vasculitis. The associ-
ated mesangiocapillary glomerulonephritis can present as nephrotic 
syndrome or CKD.
Many infectious agents endemic in sub-​Saharan Africa may also 
cause a mesangiocapillary glomerulonephritis presenting as neph-
rotic syndrome. Most common is P. malariae, but filaria and schisto-
somiasis remain in the differential diagnosis.
HIV-​associated nephropathy (HIVAN) is an increasingly rec-
ognized complication of HIV infection, and it now accounts for 
around 1% of the dialysis population in the United States of America. 
Patients usually present with heavy proteinuria and nephrotic syn-
drome due a collapsing form of focal segmental glomerulosclerosis. 
HIVAN predominates in young African American men.
See Chapters 21.5, 21.10.8, and 21.11 for further discussion.
Systemic inflammatory diseases
Patients with systemic inflammatory disease are at risk of developing 
renal disease. Sometimes this may be the presenting feature of the 
condition, such as systemic vasculitis or systemic lupus, and on 
other occasions renal disease may develop as a complication later in 
the course of disease. Examples of systemic inflammatory diseases 
associated with renal involvement are detailed in Box 21.3.15. The 
presentation of an acute glomerulonephritis and progressive renal 
failure due to systemic inflammatory diseases such as the vasculit-
ides and systemic lupus erythematosus has been discussed earlier in 
the chapter, and further details can be found in Chapters 21.10.2 and 
21.10.3. Other inflammatory diseases may present in different ways.
Sarcoidosis
Renal disease is common in sarcoidosis and characterized 
histologically by granulomatous tubulointerstitial nephritis. The 
mean prevalence from biopsy studies is 35%, but this is likely to be 
an overestimate. Most renal disease is subclinical, but may be iden-
tified by the presence of proteinuria or tubular dysfunction with 
a renal tubular acidosis. However, sarcoidosis may present with 
AKI, which may be caused by an acute tubulointerstitial nephritis 
associated with an eosinophilia and eosinophiluria, or be precipi-
tated by hypercalcaemia, which may be more common in summer 
months due to ultraviolet light exposure. The presence of extrarenal 
features of sarcoidosis (including bilateral hilar lymphadenopathy 
and erythema nodosum) helps to establish the diagnosis, but some-
times the diagnosis may only become apparent on finding a high 
level of serum ACE or following a renal biopsy for unexplained renal 
impairment. See Chapters 21.10.4 and 18.12 for further discussion 
of sarcoidosis.
Systemic sclerosis
Systemic sclerosis may present with an acute crisis characterized by 
an abrupt rise in blood pressure (>160/​90 mmHg) with hypertensive 
encephalopathy, AKI, and a microangiopathic haemolytic anaemia. 
This may occur before the onset of the cutaneous features of the dis-
ease. Patients are typically tachycardic, with evidence of heart failure 
and a high systemic vascular resistance. This diagnosis should be 
suspected in any patient presenting with malignant-​phase hyperten-
sion and AKI. See Chapter 19.11.3 for further discussion of systemic 
sclerosis.
Systemic amyloidosis
Systemic amyloidosis is characterized by extracellular deposition 
of insoluble fibrillar proteins that lead to organ dysfunction. In 
AL amyloidosis this arises from light chains produced by a ma-
lignant plasma cell clone. AA amyloidosis occurs in the setting of 
long-​standing inflammation, the amyloidogenic protein being an 
N-​terminal fragment of serum amyloid A (SAA), an acute phase 
reactant. Patients may present with heavy proteinuria or neph-
rotic syndrome. Renal involvement can be demonstrated by serum 
amyloid P scanning or by renal biopsy. See Chapter 12.12.3 for fur-
ther discussion of the amyloidoses.
Drug-​induced renal disease
Numerous drugs have the potential for causing both AKI and CKD 
(Box 21.3.16). As well as prescribed and over-​the-​counter medica-
tion, renal disease may also arise from herbal and traditional Chinese 
medicines or illicit drugs. Mechanisms by which drugs cause renal 
disease include salt and water depletion, effects on renal perfusion, 
direct nephrotoxicity, and intrarenal obstruction.
Box 21.3.15  Systemic inflammatory diseases associated 
with renal involvement
	•	 Typically associated with renal involvement:
	
—​	 Systemic vasculitides
	
—​	 Systemic lupus erythematosus
	
—​	 Sarcoidosis
	
—​	 Systemic sclerosis
	
—​	 Henoch–​Schönlein purpura
	
—​	 Cryoglobulinaemia
	•	 Unusually associated with renal involvement:
	
—​	 Relapsing polychondritis
	
—​	 Ankylosing spondylitis
	
—​	 Behçet’s disease
	
—​	 Rheumatoid arthritis
	•	 Renal complications of multisystem conditions:
	
—​	 Amyloidosis (of AA type)


section 21  Disorders of the kidney and urinary tract
4778
Salt and water depletion
AKI may follow hypotension and reduced renal perfusion due to so-
dium and water depletion. This may be caused by excess diuretic use 
or diarrhoea and vomiting as a drug side effect.
Effect on renal perfusion and the regulation 
of intrarenal haemodynamics
Overdose of any hypotensive agent may compromise renal per-
fusion and interfere with renal function. Agents which block the 
renin–​angiotensin system, the ACE inhibitors, and angiotensin 
receptor blockers, require special consideration. These agents ab-
rogate the effect of angiotensin II on efferent arteriole constriction, 
which is the normal adaptive response to any reduction in renal 
perfusion. A small and acceptable deterioration in renal function 
(up to a 20% increase in serum creatinine) often occurs following 
the introduction of an ACE inhibitor. A greater increase in serum 
creatinine may indicate underlying renal artery stenosis, for which 
further investigation may need to be carefully considered. These 
agents are implicated in a significant proportion of cases of AKI in 
patients with sepsis and dehydration. This is because renal perfusion 
is frequently compromised in these settings and the kidney is unable 
to autoregulate its blood flow in the presence of renin–​angiotensin 
system blockade.
NSAIDs have numerous renal effects, including disturbances 
of autoregulation of intrinsic renal haemodynamics. These effects 
are mediated by inhibition of prostaglandin synthesis from arachi-
donic acid by nonspecific blocking of the enzyme cyclooxygenase. 
This may lead to vasoconstriction and reversible renal impairment 
in volume-​contracted states. Long-​term use of NSAIDs may cause 
chronic renal impairment, with selective COX-​2 inhibitors seeming 
to confer no renal advantage.
Direct nephrotoxicity
The mechanisms of drug toxicity on the kidney include direct 
tubulotoxicity, drug-​induced tubulointerstitial nephritis, tubular 
dysfunction, and glomerular disease. Common nephrotoxic drugs 
and mechanism are outlined in Box 21.3.16.
Tubulointerstitial nephritis is classically caused by penicillins, 
NSAIDs, and proton pump inhibitors but most drugs have the 
potential to cause the condition. Drug-​induced tubulointerstitial 
nephritis usually occurs days to weeks after starting the drug. 
Symptoms may be nonspecific, with malaise, fatigue, and anorexia. 
A low-​grade fever, fleeting rash, and arthralgia may also be reported. 
Investigations show a variable degree of renal dysfunction along 
with proteinuria and nonvisible haematuria. Urine microscopy may 
show white and red cell casts, and there may be a blood eosinophilia. 
However, in practice, the key is to suspect the diagnosis, stop the po-
tentially offending drug (or drugs), and proceed with a renal biopsy 
if renal function is severe or does not improve.
Obstruction
Specific drugs, such as aciclovir and the protease inhibitor indinavir, 
may precipitate as crystals within the tubule, causing obstruction 
and sometimes renal failure. This is more likely to occur if the pa-
tient is dehydrated, hence adequate fluid input to achieve a high 
urinary volume is advised before these drugs are taken.
See Chapter 21.19 for further discussion of drugs and the kidney.
Pregnancy
Pregnancy provides a unique set of circumstances in which renal 
disease may present. Pre-​existing renal disease may be detected as 
part of screening for proteinuria and hypertension during the first 
trimester. Alternatively, de novo renal disease may be precipitated by 
pregnancy and present with specific syndromes, such as nephrotic 
syndrome or AKI due to pre-​eclampsia. A summary of the presenta-
tion of renal disease in pregnancy is detailed in Box 21.3.17.
Box 21.3.16  Adverse effects of drugs on the kidney
AKI
	•	 Acute tubular cell injury (acute tubular necrosis, ATN)
	
—​	 Aminoglycosides
	
—​	 Amphotericin
	
—​	 Cisplatin
	
—​	 NSAIDs
	
—​	 Radiocontrast media
	
—​	 Paracetamol poisoning
	
—​	 Statins (by inducing rhabdomyolysis)
	•	 Interstitial nephritis:
	
—​	 Proton pump inhibitors
	
—​	 β-​Lactam antibiotics (penicillins, cephalosporins)
	
—​	 NSAIDs
	
—​	 Diuretics, particularly thiazides
	
—​	 Allopurinol
	
—​	 Sulphonamides
	
—​	 Other antibiotics (e.g. ciprofloxacin, rifampicin)
	
—​	 Indinavir
	
—​	 Aristolochic acid (‘Chinese herb nephropathy’)
Nephrotic syndrome
	•	 Membranous glomerulonephritis:
	
—​	 High-​dose captopril
	
—​	 Gold
	
—​	 Penicillamine
	
—​	 Phenytoin
	•	 Minimal change:
	
—​	 NSAIDs
	•	 Focal segmental glomerulosclerosis:
	
—​	 Pamidronate
	
—​	 Heroin
Tubular dysfunction
	•	 Renal tubular acidosis:
	
—​	 Acetazolamide
	
—​	 Amphotericin
	
—​	 Lithium
	•	 Nephrogenic diabetes insipidus:
	
—​	 Lithium
	
—​	 Demeclocycline
Others
	•	 Renal papillary necrosis:
	
—​	 Aspirin with phenacetin
	
—​	 NSAIDs
	•	 Crystalluria with tubular obstruction
	
—​	 Aciclovir
	
—​	 Indinavir
	
—​	 Methotrexate
	
—​	 Sulphonamides


21.3  Clinical presentation of renal disease
4779
The clinical presentation of renal disease during pregnancy is 
often varied and nonspecific, but certain features may guide the 
diagnosis. Key points to note are as follows:
	•	Is there evidence of pre-​existing renal disease?
	•	Were previous pregnancies complicated by hypertension or 
pre-​eclampsia?
	•	What was the time of onset of renal disease during pregnancy? 
Onset in late pregnancy implies that the renal disease is likely to 
be pregnancy induced.
	•	Hypertension with proteinuria and oedema suggest pre-​eclampsia 
or underlying renal disease (e.g. systemic lupus erythematosus).
	•	Hypotension and hypovolaemia suggest sepsis or haemorrhage.
See Chapter 14.5 for further discussion of renal disease in pregnancy.
Pre-​eclampsia and HELLP
Pre-​eclampsia classically presents with hypertension, oedema, and 
proteinuria. Other recognized features include elevation of serum 
urate, liver transaminases, and haematocrit, along with thrombo-
cytopenia. However, patients may not be hypertensive or demon-
strate other features, hence distinguishing pre-​eclampsia from 
pre-​existing renal disease may be difficult, and the condition may oc-
casionally present with heavy proteinuria and nephrotic syndrome. 
The HELLP syndrome (haemolysis, elevated liver enzymes, and low 
platelets) is a severe variant of pre-​eclampsia that is commonly asso-
ciated with renal failure, severe haemolysis, and coagulopathy, and 
may progress to multiorgan failure. See Chapters 14.4 and 14.9 for 
further discussion.
Haemolytic uraemic syndrome and thrombotic 
thrombocytopenic purpura
HUS and thrombotic thrombocytopenic purpura are related dis-
orders that are occasionally associated with pregnancy. Both can 
cause AKI. HUS usually occurs 2 days to 10 weeks postpartum 
and may cause severe renal failure. By contrast, thrombotic 
thrombocytopenic purpura usually presents in the first or second 
trimester with predominant neurological features and only mild 
proteinuria and haematuria. See Chapters 21.10.6, 22.7.3, and 22.7.5 
for further discussion.
FURTHER READING
Bauer SR, Carroll PR, Grady D (2019). Hematuria practice guidelines 
that explicitly consider harms and costs. JAMA Intern Med, doi: 
10.1001/jamainternmed.2019.2269.
Cohen RA, Brown RS (2003). Clinical practice. Microscopic hema-
turia. N Engl J Med, 348, 2330–​8.
Doshi SM, Friedman AN (2017). Diagnosis and management of type 2 
diabetic kidney disease. Clin J Am Soc Nephrol, 12, 1366–​73.
Hill NR, et al. (2016). Global prevalence of chronic kidney disease—​a 
systematic review and meta-​analysis. PLoS One, 11, e0158765.
Joint Specialty Committee on Renal Medicine of the Royal College 
of Physicians of London and the Renal Association (2006). 
Chronic kidney disease in adults: UK guidelines for identification, 
management and referral. Royal College of Physicians of London, 
London.
Keith DS, et al. (2004). Longitudinal follow-​up and outcomes among 
a population with chronic kidney disease in a large managed care 
organization. Arch Intern Med, 164, 659–​63.
Kodner C (2016). Diagnosis and management of nephrotic syndrome 
in adults. Am Fam Physician, 93, 479–​85.
Krogsbøll LT (2014). Guidelines for screening with urinary dipsticks 
differ substantially—​a systematic review. Dan Med J, 61, A4781.
Lamb EJ, Stevens PE (2014). Estimating and measuring glomerular fil-
tration rate: methods of measurement and markers for estimation. 
Curr Opin Nephrol Hypertens, 23, 258–​66.
Leung N, Nasr SH (2014). Myeloma-​related kidney disease. Adv 
Chronic Kidney Dis, 21, 36–​47.
Lopez-​Vargas PA, et al. (2013). Prevention, detection and management 
of early chronic kidney disease: a systematic review of clinical prac-
tice guidelines. Nephrology (Carlton), 18, 592–​604
Moroni G, Ponticelli C (2014). Rapidly progressive crescentic 
glomerulonephritis: early treatment is a must. Autoimmun Rev, 
13, 723–​9.
National Institute for Health and Care Excellence (2014). Chronic 
kidney disease in adults:  assessment and management. Clinical 
Guideline 182. http:/​www.nice.org.uk/​guidance/​cg182
Niemi MA, Cohen RA (2015). Evaluation of microscopic hematuria: a 
critical review and proposed algorithm. Adv Chronic Kidney Dis, 22, 
289–​96.
Papadopoulou-​Marketou N, Chrousos GP, Kanaka-​Gantenbein C 
(2017). Diabetic nephropathy in type 1 diabetes: a review of early 
natural history, pathogenesis, and diagnosis. Diabetes Metab Res 
Rev, 33, e2841.
Radhakrishnan J, Perazella MA (2015). Drug-​induced glomerular dis-
ease: attention required! Clin J Am Soc Nephrol, 10, 1287–​90.
Raghavan R, Eknoyan G (2014). Acute interstitial nephritis—​a re-
appraisal and update. Clin Nephrol, 82, 149–​62.
Box 21.3.17  Renal disease in pregnancy
AKI in pregnancy
	•	 Hypovolaemia:
	
—​	 Hyperemesis
	
—​	 Haemorrhage
	
—​	 Sepsis
	
—​	 Abruption
	•	 Infection:
	
—​	 Pyelonephritis
	
—​	 Septic abortion
	
—​	 Puerperal sepsis
	•	 Obstruction:
	
—​	 Gravid uterus
	•	 Endothelial dysfunction:
	
—​	 Pre-​eclampsia
	
—​	 Acute fatty liver of pregnancy
	
—​	 HELLP syndrome
	
—​	 HUS
Exacerbation of pre-​existing renal disease
	•	 CKD of any cause with deterioration of function, proteinuria, and 
pre-​eclampsia
	•	 Flare of systemic and renal disease (systemic lupus erythematosus and 
systemic sclerosis)
New-​onset nephrotic syndrome
	•	 Pre-​eclampsia
	•	 Systemic lupus erythematosus
	•	 Minimal change disease


section 21  Disorders of the kidney and urinary tract
4780
Siew ED, Davenport A (2015). The growth of acute kidney injury: a 
rising tide or just closer attention to detail? Kidney Int, 87, 46–​61.
Tesar V, Hruskova Z (2013). ANCA-​associated renal vasculitis—​an 
update. Contrib Nephrol, 181, 216–​28.
Torres PA, et al. (2015). Rhabdomyolysis: pathogenesis, diagnosis, and 
treatment. Ochsner J, 15, 58–​69.
van der Velde M, et al. (2009). Screening for albuminuria identifies 
individuals at increased renal risk. J Am Soc Nephrol, 20, 852–​62.
Webster AC, et  al. (2017). Chronic kidney disease. Lancet, 389, 
1238–​52.
Webster P, et  al. (2017). Pregnancy in chronic kidney disease and 
kidney transplantation. Kidney Int, 91, 1047–​56.
Wingo CS, Clapp WL (2000). Proteinuria: potential causes and ap-
proach to evaluation. Am J Med Sci, 320, 188–​94.
Zubair AS, et al. (2016). Loin pain hematuria syndrome. Clin Kidney J, 
9, 128–​34.