Clinical Presentation of Kidney Disease

The clinical presentation of kidney disease.


Renal disease may present in many ways, including: (1) the screening of asymptomatic individuals; (2) with symptoms and signs resulting 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 detected as chronic depression of glomerular filtration rate (known as chronic kidney disease, 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 glomerular filtration rate—‘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—also known as acute renal failure; (3) with urinary symptoms—frequency, polyuria, nocturia, oliguria, anuria, and macroscopic haematuria; 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 progressive glomerulonephritis with acute renal failure.

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 complication of the particular infection, e.g. haemolytic uraemic syndrome, poststreptococcal glomerulonephritis, hantavirus infection, leptospirosis, HIV nephropathy; (5) systemic inflammatory diseases, e.g. systemic vasculitides, rheumatological disorders, sarcoidosis, amyloidosis; (6) drug-induced renal disease; and (7) pregnancy.

Clinical Presentation of Kidney Disease in detail - technical


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 clinical findings to assess the potential risk of underlying renal disease. This evaluation should focus on features of systemic and inflammatory 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 investigations, including urinalysis and estimation of renal function.

Presentation of aymptomatic 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 function 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 below); monitoring of patients at ‘high risk’ of developing renal disease (e.g. hypertension, diabetes, multisystem disease); occupational and insurance medicals
  • screening patients admitted to hospital with acute illnesses—as an incidental finding; 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 tumours, 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 basic means of assessing renal function has been estimation of the serum creatinine, and this can be used—with or without estimation of urinary creatinine excretion—to estimate the GFR. The Cockcoft–Gault equation, 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 estimated glomerular filtration rate (eGFR) normalized to body surface area from serum creatinine, age, sex, and race. Using this method, population studies in the Western world have estimated that between 4 and 6% of the adult population have moderate to severe renal failure, with an eGFR of less than 60 ml/min per 1.73 m2 body surface area (stage 3 to 5 chronic kidney disease (CKD). Most of these are elderly, and only very few of them (1–4%) progress to endstage renal failure when followed over a 5-year period, while over the same time up to 69% die owing to cardiovascular disease.

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 intervention 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 (Bullet list 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) inhibitors in the CKD population, are now incorporated into the Primary Care Quality and Outcomes Framework, by which means funding is related to achievement of targets. As a consequence, there has been a substantial rise in the number of patients identified with asymptomatic 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 patients an eGFR in this range seems to confer a very much higher risk of cardiovascular demise than of endstage renal failure.

Bullet list 1 Summary of United Kingdom guidelines for serum creatinine measurement and estimation of GFR

Serum creatinine concentration should be measured at initial assessment and then at least annually in all adult patients with the following conditions:

  • Previously diagnosed chronic kidney disease (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 parenchymal 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 nephrotoxic drugs:
    • • ACE inhibitors, angiotensin receptor blockers, NSAIDs, lithium, mesalazine, ciclosporin, 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

Employment or insurance health screening

As well as targeted screening of ‘at-risk’ populations, asymptomatic 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 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 periodically screened for the development of hypertension, proteinuria, and renal dysfunction. Renal disease also often presents in acute medical and surgical patients. Up to 5% of acute patients have some acute deterioration in renal function during a hospital admission, mostly owing to hypotension, sepsis, or the use of nephrotoxic drugs. 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 present 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, e.g. abnormalities of potassium and acid–base homeostasis identified on a ‘routine’ sample may indicate 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 polycystic kidney disease, which may be reliably identified by ultrasonography from the third decade onwards. The identification of disease genes for inherited renal diseases such as autosomal dominant polycystic kidney disease, tuberous sclerosis, von Hippel–Lindau disease, Alport’s syndrome, and congenital nephrotic syndrome raises the possibility of future antenatal screening and earlydetection of these diseases long before they become clinically manifest.

Screening and management of asymptomatic 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. Within the general population, 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. Guidelines aimed at identifying subclinical renal disease therefore suggest proteinuria screening only for patients at increased risk of renal disease. The 2005 United Kingdom guidelines are summarized in Bullet list 2.

Bullet list 2 United Kingdom guidelines for proteinuria screening

Dipstick urinalysis for protein should be undertaken:

  • As part of the initial assessment of patients with:
    • • Newly discovered hypertension, haematuria, or reduced GFR
    • • Unexplained oedema or suspected heart failure
    • • Suspected multisystem disease, e.g. lupus, vasculitis, and myeloma
    • • Diabetes mellitus
  • As part of the annual monitoring of patients with:
    • • Urologically unexplained haematuria or persistent proteinuria
    • • Diabetes mellitus
  • As part of routine monitoring for patients receiving nephrotoxic drugs, e.g. gold and penicillamine

Detection of proteinuria

Most multireagent strips are sensitive to 100 to 200 mg/litre of protein, giving either a ‘trace’ or ‘+’, although some designed to screen for microalbuminuria are more sensitive. They do not detect low-molecular-weight proteins such as immunoglobulin light chains, and thus assay of light chains using urine immunoelectrophoresis is essential as part of the investigations for myeloma, primary amyloidosis, and light-chain glomerulopathy.

The kidney normally excretes less than 150 mg of protein in 24 h, mainly owing to failed tubular reabsorption of albumin. Urinary protein excretion also reduces overnight while recumbent, but increases during the day owing to posture and exercise. Urinary protein concentration also depends on urine flow rate. To overcome the diurnal 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.

Management of asymptomatic proteinuria without haematuria

Proteinuria may be an early presentation of renal disease, but transient proteinuria is not associated with significant renal disease. A finding of proteinuria should lead the physician to take a history focusing on risk factors for renal disease (e.g. diabetes, drugs, multisystem disease, and family history), measure the blood pressure, and examine for oedema (Bullet list 3

Bullet list 3 Approach to the patient with dipstick-positive proteinuria

Key features to establish
  • Is there any evidence of diabetes or urinary infection?
  • 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, family history of renal disease
    • • Are there any features of nephrotic syndrome (heavy proteinuria with oedema and low serum albumin)?

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 repeated a week or so later, and any positive result confirmed and quantitated by estimation of ACR (or PCR). If postural or orthostatic proteinuria is suspected, an early-morning urine specimen should be sent for ACR (or PCR), in which case the diagnosis is substantiated by the finding of normal urinary protein excretion in this specimen.

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 protein for myeloma
  • immunological screen (antinuclear antibodies, complement, antineutrophil cytoplasmic antibodies (ANCA))
  • renal ultrasonography
  • consideration of renal biopsy if heavy proteinuria (ACR >150–200 mg/mmol, PCR >200–300 mg/mmol) or renal dysfunction

Management of asymptomatic proteinuria with microscopic haematuria

Proteinuria with haematuria on urinalysis indicates intrinsic renal disease. It may be the first sign of a severe glomerulonephritis and acute renal failure, hence this presentation must be considered seriously (see later). Patients with abnormal renal function, haematuria, and proteinuria require urgent referral to a nephrologist for investigation.

Apparently asymptomatic patients with normal renal function but persistent proteinuria and haematuria may describe subtle symptoms of multisystem disease on close questioning (e.g. myalgia, arthralgia, ‘sinusitis’, rash, or fever). These may be clues to an underlying disease, hence patients with such symptoms require screening for multisystem disease with urine microscopy for red cell casts, serum ANCA, antiglomerular basement membrane antibodies, antinuclear and anti-double-stranded DNA antibodies and complement levels, and referral to a nephrologist for further evaluation and consideration of renal biopsy.

Asymptomatic microscopic (non visible) haematuria

Microscopic haematuria may potentially arise from anywhere in the urinary tract. As with renal dysfunction and proteinuria, isolated microscopic haematuria is common. Population studies indicate a prevalence between 0.2 and 16%, with a higher prevalence of 18% in men aged over 50 years. Studies of male army recruits screened and followed up for 12 years showed that 39% had microscopic haematuria on one occasion, and 16% had microscopic haematuria on two or more occasions. Although isolated microscopic haematuria may be associated with benign glomerular disease, in practice the main concern is the possibility of renal and urinary tract malignancy.

Urothelial and bladder carcinomas account for approximately 5% of microscopic 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 microscopic (non visible) haematuria

The causes of microscopic haematuria are summarized in Bullet list 4. The true prevalence of intrinsic renal disease is unknown because renal biopsies are not routinely performed in the absence of proteinuria 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.

Bullet list 4 Causes of microscopic 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
  • Exercise
  • Overanticoagulation
  • Factitious

Management strategy for microscopic (non visible) haematuria

The key to managing patients with asymptomatic microscopic haematuria 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 microscopic haematuria have been published, reflecting a lack of consensus and an insufficient evidence base. There are no indications for screening for microscopic haematuria as the positive predictive value for malignancy is as low as 5% in an elderly population, and early detection of disease has not been shown to improve prognosis.

Following the detection of microscopic haematuria without proteinuria on urine dipstick, menstruation, recent exercise, or sexual activity should be excluded, and the urine sent for microscopy and culture. Urinalysis should then be repeated after 7 days: if this remains positive, urinary tract infection must be excluded, and blood pressure, urine protein-creatinine ratio (PCR) or albumin creatinine ratio (ACR), and serum creatinine/eGFR measured.

Patients should be referred to urological services to exclude urinary tract malignancy and disease if they are over 40 years of age with:

  1. (1) persistent asymptomatic haematuria (defined as 2 out of 3 positive dipsticks), or
  2. (2) symptomatic non-visible (microscopic) haematuria, or
  3. (3) visible (macroscopic) 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. (1) declining GFR, or
  2. (2) CKD stage 4 or 5, or
  3. (3) proteinuria with urinary PCR >50mg/mmol or ACR >30mg/mmol, or
  4. (4) age <40 years and hypertension

Patients should be referred to a nephrologist if:

Patients not meeting criteria for referral to urological or renal services, or who have had negative urological or nephrological investigations, need long term monitoring in primary care due to the uncertainty of the underlying diagnosis, with appropriate referral should they develop:

  1. (1) voiding lower urinary tract symptoms (LUTS), or
  2. (2) visible haematuria, or
  3. (3) significant or increasing proteinuria, or
  4. (4) progressive renal impairment (falling eGFR), or
  5. (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-specific, e.g. loin pain or polyuria, or unrelated to the kidney and manifest 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 indicative of systemic disease.

Chronic kidney disease

The symptoms of CKD are attributed to the gradual onset of uraemia, 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 lesss than 10 ml/min per 1.73 m2 body surface area. 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 of less than 5 ml/min per 1.73 m2 may be remarkably symptom free.

Most patients have some symptoms by the time that they require dialysis (CKD stage 5, eGFR <15 ml/min per 1.73 m2) (Bullet list 5). These include anorexia, nausea, and vomiting (in 76% of patients), fatigue and weakness (72%), pruritus (40%), breathlessness and orthopnoea (26%), bleeding tendency (14%), apathy and loss of mental concentration (12%), and muscle twitching and cramps (11%).

Bullet list 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

Factors contributing to the development of ‘uraemia’ and other symptoms include small-molecule nitrogenous substances, endproducts of protein metabolism, metabolic acidosis, salt and water retention, electrolyte disturbances (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 bicarbonate, 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 20 to 40% 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 presents 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 definitive vascular access, hence patients often need to begin dialysis with temporary or semipermanent 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 chronic renal failure (‘crash-landers’) from those with acute renal failure due to potentially reversible disease. Failure to become dialysis independent by 90 days after initiation is often taken as proof that the acute presentation was with endstage rather than acute renal failure. 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 acidosis 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 pericarditis, which if unrecognized may lead to pericardial tamponade and occasionally to fatal pericardial haemorrhage.

Acute renal failure (acute kidney injury)

Acute kidney injury (in brief) causes can be classified as being prerenal, renal (due to intrinsic renal disease) or postrenal (obstruction). In the general hospital setting, 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 interstitial nephritis cause 5 to 10%.

Key features to establish sequentially when managing a patient with acute renal failure are as follows:

  1. 1 How ill are they? The condition of patients with similar biochemical abnormalities can range from the asymptomatic to the moribund: those with cardiorespiratory compromise need critical care support.
  2. 2 Does the patient need emergency haemodialysis or haemofiltration? The major indications are severe hyperkalaemia, pulmonary oedema, profound acidosis, and severe uraemia—the latter being defined more on clinical than biochemical grounds.
  3. 3 Is there a prerenal element that may respond to volume repletion or inotopic support? Clinical examination, perhaps supplemented by central venous pressure measurement, facilitates this decision.
  4. 4 Is the patient obstructed? Clinical features can be helpful, and a urinary tract ultrasound is usually diagnostic.
  5. 5 Is this acute or chronic renal failure? Sometimes this is difficult or impossible to determine on clinical grounds, but small kidneys on ultrasound signify chronic disease.
  6. 6 Is this intrinsic renal disease? Clinical features of systemic disease and relevant immunological tests (including ANCA and antiglomerular basement membrane antibody) must be pursued, and renal biopsy will usually be required to establish the diagnosis.

As with chronic kidney disease, many of the symptoms and signs attributed to loss of renal function are nonspecific and occur with advanced acute renal failure (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 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 acute renal failure. A patient developing acute renal failure postsurgery 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 unconsciousness following a drug overdose is likely to have rhabdomyolysis. 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 symptoms 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 patients with rapidly progressive glomerulonephritis 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 acute renal failure 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 sufficient clues to allow a diagnosis to be established will require a renal biopsy to avoid missing potentially reversible intrinsic renal disease. 

Urinary symptoms


Most symptoms related to micturition relate to problems arising in the lower urinary tract. Bladder outflow obstruction is commonly associated with symptoms such as urgency, hesitancy, poor urinary stream, nocturia, dysuria, and dribbling. Recognition of these symptoms is important as outflow obstruction may result in complete obstruction with acute renal failure 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 associated 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.


Patients may present with symptoms of increased frequency of micturition. 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 inflammation, stone, or tumour) or reduced volume from extrinsic compression or contraction (e.g. following radiotherapy). Increased frequency of emptying a full bladder is suggestive of polyuria, especially if the volume and frequency is unaffected during the night.


Polyuria (defined as a urinary output>3 litre/24 h) may result from solute diuresis, water diuresis, or a combination of both. Solute diuresis 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 chronic kidney disease (especially associated with ureteric obstruction, postobstructive states, and chronic interstitial nephritis), electrolyte abnormalities (hypercalcaemia and hyperkalaemia), 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 associated 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 polyuric, 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.


Nocturia is defined as the need to get up once or more times for nocturnal 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 patients 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 nocturnal urine output. These types of nocturia are distinguishable 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 polyuria 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 elderly, 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 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 acute renal failure. The recognition of oliguria 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 nephritis, 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 an urgent ultrasound of the kidneys and bladder. Very occasionally, anuria may be a manifestation of severe intrinsic renal disease, such as a rapidly progressive glomerulonephritis, cortical necrosis, or renal infarction.

Urine appearance and macroscopic haematuria

Macroscopic 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 endstream haematuria is consistent with bladder pathology. Although the causes of haematuria are numerous (Bullet list 6), infection, stones, and malignancy are the most common. Macroscopic haematuria warrants investigation in all patients.

Bullet list 6 Causes of macroscopic 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

Frank haematuria is uncommon in glomerular disease, with the notable exception of IgA nephropathy in which macroscopic haematuria classically occurs immediately following mucosal inflammation, typically an upper respiratory tract infection. In patients with polycystic disease, cysts may haemorrhage to cause loin pain and haematuria. This may be associated with infection of the cysts and usually resolves with conservative management, with antibiotics if there are signs of infection.

Red–brown–black urine is occasionally caused by haemoglobinuria due to haemolysis or myoglobinuria precipitated by rhabdomyolysis. 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, suggesting a diagnosis of porphyria or alkaptonuria.

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 typically 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. Pyelonephritis typically causes renal angle pain on the affected side and is often associated 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 involvement 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 occasionally associated with renal pain, but active destructive glomerulonephritis and interstitial nephritis are invariably pain free.

Loin pain–haematuria syndrome

Rarely, patients may present with recurrent intermittent loin pain, haematuria (microscopic or macroscopic), 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 unknown: 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 psychologically 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 uncomfortable, 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 remission. The pain is usually unilateral at presentation, but many patients eventually develop pain bilaterally. Many patients are taking large quantities of opioids and other analgaesics (e.g. amitriptyline, 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 glomerular basement membrane has been reported in about 60% of cases in some series, and appearances of IgA nephropathy are sometime seem, 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. They may request nephrectomy and/or renal autotransplantation, which the wise physician will not accede to, preferring to help the patient by sympathetic discussion and referral to pain management services.

Specific renal syndromes

Nephrotic syndrome

See this link for very detailed technical article about nephrotic syndrome: Nephrotic Syndrome


Nephrotic syndrome is the triad of oedema, proteinuria, and hypoalbuminaemia (see Bullet list 7 for an example). 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. However, in practice the definition is somewhat arbitrary, and the correlation between the degree of proteinuria, 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.

Bullet list 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.

  • 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
  • Urine dipstick test: protein 4+, no haematuria
  • Urine albumin:creatinine ratio (ACR): 4520 mg/mmol
  • 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 ultra sonography of right leg: normal
  • Renal biopsy: membranous nephropathy with subepithelial spikes on silver stain
  • Membranous nephropathy with nephrotic syndrome

Frothy urine, oedema, and hypoalbuminaemia indicate the onset of heavy proteinuria and nephrotic syndrome. The rapid onset of symptoms suggests a primary glomerular lesion rather than long-standing diabetic nephropathy. The presence of leg erythema may be due to infection 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 managed conservatively with diuretics and low-molecular-weight heparin as thromboembolic prophylaxis.

Nephrotic syndrome indicates the presence of glomerular disease. Causes can usefully be divided into primary glomerular diseases and those arising secondary to systemic disease (Bullet list 8), with the geographical context important in determining the most likely cause in any particular case. The most common cause of nephrotic 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 glomerulonephritis is also an important cause.

Bullet list 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
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 develops 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 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 appetite 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 diuretic therapy in this setting may provoke circulatory collapse from hypovolaemia, or less dramatically may further reduce renal perfusion 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 detect clinically. Patients with marked peripheral oedema often have swollen legs of unequal size and associated erythema due to an increased 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 hyperlipidaemia, 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 provide clues to an underlying cause, which may be clear, such as in a patient with long-standing diabetes and progressive diabetic nephropathy. Alternatively, the immediate cause may only become apparent 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 glomerulonephritis, 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 inflammatory 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 examination, but does not warrant further investigation apart from a chest radiograph in the absence of clinical clues, e.g. disturbance of bowel habit 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 renal failure

Around 5% of cases of acute renal failure are caused by a rapidly progressive glomerulonephritis (RPGN). Recognizing this relatively small group of patients is important because many of the causes respond well to treatment, provided the diagnosis is made early and treatment started promptly. The key to making a diagnosis is having a high index of clinical suspicion such that important features of the syndrome are identified (see Bullet list 9for an example).

Bullet list .9 Case illustration—ANCA-associated vasculitis

An 80-year-old woman presents with a 2-week history of increasing malaise 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.


  • Subtle purpuric rash on both legs
  • Bibasal crepitations
  • Reduced pinprick sensation in a glove and stocking distribution
  • Creatinine: 854 µmol/litre (56 µmol/litre 10 months before)
  • Urea: 45 mmol/litre
  • Hb: 8.3 g/dl
  • Urine dipstick test: blood 3+, protein 2+
  • Urine microscopy: red cell casts
  • Serological testing: p-ANCA positive, with myeloperoxidase titre 78%
  • Renal biopsy: focal necrotizing glomerulonephritis
  • Acute renal failure due to microscopic polyangiitis (an ANCA-associated vasculitis) with associated peripheral neuropathy

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 acute renal failure due to an inflammatory condition. Confirmation of a systemic vasculitis is made with a positive p-ANCA and renal biopsy.

The hallmarks of an 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

An RPGN may present either de novo in a previously well patient or as a complication in a patient known to have a systemic disease (Bullet list 10). Their clinical features may be diverse. Occasionally, 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 severe acute renal failure 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, haemoptysis and peripheral neuropathy. Clinical features of specific inflammatory diseases associated with an RPGN are detailed in Table 1 below.

Bullet list 10 Causes of a rapidly progressive glomerulonephritis

  • Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis:
    • • Wegener’s granulomatosis
    • • Microscopic polyangiitis
    • • Churg–Strauss syndrome
  • Other primary systemic vasculitides (ANCA-negative)
  • Other systemic disorders:
    • • Systemic lupus erythematosus
    • • Cryoglobulinaemia
    • • Henoch–Schönlein purpura
  • Infection-related glomerulonephritis:
    • • Postinfectious glomerulonephritis
    • • Infective endocarditis
  • Antiglomerular basement membrane disease (Goodpasture’s syndrome)
  • Crescentic phase of a primary glomerulonephritis:
    • • IgA nephropathy
    • • Mesangiocapillary glomerulonephritis

Table 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
  • Wegener’s granulomatosis
  • Wegener’s granulomatosis
  • 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

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 may be life-threatening if severe), and neuropathic symptoms and signs. Conversely, the clinician should have a high index of suspicion for an RPGN in patients presenting with any of the above features, and in this context suspicions are heightened by the presence of dysmorphic red cells and red cell casts on urinary microscopy.

If an RPGN is suspected, then investigations should include ANCA, antiglomerular basement membrane (anti-GBM) antibodies, antinuclear and anti-double-stranded DNA antibodies, serum complement, antistreptolysin-O titre, and immunoglobulins and serum electrophoresis (including tests for cryoglobulins). It is almost certain that a patient with an RPGN will require a renal biopsy to confirm the diagnosis and to guide management, and thus all patients with suspected RPGN should be referred urgently to a nephrologist.

Presentation of renal disease associated with other underlying diseases

Renal disease is capable of presenting in many complex and diverse ways, and many renal problems arise as either direct or indirect complications of other disease. Examples include acute renal failure caused by sepsis, and progressive chronic kidney disease due to diabetes (Bullet list 11. This section illustrates some common and important presentations of renal disease.

Bullet list 11 Important and common presentations of renal disease

  • Diabetic nephropathy with progressive chronic kidney disease
  • Vascular disease:
    • • Renal atheroemboli
    • • Renal artery stenosis
  • Underlying malignancy:
    • • Urinary tract obstruction
    • • Myeloma
    • • Hypercalcaemia
  • Infection:
    • • Acute presentation with renal failure: (1) general syndromes—sepsis, rhabdomyolysis, haemolytic uraemic syndrome, postinfectious glomerulonephritis, tubulointerstitial nephritis; (2) specific syndromes—hantavirus, leptospirosis, malaria
    • • Chronic infections associated with renal disease: hepatitis B, hepatitis C, filaria, schistosomiasis, HIV
  • Systemic inflammatory disease:
    • • Systemic vasculitides
    • • Systemic lupus erythematosus
    • • Sarcoidosis
  • Drug-induced renal disease
  • Pregnancy

Diabetic nephropathy

In the Western world, diabetes is the most common cause of renal disease, accounting for 43% of endstage renal failure in the United States of America and 19% in the United Kingdom (Bullet list 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 management 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 impairment of renal function than their nondiabetic counterparts. This leads to an earlier requirement for initiation of dialysis in patients with diabetic nephropathy.

Bullet list 12 Case illustration—progressive chronic kidney disease 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.

  • Cardiovascular—blood pressure 167/88 mmHg, jugular venous pressure +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
  • Urine dipstick test: protein 4+, no haematuria
  • Urine albumin:creatinine ratio (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: Hb 9.8 g/dl
  • HbA1C: 10.2%
Further history

Five years previously his blood pressure was 189/92 mmHg with creatinine 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 breathlessness on exertion, and noted increasing ankle swelling.

This man with long-standing diabetes presents with nonspecific symptoms 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.

Screening patients with diabetes for microalbuminuria and hypertension enables early diagnosis of complications and intensive management of glucose and blood pressure. As eGFR falls to 30 ml/min per 1.73 m2 body surface area, patients should be referred to a nephrologist to plan for renal replacement therapy.

Patients with diabetes are also subject to develop other microvascular and macrovascular complications, which may lead to superimposed renal atheroembolic disease and renal artery stenosis. These may present as an abrupt decline in renal function following the introduction of an ACE inhibitor or angiotensin receptor antagonist. Patients with diabetic nephropathy are also at increased risk of acute or chronic renal failure, with common causes 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 here for a detailed article about diabetic renal disease.

Renovascular disease

Many patients with diffuse atherosclerosis have evidence of renovascular disease, and a history of cerebrovascular, coronary, or peripheral vascular disease makes a diagnosis of renovascular disease likely. Up to 24% of patients presenting with peripheral vascular 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 extremely likely, although most of these patients remain asymptomatic from the renal point of view. Common presentations of renovascular disease are outlined in Bullet list 13

Bullet list 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 ultrasound
  • As part of the investigation for progressive CKD.
  • Symptomatically as acute (‘flash’) pulmonary oedema in the absence of cardiac failure or fluid overload
  • Postoperative acute renal failure, especially following coronary artery bypass or aortic aneurysm surgery

Myeloma and other malignancies

Myeloma can cause acute renal failure in several 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 degree of renal impairment), abrupt decline in renal function after relatively minor prerenal ‘insult’, and unremarkable urine dipstick.

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 patients 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 are the required investigations, followed—if either is positive—by bone marrow examination.

Other malignancies may present with renal involvement due to a number of mechanisms, including acute renal failure due to urinary tract obstruction by pelvic or retroperitoneal tumour. Other possible causes are outlined in Bullet list 14

Bullet list 14 Renal presentations associated with malignancy

  • Acute renal failure:
    • • Urinary tract obstruction
    • • Hypercalcaemia
    • • Tumour lysis with urate nephropathy
    • • Chemotherapy (e.g. cisplatin, ifosfamide)
    • • Leukaemic infiltration
    • • Microangiopathy
  • Paraneoplastic glomerular disease:
    • • Membranous
    • • Amyloid
    • • Mesangiocapillary glomerulonephritis

Renal presentation of infectious diseases

A wide range of systemic infections, resulting in either acute renal failure or chronic kidney disease, can affect the kidney. 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 acute and chronic kidney disease.

Acute renal failure may occur as part of a general systemic syndrome induced by infection, such as sepsis and septic shock, haemolytic uraemic syndrome (HUS), rhabdomyolysis, postinfectious glomerulonephritis, and tubulointerstitial nephritis. Alternatively, an infectious agent may cause specific nephrotoxicity, e.g. 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 acute renal failure in the context of multiorgan failure.

Other general syndromes that may be induced by infection include HUS and rhabdomyolysis. For example, the verotoxin of Escherichia coli O157:H7 causes (D+) HUS, which is a thrombotic microangiopathy characterized by diarrhoea, acute renal failure, and thrombocytopenia. Patients with influenza, legionella, or streptococcal infection may present with fever, severe myalgia, and dark urine in the context of acute renal failure due to rhabdomyolysis.

Poststreptocccal glomerulonephritis is still one of the most common causes of acute renal failure 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 infection of the throat or skin with a ‘nephritic’ syndrome characterized by hypertension, oedema, haematuria and proteinuria, and acute renal failure.

Specific nephrotoxicity caused by infection

Hantavirus and leptospirosis

Hantaviruses are endemic in specific rodent reservoirs and are transmitted to man by inhalation of infectious aerosols or rodent excreta. In Europe, the main pattern of disease is haemorrhagic fever with renal syndrome (HFRS). 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 hypotensive phase associated with haemorrhages and ecchymoses, lasting hours to 2 days; (3) an oliguric phase for 3 to 14 days, with worsening acute renal failure 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 associated with jaundice and hepatomegaly. Acute renal failure occurs in 20 to 85% of patients owing to tubulointerstitial nephritis.


Severe infection with Plasmodium falciparum occurs in nonimmune adults. Acute renal failure may occur either in the acute phase of the disease or 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 chronic kidney disease

In the developing world, CKD is commonly secondary to infectious disease, with the underlying infection often remaining subclinical until the presentation with renal manifestations. Examples of CKD secondary to infective agents include hepatitis B, hepatitis C, Plasmodium 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 associated with the development of polyarteritis nodosa, although 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, but this remains asymptomatic in most patients, with only a few developing clinical evidence of vasculitis. The associated mesangiocapillary glomerulonephritis can present as nephrotic syndrome or chronic kidney disease.

Many infectious agents endemic in sub-Saharan Africa may also cause a mesangiocapillary glomerulonephritis presenting as nephrotic syndrome: most common is P. malariae, but filaria and schistosomiasis remain in the differential diagnosis.

HIV-associated nephropathy (HIVAN) is an increasingly recognized complication of HIV infection, and it now accounts for 1% of the dialysis population in the United States of America. Patients usually present with heavy proteinuria and nephrotic syndrome due a collapsing form of focal segmental glomerulosclerosis. HIVAN predominates in young African-American men and is rare in areas endemic for HIV.

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 Bullet list 15. The presentation of an acute glomerulonephritis and progressive renal failure due to systemic inflammatory diseases such as the vasculitides and systemic lupus erythematosus has been discussed earlier in the chapter, and further details can be found in Chapters 21.10.2 (vasculitides) and 21.10.3 (renal involvement in rheumatological disorders). Other inflammatory diseases may present in different ways.

Bullet list 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)

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 identified by the presence of proteinuria or tubular dysfunction with a renal tubular acidosis. However, sarcoidosis may present with acute renal failure, which may be caused by an acute tubulointerstitial nephritis associated with an eosinophilia and eosinophiluria, or be precipitated by hypercalcaemia, which may be more common in summer months owing to ultraviolet light exposure. The presence of extrarenal features of sarcoidosis (including bilateral hilar lymphadenopathy and erythema nodosum) helps to establish the diagnosis, but sometimes the diagnosis may only become apparent following a renal biopsy for unexplained renal impairment and measurement of serum ACE. 

Systemic sclerosis

Systemic sclerosis may present with an acute crisis characterized by an abrupt rise in blood pressure (>160/90 mmHg) with hypertensive encephalopathy, acute renal failure, and a microangiopathic haemolytic anaemia. This may occur before the onset of the cutaneous features of the disease. 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 hypertension and acute renal failure. 

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 malignant 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 nephrotic syndrome. Renal involvement can be demonstrated by serum amyloid P (SAP) scanning or by renal biopsy. 

Drug-induced renal disease

Numerous drugs have the potential for causing both acute renal failure and chronic kidney disease (Bullet list 16). As well as prescribed and over-the-counter medication, 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.

Bullet list 16 Adverse effects of drugs on the kidney

Acute renal failure
  • Acute tubular cell injury (acute tubular necrosis, ATN)
    • • Aminoglycosides
    • • Amphotericin
    • • Cisplatin
    • • Nsaids
    • • Radiocontrast media
    • • Paracetamol poisoning
    • • Statins (by inducing rhabdomyolysis)
  • Interstitial nephritis:
    • • β-Lactam antibiotics (penicillins, cephalosporins)
    • • NSAIDs
    • • Furosemide
    • • Allopurinol
    • • Azathioprine
    • • Sulphonamides
    • • Aristolochic acid (‘Chinese herb nephropathy’)
Nephrotic syndrome
  • Membranous:
    • • 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
  • Renal papillary necrosis:
    • • Aspirin with phenacetin
    • • NSAIDs
  • Crystalluria with tubular obstruction
    • • Aciclovir
    • • Indinavir
    • • Methotrexate
    • • Sulphonamides

Salt and water depletion

Acute renal failure may follow hypotension and reduced renal perfusion due to sodium 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 perfusion and interfere with renal function. Agents which block the renin–angiotensin system, the ACE inhibitors and angiotensin receptor blockers, require special consideration. These agents abrogate 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, and these agents are implicated in a significant proportion of cases of acute renal failure 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 arachidonic 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 Bullet list 16.

Tubulointerstitial nephritis is classically caused by penicillins and NSAIDs, 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 microscopic 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 potentially offending drug (or drugs), and proceed with a renal biopsy if renal function does not improve.


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 patient is dehydrated, hence adequate fluid input to achieve a high urinary volume is advised before these drugs are taken.


Pregnancy provides a unique set of circumstances in which renal disease may present. Renal disease may be present before pregnancy and 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 acute renal failure due to pre-eclampsia. A summary of the presentation of renal disease in pregnancy is detailed in Bullet list 17.

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 (PET)?
  • 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 PET or underlying renal disease (e.g. systemic lupus erythematosus).
  • Hypotension and hypovolaemia suggest sepsis or haemorrhage.

Bullet list 17 Renal disease in pregnancy

Acute renal failure 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
    • • Syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP)
    • • Haemolytic uraemic syndrome (HUS)
Exacerbation of pre-existing renal disease
  • Any chronic kidney disease 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
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 thrombocytopenia. However, patients may not be hypertensive or demonstrate other features, hence distinguishing pre-eclampsia from pre-existing renal disease may be difficult, and the condition may occasionally 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 associated with renal failure, severe haemolysis, and coagulopathy, and may progress to multiorgan failure. See Chapters 14.4 (hypertension in pregnancy) and 14.9 (liver and gastrointestinal disease in pregnancy) for further discussion.

Haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura

Haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura (HUS/TTP) are related disorders that are occasionally associated with pregnancy and can both cause acute renal failure. HUS usually occurs 2 days to 10 weeks postpartum and may cause severe renal failure. By contrast, TTP usually presents in the first or second trimester with predominant neurological features and only mild proteinuria and haematuria.