Kidney and urinary tract disease

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10 Kidney and urinary tract disease

Approach to the Patient

The history should include a history of prior tests of renal function, previous urinary dipstick and BP recordings, and an obstetric (e.g. hypertension during pregnancy) and family history (e.g. inherited disorders).

Clinical presentations

Presentation with local symptoms

These include dysuria (infection, stones) and pain (loin pain, suprapubic pain, infection, stones, tumour, obstruction, sloughed papilla) from lower urinary tract symptoms including obstructive symptoms (poor stream, hesitancy, incomplete bladder emptying) and voiding symptoms (frequency, nocturia, urge incontinence).

Presentation with particular renal syndromes

Patients can present with the syndromes shown in Table 10.1.

Table 10.1 Presenting syndromes of renal disorders

Syndrome	Clinical findings
Asymptomatic proteinuria ± microscopic haematuria	Protein and/or blood on urine dipstick ± renal impairment
Nephrotic syndrome	Proteinuria +++ Hypoalbuminaemia Peripheral oedema
Nephritic syndrome	Microscopic haematuria and proteinuria Renal impairment Hypertension
Rapidly progressive glomerulonephritis	Rapidly worsening renal function with red cell casts in an active urinary sediment
Macroscopic haematuria	Visible bloody discoloration of the urine

Consequences of renal disease

• Uraemic symptoms. These do not develop until renal function is severely impaired (glomerular filtration rate (GFR) < 15 mL/min). Anorexia, nausea and vomiting, weight loss and loss of energy occur. Acidosis (with respiratory compensation) leads to shortness of breath. Confusion, fits and other neurological symptoms are signs of severe uraemia.

• Disturbance of salt and water homeostasis

• Salt and water overload — hypertension, peripheral oedema, distended central veins. This may progress to overt pulmonary oedema, which commonly occurs as GFR falls.

• Hypovolaemia — may be a cause of acute kidney injury in the context of acute illness. Polyuria is characteristic of tubulointerstitial diseases and may lead to hypovolaemia.

Examination of the urine

• Specific gravity (SG). SG is usually 1.003–1.035. As kidney disease progresses, the ability to concentrate the urine is lost. Urine may eventually have similar osmolality to plasma (which has SG = 1.010).

• Proteinuria. Normally the amount of protein in the urine should not exceed 150 mg/L, of which albumin should be < 20 mg/L. Significant proteinuria is a sign of glomerular disease, and usually consists predominantly of albumin (Bence Jones protein, as found in multiple myeloma, is an exception). ‘Nephrotic range proteinuria’ is a loose term, usually implying > 3 g/day of urine albumin loss and usually sufficient to cause hypoalbuminaemia. The urine dipstick is a sensitive marker of proteinuria. Quantification can be performed by measurement of:

• Microalbuminuria. Normal individuals excrete < 20 µg of albumin per min (30 mg in 24 hours) but dipsticks only detect levels above 200 µg (300 mg in 24 hours). The level between these two is called microalbuminuria. This is an early indicator of glomerular disease and a useful prognostic marker for future cardiovascular disease. Kits are available for testing.

• Albumin/creatinine ratio (ACR) can be tested on a random urine specimen. Because creatinine excretion is constant, correction by the creatinine concentration provides a correction for dilution. ACR may be useful in specific circumstances (e.g. early diabetic nephropathy). A ratio of 2.5–20 corresponds to albuminuria of 30–300 mg daily. Protein/creatinine ratio (PCR) is commonly measured if the dipstick is positive for protein.

• 24-hour urine protein collection. This is inconvenient for the patient, is expensive, and may be inaccurate due to incomplete urine collection.

• Haematuria. Red blood cells are not a normal finding in the urine. Between 5 and 10% of asymptomatic adults have microscopic haematuria. Causes include:

• glomerular disease

• infection

• stone disease

• renal or urological malignancies.

The urine dipstick is a sensitive detector of haem and if the dipstick is negative, blood is most unlikely to be present in the urine. If haematuria is found, then infection should be excluded (by sending a specimen of urine for culture) and the dipstick should then be repeated. Urine microscopy is useful to:

• confirm the presence of red cells in the urine (not routinely necessary if the dipstick is positive) and to exclude myoglobinuria (absence of red cells with dipstick-positive haematuria)

• diagnose red cell casts and dysmorphic red cells (normal morphology altered by passage through the renal tubules), pathognomonic of a glomerular cause of haematuria.

• Leucocyte esterase and nitrites. If white cells are present in the urine, then leucocyte esterase activity should be detectable. Nitrites are formed from nitrates by some bacteria. When both tests are positive, they are highly predictive of an acute urinary tract infection (UTI), with a sensitivity of 75% and specificity of 82%.

Evaluation of Renal Function

Glomerular disease

Plasma is filtered by the glomerulus. Failing glomeruli filter progressively less of the plasma, leading to a fall in glomerular filtration rate (GFR). Filtered uraemic toxins accumulate and lead to the uraemic syndrome. Large molecules (such as proteins) and cells are not normally filtered, but may appear in the urine as proteinuria or haematuria if the glomerular filter is injured (as occurs in glomerulonephritis).

Tubular disease

In the tubules (proximal convoluted tubule, loop of Henle, distal tubule and collecting duct), solute reabsorption, maintenance of salt and water homeostasis, acid–base balance and excretion of some drugs occur. Tests of tubular function include:

• urine pH (renal tubular acidosis, p. 347)

• urine-concentrating defects (inappropriately dilute urine)

• glycosuria (despite normoglycaemia)

• phosphaturia, uricosuria and aminoaciduria (all markers of proximal tubular disease but rarely measured).

See p. 351 for the diagnosis and management of acute and chronic tubulointerstitial nephritis.

Imaging in renal disease

Many renal disorders are associated with normal imaging. The choice of imaging depends on the clinical presentation and on the information required.

• Ultrasound (US) is non-invasive and relatively simple to perform. It provides information about the renal size (normally 9–13 cm; small kidneys are a sign of chronic kidney disease) and the cortical thickness (thin cortices are a sign of chronic renal damage; irregular cortices may suggest that scarring has occurred). Obstruction is shown by a dilated ureter and renal pelvis, and a bladder US can assess for incomplete voiding. A US can pick up anatomical abnormalities, e.g. cysts (single or multiple, benign or malignant), polycystic kidney disease, congenital absence of a kidney and other congenital abnormalities.

• Computed tomography of the kidneys, ureters and bladder (CT-KUB) is sensitive in the detection of renal stone disease. It is used for the differentiation of benign and potentially malignant cysts or renal masses. In obstruction, it may show the level of obstruction and the cause (extrinsic compression, stone disease, sloughed papilla, ureteric, bladder or prostatic tumour). It is used to stage renal and bladder tumours.

• Intravenous urography (IVU) provides anatomical detail of the calyces, renal pelvis, ureters and bladder. After a single injection of IV contrast, serial X-rays are taken of the kidneys, ureters and bladder. IVU is used (with a control plain film) in the diagnosis of stone disease, to diagnose or rule out tumours in the kidney or ureter, and to rule out anatomical abnormalities in recurrent UTI. It requires contrast and is contraindicated in moderate–severe renal impairment. Multiple films involve high exposure to ionizing radiation. IVU is time-consuming and relatively expensive, and has now been largely superseded by CT, which provides similar or more information in less time.

• Radio-isotope imaging uses the radio-isotopes DMSA (di-mercapto-succinic-acid), DTPA (diethylene-triamine-pentaacetic-acid) and MAG-3 (mercapto-acetyl-triglycine) to obtain functional and anatomical information. It:

• Demonstrates scarring. DMSA will fail to be taken up in scarred areas.

• Diagnoses obstruction. DTPA or MAG-3 will be ‘held up’ on the obstructed side compared to the other side. This is useful if the US result is equivocal (a ‘baggy’ renal pelvis). Functional obstruction may be relieved after injection of diuretic, e.g. at the pelvi-ureteric junction.

• Compares split renal function. This is necessary if nephrectomy is planned and asymmetrical renal function is suspected. It is also useful when assessing renovascular disease, in deciding whether intervention is justified.

Renovascular disease may be suggested if uptake is slower in one kidney than the other. If repeated after administration of an ACE inhibitor (‘captopril renography’), uptake may be reduced on the affected side.

• Magnetic resonance imaging (MRI) has a growing role in the assessment of renal tumours. It is useful in place of CT if contrast is contraindicated (renal impairment). MR angiography with gadolinium is a non-invasive, non-iodinated contrast used as an alternative to invasive angiography in the assessment of renovascular disease. Gadolinium should not be used in patients with renal insufficiency because of the risk of developing nephrogenic systemic fibrosis.

• Renal angiography is the gold standard investigation for renovascular disease. It can be combined with therapeutic angioplasty ± stent insertion. Complications include contrast-induced nephropathy (CO₂ angiography is an alternative, though images are not as clear) and cholesterol emboli, and may worsen renal function.

• Plain KUB (kidneys, ureters, bladder) X-ray centred on the umbilicus may be useful if stone disease is suspected (90% of renal stones are radio-opaque).

Uroradiology

• Percutaneous nephrostomy involves percutaneous placement under US guidance of a nephrostomy tube; it can relieve obstruction. It can be followed by a nephrostogram (injection of contrast down the nephrostomy tube, followed by X-ray) to diagnose the site of obstruction.

• Urethroscopy, cystoscopy and ureteroscopy will allow diagnosis and surveillance of bladder tumours and the placement of retrograde stents in obstruction.

• Micturating cystourethrography allows diagnosis of ureteric reflux in children.

Renal biopsy

Obtain written consent. Under US guidance and after infiltration of local anaesthetic, a spring-loaded biopsy needle is passed into the lower pole of one kidney via the loin. A sample of renal cortex is obtained for histological examination, immunofluorescence and electron microscopy (EM) examination for diagnosing kidney disease.

• Complications include bleeding (1% risk of requiring blood transfusion, 0.1% risk of death), clot colic with or without obstruction and pain (usually mild and transient).

• Indications include unexplained acute kidney injury, progressive chronic kidney disease where the cause is uncertain, nephrotic syndrome and nephritic syndrome.

• Relative contraindications include single (functioning) kidney, clotting or platelet abnormality (both should be checked pre-biopsy), small kidneys (likely to show end-stage glomerulosclerosis and tubulointerstitial fibrosis, and unlikely to result in any firm diagnosis or alter management) and uncontrolled hypertension, e.g. > 140/90 mmHg (increased risk of bleeding).

Urinary Tract Infection (UTI)

Half of all women will have at least one UTI in their lifetime. Serious morbidity is unusual. Most patients have no anatomical abnormality of the renal tract and do not require further investigation, but patients with recurrent infections should be investigated. Renal stones, incomplete bladder emptying, duplex ureters, tumour or any other cause of disturbed urinary flow or stasis are predisposing factors, as are increasing age (loss of oestrogen in vaginal secretions) and recent or frequent intercourse. UTIs in men are unusual, and should always be investigated with imaging to look for abnormalities of urinary flow.

Lower urinary tract infection

Lower UTIs are diagnosed on history (dysuria, frequency, cloudy urine) combined with urine dipstick results showing positive nitrites and leucocyte esterase activity. Urine culture allows confirmation of the diagnosis, identification of the responsible organism and sensitivity to antibiotics, but uncomplicated patients can be treated without a urine culture. The most common organisms are Escherichia coli (70–90%), Staphylococcus saprophyticus (or epidermidis) (5–20%), Klebsiella, Enterococcus faecalis and Proteus mirabilis.

Upper urinary tract infection

Upper UTIs (acute pyelonephritis) present with systemic symptoms (fever, chills, nausea and vomiting) and loin pain. In the elderly the presentation may be non-specific with confusion.

Management

Uncomplicated lower UTIs should be treated with a short (3-day) course of antibiotic agents, e.g. trimethoprim 200 mg twice daily, levofloxacin 250 mg daily or a cephalosporin. The choice of antibiotic should be governed by local microbiological guidelines. Alternatively, a longer (7–10-day) course can be given. Complicated lower UTI (i.e. occurring in patients at risk of complications, e.g. immunosuppressed patients, renal transplant recipients, pregnancy or recurrent infection) and acute pyelonephritis should always be managed knowing sensitivity to antibiotics; a prolonged course may be required.

Recurrent urinary tract infection

Recurrent UTI is defined as more than four infections in a year. Imaging should be performed to exclude abnormalities of the renal tract. A high fluid intake should be maintained. Rotating prophylactic antibiotics are sometimes beneficial.

Glomerular Disease

Nephritic syndrome

This can present insidiously or as rapidly progressive glomerulonephritis (RPGN), which is the most severe form of nephritic syndrome with rapidly progressing renal failure.

• Presentation is with haematuria (usually microscopic), proteinuria, red cell casts, renal impairment (often progressive), hypertension and fluid retention (puffy face), with or without oliguria. These findings indicate inflammation of, and damage to, glomeruli and this is usually immune-mediated. If this is not reversed, irreversible glomerular loss and chronic kidney disease occur. An urgent renal biopsy will demonstrate glomerular nephropathy (GN) and, if rapidly progressive, may contain crescents (macrophage invasion of Bowman’s space, causing irreversible glomerular damage).

• Causes of the nephritic syndrome include vasculitis (e.g. ANCA-positive small-vessel vasculitis), SLE, antiglomerular basement membrane (GBM) disease (Goodpasture’s syndrome), post-infectious (proliferative) glomerulonephritis, mesangiocapillary GN, IgA nephropathy and Henoch–Schönlein purpura.

Nephrotic syndrome

Nephrotic syndrome presents with:

• peripheral oedema

• proteinuria (> 3 g daily)

• hypoalbuminaemia

• hypercholesterolaemia (usually present)

• hypertension that accompanies the fluid overload

• microscopic haematuria (may or may not be present, depending on the cause).

Nephrotic syndrome is the result of damage to the glomerular filtration barrier. The barrier is made up of the endothelium, the GBM, and podocytes and their slit diaphragms. Both molecular size and charge affect the selectivity of the barrier, which is disrupted in the nephrotic syndrome.

• Causes of the nephrotic syndrome include minimal change disease, membranous GN, focal and segmental glomerulosclerosis, diabetic nephropathy, amyloidosis, light chain deposition disease, cryoglobulinaemia, HIV-associated nephropathy, mesangiocapillary GN and SLE.

Isolated microscopic haematuria

This is defined as non-visible blood in the urine, in the absence of proteinuria, renal impairment or hypertension. It is common (5–10% of the adult population).

• Causes

• Lower urinary tract causes, including stones and tumours, should be excluded.

• Once urological causes have been ruled out, then it can be assumed to be a benign glomerulopathy. Further investigation is not usually indicated; the prognosis is excellent without any treatment, though long-term follow-up is recommended.

Asymptomatic proteinuria

Presentation is incidental when urine is dipsticked as part of routine medical examination or in the context of another medical problem. Hypertension may be the cause or an associated cause. Poor BP control is likely to worsen the degree of proteinuria. By definition, the level of proteinuria is not sufficient to cause hypoalbuminaemia (< 3 g/day).

• Causes of asymptomatic proteinuria include IgA nephropathy, membranous GN, mesangiocapillary GN, hypertension, diabetic nephropathy and HIV-associated nephropathy.

Management of glomerular disease: general principles

• Salt and water balance. Accurate assessment of fluid balance is necessary (p. 368), as in severe nephrotic syndrome there may be intravascular depletion despite expansion of the extracellular compartment. Hypovolaemia should be corrected with oral or IV fluids. Volume expansion should be managed with salt and water restriction, with or without diuretics. High doses of loop diuretics are often required to establish and maintain a diuresis, e.g. furosemide 40–250 mg twice daily.

• BP. Hypertension is usual in glomerular disease. Reducing BP leads to decreased intraglomerular pressure, and decreased levels of proteinuria, preservation of renal function and protection of other organs from hypertension-induced damage. ACE inhibitors and/or angiotensin receptor blockers (ARBs) have theoretical and evidence-based advantages over other agents, especially for those with significant proteinuria. Target BP should be 130/80 mmHg (120/75 mmHg if there is proteinuria).

• Proteinuria. ACE inhibitors or ARBs reduce intraglomerular pressure and proteinuria.

• Lipids. Statins are given to lower the serum cholesterol (< 4.5 mmol/L) (to convert mmol to mg/dL multiply by 38).

• Dialysis. This is required if renal impairment is severe. For indications for dialysis see p. 357. With definitive treatment and renal recovery, dialysis is discontinued after a period of time.

• Diet. A normal protein diet of 1.8 g/kg body weight is given.

• Anticoagulants. Risk of venous thromboembolism is high; give prophylactic anticoagulants (p. 247).

• Pneumococcal vaccination.

General principles for immunosuppressive treatment

• The decision to treat is based on balancing the potential benefits of the treatment with the potential risks. With potent immunosuppression, the side-effects may be life-threatening.

• A histological diagnosis is usually required before treatment.

• Many treatment regimes use the principle of induction (with a potent drug combination) to induce ‘remission’ and then maintenance therapy with less toxic treatment to prevent relapse.

• Monitoring must be appropriate and robust (e.g. weekly or fortnightly blood tests initially when on cyclophosphamide or azathioprine, checks of GFR and monitoring of serum levels when on ciclosporin or tacrolimus).

• Use adjunctive therapies to minimize the risk of side-effects whenever possible. These include:

• Bone protection treatment for all on long-term steroids (yearly dual energy X-ray absorptiometry (DEXA) scans). Use a long-acting oral bisphosphonate (e.g. alendronate 5 mg daily) and/or calcium and vitamin D combinations (e.g. calcium carbonate 1.25 g and cholecalciferol 5 mcg).

• Co-trimoxazole 480 mg twice daily as prophylaxis against Pneumocystis jiroveci infection for patients on cyclophosphamide.

• Isoniazid 100 mg daily as anti-TB prophylaxis for at-risk patients (history of TB or TB exposure) on cyclophosphamide.

• Statins (e.g. atorvastatin 20 mg daily) for steroid-exacerbated hyperlipidaemia.

• All immunosuppressive regimes have an associated risk of infections and, in the longer term, malignancy. Other common side-effects are shown in Table 10.2.

Table 10.2 Commonly used immunosuppressive drugs in glomerulonephritis

Specific glomerular diseases and their management

Minimal change disease

Minimal change disease presents as the nephrotic syndrome, often of sudden onset with no haematuria. It is most common in children (boys > girls) and accounts for > 95% of all cases of nephrotic syndrome in children, although it can occur at any age and accounts for up to 25% of all nephrotic syndrome in adults.

• Renal biopsy shows normal appearances on light microscopy with no immune complex deposition (‘minimal change’). EM shows epithelial cell (podocyte) foot process fusion — a non-specific finding seen in any condition associated with the nephrotic syndrome.

• An immunological cause is suggested by the fact that the condition responds to immunosuppression. Production of a circulating factor (not yet identified) by T-cells or immature CD34-positive stem cells has been suggested.

• Renal function is usually normal, and does not normally deteriorate.

• Spontaneous remissions occur, so treatment should not be commenced unless hypoalbuminaemia and oedema are present.

• Management

• Start with high-dose corticosteroids, i.e. prednisolone 1 mg/kg/day in adults or 60 mg/m² in children up to a maximum of 80 mg/day for 4–6 weeks, and then 40 mg/m² for 4–6 weeks. Remission may occur within days, but can take weeks.

• Once in remission, prednisolone dose should be reduced slowly (cut dose by 30% after 4–6 weeks). Steroids should be tapered and the patient weaned off them over a total of 12 more weeks.

• Relapse frequently occurs (but one-third of children will not relapse), especially if steroids are tapered too quickly, and this should be treated in the same way with prednisolone.

• Frequent relapsers may be steroid-dependent (relapse when steroids are withdrawn) or steroid-resistant (fail to go into remission with steroids). Cyclophosphamide (1.5–2 mg/kg/day) for 8–12 weeks given with prednisolone 7.5–15 mg/day increases the likelihood of long-term remission. Ciclosporin (3–5 mg/kg/day aiming for trough blood level of 80–150 ng/mL) is an alternative but needs to be continued long-term to prevent relapse; it carries its own risks of nephrotoxicity so frequent monitoring of levels and kidney function is required. Levamisole 2.5 mg/kg (max. 150 mg) on alternate days has been found to be effective in maintaining remission in children.

Focal segmental glomerulosclerosis (FSGS)

FSGS usually presents with the nephrotic syndrome, often with microscopic haematuria. Hypertension and/or progressive renal impairment are often present.

• Primary FSGS is of unknown cause. A circulating permeability factor with serine protease activity has been implicated (the disease may recur after transplantation, often immediately). A renal biopsy is required to make the diagnosis, determine therapy and indicate prognosis. Segmental scleroses in affected glomeruli are seen, with other glomeruli looking normal on light microscopy. C3 and IgM may be present on immunofluorescence in affected segments. Mesangial hypercellularity may be present. Interstitial fibrosis and focal tubal atrophy are common. On EM, affected glomeruli show capillary obliteration with hyaline deposits and lipids. Patchy foot process effacement is present, even on ‘normal’-looking glomeruli. Five histological types are described by light microscopy:

• Classic — the glomerular changes may occur in any part of the glomerulus.

• Tip lesion — scleroses occur at the tubular pole of affected glomeruli, with foam cell-filled capillaries and adhesion of epithelial cells to the proximal portion of the tubule.

• Collapsing FSGS — with enlarged and vacuolated visceral cells, and collapsed capillary walls. This variant is often associated with HIV infection (especially in black people), when it is classified as HIV-associated nephropathy (HIVAN).

• Perihilar variant — with perihilar sclerosis and hyalinosis, frequently present in secondary FSGS (see below).

• Cellular — at least one glomerulus has segmental endocapillary hypercellularity, while other glomeruli may have changes similar to the classic form.

• Secondary FSGS occurs as a result of a loss of functioning nephrons of almost any cause, e.g. hypertension, obesity, previous nephrectomy or renal damage, with the remnant nephrons having to hyperfilter. This leads to hydraulic injury over time.

• Management. Mild to modest proteinuria should be managed with good BP control (ACE inhibitors), a statin and follow-up (Box 10.1). Overt nephrotic syndrome and/or progressive renal impairment (drop in eGFR of > 15% in 1 year or > 10% in 2 successive years) are risk factors for progression and indications for immunosuppression. Prednisolone 0.5–2 mg/kg/day should be continued for up to 6 months before steroid resistance is diagnosed. Commonly this is the case, and other disease-modifying drugs are required. Ciclosporin aiming for trough level 150–300 ng/mL may be effective, but relapse may occur when it is discontinued. Cyclophosphamide 1–1.5 mg/kg/day with high-dose prednisolone for 3–6 months, followed by maintenance treatment with prednisolone and azathioprine, may reduce proteinuria and slow progression, especially if there is mesangial hypercellularity and tip lesions. Chlorambucil has also been used with some success. Despite treatment, 50% progress to end-stage kidney disease within 10 years of diagnosis. HIVAN is managed with anti-retroviral therapy. Renal function may stabilize or improve.

Box 10.1 Renoprotection in patients with CKD