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

Goals of treatment

• BP < 130/80 mmHg or < 120/75 mmHg if proteinuria and/or diabetes

• Proteinuria < 1 g/24 hours or lower if possible

BP and proteinuria: treatment

• ACE inhibitor increasing to maximum dose

• Add angiotensin receptor antagonist if proteinuria goals are not achieved (risk of hyperkalaemia — monitor serum potassium)*

• Add diuretic to prevent hyperkalaemia and help to control BP

• Add calcium channel blocker (e.g. amlodipine 5–10 mg daily) if goals not achieved

• If another agent is needed, consider: β-blocker (e.g. bisoprolol 5–10 mg daily), α-blocker (e.g. doxazosin 4–16 mg daily), centrally acting agent (e.g. moxonidine 200–400 mg daily) or vascular smooth muscle relaxant (e.g. minoxidil 2.5–50 mg daily)

Additional measures

• Statins to lower cholesterol if high cardiovascular risk

• Stop smoking (three-fold higher rate of deterioration in CKD)

• Treat diabetes (HbA1c < 7%)

• Attention to other cardiovascular risk factors (BMI, exercise, diet)

^* In type 2 diabetes start with angiotensin receptor antagonist.

Membranous glomerulonephritis

Membranous glomerulonephritis presents with nephrotic syndrome or asymptomatic proteinuria with or without renal impairment, microscopic haematuria and hypertension. It usually affects adults, mainly men. Spontaneous remission can occur. Specific treatment should be reserved for those with overt nephrotic syndrome and/or progressive renal impairment. Older age at presentation, male sex and heavy proteinuria are risk factors for progression.

• In 75% of cases no underlying cause is found. Causes include drugs (e.g. gold, penicillamine, NSAIDs), autoimmune disease (e.g. SLE, thyroiditis), infections (e.g. hepatitis B or C, schistosomiasis, Plasmodium malariae, leprosy) and neoplasia (e.g. solid organ tumours and lymphomas).

• Pathology shows thickening of the capillary basement membrane on light microscopy and deposition of C3 and IgG on immunofluorescence. EM changes are detectable earlier in the course of the disease and mirror light microscopy changes, with electron-dense sub-epithelial capillary wall deposits. It is thought that immune complexes are formed in situ in the podocyte basement membrane and the target auto-antigen(s) in humans is the M-type phospholipase A₂ receptor (PLA₂R).

• Management (Box 10.1)

• If an underlying condition is present, it should be treated. This may slow or halt the progression of disease.

• In primary disease, spontaneous remission is common (up to 40%), so specific treatment should be withheld for up to 6 months unless there is progression. Even then, only those with severe proteinuria and/or progressive renal impairment should be treated with immunosuppression.

• For such high-risk patients, steroids are ineffective if given alone. Combinations which have been used with some success include:

a) Prednisolone 1 mg/kg/day on alternate days with cyclophosphamide 1.5–2.5 mg/kg/day for 6–12 months.

b) Chlorambucil 0.2 mg/kg/day in months 2, 4 and 6 with prednisolone 0.4 mg/kg/day in months 1, 3 and 5.

c) Ciclosporin 3.5 mg/kg/day for 12 months, with low-dose prednisolone.

d) Rituximab, an anti-CD25 antibody that ablates B lymphocytes; this has been shown to improve renal function and reduce proteinuria without significant side-effects in short-term studies. Long-term outcome is not yet known.

The effectiveness of the various drug regimens is unclear, and good controlled trials are lacking.

Amyloidosis

Amyloidosis is a systemic condition of abnormal protein folding, in which normally soluble proteins or fragments are deposited extracellularly. It may present with renal disease, usually nephrotic syndrome with or without renal impairment. Renal biopsy should be performed if renal involvement is suspected.

• There are two types:

• AA amyloid is associated with chronic infections or inflammatory conditions (e.g. TB, bronchiectasis, IV drug use, rheumatoid arthritis, ankylosing spondylitis, familial Mediterranean fever, inflammatory bowel disease).

• AL amyloid is associated with abnormal production of immunoglobulin light chains, and hence with haematological malignancies, especially myeloma.

• On renal biopsy, the mesangium is filled with abnormal eosinophilic deposits, which stain with the Congo red stain with apple green birefringence under polarized light. EM reveals the amyloid fibrils.

• The kidney is only one of the organs affected by amyloid. Serum amyloid protein (SAP) scanning can delineate the extent of involvement in other organs. Serial SAP scans are useful for documenting progression or regression.

• Management

• Use renoprotective measures, as for all proteinuric renal disease (Box 10.1).

• Remove/treat the underlying condition. The aim is to switch off production of the amyloid protein. In AA amyloid, infections or causes of chronic inflammation should be treated. Eprodisate is a drug that reduces deposition of the amyloid protein, and shows promise. In familial Mediterranean fever, colchicine 0.5–2 mg 3 times daily reduces the frequency of acute attacks and improves prognosis. In AL amyloid, treatments that reduce abnormal production of light chains can improve the renal prognosis and survival. Dexamethasone and melphalan are used. High-dose melphalan followed by autologous stem cell transplantation has also been used.

• Despite this, specific treatment is often ineffective. Renal prognosis, once nephrotic-range proteinuria has developed, is poor. Survival depends mainly on the extent of involvement of other organs, especially the heart.

Diabetic nephropathy

This is the most common cause of chronic kidney disease in the developed world. Similar changes occur in both type 1 and type 2 diabetes. Thickening of the GBM and expansion of the mesangium are associated with glomerular hypertension and glomerular ischaemia, progressing to glomerulosclerosis with nodules (Kimmelstiel–Wilson lesions). Microalbuminuria progresses to overt albuminuria and then progressive renal impairment with or without nephrotic syndrome. Renal biopsy is usually not required unless there are grounds for doubt about the diagnosis (e.g. features suggestive of another cause of glomerulopathy).

• Management (Box 10.1)

• Tight glycaemic control and lifestyle measures to reduce cardiovascular risk (stopping smoking, maintaining an ideal weight, healthy diet, regular exercise) and good BP control are the key to management in all patients with diabetes.

• Microalbuminuria and overt proteinuria should be treated with an ACE inhibitor or ARB, irrespective of the BP. These drugs have been shown to slow the decline in renal function. Combined ACE inhibitor and ARB may reduce proteinuria further, usually under specialist supervision.

• BP targets are more stringent if there is proteinuria, e.g. 120/75 mmHg.

Even with all of these measures, relentless progression is common.

Mesangiocapillary glomerulonephritis (MCGN)

MCGN may present with nephrotic syndrome, nephritic syndrome, or haematuria with hypertension. Progressive renal impairment may occur. Most cases progress to end-stage renal failure over several years. Histologically, all are associated with mesangial cell proliferation and basement membrane changes. Three sub-types are defined by appearances on EM:

• Type 1 — sub-endothelial immune deposits with ‘splitting’ of the GBM. Plasma C3 levels are reduced with normal C4, with activation of the classical pathway of the complement cascade. It is either idiopathic or associated with chronic infections, e.g. abscesses, infective carditis, or with cryoglobulinaemia and hepatitis C infection.

• Type 2 — electron-dense linear intramembranous deposits. C3 levels are also low, but with activation of the alternative pathway of the complement cascade. It may be idiopathic or associated with partial lipodystrophy.

• Type 3 — features of both type 1 and type 2, associated with activation with the final common pathway of the complement cascade.

Recurrence after transplantation is very common in type 2 (100%) and can occur in type 1 (25%), though rarely leads to graft loss.

• Management. Renoprotective measures (Box 10.1) are the key, especially BP control. Corticosteroids (prednisolone 40 mg/m² for 12 months) may be tried in children with progressive renal impairment but may not be effective. In adults, antiplatelet agents (aspirin 325 mg/day and dipyridamole 75 mg/day) may slow the rate of progression if there is renal impairment, and should be given for 6–12 months.

Cryoglobulinaemic renal disease

Cryoglobulins are immunoglobulins that precipitate with complement in the cold. Presentation is usually in fourth or fifth decade, and is more common in women than men. Renal glomerular changes resemble MCGN. Three types are described:

• Type I (10%): monoclonal immunoglobulin, associated with multiple myeloma and lymphoproliferative disorders

• Type II (50%): polyclonal IgG bound to a monoclonal IgA or IgM antiglobulin with rheumatoid factor properties

• Type III (40%): polyclonal IgG bound to a polyclonal IgA or IgM antiglobulin.

Recognized associations are as follows:

• viral infections: hepatitis B and C, HIV, cytomegalovirus (CMV), Epstein–Barr virus (EBV)

• fungal and spirochaete infections

• malaria

• infective endocarditis

• autoimmune rheumatic diseases: SLE, rheumatoid arthritis, Sjögren’s syndrome.

• Systemic features include purpura, arthralgia, leg ulcers and Raynaud’s phenomenon.

• Specific treatment for underlying diseases may halt renal decline. Renoprotective measures (Box 10.1) should be undertaken. For those with renal progression and or severe extra-renal disease, corticosteroids with intensive immunosuppression have been used. Plasma exchange (to remove circulating cryoglobulins) or rituximab may induce remission, but the evidence base is weak.

Lupus nephritis

SLE is an auto-antibody-mediated, T-cell-dependent and B-cell-mediated disease. Between 30 and 70% of patients with SLE develop renal involvement. Presentation is with proteinuria and/or haematuria and/or renal impairment. Early diagnosis and treatment improves prognosis, and hence all patients with lupus should receive regular checks of renal function, including urine dipstick and BP measurement.

• SLE is associated with characteristic serum immunological features. Auto-antibodies against cellular antigens include positive antinuclear antibodies, double-stranded DNA and anti-Ro, and serum complement components are reduced (C3, C4, C1q).

• Renal biopsy is essential, as it guides how aggressive treatment needs to be. Six histological types (International Society of Nephrology/Renal Pathological Society 2004) have been described:

• Type 1 (normal glomeruli on light microscopy, mesangial immune deposits) just requires monitoring.

• Type II (more deposits and mesangial hypercellularity and matrix expansion on light microscopy) does not usually progress.

• Type III (focal proliferative, i.e. < 50% of glomeruli affected) and type IV (diffuse proliferative GN, i.e. > 50% glomeruli affected) have the worst prognosis and should always be treated with immunosuppression.

• Type V (membranous changes) is treated if the nephrotic syndrome or type III or IV coexist.

• Type VI shows advanced sclerosing lesions and progressive renal failure is invariably present.

• Immunofluorescence staining reveals positivity in the mesangium for C3, C4, C1q, IgM, IgG and IgA.

• Extraglomerular lesions may occur in SLE, including tubulointerstitial nephritis, and thrombotic lesions (renal vein or artery thrombosis, usually associated with antibodies against phospholipids, e.g. lupus anticoagulant or anticardiolipin).

• Management. Types I and II do not usually require immunosuppression. Types III and IV do. Most regimes include prednisolone and cyclophosphamide or mycophenolate for induction, with mycophenolate or azathioprine used for maintenance therapy. The use of mycophenolate for induction therapy is growing, though the evidence base for its use in advanced renal disease is not (yet) convincing. For resistant disease, rituximab (anti-CD20 monoclonal antibody causing B-cell depletion) shows early promise, though long-term results are still awaited.

Post-infectious glomerulonephritis

This classically occurs in children 2–3 weeks after a Lancefield group A streptococcal throat infection and presents with acute nephritic syndrome. It is now rare in developed countries but can occur after infections, e.g. bacterial, malaria, schistosomiasis, viral infections and syphilis. Abscesses and deep-seated infections, including infectious endocarditis, may cause a similar clinical picture.

• Investigations may reveal renal impairment. There is a low C3 level with normal C4. Antistreptolysin O titres may be raised post streptococcal infection. Renal biopsy characteristically shows neutrophil infiltration in the glomerulus, with IgG and complement deposition (this is an immune complex disease). EM is consistent with this, with electron-dense deposits in the sub-epithelium of the capillary walls.

• Management

• Active infection is treated aggressively.

• The disease is usually self-limiting, so management is supportive with general measures including control of BP. A short course of steroids may be used if recovery is slow, provided the infection has been adequately treated.

• Residual renal impairment and/or urinary abnormalities may occur, with increased risk of progression of chronic kidney disease in the future (though in children complete recovery is the rule).

IgA nephropathy

This is the most common GN, with a wide spectrum of presentation from asymptomatic, isolated microscopic haematuria with or without proteinuria to rapidly progressive renal failure and nephrotic syndrome. It may present with macroscopic haematuria (sometimes after an upper respiratory tract infection). It is commoner in children and young males. Hypertension is usual.

• Renal biopsy shows deposition of IgA in the mesangium, with or without mesangial cell proliferation. Crescent formation may occur.

• Management

• ACE inhibitors and ARBs are used together if necessary, irrespective of BP, to reduce proteinuria to < 1 g/day and BP < 125/75 mmHg.

• If there is modest proteinuria (< 1 g/day) with normal renal function, no specific measures improve outcome (which is likely to be good).

• Fish oil 3 g 3 times daily may slow decline in renal function.

• Steroids may be used if there is significant proteinuria 1–3 g daily, despite general measures and if renal function is preserved (prednisolone 0.5 mg/kg on alternate days).

• Transformation to crescentic disease may occur, with rapidly declining renal function. Treat as for RPGN, with prednisolone and cyclophosphamide for 3 months followed by prednisolone + azathioprine, though the evidence base is not strong.

Henoch–Schönlein purpura

This vasculitis presents with a purpuric rash, usually in children. Renal pathology is identical to that of IgA nephropathy, as is management. The prognosis is good.

Rapidly progressive glomerulonephritis (RPGN)

Renal disease presents with acute nephritic syndrome and rapid deterioration of renal function (usually over several weeks). It may be limited to the kidney or there may be extra-renal disease. This includes a vasculitic rash or ulceration, arthralgia/arthritis, systemic symptoms (e.g. fatigue, anorexia, weight loss), gut or myocardial ischaemia, and pulmonary haemorrhage (may be life-threatening)

• Renal biopsy is essential to make the diagnosis and guide treatment. RPGN is characterized by inflammation and necrosis of the walls of small vessels, and by crescent formation (epithelial cells and macrophages that aggregate in Bowman’s space). The pattern (or absence) of immune deposit deposition at biopsy is helpful in discriminating RPGN. Three staining patterns are seen:

• linear immunofluorescence with IgG and C3, e.g. anti-GBM disease

• granular immunofluorescence, e.g. idiopathic immune complex-mediated RPGN, associated with other primary GN, e.g. MCGN, IgA nephropathy, membranous GN, or associated with secondary GN, e.g. post-infectious GN, SLE, Henoch–Schönlein purpura, cryoglobulinaemia

• negative immunofluorescence (‘pauci-immune’), e.g. ANCA-positive vasculitis.

Anti-GBM disease

• (15–20% of all RPGN cases) is rare, usually presenting in men aged 20–30 or > 60 years (when male = female).

• Antibodies against the α3 chain of type 4 collagen develop, which bind to the GBM with or without the alveolus (lung disease occurs only in cigarette smokers).

• Lung haemorrhage occurs in ~66% of cases (‘Goodpasture’s syndrome’).

• Renal biopsy is mandatory, as is measurement of anti-GBM antibodies in the serum.

• Management

• Plasma exchange removes circulating pathogenic antibodies.

• Steroids are used to suppress inflammation, e.g. methylprednisolone IV 500 mg daily for 3 days, followed by prednisolone 60–80 mg daily for up to 3 months, with gradual taper.

• Cyclophosphamide is used to switch off antibody production.

• Ventilatory support and/or dialysis may be required if pulmonary haemorrhage or severe renal failure are present.

The renal prognosis is poor if there is oliguria or the patient is dialysis-dependent. Recurrence does not occur, however, and immunosuppression can be tailed off and discontinued once anti-GBM titre is negative.

Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis

A group of small-vessel vasculitides are characterized by a positive ANCA titre. These include:

• Wegener’s granulomatosis

• microscopic polyangiitis

• Churg–Strauss syndrome.

These diseases share a common pathology with focal necrotizing lesions that may be limited to the kidney or affect other organs, including the lungs (pulmonary haemorrhage), the dermis (vasculitic rash), and the nose and ear (vasculitic ulceration). Systemic symptoms may predominate (fever, weight loss, malaise) or be absent.

• ANCA are auto-antibodies directed against neutrophil antigens. They are sub-divided into two groups according to ELISA assays, binding either to proteinase 3 (PR3, or c-ANCA for cytoplasmic) or to myeloperoxidase (MPO, or p-ANCA for perinuclear). ANCA titres may be weakly positive in other autoimmune diseases or with some drugs.

• PR3 ANCA is associated with Wegener’s granulomatosis and MPO ANCA with microscopic polyangiitis, but there is much overlap. It is more useful to group these disorders by clinical syndromes than ANCA (although ANCA may offer prognostic information regarding likelihood of relapse).

• Disease presents as RPGN with or without signs of small-vessel vasculitis affecting other organs (see above). Differential diagnosis includes anti-GBM disease and lupus, which should be excluded by measuring anti-GBM and anti-dsDNA titres. Drug-induced disease, e.g. propylthiouracil, hydralazine and penicillamine, is well described.

• The prognosis is very poor if disease is untreated, but better (80% 1-year patient survival) if treated aggressively and early, though dialysis dependence is common.

• Management

• High-dose steroids are used (IV methylprednisolone 500 mg daily for 3 days for fulminant disease, and then prednisolone 60–80 mg/day reducing to 15 mg/day over 3 months).

• Add cyclophosphamide. (Oral treatment appears to be associated with a lower rate of relapse, but IV treatment is better tolerated.)

• Plasma exchange (3–4 L exchange daily for 14 days) is recommended if pulmonary haemorrhage or dialysis dependence is present at presentation, and may improve outcome in these circumstances.

• Once remission is achieved, azathioprine should be substituted for cyclophosphamide. Mycophenolate or methotrexate is an alternative agent if azathioprine is not tolerated.

• Treatment with sulfamethoxazole/trimethoprim reduces Staphylococcus aureus colonization of the upper respiratory tract and reduces the incidence of relapse.

• Relapse is common (especially in Wegener’s), and low-dose immunosuppression should be continued long-term.

Thrombotic microangiopathies (p. 231)

These are characterized by haemolysis, a low platelet count and tissue ischaemia secondary to thrombotic occlusion of small vessels. There are a number of causes, including:

• thrombotic thrombocytopenic purpura (p. 233)

• antiphospholipid syndrome

• haemolytic uraemic syndrome (HUS)

• malignant hypertension

• HELLP syndrome and pre-eclampsia

• SLE, rheumatoid disease, systemic sclerosis

• disseminated intravascular coagulation (DIC)

• metastatic malignancy.

The renal biopsy changes are similar, whatever the cause of the microangiopathy, with fibrin thrombi in glomerular capillaries and associated ischaemic changes.

• Haemolytic uraemic syndrome is characterized by intravascular haemolysis with red cell fragmentation, thrombocytopenia and acute kidney injury due to thromboses in small arteries and arterioles. Coagulation tests are normal, in contrast to DIC. HUS may follow a diarrhoeal infection (D+HUS) or occur spontaneously (D−HUS).

• D+HUS usually follows gastroenteritis due to E. coli O157 (verocytotoxin). Treatment is mainly supportive, with fluid balance, antihypertensives and nutritional support; dialysis is often required. There is no evidence that plasma exchange has a role. There is a 5% mortality, and 30% go on to long-term renal damage.

• D−HUS may be recurrent and may be related to abnormalities in the regulation of the complement cascade, e.g. factor H deficiency or membrane cofactor protein abnormalities. Plasma exchange or infusion is recommended.

• Other cases of HUS are related to drugs (mitomycin C, ciclosporin, cisplatin), infections (HIV, pneumococcus), malignancies, scleroderma and accelerated hypertension. Treatment is to address the underlying condition or remove the offending drug, and is otherwise supportive.

• Malignant (accelerated) hypertension and systemic sclerosis both cause similar renal histological changes with fibrin thrombi, fibrinoid necrosis and onion skin intimal thickening, and may precipitate acute kidney injury. Management consists of control of the BP. ACE inhibitors have a key role and should be used as first-line therapy; this has led to a significant improvement in renal outcome. Long-term follow-up is essential, as hypertension and chronic kidney disease often ensue. Prostacyclin infusion IV is sometimes used in severe systemic sclerosis, though its benefit for the kidneys is unproven.

Multiple myeloma

Acute or chronic kidney disease may occur, by one or more of the following mechanisms:

• cast nephropathy: deposition of light chains within the tubular lumen

• AL amyloidosis

• light chain deposition disease: Congo red-negative nodular glomerulosclerosis caused by deposits of (usually λ) light chains

• direct plasma cell infiltration

• hypercalcaemia

• hyperuricaemic nephropathy: may occur in the context of tumour lysis syndrome, with tubular deposition of urate crystals.

The management is to treat the underlying condition; renal management is supportive and dialysis may be required.

Renal Hypertension

Hypertension is both a cause and effect of renal disease, and a renal biopsy is often needed to ensure there is no other underlying condition. Many renal diseases are associated with hypertension. The mechanisms include activation of the renin–angiotensin system and salt and water retention. BP control is essential to prevent target organ damage and to improve renal prognosis. ACE inhibitors and/or ARBs have renoprotective effects over and above their effect on BP for many proteinuric renal diseases.

Renovascular disease

Renal artery stenosis leads to production of renin by the kidney and hypertension. Bilateral renovascular disease may cause renal impairment. Two groups of patients develop renovascular disease:

• Atherosclerotic renovascular disease occurs in older people, as with other diseases caused by atherosclerosis, and often alongside them. The stenosis tends to be at the ostium of the renal artery and may be bilateral. The diagnosis is suggested by the presence of vascular disease elsewhere, modest proteinuria, hypertension and asymmetrical kidneys on US. Confirmation of the diagnosis may be via MR angiography (if renal function is sufficiently preserved to allow the use of gadolinium) or CT angiography (though with the risk of contrast nephropathy). Arteriography is the gold standard investigation.

• Treatment is aggressive management of risk factors for progression of atherosclerosis (BP, statins, aspirin, stopping smoking). Angioplasty ± stenting may be indicated if there is rapidly declining renal function, flash pulmonary oedema or resistant hypertension along with significant (> 75%) stenotic lesions. However, angiography may lead to cholesterol emboli and may worsen ischaemic renal disease. Further trials are needed to clarify which patients benefit most from this treatment.

• Fibromuscular dysplasia accounts for 30% of renovascular disease. It is not associated with atherosclerosis, occurring most commonly in young women. It presents with hypertension and usually with well-preserved renal function.

• Therapeutic angioplasty may be curative and the prognosis is usually good.

Renal Stone Disease

Stone disease affects 8–15% of the population. The male : female ratio is 2 : 1. Risk factors include living or working in a hot environment (and dehydration), hypercalcaemia, hypercalciuria, recurrent UTI, renal tubular acidosis, hyperoxaluria, hyperuricaemia, cystinosis and some drugs (loop diuretics, vitamins D and C, indinavir, sulfadiazine). Patients with polycystic kidney disease have an increased risk of stone formation. Many people have none of these and nevertheless develop stones (‘idiopathic stone formation’).

Over 90% of stones are calcium-based. Uric acid stones are radiolucent and occur in those with hyperuricaemia; uric acid is more likely to crystallize out in an acid urine.

Most stones are formed in the upper urinary tract but bladder stones may form when there is urinary stasis or abnormal flow (diverticula, surgical reconstruction, long-term catheterization).

Presentation is with loin pain (may radiate to perineum/testis), suprapubic pain, haematuria, dysuria and/or UTI. Signs may include loin or suprapubic tenderness and urinary dipstick abnormalities. Most stones are asymptomatic.

Investigations

These should include:

• Imaging. Carry out a plain X-ray (90% of stones are radio-opaque, urate stones are not). CT-KUB delineates anatomy and demonstrates opacifications in the renal tract. IVU is still widely used instead of CT.

• Chemical analysis of stone. Perform chemical analysis of the stone if one is passed. Also do U&E, Ca²⁺, bicarbonate, urate and urine for culture.

• 24-hour urine analysis for Ca²⁺, urate, citrate and oxalate. This should be carried out in recurrent stone-formers (> 1 stone in 3 years). A spot urine should be sent for cystine.

Management of acute renal stone disease 75 mg by IV infusion

• Analgesia (NSAIDs, e.g. diclofenac, and/or opiate may be required).

• Small asymptomatic stones are managed conservatively.

• Larger stones (> 0.5 cm), especially if symptomatic, should be treated by:

• Extracorporeal shock wave lithotripsy (ESWL), which shatters the stone and allows the fragments to pass. A ureteric stent may be required to prevent fragments becoming lodged in the ureter.

• Retrograde removal with ureteroscopy.

• Antegrade removal via a nephrostomy tube for larger renal stones, e.g. stag-horn calculus.

Prophylaxis and prevention

• A daily urine output > 2 L/day should be maintained and any UTI treated aggressively.

• Hypercalciuric patients should eat a diet normal in calcium intake (30 mmol/day) and oxalate (oxalate absorption promotes calcium absorption). A thiazide diuretic can be added to reduce urine calcium excretion if necessary.

• Allopurinol and a high fluid intake may prevent formation of uric acid stones.

• Cystine stones are rare (1–2% of all stones), associated with cystinuria, and inherited in an autosomal recessive pattern. A urine output of > 5 L/day should be maintained. Penicillamine is effective in dissolving cystine stones.

• Hypocitraturia predisposes to calcium stone deposition (citrate has a calcium-chelating action). Potassium citrate is effective in increasing urinary citrate levels.

Acute Kidney Injury

Acute kidney injury (AKI) is a deterioration in renal function over the course of days or weeks, which is usually (but not always) reversible. It occurs in 5–10% of all hospital admissions and up to 25% of all ICU admissions. AKI may not be easily distinguishable from chronic (or acute on chronic) kidney disease when the patient first presents.

The Acute Dialysis Quality Initiative group proposed the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria based on increases in serum creatinine or decreases in urine output (Table 10.3). They characterize three levels of renal dysfunction (R, I, F) and two outcome measures (L, E). These criteria indicate an increasing degree of renal damage and have a predictive value for mortality. The mortality of patients with AKI requiring dialysis is 50%.

Table 10.3 RIFLE classification of acute kidney injury

Grade	GFR criteria	UO criteria
Risk	SCr × 1.5	UO < 0.5 mL/kg/hour × 6 hours
Injury	SCr × 2	UO < 0.5 mL/kg/hour × 12 hours
Failure	SCr × 3 or SCr > 350 µmol/L with an acute rise > 40 µmol/L	UO < 0.3 mL/kg/hour × 24 hours
Loss	Persistent AKI > 4 weeks
ESKD	Persistent renal failure > 3 months

AKI, acute kidney injury; ESKD, end-stage kidney disease; GFR, glomerular filtration rate; SCr, serum creatinine; UO, urine output.

The causes of AKI can be divided into pre-renal, renal and post-renal.

• Pre-renal injury results from impairment of renal blood flow leading to acute tubular necrosis (ATN). It accounts for > 80% of all AKI. This may be the result of hypovolaemia (e.g. haemorrhage, burns, diarrhoea), hypotension, changes in the effective circulating arterial volume (e.g. myocardial infarction, severe sepsis, congestive cardiac failure) or impairment of renal blood flow autoregulation by drugs (e.g. ACE inhibitors, NSAIDs).

• Renal causes include vascular lesions, e.g. large vessels (bilateral renal artery disease ± ACE inhibitor treatment, cholesterol emboli), small vessels and glomeruli (e.g. vasculitis, glomerulonephritis (p. 338, 341), accelerated hypertension), and tubulointerstitial disease (e.g. tubular interstitial nephritis, cast nephropathy (in multiple myeloma) and the tumour lysis syndrome).

• Post-renal injury is due to bilateral urinary tract obstruction, or obstruction of a single functioning kidney.

Clinical features

The history usually points clearly to the diagnosis. Diarrhoea, vomiting, nephrotoxic drug ingestion, symptoms of a multi-system disorder, intercurrent illness or lower urinary tract symptoms may be present. Oliguria is not invariable. Polyuria occurs in other conditions, e.g. partial obstruction, tubulointerstitial disease. Clinical examination may reveal hypovolaemia, signs of vasculitis (e.g. rash, fever) or a palpable bladder.

Investigations

• Serum and urine samples should be obtained for a full biochemical analysis of the blood and urine, including microscopy of the urine. If a systemic disease is suspected, the relevant test should be performed, e.g. dsDNA for SLE, hepatitis B and C serology. It can be difficult to differentiate between pre-renal and intrinsic causes of uraemia. A fluid challenge can be performed (see below). In pre-renal failure, there is a fractional excretion rate of sodium (FE_Na) of < 1%, as the kidney retains sodium, resulting in a low urine sodium concentration.

• Renal biopsy is not required if the diagnosis is obvious. ATN can be presumed if there is a clear precipitating cause and no significant proteinuria.

• Imaging should include a US to exclude obstruction. AKI secondary to another cause is usually associated with normal-looking kidneys on US. Small kidneys (< 9 cm) imply chronic kidney disease. IV contrast should be avoided, as the nephrotoxicity may exacerbate the ATN already present.

Management

• Managing fluid balance

• Optimization of fluid balance is essential to allow renal recovery to occur and to maintain homeostasis for the rest of the body. If hypovolaemia is present, correct by giving IV 0.9% NaCl. A central line should be inserted. Give a fluid challenge of 200–300 mL and reassess clinical parameters if there is uncertainty about volume status (p. 368).

• Pre-renal causes can coexist with established ATN, so beware persisting oliguria despite fluid replacement, leading to fluid overload.

• Hypervolaemia should be managed with salt and water restriction (500 mL/day + losses). Diuretics do not improve outcome, but can sometimes simplify management by establishing some diuresis. High doses of loop diuretics are required (e.g. furosemide 80–250 mg/day).

• Drugs that impair renal autoregulation (ACE inhibitors, NSAIDs) should be discontinued.

• Hyperkalaemia requires urgent management (p. 376 and 711).

• Dialysis may be required (Box 10.2).

• Treatment of the underlying cause. Any precipitating factor or cause should be removed. In addition, specific therapy should be given, e.g. immunosuppression for vasculitis (p. 321).

Box 10.2 Indications for dialysis in acute kidney injury

• Pulmonary oedema with oliguria unresponsive to diuretics

• Hyperkalaemia (K⁺ > 6 mmol/L if oliguria or if unresponsive to emergency measures)

• Severe acidosis (but if hypovolaemic IV sodium bicarbonate can be given first)

• Symptomatic uraemia (neurological symptoms, e.g. fits, twitching, confusion; pericarditis; vomiting)

• Raised urea and creatinine — not an indication per se for dialysis, but if urea > 40 mmol/L for several days then symptoms are likely to develop.

• Specific indications for removal of toxins, e.g. gentamicin, lithium, aspirin

Some Renal Causes of Acute Kidney Injury

Acute tubular necrosis (ATN)

This is the most common cause of AKI, especially in hospital practice. Renal impairment secondary to pre-renal causes (p. 348) will progress to ATN if pre-renal factors are not corrected; patients may be oliguric or non-oliguric.

The cause is often multi-factorial, e.g. hypotension + sepsis + NSAIDs. Renal tubular cells are sensitive to hypoxia — hence necrosis occurs when the renal blood supply is impaired. ATN can also be the result of toxic damage, e.g.:

• myoglobin (rhabdomyolysis)

• haemoglobinuria (malaria, intravascular haemolysis)

• contrast media (see below)

• drugs (e.g. gentamicin, amphotericin B and cisplatin).

• Management is supportive until renal recovery occurs (usually within 6 weeks — prognostic renal biopsy is often performed at around this time if no recovery). Optimize fluid balance, avoid nephrotoxic agents, give dialysis if necessary (Box 10.2), and monitor urine output and serum biochemistry. Recovery is often accompanied by a brisk diuresis, which might even necessitate IV fluid replacement for a few days.

Acute tubulointerstitial nephritis (TIN)

TIN presents with AKI (caused by an intense inflammatory cell infiltrate into the renal interstitium), with modest or no proteinuria. There may be fever, arthralgia and a rash, reflecting the probable hypersensitivity reaction that is responsible for the renal damage.

• Causes include drugs (70%) and infections (15%), though no cause may be apparent. Non-infectious chronic inflammatory diseases may cause TIN, including SLE, sarcoidosis and Sjögren’s syndrome (when renal tubular acidosis may also be present). They generally respond to management of the underlying condition.

• Drug-induced TIN is classically associated with an eosinophilia and eosinophils are seen in the infiltrate on renal biopsy. Common drugs include penicillins, sulphonamides, NSAIDs, allopurinol, cephalosporins, rifampicin, diuretics, cimetidine and phenytoin.

• Infectious causes include direct bacterial infection of the kidney with a neutrophil infiltrate. Systemic viral (HIV, measles, EBV) and bacterial (Legionella, Leptospira, Mycoplasma, Brucella, streptococcus) infections may cause an inflammatory infiltrate without evidence of direct bacterial invasion in the kidney. Treatment is to eradicate the causative organism.

Treatment

• Withdraw the offending drug(s) or treat the underlying infection/disease process. The prognosis is generally good, though residual renal impairment may result.

• Treat AKI as above.

• Steroids, e.g. prednisolone 30–60 mg daily, are often given for drug-induced TIN but there is no good evidence that steroids improve long-term outcome.

Contrast nephropathy

In patients with impaired renal function, e.g. from diabetes mellitus, heart failure or hypovolaemia, iodinated radiological contrast media may be nephrotoxic, possibly by causing renal vasoconstriction and producing a direct toxic effect on renal tubules. In many patients the effect is small but severe deterioration in renal function can occur in some. Pre-hydration with an infusion of 1 L of 0.9% saline during the 12-hour period before and also 12 hours after contrast exposure is helpful. Be careful not to overload susceptible patients when furosemide may be required. N-acetylcysteine (NAC; a potent antioxidant) given 48 hours prior to the radiological intervention may also prevent the worsening of the pre-existing renal disease.

N.B. Gadolinium used in contrast MRI causes nephrogenic fibrosing nephropathy (nephrogenic systemic fibrosis).

Post-renal AKI

Urinary tract obstruction

Complete obstruction occurs when there is no urine flow. Partial obstruction occurs when there is some urine flow, but increased pressure proximal to the obstruction. Both cause renal damage. Obstruction may be bilateral (as occurs in lower urinary tract obstruction) or unilateral (e.g. single ureter), when urine flow and serum creatinine are unaltered.

• Complete obstruction presents acutely with anuria. Depending on the cause and the level of obstruction there may be pain (full bladder, stones, associated infection). Examination can show a palpable bladder and/or loin tenderness/fullness. Serum biochemistry will show rising serum creatinine.

• Partial obstruction is often asymptomatic, or presents with similar signs and symptoms as complete obstruction. Tests of renal function may be normal. Symptoms of coexistent UTI may predominate.

• If the bladder is palpable, urethral catheterization should be attempted prior to imaging. Measurement of the residual urine volume makes the diagnosis.

Imaging

• US of the kidneys and bladder is quick, non-invasive and sensitive. It will show a dilated renal pelvis and collecting systems. The ureter is visualized and can show the level or cause of obstruction. Occasionally US is misleading, e.g. when ATN and oliguria are established and no dilatation is seen, in pregnancy and post renal transplant (in which cases the renal pelvis may be ‘baggy’ but not obstructed).

• Other imaging depends on the site and the cause of obstruction, e.g. CT for stone disease, CT-KUB for suspected PUJ or VUJ obstruction.

Management

• Relieving the obstruction

• Lower urinary tract obstruction requires urethral catheterization. If a urethral stricture or prostatic obstruction is present, suprapubic catheterization is occasionally required.

• Upper tract obstruction should be relieved from either above (with percutaneous nephrostomy) or below (with ureteric stenting).

• Complete obstruction should always be treated without delay. Infection + obstruction is a medical emergency.

• A post-obstructive diuresis often follows relief of bilateral obstruction. Measure urine output and replace fluid with IV 0.9% saline.

• Treating the underlying cause will relieve symptoms and preserve renal function. Bilateral ureteric stenting or long-term urethral catheterization is used if relief of obstruction is not possible.

Pelvi-ureteric junction (PUJ) or vesico-ureteric junction (VUJ) obstruction

This results from a functional disturbance of peristalsis at the PUJ in the absence of mechanical obstruction. Surgery (pyeloplasty) is indicated if loin pain is persistent or there is evidence of progressive kidney damage. VUJ obstruction also occurs in childhood but may only become evident in adult life. It is more common in males, presenting with a mega-ureter. Surgery (reimplantation of ureter) is indicated for children and adults with symptoms, recurrent UTI, stones or progressive kidney damage.

Retroperitoneal fibrosis (RPF) (peri-aortitis)

In this condition, the ureters become encased in fibrous tissue with resultant obstruction. The cause is often unknown but drugs (methysergide, ergot-derived dopamine agonists, e.g. cabergoline) are causal; with an inflammatory aortic aneurysm, ceroid is thought to leak out from the atheromatous aorta and cause a fibrotic reaction. The male : female ratio is 3 : 1.

• Investigations show a raised ESR and a normochromic normocytic anaemia. CT scan makes the diagnosis, but biopsy is sometimes required to rule out lymphoma or other malignancy.

• Management is initially by ureteric stenting. Steroids (prednisolone 40–60 mg tapering over several weeks) may shrink the mass. Following this, options are surgical ureterolysis or permanent ureteric stenting. Mycophenolate and tamoxifen have also been used with some success. Monitor by ESR and CT scanning for recurrence.

Benign prostatic hypertrophy

Non-malignant enlargement of the prostate gland is a common cause of lower urinary tract symptoms with or without urinary obstruction in men. It is increasingly common in older age.

• Management

• Mild disease requires no specific treatment.

• Moderate disease can usually be managed medically with α-blockers (e.g. tamsulosin) with or without 5α-reductase inhibitors (e.g. finasteride), which block conversion of testosterone to dihydrotestosterone (the androgen primarily responsible for prostate growth).

• Acute urinary retention should be managed with a bladder catheter. With the above drugs a successful trial without the catheter may be possible.

• Transurethral resection of the prostate is reserved for those in whom medical therapy fails or is inadequate.

Chronic Kidney Disease

Chronic kidney disease (CKD) is a longstanding condition with (usually) a progressive impairment of renal function; it is common, up to 5% of the adult population having CKD.

The loss of glomeruli is associated with hyperfiltration in the remaining glomeruli. Local activation of angiotensin II and cytokine release cause mesangial cell activation and progressive fibrosis and sclerosis. Protein in the proximal convoluted tubule also stimulates cytokine activation and inflammation, eventually causing peritubular fibrosis. Hypertension worsens hyperfiltration injury and proteinuria. CKD is usually (but not invariably) associated with hypertension. Once established, whatever the cause, CKD tends to progress.

CKD can occur from any kidney disease, either congenital or acquired, or from post-renal causes. Acute on chronic deterioration in renal function sometimes occurs due to:

• decreased renal perfusion

• drugs

• urinary tract obstruction or infection

• renal vein thrombosis.

Classification

The US National Kidney Federation Dialysis Outcomes Quality Initiative classification of CKD has been universally adopted (Table 10.4).

Table 10.4 Classification of chronic kidney disease

	GFR (mL/min)	Description
1*	> 90	Normal kidney function
2*	60–90	Mild reduction of kidney function, with other evidence of kidney damage
3	30–60	Moderately reduced kidney function
4	15–30	Severely reduced kidney function
5	< 15	End-stage or approaching end-stage kidney disease

* eGFR of > 60 is normal, unless there is other evidence of kidney disease, e.g. proteinuria, haematuria.

Clinical features

• History. The history often elicits the cause; previous tests of renal function, BP and urinalysis help document the decline in renal function. Previous surgery, drug treatment or medical history may point to the diagnosis. CKD is often asymptomatic, especially in the early stages, with symptoms and signs of advanced CKD occurring in stage 4 of disease.

• Assessment of renal function. Serial measurement of eGFR is practical and useful. If a sudden or non-linear decline in renal function is detected, a cause for that decline should be sought. As a guide, eGFR decline should be < 5 mL/min/year in a CKD patient with well-controlled BP.

• Urinalysis. Significant proteinuria and/or haematuria suggest a glomerular cause. UTI may cause a more modest proteinuria. Haematuria may reflect bleeding from a renal tract tumour and should be investigated unless another cause is known. Red cell casts on urine microscopy indicate a glomerulonephritis.

• Urine culture. This will exclude infection. Sterile pyuria suggests TB; send early morning urine samples for TB culture.

• Haematology. Anaemia is a feature of more advanced CKD (see below). Raised ESR may suggest multiple myeloma or vasculitis.

• Immunology. Antibody screening for autoimmune conditions and viral infections is performed.

• Imaging. Renal US provides details of renal size and anatomy, and usually excludes obstruction. Small kidneys with thin cortices imply that the process is chronic (months or years). CT (e.g. for diagnosis of retroperitoneal fibrosis) or MRI (for assessment of renovascular disease) is sometimes indicated.

• Renal biopsy. This should be performed for all unexplained progressive renal failure with normal-sized kidneys, unless there is a contraindication.

Complications of CKD

• Anaemia

• The causes are multifactorial but the major cause is decreased production of erythropoetin as renal function declines. Iron deficiency and blood loss also contribute.

• If the GFR is < 45 mL/min and Hb < 10 g/dL, then a therapeutic trial of erythropoetin should be commenced (IV or SC 50 U/kg epoetin alfa or beta) over 1–5 mins 3 times weekly. Check iron indices, B₁₂ and folate first and correct if abnormal. Darbepoetin alfa is given weekly and pegzerepoetin alfa is given monthly.

• Most patients on erythropoetin require supplementary iron treatment with a ferritin > 100 mg/L and transferrin saturation > 20% to optimize response to EPO, e.g. ferrous sulphate 200 mg 3 times daily. Those who do not respond to or do not tolerate oral iron should receive IV iron replacement, e.g. iron sucrose 200 mg IV weekly for 3 weeks.

• BP, Hb and reticulocyte count should be measured every 2 weeks and the dose adjusted to maintain target Hb of 11–12 g/dL. An increase in stroke on treatment has been reported and therapy continues to be evaluated.

• Renal bone disease

• The kidney is the site of 1α-hydroxylation of 25-hydroxy vitamin D. Renal failure leads to loss of this function, in turn leading to secondary hyperparathyroidism.

• Decreased renal excretion of phosphate in renal failure leads to hyperphosphataemia.

• Secondary hyperparathyroidism leads to increased and uncontrolled bone turnover and eventually cyst formation and bone marrow fibrosis.

• Derangement of calcium and phosphate metabolism and secondary hyperparathyroidism have non-skeletal effects as well, including increased arterial calcification, left ventricular hypertrophy and cardiac fibrosis, with increased risk of cardiovascular morbidity and mortality.

• Management of renal bone disease

– Hyperphosphataemia should be treated by dietary restriction of phosphate with or without the use of phosphate binders (Table 10.5). Phosphate binders bind phosphate in the stomach, preventing gastrointestinal absorption.

– Hyperparathyroidism (parathyroid hormone (PTH) level 3 times normal) should be treated with activated vitamin D, e.g. calcitriol, alfacalcidol 0.25–1 mcg daily orally. Hypercalcaemia may result and may limit treatment — aim to keep serum calcium in the lower half of the normal range. Vitamin D may worsen hyperphosphataemia, so serum phosphate should be controlled first. The calcium-phosphate product correlates with the risk of ectopic calcification and hypercalcaemia should be avoided. Concern over high calcium loads (with use of calcium-containing phosphate binders) exists; alternative binders are often used first-line for this reason.

– Calcimimetics (e.g. cinacalcet, a calcium-sensing receptor agonist 30–180 mg daily orally) mimic the effect of calcium on the parathyroids, thus driving down PTH production without causing hypercalcaemia. Cinacalcet has a role in patients on dialysis with secondary hyperparathyroidism, when hypercalcaemia prevents further increase in activated vitamin D doses.

– Surgical parathyroidectomy may be necessary when optimal medical therapy fails to suppress PTH. Low PTH levels are associated with adynamic bone disease, decreased bone turnover and increased ectopic calcification. This may occur after parathyroidectomy or with over-treatment with vitamin D.

Table 10.5 Phosphate binders used in chronic kidney disease

Preparation	Limitations	Side-effects
Calcium salts, e.g. calcium acetate 500 mg 3 times daily	Calcium load may worsen or precipitate arterial calcification	Hypercalcaemia
Sevelamer 2.4–12 g in divided doses chewed with meals 3 times daily	Only used in dialysis patients	GI disturbances
Lanthanum 1.5–3 g in divided doses chewed with meals 3 times daily	Only used in dialysis patients	GI disturbances
Aluminium hydroxide 475 mg tabs, 1–3 times daily with meals	Aluminium toxicity: avoid except for short-term use

• Cardiovascular disease

• This is the biggest killer of patients with chronic kidney disease. Cardiovascular disease is 16 times as prevalent as in the normal population.

• The reasons include increased arterial stiffness and calcification, left ventricular hypertrophy, hypertension, calcium and phosphate abnormalities and high levels of oxidative stress.

Management of patients with CKD (Box 10.1)

• Underlying cause. Treat the underlying cause of CKD if possible.

• BP control. Poor control of BP accelerates progression and also imposes adverse cardiovascular risk.

• Target BP should be 130/80 mmHg, or 120/75 mmHg if significant proteinuria and/or diabetes is present.

• If proteinuria is present, ACE inhibitors are the first-line treatment, as they reduce proteinuria over and above their antihypertensive effects in both diabetic and non-diabetic renal disease. Proteinuria is an independent marker for progression and must be treated.

• ARBs are an alternative, with similar effects on proteinuria and prevention of progression.

• Combined ACE inhibitors and ARBs have a synergistic effect on proteinuria. Use both if necessary to reduce proteinuria to < 1 g/24 hours.

• Patients with CKD often need three or more agents to achieve BP control, and should be warned of this (Box 10.1).

• In stages 4 and 5 CKD, salt and water retention may be significant factors in hypertension. Manage with loop diuretics, e.g. furosemide 40–250 mg per day in divided doses.

• Diet. Dietary protein restriction may slow progression, but malnutrition is a significant risk and a normal protein diet (0.8–1 g/kg/day) is recommended. Dietary education is necessary as renal failure progresses and includes the following:

• An adequate energy intake (carbohydrates and lipids) is essential.

• Restriction of sodium to < 5–6 g/day helps to control fluid overload, hypertension and thirst.

• Potassium restriction is almost always necessary as CKD becomes advanced, especially if taking ACE inhibitors and/or ARBs. Avoid potassium-sparing diuretics in these circumstances.

Preparation for renal replacement therapy

• Less than 5% of all patients with stage 3 CKD reach end-stage renal disease (most patients die with their CKD rather than from it).

• Once the eGFR is < 30 mL/min, dialysis should be discussed with the patient. Timely preparation for dialysis improves outcome. The patient needs to understand and be prepared for:

• what dialysis involves for the patient

• which modality of dialysis is most suitable for the individual

• insertion of a peritoneal dialysis catheter or creation of an arterio-venous fistula

• whether kidney transplantation is feasible; if so, whether there is a suitable living donor (consider pre-emptive transplant).

• Specialized clinics for pre-dialysis preparation and conservative management facilitate management and are recommended. Dialysis should be commenced before uraemic symptoms supervene.

Non-dialysis management of end-stage renal failure

Some patients may make an informed decision not to commence dialysis, as survival on dialysis in patients with high co-morbidity is often measured in months rather than years. Dialysis can be arduous, especially if the patient is frail with co-morbidity at the outset. Non-dialysis management may keep such patients at home and with a better quality of life, with little or no reduction in the length of life.

The decision not to dialyse should always be made by the medical team and patient (with carers if appropriate) together. No patient should have dialysis withheld against his/her wish or knowledge.

Renal Replacement Therapy

Approximately 100 white individuals per million population in the UK commence renal replacement therapy (RRT) each year (the figure for blacks and Asians is 3–4 times higher, mainly because of the higher incidence of hypertensive and diabetic nephropathy in these groups).

RRT is delivered either by dialysis (haemodialysis or peritoneal dialysis) or by renal transplantation. The aim of dialysis is to mimic the functions of the normal kidney, including fluid and electrolyte balance and excretion of nitrogenous wastes. Erythropoetin production and hydroxylation of vitamin D are not affected by dialysis and require additional treatment.

Haemodialysis

Blood is removed from the circulation and passed across a semi-permeable membrane. On the other side of that membrane flows dialysate in a counter-current fashion. Dialysate (Table 10.6) consists of ions at physiological concentrations, allowing homeostasis to be maintained/restored by dialysis treatment by diffusion and equilibration across the membrane. Water (and salt) removal can be controlled by controlling the trans-membrane pressure.

Table 10.6 Composition of dialysate (mmol/L)

	Haemodialysis	Peritoneal dialysis
Sodium	130–145	130–134
Potassium	0.0–4.0	0.0
Calcium	1.0–1.6	1.0–1.75
Magnesium	0.25–0.85	0.25–0.75
Chloride	99–108	95–104
Lactate	35–40 (or acetate 35–40)	35–40
Glucose	0–10	77–236
Total osmolality		356–511 mOsm/kg

Blood flow required is typically 200–350 mL/min. The most reliable method of achieving such flow is by creation of an arterio-venous fistula (surgical anastomosis of an artery to a vein, usually the cephalic vein to the radial or brachial artery). The high flows and pressures thus created in the vein allow needles to be inserted and removed at the beginning and end of each treatment. If no suitable vein exists, a polytetraflouroetheylene (PTFE) graft can be inserted between artery and vein. For emergency dialysis, a dual lumen catheter inserted into the jugular vein allows satisfactory blood flows. Tunnelled catheters may be used in place of an arterio-venous fistula in patients unsuitable for fistula creation, but are associated with a high incidence of sepsis and may cause venous stenosis. Anticoagulation (usually with heparin) is required to prevent the blood clotting.

Haemofiltration

Haemofiltration involves removal of plasma water and electrolytes by convective flow across a high-flux semi-permeable membrane, with replacement by a solution of physiological biochemical composition. Haemofiltration is rarely used as treatment for chronic kidney disease, but is useful in acute kidney injury in critically ill patients. Continuous low-volume haemofiltration (e.g. 1 L/hour) is a gentler treatment than intermittent dialysis and confers greater cardiovascular stability.

Haemodiafiltration

Haemodiafiltration combines the principles of dialysis and filtration. Long-term outcome trials are awaited, but clearance of ‘middle’ molecules appears to be improved, with a reduction of β₂-microglobulin deposition, leading to reduced dialysis amyloid-associated carpal tunnel syndrome and possibly other more significant benefits.

Prescription and adequacy of haemodialysis

• Dry weight. Each patient should have an ideal dry weight established, i.e. that weight at which salt and water balance is optimal. The dry weight should be attained during the dialysis session by removal of salt and water.

• Dialysate composition. A high dialysate sodium concentration may stimulate thirst and hypertension. High calcium in the dialysate may lead to hypercalcaemia. Low calcium may worsen secondary hyperparathyroidism. The buffer used is usually bicarbonate (or acetate).

• Frequency. Unless there is significant renal function, most patients need to dialyse at least 3 times per week for 4–5 hours per session to allow adequate clearance of small molecules and control of fluid status. More frequent dialysis leads to better control of BP, serum phosphate and other biochemical parameters.

• Membranes. Biocompatible membranes are superseding cellulose-based membranes, as they cause less activation of inflammatory cascades.

• Adequacy. Insufficient dialysis is associated with increased morbidity and mortality. Measures of dialysis adequacy (measuring the amount of urea removed per session) should occur regularly for all patients on chronic dialysis treatment.

Complications of haemodialysis

These include hypotension, which can be avoided by careful management of fluid balance, infection of indwelling lines (treat with IV antibiotics) and thrombosis of vascular access. Long-term complications include an increase in cardiovascular disease, bone disease and dialysis amyloid.

Peritoneal dialysis

The peritoneum is a semi–permeable membrane. If dialysis fluid is infused into the peritoneal cavity, equilibration occurs between the dialysate and the extracellular fluid of small molecules, ions and water.

A peritoneal dialysis catheter is inserted into the peritoneal cavity. This single-lumen tube is usually inserted through the midline and tunnelled subcutaneously to exit on the anterior abdominal wall. Dialysate (Table 10.6) can be infused into the peritoneal cavity using gravity, and after a period of time drained out (again using gravity). Typically the peritoneal cavity can accommodate 1.5–2.5 L of dialysate at any time. Attention to sterile technique is essential.

• Chronic ambulatory peritoneal dialysis (CAPD) involves regular exchanges of dialysate through the day (typically 6 hour dwells, with 4 exchanges per day). Automated peritoneal dialysis (APD) is the process in which a machine automatically drains fluid in and out; it is usually performed at night, with multiple exchanges overnight (e.g. 2-hour dwells).

• Variation of the amount of glucose in the dialysate allows the osmolar ‘pull’ of the dialysate to be varied, and hence the amount of water removed with each dwell (Table 10.6).

Adequacy of peritoneal dialysis

• Urea clearance can be measured. In addition, the ‘transporter’ status of the peritoneum can be assessed. ‘High transporters’ have rapid equilibration of ions and small molecules across the membrane. Fluid removal is less efficient as the osmolar gap is less pronounced. ‘Low transporters’ clear small ions and molecules less efficiently, but fluid removal is easier.

• For patients with little residual renal function, peritoneal dialysis alone frequently provides inadequate dialysis. Loss of membrane function (see below) with loss of residual function necessitates a transfer to haemodialysis.

Complications of peritoneal dialysis

• Peritonitis. This is the most common serious complication of peritoneal dialysis. It presents with abdominal pain, fever and cloudy dialysate (microscopy shows white blood cells). Organisms are usually staphylococci (epidermidis or aureus) or Gram-negative bowel organisms. Diagnosis is by culture of peritoneal fluid with or without blood. Intraperitoneal or IV antibiotics (p. 64) are usually effective. Failure to resolve after 48 hours usually requires removal of the peritoneal dialysis catheter. Reinsertion may be possible after a few weeks.

• Drainage problems. Constipation, catheter malposition or fibrin clots may all contribute. Plain abdominal X-ray may facilitate management. Occasionally surgical repositioning is required.

• Membrane failure. Eventually the peritoneal membrane becomes thickened and less efficient. Factors contributing to this are sepsis and high glucose concentrations. Falling dialysis adequacy and less effective fluid removal require more intensive dialysis and may eventually necessitate transfer to haemodialysis. Sclerosing peritonitis is caused by sepsis and/or prolonged exposure of the peritoneal membrane to high glucose concentrations. Thickening of the peritoneal membrane leads to recurrent small bowel obstruction, pain and malnutrition. Peritoneal dialysis should be abandoned in this situation.

Renal Transplantation

Renal transplantation is the most effective form of renal replacement therapy. It replaces all the functions of the kidney, and is associated with longer and better quality of life compared to dialysis.

• Cadaveric transplantation involves the removal of the kidney from a brain-dead donor (either heart-beating if brain death is diagnosed on a ventilator, or non-heart-beating if criteria for brain death diagnosis are not met). The organ is immediately cooled with ice and cold perfusate. After cross-matching with the recipient is completed, the organ is implanted into the recipient. Transplant outcome is best if ‘cold ischaemic time’ (the time from removal to implantation) is minimized, and should certainly be kept below 24 hours.

• Living donor transplantation involves the removal of a kidney from a healthy living donor, usually but not always a family member. Donors require assessment to ensure that they are fit and both kidneys are functioning normally. In the UK, donation can only be on altruistic grounds and no material or financial gain to the donor should be involved.

Graft survival is now typically 80% 5–10-year survival. Around 50% of grafts can be expected to last 10–30 years. Graft outcome is better after living donor transplantation, mainly because the cold ischaemic time is shorter.

Immunosuppression in renal transplantation

The most commonly used drugs are shown in Table 10.7. Immunosuppression is tailored to the individual, balancing the risks of rejection with those of over-immunosuppression and other side-effects. There are many different combinations of drugs used, varying by patient and by transplant unit, and with trial data continually leading to modifications and refinements in regimes. Monotherapy is unusual — most patients are on 2–3 different immunosuppressive drugs, e.g. ciclosporin (or tacrolimus) + mycophenolate MMF (or azathioprine) + prednisolone. Steroid-free regimes (or early withdrawal of steroids) and calcineurin-free regimes exist and may be suitable for those at highest risk of side-effects from these drugs. In addition, induction agents (e.g. daclizumab, basiliximab, anti-thymocyte globulin) are often given to those at higher risk of rejection at the time of transplantation.

Table 10.7 Immunosuppressive drugs used in renal transplantation