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Ovid: Oxford Handbook of Clinical Medicine

Editors: Longmore, Murray; Wilkinson, Ian B; Turmezei, Tom; Cheung, Chee Kay Title: Oxford Handbook of Clinical Medicine, 7th Edition Copyright ©2007 Oxford University Press > Table of Contents > 8 – Renal Medicine 8 Renal Medicine

Fig 1. Electron microscopy image of arterioles in a glomerulus.

Renal disease typically presents with one or more of rather a short list of clinical syndromes—listed from 1 to 7 below. One underlying pathology may have a variety of clinical presentations.

  • Proteinuria and nephrotic syndrome: Normal protein excretion is <150mg/d. This may rise to ~300mg/d—eg orthostatic proteinuria (related to posture), during fever, or after exercise. Proteinuria (excessive protein excretion) is a sign of glomerular or tubular disease. Nephrotic syndrome (p290) is the triad of proteinuria (>3g/d), hypoalbuminaemia (albumin <30g/L) and oedema.
  • Haematuria and nephritic syndrome: Blood in the urine may arise from anywhere in the renal tract. It may be macroscopic (visible to the naked eye) or microscopic (found on dipstick testing and microscopy). Haematuria with dysuria is usually from a UTI. Painless haematuria is more ominous, eg bladder or other GU cancer (eg if >40yrs old, esp if a smoker) or glomerulonephritis. Nephritic syndrome comprises haematuria and proteinuria—often with hypertension, pulmonary and peripheral oedema, oliguria (urine output <400mL/d), and a rising plasma urea and creatinine. The question of who to refer haematuria patients to (urologist or nephrologist) is answered on p278.
  • Renal pain and dysuria: Renal pain is usually a dull and constant and in the loin. It may be due to renal obstruction (look for swelling ± tenderness), pyelonephritis, acute nephritic syndrome, polycystic kidneys, or renal infarction. Renal (ureteric) colic is severe waxing and waning loin pain radiating to groin or thigh eg with fever and vomiting. It is caused by a renal stone, clot, or a sloughed papilla. Urinary frequency with dysuria (pain on voiding) suggests a UTI.
  • Oliguria and polyuria: Oliguria is a urine output of <400mL/d—a normal response to hot climates or fluid restriction. Pathological causes: renal perfusion↓, renal parenchymal disease, renal tract obstruction. Polyuria is the voiding of abnormally high volumes of urine, usually from high fluid intake—or diabetes mellitus, diabetes insipidus (p224), hypercalcaemia, renal medulla disorders (urine concentration is impaired), and SVT (p112).
  • Acute renal failure (ARF) is significant decline in renal function occurring over hours or days, detected by a rising plasma creatinine (± oliguria). ARF usually occurs secondary to a circulatory dysfunction (hypotension, hypovolaemia, sepsis) or urinary obstruction. Primary renal disease is a less common cause.
  • Chronic renal failure (CRF) or chronic kidney disease (CKD) is defined as irreversible, substantial, and long-standing loss of renal function. It is classified according to glomerular filtration rate (GFR): see p661. There is often a poor correlation between symptoms and severity of CRF. Progression may be so insidious that patients attribute symptoms to age or a minor illnesses. Current guidelines advise nephrology referral if CKD stage ≥3 (p661),image1 ie GFR <60mL/min, if other features are present: • GFR is falling progressively • Microscopic haematuria • Urine protein:creatinine ratio (PCR)↑, p301 •Unexplained anaemia, hyperkalaemia, or calcium or phosphate imbalance •Suspected systemic illness (eg SLE) •BP uncontrolled despite taking 3 drugs. Refer urgently if GFR 15-29 (same-day if <15) even if no other features present.
  • Silence: Serious renal failure may cause no symptoms at all. This is why we do U&Es before surgery and other major interventions. The silence of renal disease creeps up on us (doctors and patients)—with uncanny stealth which is as alarming as the image opposite—‘Silence’, by Tiago Phelipe. This picture serves to remind us not to dismiss odd chronic symptoms such as fatigue or ‘not being quite with it’—without doing a blood test. Microalbuminuria is a famously silent harbinger of serious renal and cardiovascular risk. It is described on p306. In one study, 30% of those with type 2 diabetes mellitus died within ~5 years of developing microalbuminuria.

Urine Examine mid-stream urine (MSU) whenever you suspect renal disease. Dipstick:

  • Haematuria: Renal causes: Neoplasia, glomerulonephritis (often IgA nephropathy, p288), tubulointerstitial nephritis, polycystic kidney, papillary necrosis, infection (pyelonephritis), trauma. Extrarenal: Calculi, infection (cystitis, prostatitis, urethritis), neoplasia (bladder, prostate, urethra), trauma (eg from catheter). Tests: Urine MC&S, FBC, ESR, CRP, U&E, clotting. Others: AXR/KUB, p284 (stones), urine cytology, estimation of proteinuria (see below), renal ultrasound ± renal biopsy. Management: Usually refer first to a urologist, and do ultrasound. Only refer initially to renal physician if the risk of urothelial malignancy is low and risk of glomerulonephritis is not negligible (eg <40yrs old, creatinine↑, BP↑, proteinuria, systemic symptoms, family history of renal disease).image2 Not all women with recurrent UTI + haematuria need cystoscopy, but have a good reason not to do cystoscopy (Reynard’s rule).image3False +ve dipstick haematuria: Haemoglobinuria, myoglobin (eg in rhabdomyolysis), beetroot, porphyria, alkaptonuria, rifampicin, phenindione, phenolphthalein.
  • Proteinuria: Normal protein excretion is <150mg/d, consisting of <30g/d of albumin. Renal causes of proteinuria: UTI, orthostatic proteinuria, glomerulonephritis (GN), ↑BP, DM, myeloma, amyloid. Extrarenal: Fever, exercise, pregnancy, CCF, vaginal mucus, recent ejaculation. Tests: BP, urine MC&S. Estimation of proteinuria: 24h urine collection for protein and creatinine quantifies proteinuria if collected accurately: spot tests for urine albumin:creatinine ratio or urine protein:creatinine index are much easier and provide reasonably accurate information; renal ultrasound; autoantibodies eg immunoglobulins, serum electrophoresis, urinary Bence Jones protein (p288); consider a renal biopsy if renal function is deteriorating. Microalbuminuria is undetectable on dipstick, with albuminuria of 30-300mg/24h on lab tests. Causes: DM, ↑BP, minimal change GN.
  • Other substances—Glucose: Low renal threshold (eg chronic renal failure), DM, pregnancy, sepsis, renal tubular damage. Ketones: Starvation, ketoacidosis. Leucocytes: UTI, vaginal discharge. Nitrites: UTI, high-protein meal. Bilirubin: Obstructive jaundice. Urobilinogen: Pre-hepatic jaundice. Specific gravity: Normal range: 1.000-1.030 (useful to assess degree of proteinuria or haematuria). pH: Normal range: 4.5-8 (acid-base balance: p658).

Microscopy Put a drop of fresh urine (MSU or suprapubic aspirate) on a microscope slide, cover with a coverslip and examine under low (×100) and high (×400) power for leucocytes, red cells, bacteria, casts and crystals. If renal disease is suspected, a centrifuged urine should be examined. Leucocytes: >10/mm3 in an unspun urine specimen is abnormal. Usually due to a UTI, see p283 for causes of sterile pyuria (when no bacteria are found). Red cells: >2/mm3 in unspun urine is abnormal. Causes: See haematuria. Casts are cylindrical bodies formed in the lumen of distal tubules.

  • Finely granular and hyaline casts (clear, colourless) are found in normal concentrated urine. They are increased in fever, exercise or loop diuretics.
  • Densely granular: Glomerular or tubular disease eg GN, interstitial nephritis.
  • Fatty casts: Moderate-heavy proteinuria. Don’t mistake fat globules for RBCs.
  • Red cell casts are a diagnostic marvel, as they prove that haematuria is glomerular, allowing you to start an interesting dialogue with a nephrologist: ‘is there vasculitis (p542), glomerulonephritis, or malignant hypertension?’
  • White cell casts occur in pyelonephritis.
  • Tubular cell casts occur in acute tubular necrosis.

Crystals are common in old or cold urine and may not signify pathology. They are important in stone formers: cystine crystals are diagnostic of cystinuria, and oxalate crystals in fresh urine may indicate a predisposition to form calculi. 24h urine for Na+, K+, Ca2+, urea, creatinine ± protein excretion. Take blood simultaneously for creatinine to calculate creatinine clearance (p661). P.279
Urine microscopy


Principal source: Atlas of Bedside Microscopy ©JM Longmore; RCGP ▶When you find red cells, consider their morphology to understand where in the GU tract they come from. If >10% of RBCs are dysmorphic G1 cells, suspect glomerular bleeding, and look hard for red cell casts. G1 cells have doughnut shapes, target configurations, and membrane protrusions or blebs. NB: identifying dysmorphic red cells is subjective and often difficult. Acanthocyturia ≈ RBCs with spicules. G1 cell images (stained urine cytology): www.uninet.edu/cin2003/conf/nguyen/nguyen.html P.280
Images of renal histology

Fig 1. Crescentic glomerulonephritis: a proliferation of epithelial cells and macrophages with rupture of Bowman’s capsule, in this patient caused by antiglomerular basement membrane (Goodpasture’s) disease, see p692.
Fig 2. Immunofluorescence for IgG, showing linear staining for glomerular basement, characteristic of anti-glomerular basement membrane (Goodpasture’s) disease.
Fig 3. US-guided biopsy of a transplant kidney— this reduces the risk of damaging the renal vessels and pelvis, as well as any nearby bowel (although the graft is usually extra-peritoneal). The red arrow is point of entry of the biopsy needle (hyperechoic and casting an acoustic shadow deeper). The hypoechoic tissue around the needle is from the infiltration of local anaesthetic. 3 separate ‘shots’ of the biopsy ‘gun’ are usually enough to get a good sample, though let the patient know what a ‘shot’ sounds like before starting, so that they don’t start off down the ward!
Fig 4. Renal allograft rejection: Cellular rejection, showing a tubulointerstitial infiltrate of lymphocytes—this is usually graded according to the Banff criteria. Although ‘rejection’ may sound fierce, it is usually easily and well-treated by increasing immunosuppression eg with a pulse of methylprednisolone. ▶ Watch for infection (eg CMV).
Fig 5. Renal allograft rejection: Antibody-mediated rejection, with diffuse peritubular capillary staining for C4d complement. Humoral (antibody-mediated) rejection is more problematic than cell-mediated rejection (above); it may need immunoglobulin therapy with plasma phoresis in an attempt to clear the system of donor-specific antibodies.

Renal biopsy Most acute renal failure is due to pre-renal causes or acute tubular necrosis, and recovery of renal function typically occurs over the course of a few weeks. Renal biopsy should be performed only if knowing histology will influence management. Once chronic renal failure is established, the kidneys are small, there is a higher risk of bleeding from biopsy, and the results are usually unhelpful. Indications for renal biopsy:

  • What is the cause of this acute renal failure (p292)?
  • Investigating glomerulonephritis, eg is persistent haematuria from IgA nephropathy, thin basement membrane disease, or hereditary nephropathy?
  • What is the cause of this heavy proteinuria (eg >1g/d, when you know that diabetes mellitus is not the cause).
  • Renal dysfunction post-transplantation (p297): is the cause rejection, acute tubular necrosis, drug toxicity, or recurrence of renal disease?image4

Pre-procedure: Check FBC, clotting, group & save. Obtain written informed consent. Ultrasound (if only 1 kidney, risk is magnified). Stop aspirin 1 week and warfarin at least 2 days in advance. Contraindications: • Abnormal clotting • Hypertension >160/>90 • Single kidney • Chronic renal failure with small kidneys (<9cm) •Uncooperative patient Procedure: Biopsy is done under ultrasound guidance with the patient lying in the prone position and the breath held. Samples should be sent to histology. A clear indication on the request form of why the test has been done, eg exclude amyloidosis, will help in the selection of special stains, immunofluorescence and use of electron microscopy. Post procedure: Bed rest for a minimum of 6hrs. Monitor pulse, BP, symptoms, and urine colour. Bleeding is the main complication; most occurs within 8 hrs, although it may be delayed by up to 72hrs. Macroscopic haematuria occurs in ~10%, although blood transfusion is only needed in ~1-2%. Aspirin or warfarin can be restarted the next day if uncomplicated. P.282
Urinary tract infection (UTI) Childhood UTI: OHCS p174 Definitions Bacteriuria: Bacteria in the urine, may be asymptomatic or symptomatic. UTI: The presence of a pure growth of >105 organisms per mL of fresh MSU. UTI sites: urethra (urethritis), bladder (cystitis), prostate (prostatitis), or renal pelvis (pyelonephritis). Up to À of women with symptoms have bacteriuria; (=abacterial cystitis or the urethral syndrome). Classification: UTIs may be uncomplicated (normal renal tract and function) or complicated (abnormal renal/GU tract, ↓renal function, impaired host defences, or virulent organism eg Staph. aureus). Assume that UTI in men without risk factors (below) is complicated until proved otherwise. A recurrent UTI is a further infection with a new organism. A relapse is a further infection with the same organism. For urethritis, see p406. Risk factors ♀, sexual intercourse, exposure to spermicide in ♀ (by diaphragm or condoms), pregnancy, menopause; ↓host defence: immunosuppression, DM; urinary tract: obstruction (p286), stones, catheter, malformation. NB: in pregnancy, UTI is common and often asymptomatic, until serious pyelonephritis, premature delivery (± fetal death) supervenes, so do routine dipstix in pregnancy. Urine in catheterized bladders is almost always infected—it is pointless sending samples or treating unless the patient is ill. Organisms E. coli is the main organism (>70% in the community but ¢41% in hospital). Also Staphylococcus saprophyticus, Proteus mirabilis. Rarer: Enterococcus faecalis, Klebsiella, Enterobacter and Acinetobacter species, Pseudomonas aeruginosa, Serratia marascens, Candida albicans, and Staph. aureus. Symptoms Cystitis: Frequency, dysuria, urgency, strangury, haematuria, suprapubic pain. Acute pyelonephritis: High fever, rigors, vomiting, loin pain and tenderness, oliguria (if acute renal failure). Prostatitis: Flu-like symptoms, low backache, few urinary symptoms, swollen or tender prostate on PR. Signs Fever, abdominal or loin tenderness, foul-smelling urine. Occasionally distended bladder, enlarged prostate. NB: see Vaginal discharge, p406. Tests If symptoms are present, dipstick the urine and treat empirically if nitrites or leucocytes are positive. If they are negative, consider sending an MSU for lab MC&S to confirm this. Send a lab MSU anyway if male, a child (OHCS p174), pregnant, immunosuppressed or ill, or if symptoms don’t resolve after one course of empirical treatment. A pure growth of >105 organisms per mL is diagnostic. If <105 organisms/mL and pyuria (eg >20 WBCS/mm3), the result may still be significant. Cultured organisms are tested for sensitivity to a range of antibiotics (p368). Blood tests: FBC, U&E, CRP, and blood cultures eg if systemically unwell. Ultrasound or IVU/cystoscopy: Consider for UTI in children; men; if failure to respond to treatment; recurrent UTI (>2/year); pyelonephritis; unusual organism; persistent haematuria. In one study on men, ultrasound combined with plain XR of kidneys, ureters and bladder (KUB) was as effective as IVU in detecting urinary tract abnormalities, and avoided exposure to IV contrast.image5 Treatment ▶ Drink plenty of fluids; urinate often (don’t ‘hold on’). In pregnancy, get expert help. Know your local pattern of resistance. Until the organism is known:

  • Cystitis: Trimethoprim 200mg/12h PO (3d course in ♀, 7d in ♂). Alternative: cefalexin 1g/12h. 2nd line: ciprofloxacin or co-amoxiclav PO (7d course).
  • Acute pyelonephritis: Cefuroxime 1.5g/8h IV then oral × 7d course.
  • Prostatitis: Ciprofloxacin 500mg/12h PO for ~ 4wks.

Prevention Antibiotic prophylaxis, continuously or post-coital, ↓infection rates in women with recurrent UTIs. Self-treatment with a single antibiotic dose as symptoms start is an option. Drinking 200-750ml of cranberry or lingonberry juice a day, or taking cranberry concentrate tablets, reduces the risk of symptomatic recurrent infection in women by 10-20%,image6 may be by inhibiting adherence of bacteria to bladder uroepithelial cells. There is no evidence that postcoital voiding or advice on wiping patterns in females is of benefit.image7 P.283
Causes of sterile pyuria ▶ Always remember renal TB (do 3 early morning urines). Other causes:

  • Treated UTI <2 weeks prior
  • Inadequately treated UTI
  • Appendicitis
  • Calculi
  • Prostatitis
  • Bladder tumour
  • UTI with fastidious culture requirement
  • Papillary necrosis (eg DM or analgesic excess)
  • Tubulointerstitial nephritis
  • Polycystic kidney
  • Chemical cystitis (eg cyclophosphamide).

What is the predictive value of urinary symptoms and dipstick for diagnosing UTI? This is a controversial area, with a meta-analysis on 70 studies concluding that in the general population, a combination of negative nitrite and leucocyte tests on dipstick was sufficient to rule out UTI.MET8 However, a recent small prospective study (n=59) showed that although a negative dipstick test accurately predicted the absence of UTI according to urine culture, treating these patients with trimethoprim still reduced symptoms of dysuria, suggesting that the cause in these patients may be infection not detected by current urine dipstick or culture techniques.image9 P.284
Renal calculi (nephrolithiasis) Renal stones (calculi) consist of crystal aggregates. Stones form in collecting ducts and may be deposited anywhere from the renal pelvis to the urethra. Prevalence Common: lifetime incidence up to 15%. Peak age: 20-40yr. ♂:♀~3:1. Types of stone

  • Calcium oxalate: 75%.
  • Magnesium aluminium phosphate (struvite, triple phosphate): 10-20%.
  • Others: urate (5%), hydroxyapatite (5%), brushite, cystine (1%), mixed.

The patient may be asymptomatic or present with a variety of symptoms. Pain: Stones in the kidney cause loin pain. Stones in the ureter cause renal (ureteric) colic. This occurs in spasms, classically radiates from the ‘loin to the groin’, and is associated with nausea and vomiting. Patients often cannot lie still, differentiating this from peritonitis. Bladder or urethral stones cause pain on micturition, strangury or interruption of urine flow. Infection can co-exist with renal stones, presenting with cystitis (frequency, dysuria), pyelonephritis (fever, rigors, loin pain, nausea, vomiting), or pyonephrosis (infected hydronephrosis). Others: Haematuria, proteinuria, sterile pyuria, anuria. Tests: FBC, U&E, Ca2+, POimage, glucose, bicarbonate, urate. Urine dipstick: Usually +ve for blood. MSU: MC&S. Further tests for cause: Urine pH (on dipstick); 24h urine for: calcium, oxalate, urate, citrate, sodium, creatinine; stone biochemistry. Imaging: KUB XR (kidneys+ureters+bladder). Look along the ureters for calcification, over the transverse processes of the vertebral bodies: 80% of stones are visible (99% on CT). Ultrasound to look for hydronephrosis or hydroureter. CT is superior to IVU for imaging stones, and helps exclude differential causes of an acute abdomen. ▶A ruptured abdominal aortic aneurysm may present similarly. Management Give prompt analgesia, ideally an NSAID: eg diclofenac 75mg IV or IM, or 100mg suppository.MET10 If contraindicated: morphine 5-10mg IV with metoclopramide 10mg IV. Give IV fluids if unable to tolerate orally; antibiotics (eg cefuroxime 1.5g/8h IV) if infection. After imaging ▶seek urological help urgently if evidence of obstruction, delay may lead to infection and permanent loss of renal function. Procedures include extracorporeal shockwave lithotripsy (ESWL) using ultrasonic waves to shatter the stone, percutaneous nephrostomy to relieve obstruction, ureteroscopy ± laser, or percutaneous nephrolithotomy (PCNL), using keyhole techniques to remove stones. Open surgery is rarely done. Stones not causing obstruction between attacks of renal colic may be managed conservatively. Advise to increase fluid intake and sieve the urine to catch the stone for biochemical analysis. Most pass within 48h, although some take >30d. Stones <5mm in diameter pass spontaneously in ~90% and so are treated conservatively, with their progress monitored on serial abdominal films every 1-2 weeks. The remainder may require intervention to remove the stone. Ureteric stones <1cm are suitable for ESWL, with ureteroscopy preferred if >1cm, (although there is some debate over the preferred approach in distal stones). For renal stones, ESWL is preferred if <2cm; PCNL is reserved for larger stones.image11 Prevention General: Drink plenty of fluid, especially in the summer or warm weather (aim for 2-3L/day of colourless urine). A normal calcium intake is now recommended, as low calcium diets increase oxalate excretion. Specifically: •Calcium stones: if there is hypercalciuria, a thiazide diuretic (eg bendroflumethiazide) is used to ↓calcium excretion •Oxalate: ↓oxalate intake (less tea, chocolate, nuts, strawberries, rhubarb, spinach, beans, beetroot); pyridoxine may be used (p304) •Magnesium aluminium phosphate: treat infection promptly •Urate: allopurinol (100-300mg/24h PO) to ↓uric acid. Urine alkalinization may also be recommended, as urate is more soluble at pH>6 (eg with potassium citrate or sodium bicarbonate) •Cystine: vigorous hydration to keep urine output >3L/day and urinary alkalinization (as above). D-penicillamine is used to chelate cystine, given with pyridoxine to prevent Vitamin B6 deficiency. P.285
Questions to address when confronted by a stone • What is its composition?


Causative factors

Appearance on XR

Calcium oxalate

Metabolic or idiopathic

Spiky, radiopaque

Calcium phosphate

Metabolic or idiopathic

Smooth, may be large, radiopaque

Magnesium aluminium phosphate


Large, horny, ‘staghorn’ radiopaque



Smooth, brown, radiolucent


Renal tubular defect

Yellow, crystalline, semi-opaque

• Why has he or she got this stone now?

  • ‘What do you eat? ‘ Chocolate, tea, rhubarb and spinach ↑oxalate levels.
  • ‘Is it summer? ‘ Seasonal variations in calcium and oxalate levels are thought to be mediated by vitamin D synthesis via sunlight on skin.
  • ‘What’s your job? ‘ Can he/she drink freely? Is there dehydration?
  • ‘Are there any precipitating drugs?’ These include:
    • Loop diuretics, antacids, acetazolamide, corticosteroids, theophylline, aspirin, thiazides, allopurinol, vitamin C & D, indinavir.
  • ‘Are there any predisposing factors? ‘ eg:
  • Recurrent UTIS (in magnesium aluminium phosphate calculi).
  • Metabolic abnormalities:
    • Hypercalciuria/hypercalcaemia (p672): hyperparathyroidism, neoplasia, sarcoidosis, hyperthyroidism, Addison’s, Cushing’s, lithium, vit D excess.
    • Hyperuricosuria/↑plasma urate: on its own, or with gout.
    • Hyperoxaluria (p304).
    • Cystinuria (p304).
    • Renal tubular acidosis (p302).
  • Urinary tract abnormalities: eg pelviureteric junction obstruction, hydronephrosis (renal pelvis or calyces), calyceal diverticulum, horseshoe kidney, ureterocele, vesicoureteric reflux, ureteral stricture, medullary sponge kidney.1

• Is there a family history? ↑risk of stones × 3-fold. Specific diseases include X-linked nephrolithiasis and Dent’s disease: proteinuria, hypercalciuria and nephrocalcinosis.image12 ▶Is there infection above the stone? eg fever, loin tender, pyuria? This needs urgent intervention. 1 Medullary sponge kidney is a typically asymptomatic developmental anomaly of the kidney mostly seen in adult females, where there is dilatation of the collecting ducts, which if severe leads to a sponge-like appearance of the renal medulla. Complications/associations: UTIs, nephrolithiasis, haematuria and hypercalciuria, hyperparathyroidism (if present, look for genetic markers of MEN type 2A, see p207).image P.286
Urinary tract obstruction ▶Urinary tract obstruction is common and should be considered in any patient with impaired renal function. Damage can be permanent if the obstruction is not treated promptly. It occurs anywhere from the renal calyces to the urethral meatus, and may be partial or complete, unilateral or bilateral. Obstructing lesions are luminal (stones, blood clot, sloughed papilla, tumour: renal, ureteric, or bladder), mural (eg congenital or acquired stricture, neuromuscular dysfunction, schistosomiasis), or extra-mural (abdominal or pelvic mass/tumour, retroperitoneal fibrosis). Unilateral obstruction may be clinically silent (normal urine output and U&E), if the other kidney is functioning. ▶Bilateral obstruction or obstruction with infection requires urgent treatment. See emergency box 603. Clinical features

  • Acute upper tract obstruction: Loin pain radiating to the groin. There may be superimposed infection ± loin tenderness, or an enlarged kidney.
  • Chronic upper tract obstruction: Flank pain, renal failure, superimposed infection. Polyuria may occur owing to impaired urinary concentration.
  • Acute lower tract obstruction: Acute urinary retention typically presents with severe suprapubic pain, often preceded by symptoms of bladder outflow obstruction (as below). Clinically: distended, palpable bladder, dull to percussion.
  • Chronic lower tract obstruction: Symptoms: urinary frequency, hesitancy, poor stream, terminal dribbling, overflow incontinence. Signs: distended, palpable bladder ± large prostate on PR. Complications: UTI, urinary retention.

Tests Blood: U&E, creatinine. Urine: MC&S. Ultrasound (p730) is the imaging modality of choice. If there is hydronephrosis or hydroureter (distension of the renal pelvis and calyces or ureter), the next test is antegrade or retrograde ureterograms (p730): it offers a therapeutic option of drainage. NB: In ~5% of cases of obstruction, no distension is seen on ultrasound. Radionuclide imaging enables functional assessment of the kidneys. CT & MRI also have a role. Treatment Upper tract obstruction: Nephrostomy or ureteric stent. Pyeloplasty, to widen the PUJ, may be performed if obstruction is at this level. Lower tract obstruction: Urethral or suprapubic catheter (p750). Treat the underlying cause if possible. Beware of a large diuresis after relief of obstruction; a temporary salt-losing nephropathy may occur resulting in the loss of several litres of fluid a day. Monitor weight, fluid balance, and U&E closely. Peri-aortitis (retroperitoneal fibrosis et al) Causes include idiopathic retroperitoneal fibrosis (RPF), inflammatory aneurysms of the abdominal aorta, and perianeurysmal RPF. Idiopathic RPF is an autoimmune disorder, where there is B-cell and CD4(+) T-cell associated vasculitis. This results in fibrinoid necrosis of the vasa vasorum, affecting the aorta and small and medium retroperitoneal vessels. The ureters get embedded in dense, fibrous tissue resulting in progressive bilateral ureteric obstruction. Secondary causes of RPF include malignancy, typically lymphoma. Associations: Drugs (eg Ò-blockers, bromocriptine, methysergide, methyldopa), autoimmune disease (eg thyroiditis, SLE, ANCA+ve vasculitis), smoking, asbestos. Typical patient: Middle-aged ♂ with vague loin, back or abdominal pain, BP↑. Tests:

  • Blood: ↑urea and creatinine; ↑ESR; ↑CRP; anaemia.
  • Ultrasound/IVU: dilated ureters (hydronephrosis) + medial deviation of ureters.
  • CT/MRI: peri-aortic mass (this allows biopsy, to rule out malignancy).

Treatment: Retrograde stent placement to relieve obstruction ± ureterolysis (dissection of the ureters from the retroperitoneal tissue). Immunosuppression with steroids or other agents is controversial, but some studies show benefit.image13 P.287
Problems of ureteric stenting (depend on site) Common Trigonal irritation Haematuria Fever Infection Tissue inflammation Encrustation Biofilm formation Rare Obstruction Kinking Ureteric rupture Stent misplacement Stent migration (especially if made of silicone) Tissue hyperplasia

Fig 1. CT scan of retroperitoneal fibrosis (RPF), with subsequent obstruction and dilatation of the ureters (thick arrows).

Glomerulonephritis (GN) (images: p280) Features GN is a common cause of ESRF1 in adults in the UK, along with diabetes and hypertension. They are a group of disorders where there is damage to the glomerular filtrating apparatus. This causes a leak of protein ± blood into the urine, depending on the disease. Patients may be asymptomatic or present with haematuria (may be microscopic, ± red cell casts, p278), proteinuria, nephrotic syndrome, nephritic syndrome, renal failure, or hypertension. Tests Blood: FBC, U&E, LFT, ESR, CRP; immunoglobulins, electrophoresis, complement (C3, C4); autoantibodies (p539): ANA, ANCA, anti-dsDNA, anti-GBM; blood culture, ASOT, HBsAg, anti-HCV (p394). Urine: RBC casts, MC&S, Bence-Jones protein. 24h urine: protein. CXR, renal ultrasound ± renal biopsy (p280). General management ▶Refer to a nephrologist. Keep BP ≤130/80, or ≤125/75 if proteinuria >1g/d. Include an ACE-i or A2A; in a recent study, a combination of both was better in preventing progression to renal failure in proteinuria.image14 Thin basement membrane nephropathy Genetic cause, autosomal dominant: persistent microscopic haematuria, rarely minor proteinuria. Diagnosis: Renal biopsy: thin glomerular BM on electron microscopy (EM). Prognosis: Usually benign. Small risk of CRF, preceded by ↑BP and proteinuria—monitor 1-2 yearly. Minimal change glomerulonephritis (MCGN) Commonest cause of nephrotic syndrome in children (76%, and 20% of nephrotic adults), and is thought to be T-lymphocyte mediated. May also present with haematuria or ↑BP. Associations: Hodgkin’s lymphoma, drugs. Tests: Selective proteinuria: only smaller proteins leaked eg albumin. Renal biopsy: Normal on light microscopy (hence the name); EM: fusion of podocytes. [prescription take]: 95% of children and 70% of adults undergo remission with corticosteroids, but are prone to relapse. Cyclophosphamide or ciclosporin are used if frequent relapses or steroid SE/dependence. Prognosis: ~1% → ESRF. Membranous nephropathy Accounts for 20-30% of nephrotic syndrome in adults; 2-5% in children. Unknown cause. Associations: Malignancy, drugs (gold, penicillamine, captopril), autoimmune (RA, SLE, thyroid disease), infections (HBV, syphilis, leprosy, filiariasis). Presentations: Usually nephrotic syndrome. Risk of renal vein thrombosis (p290). Diagnosis: Biopsy shows diffuse thickened glomerular BM: IF shows IgG and C3 subepithelial deposits. [prescription take]: Corticosteroids with cyclophosphamide or chlorambucil are used if renal function deteriorates. Prognosis: If untreated ~40% have spontaneous remission—treatment is based on poor prognostic factors: ie deteriorating renal function, heavy proteinuria. Focal segmental glomerulosclerosis (FSGS) may be primary (idiopathic) or secondary (reflux or IgA nephropathy, Alport’s syndrome, vasculitis (p542), sickle-cell disease, heroin use). HIV is associated with a subtype. Presentations: Usually nephrotic syndrome or proteinuria. ~50% have impaired renal function. Renal biopsy: Some glomeruli have scarring of certain segments (ie focal sclerosis). IF (immunofluorescence): IgM and C3 deposits in affected areas. [prescription take]: Responds to corticosteroids in ~30%. Cyclophosphamide or ciclosporin are considered if steroidresistant. Prognosis: 30-50% → ESRF. There is a risk of recurrence post-renal transplant in 20-50%, which may respond to plasma exchange. IgA nephropathy (Berger’s disease) Commonest GN in the developed world. Most present with macro- or microscopic haematuria; occasionally nephritic syndrome. Typical patient: Young ♂ with episodic macroscopic haematuria, occurring a few days after URTI eg pharyngitis. Recovery is often rapid between attacks. There is overproduction of IgA, possibly due to infection, which forms immune complexes and deposits in mesangial cells. Renal biopsy: Mesangial proliferation, IF shows deposits of IgA and C3. [prescription take]: General measures. With renal impairment, immunosuppression (eg cyclophosphamide, mycophenolate) may be used, although P.289
benefit is unclear. Prognosis: Worse if ↑BP, male, proteinuria or renal failure at presentation. 20% of adults develop ESRF over ~20yrs. Henoch-Schönlein purpura (HSP) is a systemic variant of IgA nephropathy, causing a small vessel vasculitis. Features: Purpuric rash on extensor surfaces (typically on the legs), flitting polyarthritis, abdominal colic and GN. Diagnosis: Usually clinical. Confirmed with positive IF for IgA and C3 in skin or renal biopsy (identical to IgA nephropathy). [prescription take]: As IgA nephropathy. Prognosis: 15% nephritic patients ↑ ESRF; if both nephritic & nephrotic syndrome, 50% ↑ESRF. Proliferative GN is classified histologically: focal, diffuse, or mesangiocapillary GN. The chief cause is post-streptococcal GN (a diffuse proliferative GN), occurring 1-12 weeks after a sore throat or skin infection. A streptococcal antigen is deposited on the glomerulus, causing a host reaction and immune complex formation. Presentation: Usually nephritic syndrome. Renal biopsy: Inflammatory reaction affecting mesangial and endothelial cells, IF: IgG and C3 deposits. Serology: ↑ASOT; ↓C3. [prescription take]: Supportive: >95% recover renal function. Mesangiocapillary GN A rare GN, often presenting with nephrotic syndrome, ~30% nephritic syndrome. Diagnosis: Biopsy shows large glomeruli: mesangial proliferation and thickened capillary walls ↑ ‘tramline’ appearance of a double BM. 2 types: Type I (subendothelial immune deposits): Idiopathic or seen with HCV, also endocarditis, visceral abscess, infected arteriovenous shunts, HBV. ↓C4 levels (classical complement activation); Type II (intramembranous deposits): sometimes with partial lipodystropy (gaunt facial appearance). ↓serum C3 and +ve C3 nephritic factor (alternative complement activation) Treatment: None proven of benefit so far; steroids are used in children, and use of anti-CD20 (Rituximab) therapy has been reported.image15 Prognosis: 50% develop ESRF. Rapidly progressive GN (RPGN) The most aggressive GN, with potential to cause ESRF over days. There are different causes, all have the biopsy finding of crescents affecting most glomeruli (a proliferation of parietal epithelial cells and macrophages in Bowman’s capsule). Causes: Often microscopic polyangiitis (cANCA +ve), Wegener’s granulomatosis (PANCA +ve, p706) or anti-GBM disease (Goodpasture’s disease, p692). Also seen with other causes of GN (eg IgA nephropathy), infections (eg endocarditis, shunt nephritis), or with multi-system disease (eg SLE). Clinically: Signs of renal failure. There may be features of the individual systemic disease (eg fever, malaise, myalgia, weight loss, haemoptysis). Treatment: Aggressive immunosuppression with high-dose corticosteroids and cyclophosphamide, with plasma exchange to remove existing antibodies. Prognosis: Poor if initial serum creatinine >600µmol/L. Below this, ~80% have some improvement of renal function with treatment.

Fig. 1 A normal glomerulus. Blood is filtered from the capillary lumen, through the fenestrated endothelial layer, glomerular basement membrane and the epithelial cell layer.

The nephrotic syndrome ▶If there is oedema, dipstick an MSU for protein to avoid missing this diagnosis. Definition Nephrotic syndrome is a triad of proteinuria (>3g/24h), hypoalbuminaemia (albumin <30g/L), and oedema. It was thought that protein loss caused ↓serum albumin, resulting in ↓plasma oncotic pressure and oedema. However, plasma oncotic pressure remains unchanged in nephrotic syndrome, and oedema is now thought to result from sodium retention in the extracellular compartment and molecular changes in the capillary barrier. Causes >80% are due to glomerulonephritis (GN, p288), especially minimal change GN (commonest cause in children), focal segmental glomerulosclerosis, membranous GN (commonest cause in adults), mesangiocapillary GN or proliferative GN. Also seen with DM, amyloidosis, SLE, drugs and allergies. Clinical features Ask about acute or chronic infections, drugs, allergies, systemic symptoms (vasculitis, p542; malignancy). Signs: Oedema: typically pitting and dependent (↑ with gravity). It occurs periorbitally (tissue resistance is low here), and peripherally in limbs—genital oedema, ascites and anasarca1 develop later. Hypertension may be present. Differentials: Cardiac failure (↑JVP, pulmonary oedema, mild proteinuria) or liver disease (↓albumin). Complications

  • ↑susceptibility to infection, due in part to loss of immunoglobulin in urine and also to immunosuppressive treatments. Patients are prone to cellulitis, Streptococcus infections and spontaneous bacterial peritonitis.
  • Thromboembolism (up to 40%): eg DVT/PE, renal vein thrombosis. This hypercoagulable state is partly due to ↑clotting factors & platelet abnormalities.
  • Hyperlipidaemia: ↑cholesterol and triglycerides, thought to be due to hepatic lipoprotein synthesis in response to low oncotic pressure.

Tests As for GN (p268). Also check cholesterol. Renal biopsy: Do in all adults. In children, the majority of cases are due to minimal change GN, so a course of steroids is usually tried initially. Biopsy is reserved for those whose proteinuria has not reduced after 1 month, or if features suggest another cause eg age<1yr, family history, extrarenal disease (eg arthritis, rash, anaemia), renal failure, haematuria. General measures ▶Monitor U&E, BP, fluid balance and weight regularly. The individual disease should be treated as appropriate (eg GN, see p288).

  • Salt intake should be restricted. A normal protein intake is advised.
  • In adults, diuretics are often used, eg furosemide 80-250mg/24h PO ± metolazone or spironolactone, with monitoring of U&E. Aim ~1kg/day loss.
  • In chronic nephrotic syndrome, ACE-i are proven to ↓proteinuria and slow progression of renal impairment. Some advocate combination with an A2A.image16
  • Treat infections promptly. Pneumococcal vaccinations are recommended.
  • Prophylactic heparin if immobile (adjust dose if renal impairment eg enoxaparin 20mg SC daily). Avoid prolonged bed rest.
  • Treat hypertension (p126). Proteinuria is an independent risk factor for cardiovascular disease: if >1g/24h, target BP is 125/75.image17ACE-i or A2A should be used 1st line. Address other risk factors such as smoking, exercise, diet. Persisting hyperlipidaemia should be treated with a statin (p682).

Renal vein thrombosis The hypercoagulable state in nephrotic syndrome predisposes to renal vein thrombosis, with an increased incidence noted in patients with membranous nephropathy. Other causes: Invasion by renal cell carcinoma, thrombophilia. Clinically: Often asymptomatic, but may present with loin pain, haematuria, palpable kidney, sudden deterioration in renal function (eg in known GN), or with pulmonary embolism. Diagnosis: Doppler ultrasound, CT, MRI or renal angiography (venous phase). Treatment: Anticoagulate with warfarin for 3-6 months (or until albumin >25g/L) if no contraindications. Target INR is 2-3. P.291
Acute renal failure (ARF): diagnosis Definition A significant deterioration in renal function occurring over hours or days. Clinically, there may be no symptoms or signs, but oliguria (urine volume <400mL/24h) is common. Biochemically, ARF is detected by rising plasma urea and creatinine. ARF may arise as an isolated problem; more commonly it occurs in the setting of circulatory disturbance, eg severe illness, sepsis, trauma, or surgery—or in the context of nephrotoxic drugs. Causes NB: Pre-renal failure and ATN accounts for >80%. 1 Pre-renal: Due to renal hypoperfusion eg hypovolaemia, sepsis (causing systemic vasodilatation), congestive cardiac failure, liver cirrhosis, renal artery stenosis, NSAIDs or ACE-i (these interfere with renal blood flow). 2 Intrinsic: acute tubular necrosis (ATN): this is damage to the renal tubular cells, caused by ischaemia (with causes of renal hypoperfusion as above) or nephrotoxins (see p299 for fuller list): often due to drugs (aminoglycosides, amphotericin B, tetracyclines), radiological contrast agents, uric acid crystals, haemoglobinuria (in rhabdomyolysis), or myeloma. Recovery of renal function usually occurs within weeks, although mortality remains ~50%. Others: Vascular: vasculitis, malignant hypertension, cholesterol emboli, haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura (p300); glomerulonephritis; interstitial nephritis (p298); hepatorenal syndrome. 3 Post-renal: Due to urinary tract obstruction. Assessment ▶Make sure you know about the renal effects of all drugs taken.

  • Is the renal failure acute or chronic? Suspect chronic renal failure if:
    • History of co-morbidity eg diabetes, ↑BP, signs of chronic renal failure.
    • Previously abnormal blood tests (GP records, laboratory results).
    • Small kidneys on ultrasound (<9cm), with increased echogenicity.

    The presence of anaemia, Ca2+↓ or POimage↑ may not help to distinguish ARF from CRF, as these can occur within days, but their absence suggests ARF.

  • Is there urinary tract obstruction? Obstruction should always be considered as a cause of ARF because it is reversible and prompt treatment prevents permanent renal damage. Obstruction should be suspected in patients with a single functioning kidney, or in those with history of renal stones, anuria, prostatism, or previous pelvic/retroperitoneal surgery. Examine for a palpable bladder, pelvic or abdominal masses, or an enlarged prostate.
  • Is there a rare cause of ARF?—eg glomerulonephritis. These are usually associated with haematuria or proteinuria, and warrant urgent renal referral for consideration of a renal biopsy and treatment.

Tests • Blood tests: U&E (▶▶beware K+↑), FBC, LFT, clotting, CK, ESR, CRP. Consider ABG, blood cultures, and also hepatitis serology if dialysis is considered. If the cause is unclear, consider: serum immunoglobulins, electrophoresis, complement levels (C3/C4), autoantibodies (ANA, ANCA, anti-dsDNA, anti-GBM—p288 & p539) and ASOT. • Urine: Dipstick for leucocytes, nitrite, blood, protein, glucose. Microscopy for RBC, WBC, crystals, casts. Culture and sensitivity. Chemistry: it U&E, creatinine, osmolality, Bence-Jones protein. • CXR: Pulmonary oedema? • ECG: Signs of hyperkalaemia? • Renal ultrasound: Renal size or obstruction? Distinguishing pre-renal failure and ATN



Urine Na (mmol/L)



Urine osmolarity (mosm/L)



Urine/plasma urea



Urine/plasma creatinine



Fractional Na excretion (%)



In pre-renal failure, urine is concentrated and sodium is reabsorbed by working tubular cells. This fails to happen in ATN. NB: Values are influenced by diuretics and pre-existing disease, and they do not predict prognosis.

Acute renal failure (ARF): management ▶Enlist specialist help. While awaiting this, make sure that recent U&E and urine microscopy results are to hand. Treat the treatable:

  • If shock is the cause (↓intravascular volume, below), use protocol on p779.
  • Urgent US scan (today); you must check for a palpable bladder, but its absence does not rule out obstruction.
  • Stop nephrotoxic drugs—eg NSAIDs, ACE-i, gentamicin, vancomycin, amphotericin. Stop metformin if creatinine is >150mmol/L, see p192.
  • Signs of vasculitis? Nosebleed, haematuria, rash, ESR/CRP↑? do autoantibodies.
  • Find and treat exacerbating factors: eg hypovolaemia, sepsis, BP↑↑.

NB: Assessing signs of ↓intravascular volume can be difficult: look for ↓urine volume, invisible JVP, poor tissue turgor, ↓BP, ↑pulse. When in doubt, insert a CVP line to measure the venous pressure. Signs of fluid overload: gallop rhythm on cardiac auscultation, ↑BP, ↑JVP, lung crepitations, peripheral oedema. Monitoring Consider transfer to HDU or ICU. Pulse, BP, CVP, & urine output hourly (insert a urinary catheter). Daily fluid balance + weight chart. Match input to loss (urine, vomit, diarrhoea, drains) + 500mL for insensible loss (more if T°↑).

  • Correct volume depletion with intravenous fluid—colloid, saline, or blood (only if hyperkalaemia is not a problem) as appropriate.
  • If the patient is septic, take appropriate cultures and treat empirically with antibiotics (p372). Remove any potential sources of sepsis when no longer required, eg IV or urinary catheters.
  • Re-check if any nephrotoxic drugs; adjust doses of renally excreted drugs (p295).
  • Nutrition is vital: aim for normal calorie intake (more if catabolism↑↑, eg burns, sepsis) and protein ~0.5/kg/d. If oral intake is poor, consider nasogastric nutrition early (parenteral if NGT impossible, p574).

Treat complications Hyperkalaemia may cause arrhythmias or cardiac arrest. ECG changes (in order): Tall ‘tented’ T waves; small or absent P wave; increased P-R interval; widened QRS complex; ‘sine wave’ pattern; asystole. ECG p786. [prescription take]:

  • ▶▶Intravenous calcium: 10mL of 10% calcium gluconate IV via a big vein over 2min, repeated as necessary until ECG improves. This is cardioprotective.
  • ▶▶Intravenous insulin + glucose: 10U Actrapid® insulin + 50mL 50% glucose IV over 30min. Insulin stimulates intracellular uptake of K+, lowering serum K+ by 1-2mmol/L over ~60min. Check capillary glucose ~30 minutes after giving insulin.
  • ▶▶Salbutamol 5mg nebulizer. ▶▶Consider calcium resonium, 15g/8h, p821, PO or PR to bind K+ in the gut. This works over a longer period. SE: constipation.
  • ▶▶Haemodialysis or haemofiltration is usually required if anuric.

Pulmonary oedema (p786):

  • ▶▶Sit up and give high-flow oxygen by face mask.
  • ▶▶Venous vasodilator, eg morphine 2.5mg IV (+metoclopramide 10mg IV).
  • ▶▶Furosemide 120-250mg IV over 1 hour (larger doses are needed in renal failure).
  • ▶▶If no response, urgent haemodialysis or haemofiltration is necessary.
  • ▶▶Consider continuous positive airways pressure ventilation (CPAP) therapy.
  • ▶▶Consider venesection (100-200mL) if the patient is in extremis.
  • ▶▶Intravenous nitrates also have a role (see p786).

Bleeding: Impaired haemostasis due to ↑urea may be compounded by the precipitating cause. In patients with ARF who are actively bleeding, give:

  • Fresh frozen plasma & platelets as needed—if there are clotting problems.
  • Blood transfusion to maintain Hb >10g/dL and haematocrit >30%.
  • Desmopressin (p330) to ↑factor VIII activity, normalizing bleeding time.

Indications for acute dialysis •Refractory pulmonary oedema •Persistent hyperkalaemia (K+ >7mmol/L) •Severe metabolic acidosis (pH<7.2 or base excess <10) •Uraemic encephalopathy • Uraemic pericarditis (pericardial rub). Prognosis Worse if oliguric. Mortality depends on the cause: burns (80%); trauma/surgery (60%); medical illness (30%); obstetric/poisoning (10%). P.294
Chronic renal failure (CRF) Chronic renal failure (or chronic kidney disease, CKD) is classified into 5 stages (p661). Symptoms usually only occur once stage 4 is reached (GFR <30). Endstage renal failure (ESRF) occurs when dialysis or transplant is required to prolong life. Causes Common: Glomerulonephritis, DM, renovascular disease, BP↑, pyelonephritis, polycystic disease. Also prostatic hypertrophy, interstitial nephritis, analgesic nephropathy, nephrolithiasis. Rarer: Myeloma, amyloidosis, SLE, scleroderma, vasculitis (p542), haemolytic uraemic syndrome, nephrocalcinosis, gout, renal tumour, cystinosis, oxalosis, Alport’s syndrome, Fabry’s disease (p690). History Ask about: past UTI, known ↑BP, DM, family history. Take a careful drug history. Any fatigue, weakness, anorexia, vomiting, metallic taste, pruritus, restless legs, bone pain, impotence/infertility? Symptoms are common when urea is>40mmol/L. Dyspnoea, ankle swelling (fluid overload?) Urine output? Signs: Pallor, yellow skin pigmentation, brown nails, purpura, bruising, excoriation, BP↑, cardiomegaly, pericardial rub, pleural effusion, pulmonary or peripheral oedema, proximal myopathy (+ cause eg DM: peripheral neuropathy, retinopathy). Later if untreated: arrhythmias, encephalopathy, seizures, and coma. Tests •Blood: Hb↓ (normochromic, normocytic), ESR, U&E (↑urea, ↑creatinine), glucose (DM); ↓Ca2+, ↑POimage, ↑alk phos (renal osteodystrophy); ↑PTH (hyperparathyroidism, p206). •Urine: MC&S, dipstick, urine PCI or 24h urinary protein. •Imaging: Renal ultrasound to exclude obstruction and look at renal size (usually small, eg <9cm, but may be normal or large with CRF in DM, polycystic kidney disease, amyloidosis, myeloma, systemic sclerosis, asymmetric renal vascular disease). Consider DTPA scan. CXR: Cardiomegaly, pleural/pericardial effusions or pulmonary oedema. Bone X-rays may show renal osteodystrophy. •Renal biopsy should be considered if the cause is unclear and there are normal-sized kidneys. Treatment ▶Refer early to a nephrologist. Treat reversible causes: relieve obstruction, stop nephrotoxic drugs, deal with Ca2+↑ and cardiovascular risk: in CKD stages 1 & 2, risk from cardiovascular death is higher than the risk of reaching ESRF.

  • Hypertension: Even a small BP drop may save significant renal function.image18ACE-i or A2A can ↓rate of loss of function even if BP is normal, if proteinuric, aim for BP of <130/80 (<125/75 if >1g proteinuria/d).image19Hyperlipidaemia: Statins (p682).
  • Oedema: This may require high doses of loop diuretics (eg furosemide 250mg-2g/24h ± metolazone 5-10mg/24h PO mane), and restriction on fluid intake.
  • Anaemia: Exclude iron deficiency & chronic infection; consider erythropoietin.1
  • Renal bone disease (osteodystrophy): Treat if ↑PTH. PO4 rises in CRF, which ↑PTH further, and also precipitates in the kidney and vasculature. Restrict dietary PO4 (milk, cheese, eggs). Give binders (eg Calcichew®)2 to bind POimage in the gut to ñ its absorption. Vit. D analogues (eg alfacalcidol=1α-hydroxycholecalciferol)3 & Ca2+ supplements ↓bone disease and hyperparathyroidism (2° & 3°, p206).
  • Diet: Match dietary and fluid intake with excretion. Na+ restriction: helps control BP and prevent oedema. A moderate protein diet is recommended. K+ restriction only if hyperkalaemia; HCOimage supplements to correct acidosis.
  • Restless legs: Clonazepam (0.5mg-2mg daily) or gabapentin (p496) may help.
  • Prepare for dialysis/transplantation: See p296.


Fig 1. Plot of reciprocal plasma creatinine (µmol/L) against time in a patient with adult polycystic kidney disease. The letters represent life events: (a) work promotion, (b) arterio-venous fistula, and (c) haemodialysis. Some patients with CRF lose renal function at a constant rate. Creatinine is made at a fairly constant rate and rises on a hyperbolic curve as renal function declines, so the reciprocal creatinine plot is a straight line, parallel to the fall in GFR. This is used to monitor renal function and to predict need for dialysis—but there is much individual variation in progression, so the plot is of limited use.image20 Rapid decline in renal function greater than that expected may be due to: infection, dehydration, uncontrolled ↑BP, metabolic disturbance (eg Ca2+↑), obstruction, nephrotoxins (eg drugs). Intervention at this point may delay ESRF. Background decline may be retardable by using ACE-i ± A2A (angiotensin-II antagonists). In the COOPERATE randomized prospective trial (over 3yrs) in non-diabetic renal disease, the NNT was ~9 for preventing one case of ESRF (or a doubling of plasma creatinine) by adding losartan (100mg/d) to trandolapril (3mg/d)—ie 11% progressed rather than 23% on ACE-i alone.image21

3 Alfacalcidol & calcitriol (=1,25-dihydroxycholecalciferol) help by ↓parathyroid hormone, but greatly ↑ intestinal Ca2+ & POimage absorption and bone mineral mobilization, leading to POimage ↑ & Ca2+↑ (risks vascular calcification). New vit. D analogues (eg paricalcitol weekly IVimage) retain suppressive action on PTH & gland growth, but have less effect on Ca2+ & PO4 absorption, and help cardiovascular status.image Prescribing in renal failure Relate dose modification to GFR, and the extent to which a drug is renally excreted. This is significant for aminoglycosides (gentamicin, p738), cephalosporins, and a few other antibiotics (p368, p369, p370, p371), heparin, lithium, opiates, and digoxin. ▶Never prescribe in renal failure before checking how its administration should be altered. Loading doses (eg digoxin) should not be changed. If the patient is on dialysis (peritoneal or haemodialysis), dose modification depends on how well it is eliminated by dialysis. Consult the drug’s Data Sheet or the pharmacist. Dosing should be timed around dialysis. Nephrotoxic drugs: Reduce the dose (the dose adjustment factor, DAF, reflects the fraction excreted unchanged in the urine—F). DAF = 1/(F (kf – 1) + 1), where the kf is the relative kidney function = creatinine clearance/120. The usual dose (but not the loading dose) should be divided by the DAF. In only a few drugs is F big enough to be important, as below.

















Renal replacement therapy Optimal timing to start dialysis is widely debated; guidelines suggest starting when GFR <15mL/min with symptoms.image22Early psychological preparation is vital. Medical preparation involves Hep B vaccination and creating an arteriovenous fistula (p307) for haemodialysis, or inserting a Tenchkoff catheter for peritoneal dialysis. Choice of haemo- vs peritoneal dialysis depends on medical, social,1 and psychological factors. Mortality was higher in peritoneal vs haemodialysis in one study: more are needed.image23NB: Kidney function is only partly replaced by dialysis. Haemodialysis (HD) Blood flows on one side of a semi-permeable membrane while dialysis fluid flows in the opposite direction on the other side. Solute transfer occurs by diffusion. Ultrafiltration is the removal of excess fluid by creating -ve transmembrane pressure. Problems: • Disequilibration syndrome2•BP↓/arrhythmias •Time consuming •Access: fistula: thrombosis, stenosis, aneurysm, steal syndrome, ischaemia or temporary line: infection, blockage. Haemofiltration Blood is filtered continuously across a highly permeable synthetic membrane, allowing removal of waste products by a process of convection (not diffusion). The ultrafiltrate is substituted with an equal volume of replacement fluid. It is more expensive and takes longer than HD, but there is less haemodynamic instability and so is used for critically ill patients. Peritoneal dialysis (PD) is simple to perform, requires less complex equipment than haemodialysis and is easier at home. It is useful in children, the elderly, and in those with cardiovascular disease. PD fluid is introduced into the peritoneal cavity via a Tenchkoff catheter and uraemic solutes diffuse into it across the peritoneal membrane. Ultrafiltration is achieved by adding osmotic agents, eg glucose to the dialysis fluid. Problems: •Peritonitis (60% Staphylococci, 20% Gram -ve organisms, <5% fungi) •Exit-site infection •Catheter malfunction •Loss of membrane function. •Obesity (glucose in dialysis fluid) •Hernias •Back pain. Continuous ambulatory peritoneal dialysis (CAPD) uses the smallest daily volume of dialysate fluid to prevent uraemia. 2L bags are changed 3-5 times a day to produce, with ultrafiltration, a total dialysate of 10L. Automated peritoneal dialysis uses a cycler machine to enhance solute and fluid removal. Techniques include continuous cyclic peritoneal dialysis (CCPD), intermittent peritoneal dialysis (IPD), night intermittent peritoneal dialysis (NIPD), and tidal intermittent peritoneal dialysis (TIPD). Complications of dialysis Cardiovascular disease, eg IHD, cardiac failure and stroke are much more common in dialysis patients and are a major cause of mortality. Hypertension persists in 25-30% of patients on haemodialysis. Anaemia is common and is treated with erythropoietin (± haematinic supplements). Bleeding tendency is due to platelet dysfunction. Acute bleeding is treated with desmopressin and transfusion, as necessary. Renal bone disease is treated with dietary modification, alfacalcidol, Ca2+ supplements, and phosphate binders (p294). Infection may be due to non-sterility in peritoneal dialysis or intravascular lines in haemodialysis. Ò2- microglobulin amyloidosis is due to amyloid which accumulates in long-term dialysis patients: it may cause carpal tunnel syndrome, arthralgia, and fractures. Acquired renal cysts occur years after dialysis and may present with haematuria or malignant transformation. Malignancy is commoner in dialysis patients; this may be related to the cause, eg urothelial tumours in analgesic nephropathy. Stopping dialysis Dialysis exerts a big toll on quality of life, and it may all become too much for patients, eg if very oldimage24 or there is co-morbidity (eg psychiatric or mobility issues).1 8-20% of deaths in dialysis patients are due to its withdrawal.image25 ▶Good palliation allows a good death and mitigates discomfort caused by uraemia: •Respiratory distress: morphine •Myoclonic jerks: clonazepam •Hallucinations: haloperidol ± midazolam •Secretions: hyoscine. Doses: p438. Good communication in the renal team, well-rehearsed protocols, and advance directives (living wills) help the big ethical dilemma.image26 P.297
Renal transplantation This is the treatment of choice for end stage renal failure (ESRF). Each patient requires careful assessment and consideration of the advantages and disadvantages of dialysis vs transplantation. Assessment Note the following: Virology status: CMV, Hepatitis B & C, HIV: these may cause severe disease while immunocompromised. Note if there is existing urine output, and cardiovascular disease. Previous TB may reactivate so isoniazid and pyridoxine prophylaxis is given to proven cases and high risk groups.

  • ABO blood group and tissue typing for HLA is required.
  • Make sure pre-op potassium is ¢5. If above, dialysis may be needed.

Contraindications Active infection, Ca, severe heart disease or co-morbidity. Types of graft >6000 are waiting in the UK, often in vain, for a transplant. Cadaveric donor grafts are obtained from a brainstem dead donor with supported circulation and ventilation. Non-heart beating donor grafts are retrieved from patients without an active circulation, and hence rapid retrieval is needed to minimise ischaemia. Success rates from these is approaching that of cadaveric grafts. Living related donor (LRD) grafts offer the advantages of an optimally timed surgical procedure, HLA haplotype matching, and improved graft survival. Live unrelated donation has become increasingly common, between spouses or friends who satisfy the complex rules of ULTRA.3 Consent is problematic: p251. Immunosuppressants Most regimes involve 1 ciclosporin or tacrolimus, 2 azathioprine or mycophenolate ± 3 prednisolone. Pre-op anti-interleukin 2 receptor antibodies (eg basiliximab) reduce rates of early rejection.image27 Complications Post-op: Bleed, thrombosis, infection, urinary leaks, oliguria. Acute rejection: (<6 months) This is characterized by rising serum creatinine ± fever and graft pain. Graft biopsy shows an immune cell infiltrate and tubular damage. [prescription take]: High-dose IV methylprednisolone. Resistant cases require antithymocyte globulin (ATG). Chronic rejection: (>6 months) Presents with a gradual rise in serum creatinine and proteinuria. Graft biopsy shows vascular changes, fibrosis, and tubular atrophy. It is not responsive to ↑immunosuppression. Ciclosporin/tacrolimus toxicity: Acute: afferent arteriole vasoconstriction, causing ↓renal blood flow and ↓GFR. Chronic: tubular atrophy and fibrosis. Infection: Often community acquired infections or those related to ↓T-cell immunity (Á immunosuppression), eg skin infections (fungi, warts, HSV, zoster) and opportunists (TB, fungi, Pneumocystis carinii pneumonia, CMV). Malignancy: Immunosuppression causes ↑risk of neoplasia 5-fold and ↑ infection with viruses of malignant potential (EBV, HBV, HHV-8: p694). Typical tumours: skin (basal & squamous) Ca, lymphoma (EBV-related), anogenital Ca. Atheromatous vascular disease: This is commoner in transplant patients than in the general population and is a leading cause of death. Hypertension: This occurs in >50% of transplant patients and may be due to diseased native kidneys, immunosuppressant drugs or dysfunction in the graft. Management is along standard lines (p126). Prognosis 1yr graft survival: HLA identical 95%; 1 mismatch 90-95%; complete mismatch 75-80%. Average half-life of cadaveric grafts is ~10yrs, 20yrs for HLA-identical living related donor grafts—this is increasing. P.298
Interstitial nephritides and nephrotoxins Tubulointerstitial nephritis: Inflammation of the renal interstitium may be acute or chronic. Acute tubulointerstitial nephritis is mediated by an immune reaction to medications, infections and other causes. Drugs: NSAIDs, antibiotics: cephalosporins, penicillins, sulphonamides, rifampicin; diuretics: furosemide, thiazides; also allopurinol, cimetidine, amphotericin; infections: Staphylococci, Streptococci, Brucella, Leptospira, hantaviruses; immune disorders eg SLE, glomerulonephritis— or no obvious cause. Features: May present with renal impairment, hypertension, or acute renal failure. Systemic symptoms eg fever, rash, arthralgia, with eosinophilia, uveitis, and ↑IgE. Diagnosis: Renal biopsy: infiltration of the renal interstitium and tubules with T lymphocytes, macrophages, and plasma cells. Urinary eosinophils may be seen. Treatment: Stop any cause. ARF: p293. Prednisolone 1mg/kg is used, but has not been studied in a randomised trial. Prognosis: Most have full recovery of renal function. Chronic tubulointerstitial nephritis results from many disorders, leading to extensive fibrosis and tubular loss on renal biopsy. Patients present with chronic renal failure. Causes: chronic pyelonephritis often with reflux nephropathy, sickle cell disease, lead or cadmium intoxication. Balkan nephropathy is a form of chronic tubulointerstitial nephritis causing progressive renal impairment to ESRF. It is endemic in areas along the River Danube. Environmental and genetic factors are thought to be important. Features: coppery-yellow pigmentation of the palms and soles, Ò2-microglobinuria. There is an ↑ risk of urothelial tumours, reported in up to 40%.image28 Analgesic nephropathy is associated with the prolonged, heavy ingestion of compound analgesics, especially those containing caffeine (as it leads to habituation), NSAIDs, paracetamol, and phenacetin (now withdrawn), leading to interstitial nephritis and papillary necrosis. There is often a history of chronic pain. Signs: Presents with sterile pyuria, UTI, or symptoms of chronic renal failure, or hypertension. Renal colic and haematuria can result from a sloughed papilla. Tests: IVU demonstrates papillary necrosis. CT may also be used. Biopsy shows chronic interstitial nephritis. Treatment: Stop analgesics, antibiotics for infection. Sudden flank pain should prompt an ultrasound or IVU to look for obstruction from a sloughed papilla. There is an ↑ risk of urothelial tumours. Urate nephropathy Acute crystal nephropathy occurs when insoluble uric acid crystals deposit causing blockage of the tubules. It is mainly caused by excess uric acid released during cell lysis in chemotherapy eg in myeloid tumours. The renal parenchyma appears bright on ultrasound. Plasma urate is often markedly raised ± urinary birefringent crystals on microscopy (p351, fig 1). Treatment: p336: keep well hydrated, allopurinol pre-chemotherapy, urinary alkalinization with sodium bicarbonate (as uric acid is more soluble in alkaline urine). Chronic urate nephropathy: Whether chronic hyperuricaemia (eg with gout) leads to renal failure is debated. This does, however, occur in Lesch-Nyhan syndrome1. Treatment: allopurinol (↓dose in renal impairment). Uric acid calculi, see p284. Hypercalcaemia is associated with the following renal diseases: nephrogenic diabetes insipidus (p224), renal calculi (p284) and nephrocalcinosis: diffuse renal parenchymal calcification, often asymptomatic, causing progressive renal impairment. Nephrocalcinosis is seen in hypercalcaemia (eg malignancy, hyperparathyroidism, myeloma, sarcoidosis, vitamin D intoxication) or type 1 renal tubular acidosis. Tests: AXR for renal calculi/nephrocalcinosis. [prescription take]: Treat cause. Radiation nephritis is renal impairment following radiotherapy and occurs acutely (<1 year) or chronic (years later). Signs: Hypertension, proteinuria, progression to chronic renal failure. Biopsy shows interstitial fibrosis. [prescription take]: Strict BP control, nil specific. Prevention: Exclusion of renal areas during radiotherapy. P.299
Nephrotoxins Many agents may be toxic to the kidneys and cause acute renal failure (ARF), usually by direct acute tubular necrosis, or by causing interstitial nephritis. Exogenous nephrotoxins include:

  • Analgesics (NSAIDs).
  • Antimicrobials (gentamicin, sulphonamides, tetracycline, vancomycin, amphotericin, aciclovir).
  • Radio-contrast media (see below).
  • Anaesthetic agents (methoxyflurane, enflurane).
  • Chemotherapeutic agents (cisplatin).
  • ACE-i and A2As (angiotensin II receptor antagonists).
  • Immunosuppressants (ciclosporin, methotrexate).
  • Heavy metal poisoning (mercury, lead, cadmium, arsenic, bismuth).
  • Organic solvents (ethylene glycol, carbon tetrachloride).
  • Insecticides, herbicides, Amanita mushrooms, snake venom.

Endogenous nephrotoxins include:

  • Pigments: eg haemoglobinuria in haemolysis: p322, myoglobin—see below.
  • Crystals: eg urate.
  • Proteins: eg immunoglobulin light chains in myeloma.

Aminoglycosides (gentamicin, amikacin, kanamycin and streptomycin) are well-recognized nephrotoxins. The typical picture is of mild non-oliguric renal failure, 1-2wks into therapy. Risk is increased by old age, renal hypoperfusion, pre-existing renal impairment, high dosage or prolonged treatment, and coadministration of other nephrotoxic drugs. Recovery may be delayed or incomplete. Single bolus doses of aminoglycosides can be as effective as multiple doses in treating infection and less nephrotoxic. Radiocontrast nephropathy is a very common cause of iatrogenic ARF with IV contrast radiological studies. Risk factors are diabetes mellitus, high doses of contrast medium, hypovolaemia, other nephrotoxic agents, and pre-existing renal impairment. Prevention is key: stop nephrotoxic agents peri-procedure, and pre-hydrate with IV 0.9% sodium chloride in patients with risk factors. Acetylcysteine or IV sodium bicarbonate may be used ▶follow local protocols, and inform radiology, who may use less nephrotoxic contrast. Rhabdomyolysis This results from skeletal muscle breakdown, with release of its contents into the circulation, including myoglobin, potassium, phosphate, urate and creatinine kinase (CK). Complications include hyperkalaemia and ARF: myoglobin is filtered by the glomeruli and precipitates, obstructing renal tubules. Causes: Many, including trauma: prolonged immobilisation (eg after falling), burns, crush injury, excessive exercise, uncontrolled seizures; drugs and toxins: statins, fibrates, alcohol, ecstasy, heroin, snake bite, carbon monoxide, neuroleptic malignant syndrome (p827); infections: coxsackie, EBV, influenza; metabolic: K+↓, POimage ↓, myositis, malignant hyperpyrexia (p558); inherited muscle disorders: McArdle’s disease (p696), Duchenne’s muscular dystrophy (p502). Clinical features: Often of the cause, with muscle pain, swelling, tenderness, and red-brown urine. Tests: Blood tests show a raised CK >1000iU/L (often >10000iU/L). Dark urine is +ve for blood on dipstick but without RBCs on microscopy. Confirmed by +ve urinary myoglobin. Others: K+↑, PO4 3-↑↑, Ca2+↓ (enters muscle), urate↑. ARF occurs 12-24 hours later, and disseminated intravascular coagulation is associated (p336). Compartment syndrome can result from muscle injury. Treatment: Urgent treatment for hyperkalaemia (p821). IV fluid rehydration is a priority to prevent ARF: maintain urine output at 300mL/h until myoglobinuria has ceased, initially up to 1.5L fluid/h may be needed. If oliguric, CVP monitoring is useful to prevent fluid overload. IV sodium bicarbonate is used to alkalinize urine to pH >6.5, to stabilise a less toxic form of myoglobin. Dialysis may be needed, but full renal recovery is likely. P.300
Renal vascular disease Hypertension may be a cause or consequence of renal disease. Essential hypertension (p124) The extent to which renal impairment develops in mild-moderate hypertension is debated. Accelerated (malignant) hypertension is characterized by a severe increase in BP, grade III or IV hypertensive retinopathy (p544) and renal failure. Â: p124. Pre-eclampsia: OHCS p48. ↑BP + proteinuria + oedema in 2nd/3rd trimester. Proteinuria is due to glomerular endothelial cell swelling. ARF may result. Renal diseases causing hypertension are the commonest cause of secondary hypertension. Most renal diseases are associated with ↑BP; commonly: diabetic nephropathy, glomerulonephritis, chronic interstitial nephritis, polycystic kidneys or renovascular disease. Renovascular disease This is stenosis of the renal artery or one of its branches. Causes: Atherosclerosis (in 80%: >50yrs, arteriopaths: often co-existent IHD, stroke or PVD), fibromuscular dysplasia (10%, younger ý). Rarer: Takayasu’s arteritis, antiphospholipid syndrome, post-renal transplant, thromboembolism, external mass compression. Clinically: ↑BP resistant to treatment; worsening renal function after ACE-i/A2A; ‘flash’ pulmonary oedema: sudden onset, without LV impairment on cardiac echo. Abdominal ± carotid or femoral bruits, and weak leg pulses may be found. Tests: Ultrasound: renal size asymmetry (affected side is smaller), disturbance in renal blood flow on Doppler ultrasound. CT/MR angiography are more sensitive. Renal angiography is ‘gold standard’, but done after CT/MR as it is invasive. See p731. [prescription take]: Percutaneous renal angioplasty ± stent, or revascularisation surgery. Long-term benefits of each are under study. Haemolytic uraemic syndrome (HUS) is characterised by microangiopathic haemolytic anaemia (MAHA): intravascular haemolysis + red cell fragmentation. Endothelial damage triggers thrombosis, platelet consumption and fibrin strand deposition, mainly in the renal microvasculature. The strands cause mechanical destruction of passing red blood cells. Thrombocytopenia and ARF result. Causes: 90% due to E. coli 0157: produces a verotoxin which attacks endothelial cells. This affects young children most, often occurring in outbreaks due to consumption of undercooked contaminated meat, with abdominal pain, bloody diarrhoea and ARF. Rarely sporadic. Tests: Blood film: fragmented RBC (schistocytes, p322). ↓platelets, ↓Hb. Clotting tests are normal. There may be haematuria/proteinuria. [prescription take]: Seek expert advice. Often resolves spontaneously. Dialysis for ARF may be needed. Plasma exchange is used in severe persistent disease. Prognosis: Worse in non-E. Coli cases. Mortality 3-5%. Thrombotic thrombocytopenic purpura (TTP) is a pentad of: 1 Fever 2 Fluctuating CNS signs (eg fits, hemiparesis, ↓consciousness, ↓vision) 3 MAHA (severe, often with jaundice) 4 Thrombocytopenia (severe, often mucosal bleeding) 5 Renal failure. Also: haematuria or proteinuria. Adult ♀ are chiefly affected, mortality is higher than HUS. There is a genetic or acquired deficiency of a protease which normally cleaves multimers of von Willebrand factor (vWf). Large vWf multimers form, causing platelet aggregation and fibrin deposition in small vessels, leading to microthrombi. Causes: Often unknown: drugs (eg clopidogrel, ciclosporin), pregnancy, HIV, SLE. ▶It is a haematological emergency: get expert help. Tests: As HUS. [prescription take]: Urgent plasma exchange may be life-saving. Steroids,image29 IV vincristineimage30 and splenectomy have roles in non-responders.image31 Cholesterol emboli may be released from atheromatous plaques (often aorta) which lodge in the distal microcirculation (eg renal vessels, peripheral circulation, GIT) to cause ischaemia. An inflammatory response leads to fever, myalgia and ↑eosinophils. Risks: Atheroma, ↑cholesterol, aortic aneurysm, thrombolysis, arterial catheterisation eg during interventional radiological procedures. Signs: Livedo reticularis (p542), gangrene, GI bleeds, renal failure. [prescription take]: Statins are tried (p682); avoid anticoagulants and instrumentation. Prognosis: Often progressive and fatal; some regain renal function after dialysis. P.301
Diabetes mellitus (type 2) and the kidney Diabetes is best viewed as a vascular disease—with the kidney as one of its chief targets for end-organ damage. The single most important intervention in the long-term care of DM is the control of BP, to protect the heart, the brain, and the kidney. Renal damage may be preventable. ▶Everyone with type 2 DM should be tested regularly (6-monthly) for microalbuminuria (30-300mg albumin excreted per day). A convenient way to do this test is to look for an early-morning urine (EMU) albumin:creatinine ratio of >3 (using EMUs improves consistency). Microalbuminuria gives early warning of impending renal problems and is also a strong independent risk factor for cardiovascular disease. Those who are positive should be started on an ACE-i (p123) or angiotensin-2 receptor antagonists (A2A), irrespective of blood pressure. Examples of A2A doses: irbesartan 150-300mg/24h PO or losartan 50mg/d PO; increase after 1 month to 100mg daily. SE: U&E↑ (monitor K+ & creatinine periodically, stop if there is a rise in creatinine of >20%), flushing, myalgia, headaches, dyspepsia, cough (although commoner with ACE-i). Usually, ACE-i are first-line and ARAs for ACE-i intolerant individuals. Increasingly they may be combined.image32 ▶Example of target BP in DM if no proteinuria: 140/80 (negotiate with patient; ensure he/she is well informed); if microalbuminuria/proteinuria is present, aim: 125/75mmHg. Do targets work? Target-driven, long-term, intense therapy (including prophylactic aspirin) revolving around microalbuminuria and other risk factors can halve risk of macro- and microvascular events (MI etc.).image33Steno-2N=180; 2003 Is microalbuminuria reversible? Answer: sometimes—and more likely if: •Recent onset •HbA1c <8% •Systolic <115mmHg •Cholesterol <5mmol/L.1

Fig 1. Thrombi in small arterioles due to fibrin and platelet deposition, characteristic of TTP.image34

Renal tubular disease Renal tubular acidosis (RTA) is a metabolic acidosis, due to impaired acid secretion by the kidney. There is a hyperchloraemic metabolic acidosis with normal anion gap (p658). Type 3 RTA is a rare combination of Types 1 & 2.

  • Type 1 (distal) RTA is due to an inability to excrete H+ and generate acidic urine in the distal tubule, even in states of metabolic acidosis. It may complicate many renal disorders. Features include rickets (+ growth failure) or osteomalacia, due to buffering of H+ with calcium in bone. Nephrocalcinosis with renal calculi, leading to recurrent UTIs, is due to a combination of hypercalciuria (from bone), ↓urinary citrate (reabsorbed as a buffer for H+) and alkaline urine: all favour calcium phosphate stone formation. Diagnosis: Acid load: oral ammonium chloride load is given—there is failure to lower urine pH <5.5. Treatment: Oral sodium bicarbonate or citrate. Complications are from renal calculi—end-stage renal failure may result from unrecognised obstruction.
  • Type 2 (proximal) RTA is due to a ‘bicarbonate leak’: a defect in HCO3 reabsorption in the proximal tubule resulting in excess HCO3 in the urine. The tubules are able to reabsorb some HCO3, so urine can acidify during systemic acidosis. Type 2 RTA is often associated with a more generalised tubular defect (Fanconi syndrome, below), and is rarer than Type 1. Hypokalaemia is common, due to the osmotic diuretic effect of ↓HCO3 reabsorption, causing ↑flow rate to distal tubule ∴ ↑K+ excretion. Diagnosis: IV sodium bicarbonate load: there is a high fractional excretion of HCO3 (>15%). Treatment: High doses of bicarbonate (≥10mmol/kg/d) are required (this is often intolerable).
  • Type 4 (hyperkalaemic) RTA is due to “hyporeninaemic hypoaldosteronism”. Hypoaldosteronism causes hyperkalaemia and acidosis (↓K+ and H+ excretion). Causes: Mild renal impairment (eg with tubulointerstitial disease or DM), hypoadrenalism or drugs (K+ sparing diuretics, NSAIDs, ACE-i/A2A). Treatment: Remove any cause. Fludrocortisone 0.1mg PO, furosemide or calcium resonium are used to control hyperkalaemia.

Fanconi syndrome The proximal tubule is responsible for reabsorption of many solutes, including 50% of filtered sodium, most bicarbonate and all filtered glucose and amino acids. Fanconi syndrome is a disturbance of proximal tubule function, with defective reabsorption of amino acids, K+, phosphate (leading to hypophosphataemic rickets and osteomalacia), glucose (glycosuria) and bicarbonate (Type 2 RTA: above). Also, there is polyuria (due to osmotic diuresis), and hypokalaemia (↑Na delivery to distal tubules leads to ↑exchange). Causes: Idiopathic Fanconi syndrome: No identifiable cause. Mostly sporadic, some inherited. Features: dehydration, failure to thrive. Vitamin D resistant rickets is typical. There may be progressive renal failure in early adulthood. Inherited: Errors of metabolism eg cystinosis (below), fructose intolerance, galactosaemia, glycogen storage disease, Wilson’s disease (p257), Lowe’s syndrome,1 tyrosinaemia. Acquired: Tubule damage eg heavy metals (lead, mercury, cadmium, platinum, uranium), drugs (outof-date tetracycline, iphosphamide), light chains (myeloma, amyloidosis), immunological (interstitial nephritis, transplant rejection). [prescription take]: Remove any cause and replace losses. K+, sodium bicarbonate, POimage and vitamin D supplements are used. Cystinosis There is accumulation of cystine in lysosomes due to an autosomal recessive defect. Cystine deposits cause Fanconi syndrome, visual impairment and hypothyroidism, with progression to ESRF <10yrs. [prescription take]: As Fanconi syndrome. Oral cysteamine ↓intralysosomal cystine and delays ESRF, but is poorly tolerated. Renal cystinosis does not recur after transplant; extra-renal disease progresses. Hereditary hypokalaemic tubulopathies Bartter’s syndrome: p212; Gitelman syndrome: ↓Na+Cl reabsorption at the distal tubule due to an autosomal recessive mutation, causing ↑solute loss, and ↑K+ loss due to 2° hyperaldosteronism. Also hypocalciuria and hypomagnesaemia. Nephrogenic diabetes insipidus p224. P.303
Causes of renal tubular acidosis Type 1 (distal)

  • Idiopathic.
  • Genetic (eg Marfan’s, Ehlers-Danlos syndrome).
  • Autoimmune disease (eg SLE, Sjögren’s, autoimmune hepatitis).
  • Nephrocalcinosis (eg hypercalcaemia, medullary sponge kidney).
  • Tubulointerstitial disease (eg chronic pyelonephritis, chronic interstitial nephritis, obstructive uropathy, renal transplant rejection).
  • Drugs (eg lithium, amphotericin).

Type 2 (proximal)

  • Idiopathic.
  • Fanconi syndrome.
  • Tubulointerstitial disease (eg myeloma, interstitial nephritis).
  • Drugs (eg lead or other heavy metals, acetazolamide, out of date tetracycline).
Fig 1. Cystine crystals in the bone marrow, found in cystinosis. Crystals accumulate in most tissues, especially the kidneys.image35

Inherited kidney diseases Autosomal dominant polycystic kidney disease (ADPKD) Prevalence: 1:1000. Genes on chromosomes 16 (PKD1) and 4 (PKD2). Signs: Renal enlargement with cysts, abdominal pain ± haematuria (haemorrhage into a cyst), cyst infection, renal calculi, BP↑, progressive renal failure. Extrarenal: liver cysts, intracranial aneurysm→subarachnoid haemorrhage (SAH), mitral valve prolapse. Treatment: Monitor U&E. Treating ↑BP is important to prevent cardiovascular complications and SAH. Treat infections, dialysis or transplantation for ESRF, genetic counselling. Pain may be helped by laparoscopic cyst removal or nephrectomy. Screening for SAH with magnetic resonance angiography may be done in 1st-degree relatives of those with SAH + ADPKD. Some screen with no family history. Autosomal recessive polycystic kidney disease OHCS p132. Prevalence 1:40,000, chromosome 6. Signs: Infancy: renal cysts, congenital hepatic fibrosis. Medullary cystic disease Inherited disorder with tubular loss and medullary cyst formation. The juvenile (autosomal recessive) form accounts for 10-20% of ESRF in children. The adult form (autosomal dominant; restricted to the kidney) is rare. Signs: Polyuria, polydipsia, enuresis (↓urine concentrating ability), failure to thrive, renal impairment → ESRF. Extrarenal: include retinal degeneration, retinitis pigmentosa, skeletal changes, cerebellar ataxia, liver fibrosis. Renal phakomatoses (neuroectodermal syndromes). Tuberous sclerosis: OHCS p638. A complex autosomal dominant disorder with hamartoma formation in skin, brain, eye, kidney, and heart caused by genes on chromosomes 9 (TSC1) & 16 (TSC2). Signs are variable: •Skin: adenoma sebaceum, angiofibromas, ‘ash leaf’ hypomelanic macules, shagreen patches (sacral plaques of shark-like skin), periungual fibroma •IQ↓ •Epilepsy. Von Hippel-Lindau syndrome (p704) is the chief cause of inherited renal cancers. Cause: Germline mutations of the VHL tumour-suppressor gene (also inactivated in most sporadic renal cell cancers).image36 Alport’s syndrome OHCS p638. Prevalence: 1:5000. Variable inheritance (mainly expressed in ♂: 85% are X-linked). The affected genes code for type IV collagen molecules.image37 Pathology: Thickened GBM with ‘splitting’. The Goodpasture’s antigen is missing (hence risk of anti-GBM glomerulonephritis post-renal transplant). Signs: Haematuric nephritis, sensorineural deafness, and progressive renal failure. Some have lenticonus: bulging of lens capsule seen on slit-lamp examination. [prescription take]: None specific, as for renal failure. Fabry’s disease See p690. Hyperoxaluria Primary hyperoxaluria is an autosomal recessive inherited error of metabolism due to an enzyme defect. Secondary hyperoxaluria is due to •↑intake eg rhubarb, spinach, tea •↑intestinal reabsorption due to ileal disease (Crohn’s, ileal bypass), short bowel syndrome, low Ca2+ intake. Signs: Oxalate renal stones (p284), nephrocalcinosis, progressive renal failure, cardiac conduction defects, arterial disease (oxalate crystallisation), osteodystrophy. Treatment: High fluid intake to prevent calculi (keep urine output ~3L/day), ↓dietary oxalate, calcium supplements (binds oxalate in the gut so ↓absorption). If these do not work, pyridoxine (vitamin B6) is used to ↓endogenous oxalate production (SE: peripheral neuropathy in high doses). Magnesium or cholestyramine are also used to ↓oxalate absorption. Hepatic transplantation may be curative in primary hyperoxaluria, and may be combined with renal transplant. Cystinuria The commonest aminoaciduria, causing ↓tubular reabsorption of the dibasic amino acids COAL Cystine, Ornithine, Arginine and Lysine, due to an autosomal recessive defect. Features: Manifests with cystine renal stones (p284). Treatment: ↑Fluid intake to keep urine output ~3L/day; urine alkalinization with potassium citrate (↑solubility of cystine). Penicillamine is used, which binds cystine in soluble complexes. NB: Do not confuse this condition with cystinosis where there are no stones (p302). P.305
Genetics: triumphs and disasters As soon as genetics solves one problem, others appear. You might think that the application of science to medicine is an undisputed boon. Petty has provided a compelling counter-example.image38 A man with adult polycystic kidney disease due to a PKD1 mutation is in end-stage renal failure. A transplant from a matched, living, related, unaffected donor is highly desired. There are problems in his family, but he persuades his adult children to have genetic testing to see if there are eligible donors. Each is apparently happy to donate a kidney to his/her father. A can of worms is opened when one son realizes that he is the only child who can offer a good match—and that his brother is carrying the same mutation as his estranged father (there is a 50:50 chance of passing on the PKD gene). The eligible son would rather save his kidney to help his brother than his father. Old animosities resurface, and the family is in turmoil. How will you feel if the father dies of a complication of dialysis, and both his sons feel guilty forever? We should not be too surprised at all this: often in medicine bad comes out of our good intentions. How can we make good come out of bad? By remembering this example, and not doing tests lightly, and by making genetic counselling as professional as possible, so complications can be foreseen and disasters pre-empted. Furthermore, do not have unreasonable expectations about what genetic counselling can do. The number of diseases being found to have a significant genetic component is increasing faster than geneticists can formulate rational guidelines for screening.1

Fig 1. A polycystic kidney (left) compared to a normal sized kidney (right). The progressive increase in size often leads to abdominal discomfort, and there may be haemorrhage into a cyst causing haematuria, or infection.image39

Renal manifestations of systemic disease Amyloidosis (p354) can cause proteinuria, nephrotic syndrome or progressive renal failure. Diagnosis: US: large kidneys; biopsy: see p354. Treatment p354. Diabetes This is one of the commonest causes of ESRF in the UK, accounting for ~18%. Pathology: Hyperglycaemia causes renal hyperperfusion, increasing GFR. This causes hypertrophy and ↑renal size. Mesangial hypertrophy and focal glomerulosclerosis (Kimmelstiel-Wilson lesion) occur later due to ↑glomerular pressure. This initially causes microalbuminuria (detectable on laboratory tests but not on dipstick: albuminuria 30-300mg/d), a sign of early diabetic nephropathy and a strong independent predictor of cardiovascular mortality. This progresses to proteinuria (albuminuria >300mg/d): ESRF usually occurs within 5-10 years. Diabetic retinopathy usually co-exists, and hypertension is common. It occurs in ~30%, partly due to genetic predisposition.

  • Type 1 DM nephropathy occurs typically 20-40yrs post-diagnosis.
  • Type 2 DM (‘maturity onset’) nephropathy: ▶See p301 (BOX). >10-30% have nephropathy at diagnosis, and prevalence increases linearly with time.

Treatment: Good glycaemic control delays onset and progression of nephropathy. If microalbuminuria is present, additional important interventions to slow progression of renal disease are •BP target <125/<75 •Use of ACE-i or A2A, even if normotensive (these ↓intraglomerular pressure, p301) •Smoking cessation. Once ESRF has been reached, combined pancreas and renal transplant is possible in selected patients. Infection associated nephropathies are common causes of renal disease. Glomerulonephritis occurs with many bacterial, viral and parasitic infections, including post-streptococcal, hepatitis B or C, HIV, SBE/IE, shunt nephritis, visceral abscess, syphilis, malaria, schistosomiasis and filiariasis. Vasculitis (p542) may occur with hepatitis B or C, post-streptococcal or staphylococcal septicaemia. Interstitial nephritis: Seen with bacterial pyelonephritis, viral (CMV, HIV, hepatitis B, hantavirus), fungal and parasitic (leishmaniasis, toxoplasmosis) infections. Malignancy Direct effects: Renal infiltration (leukaemia, lymphoma), obstruction (pelvic tumours), metastases. Indirect: Hypercalcaemia, nephrotic syndrome, acute renal failure, amyloidosis, glomerulonephritis. Treatment associated: Nephrotoxic drugs, tumour lysis syndrome, radiation nephritis. Myeloma (p352) is characterized by excess production of monoclonal antibody ± light chains, which are excreted and detected in 2/3 of cases as Bence-Jones proteinuria. Myeloma kidney is due to blockage of tubules by casts, consisting of light chains. The light chains have a direct toxic effects on tubular cells, causing ATN. Features: ARF, CRF, amyloidosis (may cause proteinuria and nephrotic syndrome), hypercalcaemic nephropathy. Treatment: Ensure fluid intake of 3L/day to prevent further impairment. Dialysis may be required in ARF. Rheumatological diseases Rheumatoid arthritis (RA) NSAIDs may cause interstitial nephritis. Penicillamine and gold can cause membranous nephropathy. AA amyloidosis (p354) occurs in ~15% of RA (often asymptomatic). SLE involves the glomerulus in 40-60% of adults, causing acute or chronic disease. Proteinuria and ↑BP are common. Histological patterns range from minimal change to crescentic GN. Consider a renal biopsy if nephritic syndrome or deteriorating renal function. [prescription take]: ACE-i if proteinuria. Corticosteroids and immunosuppressants (cyclophosphamide or mycophenolate) are used if biopsy shows aggressive GN (p540). Systemic sclerosis (p538) may affect the kidney, especially in diffuse disease. ‘Renal crisis’ presents with ARF + accelerated hypertension. [prescription take]: ACE-i if ↑BP or in renal crisis. Dialysis or transplant may be required. Hyperparathyroidism Clinical features are from hypercalcaemia: p298. Sarcoidosis may involve the kidney, often by abnormal calcium metabolism (p178). Interstitial nephritis and rarely glomerulonephritis are also associated. P.307
Epilogue: the man in a red canoe who saved a million lives Mostly we commute to work each day driven by motives we would rather not look at too deeply. But one renal physician used a red canoe to commute each day from his houseboat to the hospital. He could have been a very rich man but instead Belding Scribner gave his invention away, and continued his modest existence. He invented the Scribner shunt—a U of teflon connecting an artery to a vein, so allowing haemodialysis to be something which could be repeated as often as needed. Before Scribner, glass tubes had to be painfully inserted into blood vessels, which would be damaged by the procedure and haemodialysis could only be done for a few cycles. Clyde Shields was his first patient with chronic renal failure to receive the shunt—on 9 March 1960, and said that his first treatment ‘took so much of the waste I’d stored up out of me that it was just like turning on the light from darkness’.image40 Scribner took something that was 100% fatal and overnight turned it into a condition with a 90% survival. In so doing he founded a branch of bioethics because not everyone could have the treatment immediately. This is the branch of ethics that is to do with who gets what—ie distributive justice. In Scribner’s day, this was decided by the famous ‘Life and Death Committee’ which had the unenviable job of choosing who would survive by placing people in order precedence. Scribner has said that his inventions sprang from his empathy for patients, including himself. ‘I was a sickly child’ he said, and at various times he needed a heart-lung machine, a new hip, and donated corneas. He was the sort of man whose patients would inspire him to worry away at their problems during the day—and then to awake at night with a brilliant solution. On 19 June 2003, his canoe was found afloat but empty—and like those ancient Indian burial canoes found at Wiskam which have been polished to an unimaginable lustre by the action of the shifting sands around the Island of the Dead, so we polish and cherish the image of this man who gave everything away. Acknowledgements We thank Dr. Andrew Mooney who is our Specialist Reader for this chapter.

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