Endovascular (or catheter-based) renal nerve ablation has been studied in patients with resistant hypertension (patients on a mean of \201 ve drugs, inc luding a diuretic) in a series of trials (including Simplicity HTN-1 and 2). Mean reduction in SBP of 28 \200\223 32mmHg, compared to control. \200 An endovascular c atheter is placed in the femoral artery and guided to the kidneys. The sympathetic nerves are closely related to the renal arteries, and radio frequency energy is used to disrupt them at several sites along the vessel. Most patients remain on some therapy, but bene \201 ts are sustained to 3 years. No longer-term outcomes yet available. \200 7 15% treatment failure (possibly higher). \200 Invasive, uncomfortable procedure. Day case or overnight stay. \200 No evidence of new atherosclerotic lesions in the \201 eld of RF energy. \200 Limited data in patients with CKD, but those available (CKD 3 \200\223 4 with resistant i BP) show a bene \201 ci al BP-lowering effect and favorable safety pro \201 le. Simplicity HTN-3 (USA-based) is currently recruiting. It incorporates 24h BP measurements a nd a sham procedure to allow testing for placebo response. Device-guided respiration \200 Portable electronic devices that promote slow and deep bre athing (e.g. RESPeRATE ). Consist of a control box, a respiration sensor, and headphones (which provide feedback to the patient). The device analyzes breathing patterns and creates audibl e tones for the patient to then synchronize their breathing to. The device gradually slows breathing to <10 breaths per minute. Marketed as non-pharmacological treatment for BP reduction but can be used as an adjunct to drug therapy. Published trials show a small, but signi \201 cant, effect ( d SBP 3.67mmHg and d DBP 2.51 mmHg), although they have been of short duration. Evidence of long-term bene \201 t currently lacking. NON-PHARMACOLOGICAL STRATEGIES 515 Baroreceptor activation therapy (BAT) \200 Electrical stimulation of the carotid sinus ba rore \202 ex system, using a surgically implanted device. Appears effective but limited outcome data. \200 Procedure-related adverse events relativ ely common. CHAPTER 6 Hypertension 516 Resistant hypertension Introduction Variably de \201 ned but usually a failure to reach ta rget BP despite multiple antihypertensive agents, including a diuretic. It is most commonly a conse- quence of poorly controlled SBP. Although thought to be relatively common \200\224 up to 20 \200\223 30% of study populati ons in clinical trials \200\224 the experience, when recruiting to these studies, has been that true resistant hypertension is actually less common if drug therapy is optimized and contributing factors are recti \201 ed. In the UK, resistant hypertension is considered to be BP not controlled to target with maxi mal recommended and tolerated doses of an ACE-I/ ARB + CCB + thiazide. The 2011 BHS/NICE gu ideline recommends that such patients are managed with a further diuretic (consider spirono lac- tone), an A -blocker, or a B -blocker (and that a referral for specialist input is con sidered). Although evidence for treatment strategies are generally limited, more robust guidance will hopefully emerge in the next few years; for exam- ple, the BHS PATHWAY 2 study has been de signed to evaluate whether resistant hypertension is due to excess sodium retention and whe ther further diuretic is the most effective treatment. The study also hopes to determine wh ether plasma renin can be a useful guide to further treat- ment in this circumstance. At pr esent, some clinicians measure renin con- centrations in resistant patients, add a B -block er or additional ACE/ARB if high and an A -blocker if normal, and change the diuretic (usua lly to spironolactone) if low. (See Fig. 6.9 for management algorithm.) Characteristics of patients with resistant hypertension \200 Obese. \200 Elderly. \200 Black patients. \200 CKD. \200 DM. \200 High starting BP. Checklist \200 Is it really resistant BP? Does it meet the de \201 nition given earlier? Are you con \201 dent about compliance? Does the patient understand the condition, the be ne \201 ts of treatment. and the role of each tablet? Revisit dietary salt restriction (aim to restrict 24h uNa + to <100meq), alcohol consumption, and weight loss (diet and exercise). Exclude contributory drugs (e.g. NSAIDs, steroids, COC, ciclosporin, decongestants, ESAs). Reconsider secondary causes of i BP, especially renal disease, sleep apnoea, and primary hyperaldosteronism ( b p. 474). RESISTANT HYPERTENSION 517 BP not controlled ( \211 140/90mmHg) despite optimal doses of A + C + D Check 1. Compliance 2. Alcohol 3. Salt intake 4. Contributing medications 5. Obesity Exclude secondary hypertension Confirm with ABPM and ideally with supervised tablet ingestion, although the latter is not practical outside of an inpatient setting Consider specialist referral to hypertension specialist Consider further diuretic or or blocker Fig. 6.9 Algorithm for the management of resistant hypertension. CHAPTER 6 Hypertension 518 Hypertensive urgencies and emergencies De \201 nitions \200 2 Hypertensive crises are cl assi \201 ed as emergencies or urgencies , based on the presence or absence of progressive target organ dysfunction. \200 Emergencies: severe i BP complicated by evidence of acute or progressive organ dysfunction, such as cardiac ischaemia, encephalopathy, stroke, pulmo nary oedema, or renal failure. \200 Urgencies: severe i BP without evidence of acute or p rogressive target organ dysfunction. The term malignant hypertension was coined before antihypertensive therapy improved an appa lling prognosis (1-year mortality 7 90%). It is a syndrome of i BP with progressive target organ damage and papilloedema. Pathologically, arteriolar \201 brinoid necrosis is the ch aracteristic lesion. Accelerated hypertension was applied to the scenario of retinal hemorrhages and exudates without papilloedema. The distinction from malignant hypertension is unhelpful, as both carry an identical prognosis. There is no threshold of BP above which malignant hypertension develops. DBP ranges from 10 0 \200\223 180mmHg, SBP 150 \200\223 290mmHg. \200 2 Severity is not determined by BP a lone \200\224 it is the clinical context and degree of target organ dysfunction. Affects < 1% of the hypertensive population, but the hypertensive population is large. \231\202 > \231\200 . Essential hypertension accounts for 7 2 \200\223 30% of episodes in Caucasians but 7 80% in black patients ( 2 therefore, usually avoidable). Renal disease (intrinsic and renovascular) accounts for the majority of the rest. Other pre viously unrecognized forms of secondary i BP may also be responsible. The duration of hypertension prior to the development of malignant phase may range from days to years. Pathophysiology Vascular autoregulation Autoregulation describes the ability of organs to m aintain their perfusion, regardless of BP. i BP causes distal arteriolar vasoconstriction, protecting end-organs from hypertensive mechanical stress. Hypertensive emergen- cies are a ssociated with a failure of this process, resulting in transmission of i BP to the microvas culature where mechanical trauma l endothelial injury l i vascular permeability l leakage l platelet and \201 brin deposi- tion l \201 brinoid necrosis. Catecholamines and vasopr essin release also contribute. Endocrine and paracrine mediators, including RAS, are activated with i A2, leading to furth er vasoconstriction and ischaemia. Volume depletion due to pressure natriuresis stimulates further renin release and worsens i BP. A vicious cycle of vasoconstriction and worsening i BP ensues. HYPERTENSIVE URGENCIES AND EMERGENCIES 519 Pathological changes Vascular lesions are due to endothelial injury and consist of myointim al proliferation and \201 brinoid necrosis, with subendothelial lipid deposition and hyal ine thrombi. Vascular smooth muscle hypertrophy and collagen deposition contribute to media l thickening, which, with cellular intimal pro- liferation, results in the \200\230 onion skin \200\231 appearance of small vessels, with luminal narrowing. Ischaemia or infarction of end-organs may occur. These changes are particularly well seen in the kidney, with prol iferative endarteritis of the interlobular arteries, \201 brinoid necrosis of the afferen t arteriole, and glomerular ischaemia ( tubulointerstitial damage) (see Figs 6.10 and 6. 11). BP i Sympathetic activity Loss of autoregulation Pressure natriuresis i Local and systemic All RAS activation Na+ and volume depletion Endothelial damage i Local All MAHA PLATELET AND FIBRIN DEPOSITION ISCHAEMIA Fig. 6.10 The pathophysiology of malignant hypertension. Redrawn with permission from Acute Renal Failure in Practice , Imperial College Press. (MAHA: microangiopathic haemolytic ane mia.) Fig. 6.11 Proliferative endarteritis of an interlobular artery in malignant hypertension. I , arterial intima showing gross proliferative change and \200\230 onion skin \200\231 app earance; L, severely narrowed arterial lumen; M, arterial media; T, tubular atrophy and int erstitial \201 brosis. Reproduced with permission from Davison AMA, Cameron JS, Grunfeld J-P, et al . (eds) Oxford Textbook of Clinical Nephrology , 3rd edn. (2005) Oxford: Oxford University Press. CHAPTER 6 Hypertension 520 Assessing urgencies and emergencies How does the BP compare to previous readings? \200 16 0/100 may be suf \201 ciently high to cause acute TOD in a previously normotensive patient. A patient with long-standing hypertension may tolerate a higher BP without any evidence of acute TOD. Clinical assessment \200 2 Assess degree of target organ involvement. \200 Urgency if i BP without acute or progressive TOD. \200 Emergency if i BP with acute or progressive TO D. Is there evidence of target organ damage? Acute TOD 3 Manage as an inpatient as an emergency: \200 Neurological symptoms: at risk f or haemorrhagic or thrombotic stroke, encephalopathy (altered consciousness, \201 ts, foc al signs). LVF. \200 Acute kidney injury failure (send U&E, dipstick urine). \200 1 Chest pain. Ac ute coronary syndrome l MI or aortic dissection. Perform ECG, and check pulses. If in doubt: CT aorta. Visual symptoms 9 either grade III or IV hypertensive retinopathy. \200 Pancreatitis due to haemorrhagic infarction (rare). What medication has the patient been on until now? \200 Continue current medication, addi ng in further treatment, as necessary. \200 Check previous adherence to medication (recen t non-compliance is very common in this situation). 1 Beware precipitating hypotension by r estarting multiple antihypertensives in the previously non-adherent patient. 2 Remember recreational drug use (cocaine, amphetamines). Symptoms and signs \200 BP: no pathognomonic values. Usually > 220/140mmHg (range: DBP 100 \200\223 180mmHg, SBP 150 \200\223 290mmHg). Check BP in both arms; look for missing pulses, bruits, or an AAA. Eyes: visual disturbances (35 \200\223 60%) \200\224 often present to ophthalmology. \200 Neurological: headache (60%), dizziness (30%), neurological de \201 cit, e.g. hemipa resis, cortical blindness ( < 10%). Posterior reversible encephalopathy syndrome (PRES), al so known as reversible posterior leucoencephalopathy syndrome (RPLS), is increasingly recog nized. PRES is characterized by headache, confusion, seizures, visual loss, and areas of ce rebral oedema on MRI. The syndrome tends to resolve with treatment of BP, although visual d efects may persist. Renal: AKI (30%). \200 Cardiovascular: dyspnoea s to LVF ( 7 10%), chest pain ( 7 4%). ASSESSING URGENCIES AND EMERGENCIES 521 Hypertensive retinopathy Grade 1: arterial narrowing (tortuosity, \200\230 silver wiring \200\231 are subjective). Grade 2: AV nipping. Grade 3: hemorrhages and exudates. Grade 4: papilloedema. Investigations \200 Urinalysis: proteinuria (can be nephrotic range \200\224 send uPCR, haematuria, cellular casts (red cell casts may indicate parenchymal renal disease). U&E: Serum creatinine, eGFR: acute (or acute-on-chronic) kidney injury. \200 Potassium: d K + ( s hyperaldosteronism l hypokalaemic alkalosis; renin and aldosterone are both raised in m alignant hypertension), i K + ( s to AKI) also possible. FBC: microangiopathic haemolytic anemia \200\224 d Hb, d platelets, red cell fragments, d haptoglobins, i ESR. ECG ( echocardiogram): LVH, ischaemia, MI. \200 CT brain : if d GCS or neurological si gns. \200 MRI brain: PRES/RPLS. \200 Renal biopsy: a diagnostic or prognostic renal bio psy may be necessary. 1 Blood pressure must be controlled \201 rst ( b p. 80). Secondary hypertension? Some conditions require speci \201 c management. Consider the list in Box 6.6. Box 6.6 Causes of hypertensive emergencies \200 Essential hypertension. \200 Renal pare nchymal disease: \200 Glomerulonephritis. \200 Tubulointerstitial disease. Endocrine: Conn \200\231 s syndrome. \200 Phaeochromocytoma. \200 Cushing \200\231 s syndrome. Drugs: Systemic diseases: Cocaine. \200 Amphetamines. \200 Ecstasy. \200 MAOI interactions. \200 Erythropoiet in. \200 Ciclosporin. \200 Tacrolimus. \200 Tumor-related: Systemic sclerosis. \200 HUS/TTP. \200 SLE. \200 Antiphospholipid antibody syndrome. \200 Vasculitis. Renovascular disease: \200 Atheromatous. \200 Fibromuscular hyperplasia. Renal cell carcinoma. \200 Lymphoma. Pre-eclampsia/eclampsia. \200 Coarctation. CHAPTER 6 Hypertension 522 Management of urgencies and emergencies Hypertensive emergency Patients with severely raise d or rapid rise in BP, with severe grade 3 \200\223 4 hypertensive retinal changes. Often have evidence of concurrent TOD. 2 Treatment when acute, life-threatening organ damage \200 Treat in a high dependency env ironment. \200 Continuous BP monitoring. \200 Volume depletion may be present \200\224 resuscitate with 0.9% NaCl. \200 Initial aim of treatment is to d DBP to 7 110 \200\223 115mmHg. Aim to achieve this in 2 \200\223 6 hours. 1 A rapid fall may l clinical consequences with d cerebral, spinal cord, and myocardial perfusion or acute kidney injury. Parenteral agents are often required. \200 Options: see Table 6.11 for drugs used in emer gencies. Sodium nitroprusside. The parenteral drug of choice in many centers. Dose 0.25 \200\223 1. 5 micrograms/kg/min, with increase of 0.5 micrograms/kg/min every 5min until adequate respo nse. 1 Associated with cyanide toxicity (prevent by protecting drug from light; risk increa sed at >2 micrograms/kg/min and in renal failure). \200 Labetalol (combined A - and B -bl ocker) particularly logical in IHD and aortic dissection. 20mg IV initially over 1min, foll owed by infusion 0.5 \200\223 2mg/min. Safe in pregnancy. Glyceryl trinitrate (GTN) 2 \200\223 10mg/h. Useful with symptomatic coronary artery disease or acute LVF. 1 Care if volume-depleted. Tachyphylaxis occurs after 24 \200\223 48h. Once BP within target range, transfer to oral agent, and wean IV infusion over 4 \200\223 8h. 2 Treatment when no life-threatening organ damage \200 May have features of malignant hyp ertension with TOD but not life-threatening. Aim d diastolic BP to 110 \200\223 115mmHg over 24 \200\223 48h. \200 Oral agents prefe rred. \200 Low blood volume may manifest after treatment initiated ( l postural drop of > 20mmHg suggests hypovolaemia in need of correction). \200 Start with slow-release nifedip ine, e.g. nifedipine retard/MR 10mg. Repeat the same dose at 2h intervals, with maintenance doses of 20mg 3 x day. 1 Do not use capsules or LA preparations. Amlodipine is long-acting \200\224 it will reduce BP over days 6 not suitable in urgent si tuations. Consider starting concurrently with nifedipine MR and then weaning off nifedipine after 7 72 hours. Second-line therapy is a B -blocker. Particularly helpful with coexisting IHD or resting tachycardia. 1 ACE-I should be used with caution ( l abrupt d BP, potential hypoperfusion/AKI). Diuretics should also be used with caution unless clear \202 uid overload. MANAGEMENT OF URGENCIES AND EMERGENCIES 523 Hypertensive urgency 2 Severe uncontrolled hypertension (>130 DBP) with no evidence of acut e TOD \200 If no acute TOD, does not necessarily require hospital admission. \200 Repea t BP after 1 \200\223 2h to con \201 rm. If DBP still > 130mmHg l treat. \200 Use the s ame oral agents as in emergency. Start with a single agent. Aim for diastolic BP 100 \200\223 110mmHg at \201 rst. Recheck BP after 24 \200\223 48h . If still uncontrolled, increase dose, or add in second agent. Recheck after every 2 \200\223 3 days until BP at desired level. Treat according to BHS gu idelines ( b p. 488): \200 Elderly or black patients l CCB. \200 Then A + C. \200 The n A + C + D. \200 It is appropriate to start an ACE-I (e.g. ramipril) at full dose if nor mal renal function and unlikely signi \201 cant RAS. Prognosis Without effective treatment: 1-year mortality 7 90%, with effective treat- ment < 10%. Many patients who develop renal insuf \201 ciency will recover renal function, even if initially dialysis-dependent, although this may take several months. Table 6.11 Drugs used in hypertensive emergencies Drug Route and dose Comment NEVER use rapid release formulations Nimodipine used post-subarachnoid hemorrhage Oral nifedipine MR 10mg 12h; max 40mg 12h (consider concomitant amlodipine 5 \200\223 10mg ; (see text on b p. 522)) Oral Useful 2nd line (e.g. atenolol 50mg daily) Calcium channel blockers B -blockers SE: bronchospasm May cause rapid fall in BP Avoid in AKI Treatment of choice in scleroderma crisis ACE inhibitors Oral Start with low dose (e.g. ramipril 2.5mg or captopril 6.25mg), and titrate up Diuretics Oral/IV furosemide 40 \200\223 120mg 12h Beware volume depletion A -blockers Oral doxazosin MR 4mg 12h (up to 8mg 12h) Useful because of titration range (Continued) CHAPTER 6 Hypertension 524 Table 6.11 (Continued) Drug Labetalol Route and dose IV Up to 2mg/min as infusion or 20 \200\223 80mg bolus every 10min Comment Safe in pregnancy. Used in pre-eclampsia Can be converted IV to PO SE: bronchospasm , LVF, heart block Very short half-life SE: as for labetalol Esmolol IV25 \200\223 200 micrograms/ kg/min Initial bolus of 0.5 \200\223 1.0mg/ kg Potent, rapid-acting, vasodilator Requires close monitoring (? arterial line) and light-res istant delivery equipment SE: nausea, vomiting, thiocyanate accumulation (esp. if renal imp airment) Sodium nitroprusside IV Start 0.25 \200\223 1.5 micrograms/ kg/min. ( i 0.5 micrograms/ kg/min every 5min until response). Range 0.25 \200\223 10 micrograms/kg/min Nitrates (GTN) IV 10 \200\223 200 micrograms/min Familiar SE: headache, tachycardia, tachyphylaxis, vomiting Arterial vasodilator used in eclampsia SE: Na + and water retention, headache, tachycardia, vomiting Hydralazine IV 5 \200\223 10mg bolus, repeated after 1h. Infusion: start 200 \200\223 300 micrograms/ min, maintenance 50 \200\223 150 micrograms/min Phentolamine IV 1 \200\223 5mg, repeated as necessary Phaeochromocytoma SE: tachycardia, dizziness, \202 ushing, nausea Fenoldopam IV 0.1 \200\223 0.3 micrograms/kg/min Dopamine-1 agonist and peripheral arterial vasodilator Also i urine \202 ow and both Na + and K + excretion attractive if d GFR R SE: headache, tachycardia, \202 ushing MANAGEMENT OF URGENCIES AND EMERGENCIES 525 CHAPTER 6 Hypertension 526 Orthostatic hypotension A frequent clinical problem, particularly in the elderly. Generally de \201 ned as a 20/10mmHg (symptomatic) fall in BP within 5min of assuming an upright po sture. Symptoms include weakness, dizziness, visual disturbance, presyncope, blackouts, and falls. See Box 6.7 for causes. See Fig. 6.12 for treatment. Normal response Standing l splanchnic and lower limb blood pooling l d venous return l card iac output l d BP l re \202 ex sympathetic and parasympathetic acti- vation l i peripheral vascular resistance l i venous return l i cardiac output l i BP. Box 6.7 Causes of orthostatic hypotension Endocrine disorders: Hypovolaemia. \200 Drugs. \200 Autonomic dysfunction: Addison \200\231 s syndrome. \200 Hypoaldosteronism. \200 Phaeochromocytoma. d baroreceptor sensitivity Miscellaneous: (elderly). Paroxysmal syndromes: \200\224 Micturition syncope. \200\224 Cough syncope. Pure autonomic failure. \200 Multiple system atrophy (Shy \200\223 Drager syndrome). Varicose veins. \200 Carcinoid syndrome. \200 Mastocytosis. \200 Postprandial hypoten sion. Parkinson \200\231 s disease. \200 Diabetes mellitus. \200 Amyloidosis. \200 Postura l tachycardia syndrome (POTS). Paraneoplastic autonomic dysfunction. Volume depletion Requires exclusion in all cases. Antihypertensive drugs A frequent culprit. Other drugs include nitrates, opiates, tricyclic antide- pressants, and alcohol. Pure autonomic failure Characterized by orthostatic d BP, with a static heart rate, i sweat ing, impotence, nocturia, constipation, anemia, and supine i BP. Symptoms are slowly progre ssive and often worse early morning and postprandi- ally. Associated with d levels of plasm a noradrenaline and degeneration of post-ganglionic neurons (with Lewy body inclusions). Multiple system atrophy Progressive neurodegenerative condition of unknown etiology. \231 \202 > \231\200 , age >50. Autonomic dysfunction (often \201 rst symptom) is accompanied by combinations of extrapyramidal, pyramidal, and cerebellar dysfunction. ORTHOSTATIC HYPOTENSION 527 Postural tachycardia syndrome (POTS) Relatively common; age < 40, \231\200 > \231\202 . E tiology uncertain but abnormali- ties of autonomic regulation implicated. The presence of t achycardia dis- tinguishes it from autonomic failure. Often little or no fall in BP. Tilt-t able testing diagnostic. Decreased baroreceptor sensitivity in the elderly Mild postural d BP in the elderly, associ ated with abnormal responses to baroreceptor re \202 exes, such as tilting. May be associa ted with i mortality. Orthostatic hypotension Symptomatic Asymptomatic No treatment necessary Non-pharmacological measures - i dietary Na+ intake - i fluid intake - Caffeinated drinks - Avoid hot environments - Limit early morning activity - Limit activity after meals - Compr ession stockings Symptomatic Asymptomatic Pharmacological measures No further treatment Long-acting Short-acting Midodrine \200 Sympathomimetic agents, e.g. pseudoephedrine \200 NSAIDs Fludrocortisone \200 Erythropoietin (if anemic) Fig. 6.12 Treatment of orthostatic hypotension. Reproduced from Jens Jordan et al. Contrast ing actions of pressor agents in severe autonomic failure. (1998). Am J Med, 105 ; 116 \200\223 24, with permission from Elsevier. 529 Chapter 7 Diseases of the kidney Approaching glomerular disease 530 Histology of glomerular disease 532 Acute nephritic synd rome 536 Nephritis: management overview 538 Nephritis: overview of immune suppression 540 I gA nephropathy 544 IgA nephropathy: management 546 Post-infectious glomerulonephritis 548 M esangiocapillary glomerulonephritis 550 MCGN: presentation and management 552 The nephrotic syndrome 554 The nephrotic syndrome: general management principles 556 Minimal change dise ase 558 Focal and segmental glomerulosclerosis (FSGS) 560 Membranous nephropathy (MN) 564 I diopathic MN: treatment 566 Hereditary nephropathies 568 Miscellaneous mesangioproliferativ e glomerulonephritides 572 Thrombotic microangiopathies 574 Thrombotic thrombocytopenic pur pura (TTP) 576 Haemolytic uraemic syndrome (HUS) 578 Acute tubulointerstitial nephritis 580 Chronic tubulointerstitial disease 582 Analgesic nephropathy 584 Renovascular disease 586 Management of ARAS 588 Other renovascular diseases 590 Autosomal dominant polycystic kidney disease (ADPKD) 592 ADPKD: complications and treatment 594 Other cystic kidney diseases 59 8 CHAPTER 7 Diseases of the kidney 530 Approaching glomerular disease Introduction Glomerulonephritis (GN) is classi \201 ed by c linical syndrome/presentation (e.g. nephritic or nephrotic syndrome), histological appearan ce (e.g. mini- mal change disease), or by etiology (e.g. post-streptococcal GN) (see Fig. 7 .1). Clinical syndromes For further investigation of these clinical syndromes, see b Chapter 1. \200 Asymptomatic urinary abnormalities ( b pp. 58 and 66). \200 Acute nephritis ( b p. 71). \200 Nephrotic syndrome ( b p. 554). These may all be accompanied by i BP 9 renal i mpairment. Dipstick-positive proteinuria ( b p. 58) Common. Usually detected on routine uri nalysis. A positive dipstick for haematuria or proteinuria should be repeated (e.g. after 1 \200\223 2 weeks). Transient proteinuria is not uncommon, esp. in concentrated urine. If persistent, verify with an albumin to creatinine ratio (uACR) or protein creatinine ratio ( uPCR) ( b p. 21). Microscopic haematuria ( b p. 66) Dipstick analysis is very sensitive but non-speci \201 c. If persistent, ide- ally arrange urine cytology to con \201 rm haematu ria (de \201 ned as >2 RBC/ hpf), and examine red cell morphology. Dysmorphic red cells, r ed cell casts, and fragmented red cells (acanthocytes) imply glomerular bleeding ( b p. 22) . Urine microscopy will also reveal pyuria and other forms of cast. Urine culture will exclude infection. Haematuria and proteinuria ( b p. 61) Suggests a glomerular lesion, although independent investigation of the haematuria may be necessary in patients aged >40 ( b p. 67). APPROACHING GLOMERULAR DISEASE 531 (A) (B) EA GBM Capillary lumen Mesangium Endothelial cell AA Podocyte Bowman \200\231s space (C) Podocyte foot processes PO US GBM Capillary lumen E (E) C US F cGBM 3 2 1 E C E mGBM M C C Fig. 7.1 (A) Glomerular vessels: AA, afferent arteriole; EA, efferent arteriole. (B) Cartoo n of the glomerular capillaries: GBM, glomerular basement membrane. (C) EM of glomerular ca pillaries: C, capillary; E, endothelial cell; cGBM, capillary GBM; mGBM, mesangial GBM; PO, podocyte; US, ultra \201 ltration space. (A \200\223 C). (D) Cartoon of glomerular \201 lter. (E) EM of glomerular \201 lter: F, podocyte foot process. Reproduced with perm ission from Davison AMA, Cameron JS, Grunfeld J-P, et al. (2005), Oxford Textbook of Clinic al Nephrology . Oxford University Press, Oxford. CHAPTER 7 Diseases of the kidney 532 Histology of glomerular disease Introduction Renal tissue is sampled via renal biopsy ( b p . 80) and prepared for: \200 Light microscopy: various histochemical stains (e.g. H+E, pe riodic acid \200\223 Schiff (PAS), Jones (silver) stains). Useful for morphology, chronici ty, and diagnosis. Immunohistochemistry: usually by immuno \202 uorescence but also immunoperoxidase staining. Localizes immune reactants (particularly immunoglobulins or comp lement fractions) within glomeruli, using \202 uorescein-labeled antibodies. The nature a nd pattern of staining are characteristic for particular glomerular lesions. Electron microscopy (EM): useful for examining cell and basement membrane structure and for characterizing glomerular deposits. The language of glomerular disease When examining a preparation of renal cortex, several gl omeruli (10 \200\223 30, on average) are sampled. The following descriptive terms (see Fig . 7.2) are then used: \200 Focal or diffuse? Focal lesions affect some (<50%) of sampled glomeruli, but not all. \200 Diffuse lesions involve most (>50%) glomeruli, if not all. Segmental or global? Segmental lesions affect part of an affected glomerulus. \200 Global lesions involve most of the glomerular tuft. Proliferative or not? Proliferative lesions describe an increase in local cell number; for instance, an increase in mesangial cells ( \200\230 mesangial proliferative \200\231 ) is a feature of IgA nephropathy. Crescentic or not? Glomerular parietal epithelial cells (lining Bowman \200\231 s capsule) proliferate in response to local in \202 ammatory and procoagulant signals, with \201 br in deposition and adhesions \201 lling some, or all, of Bowman \200\231 s space ( l \200\230 crescent \200\231 ). Matrix or membrane? Expansion of matrix produced by mesangial cells, as seen in IgA nephropathy, or increase in GBM width (and thus capillary wall thickness) characteristic of immune deposits. Necrosis or sclerosis? Necrosis refers to fresh cell death as a result of ongoing injury. \200 Sclerosis re \202 ects a scarred glomerulus or glomerular segment. Examples Focal and segmental glomerulosclerosis affects some glomeruli, but not all, and on ly part of any affected tuft. The disease leads to scarring within glomeruli. Diffuse proliferative crescentic glomerulonephritis affects most glomeruli, with hypercellu larity and the formation of crescents in Bowman \200\231 s space. HISTOLOGY OF GLOMERULAR DISEASE 533 Mesangial cells Capillary loops Normal glomerulus Sclerosis Segmental lesions affect part of the tuft, e.g. FSGS Hypercellularity and matrix expansion Crescent Global lesions affect the whole tuft, e.g. diffuse proliferative GN Fig. 7.2 The nomenclature of glomerulonephritis. CHAPTER 7 Diseases of the kidney 534 Table 7.1 A glossary of histological terms Term De \201 nition Minimal change Normal appearance by light microscopy. Note that electron microscopy may show fusion of pod ocyte foot processes, an association with glomerular proteinuria. Proliferation Increase in cell numbers, may be mesangial, endocapillary or extracapillary (which may form crescents). E.g. mesangial proliferation = >4 cells per mesangial area. Exudation In \201 ltrated by neutrophils e.g. acute post-streptococcal nephritis (Fig. 15.10). Membranous Speci \201 c type of glomerular basement membrane thickening associated with subepithelial immune deposits, e.g. idiopathic membranous nephropathy. Hyalinosis Accumulation and condensation of plasma proteins into tissues outside a blood vessel lumen, appears as homogeneous pink staining with H&E (see \200\230H&E \200\231 later in table). Sclerosis Scar tissue, a \201 brous matrix obliterates normal structure so that capillaries collaps e and normal cell nuclei are lost. Tubular atrophy Thickening and wrinkling of tubular basement membrane around a shrunken tubule with \202 attened epithelium; implies irreversible tubular damage. Crescent Collection of cells in Bowman s space in response to glomerular damage. Initially only comp osed of in \202 ammatory and epithelial cells (cellular crescent), later organizes with \201 brin and collagen ( \201 brous crescent). Diffuse Applying to all glomeruli in a biopsy. Focal Applying to some glomeruli, but not others. Global Applying to the whole of a glomerulus. Segmental Applying to part of a glomerulus, i.e. part of the glomerular capillary tuft is unaffected. \200\230Humps \200\231 Deposits of Ig and complement in a sub-epithelial site; typical of acute post-streptococcal nephritis. \200\230Spikes \200\231 Projections of basement membrane between regular sub-epithelial deposits, typical of membra nous nephropathy. Foam cells Lipid laden cells, usually histiocytes but also mesangial or tubular cells, seen in nephrot ic syndrome and Alport s syndrome. HISTOLOGY OF GLOMERULAR DISEASE 535 Table 7.1 (Continued) Term Haematoxylin and eosin (H&E) De \201 nition Routine histological technique which stains cytoplasm pink and nuclei blue. Allows inspection of all renal structures but is poor at distinguishing deposits or visual izing the basement membrane. Periodic acid-Schiff (PAS) Routine histological technique which clearly delineates basement membranes and allows visua lization of cellular components. Silver Silver stains highlight connective tissue structures such as reticulin, basement membrane, and collagen, which appears black. Very useful for assessment of glomerular capillary basem ent membrane architecture such as \200\230spike formation \200\231 (see \200\230Spikes \200\231 earlier in table). Congo red Stain used for the detection of amyloid, which appears red with \200\230apple green \200 \231 birefringence using polarized light examination. Martius scarlet blue (MSB) Stain which highlights \201 brin deposits as red, collagen in blue, and erythrocytes in y ellow. Toluidine blue Stain used primarily to visualize \200\230thin sections \200\231 prior to electron microsc opic examination. Glomerulonephritis In \202 ammation of the glomerulus. Tubulointerstitial nephritis In \202 ammation of the tubules and interstitium. Electron dense deposits Dark lesions identi \201 able on electron microscopic examination, usually corresponding t o sites of immunoglobulin or complement deposition. Immunohistochemistry (IHC) Technique for detecting and localizing speci \201 c antigens in tissue sections using a de tection system visible on routine light microscopy, e.g. immunoperoxidase. Immuno \202 uorescence (IF) Technique for detecting and localizing speci \201 c antigens in tissue sections using a de tection system visible on \202 uorescence microscopy. Sometimes more sensitive than IHC b ut requires fresh tissue and is not stable. Thin basement membrane (thin BM) disease Age 9 \200\22368 years: thin GBM: 262 \200\223330nm; normal: 331 \200\223547nm. \200\230Basket weave \200\231 GBM The disordered replication of lamina densa of the GBM in Alport s nephropathy. Modi \201 ed from Taylor CM, Chapman S (1989). Renal biopsy. In Handbook of renal investig ations in children, pp.160 \200\22371. Taylor CM, Chapman S (eds). Wright, London. CHAPTER 7 Diseases of the kidney 536 Acute nephritic syndrome Introduction The clinical syndrome associated with underlying glom erulonephritis ( b p. 71). Presents (often rapidly) as: \200 Haematuria and proteinuria. \200 Impaired renal function. \200 Oliguria with signs of salt and water retention. It is a spectrum of disease with a variety of aetiologies but with a common site of primary injury: the glomerulus. Onset may be insidious, with urinary abnormalities alone, or fulmi nant, with a rapidly progressive crescentic GN, AKI, and other organ involvement or failure ( b p. 71). Causes \200 IgA nephropathy and Henoch \200\223 Sch nlein purpura. \200 Lupus nephritis. \200 Post-infectious GN. \200 Anti-GBM disease. \200 ANCA-associat ed vasculitis. \200 Mesangiocapillary GN (MCGN). Mechanisms of glomerular injury The injury leading to most GN is immunologically mediated, with loss of tolerance to autoantigens, provoking both the cellular and humoral arms of the immune system. These antigens may be native to the glomerulus itself (occurring normally w ithin the tuft, e.g. the GBM in anti-GBM dis- ease) or circulating antigens/antigen-antibod y complexes that become trapped in glomerular structures. Antibody to antigen binding may then \201 x and activate complement (forming immune compl exes, ICs) or recruit in \202 ammatory cells (see Fig. 7.3). The nature of the injury will depend on the site of the IC (e.g. IgA-containing mesangial complexes activate mesangial c ells to cause IgA nephropathy). Local complement activation and cell recruitment (neutrophi ls, macrophages) generate oxidant species, proteases, in \202 am- matory cytokines, growth factors, vasoactive factors, and procoagulants. Damage to, and activation of, surrounding cells and matrix then lead to the changes evident on histological examination and the clini cal syn- drome of haematuria, proteinuria, and impairment of glomerular \201 ltra- tion. The number of ICs formed and the host response to them will determine the extent of the inj ury. Cellular immunity may also contribute to structural glomerular dam- age \200\224 this is e specially true of pauci-immune GN (e.g. the GN associated with ANCA-positive vasculitis) wh ere ICs play no pathological role. Resolution of in \202 ammation might return an in \202 amed glomerulus to normal or, if t he healing phase is poorly regulated, may result in cellular dropout, scarring, glomerulosc lerosis, and CKD. ACUTE NEPHRITIC SYNDROME 537 Antibody Antigen (endogenous or exogenous) Circulating or planted immune complexes GBM Capillary lumen Mesangium Podocyte Podocyte foot processes GBM Inflammatory cells causing local injury Complement Destruction of part or all of a glomerular lesion leads to renal failure Capillary rupture leads to haematuria and crescent formation Injury to the glomerular sieve leads to proteinuria Podocyte Fig. 7.3 An example of an immune complex-mediated GN. CHAPTER 7 Diseases of the kidney 538 Nephritis: management overview Investigations \200 Dipstick urine for haematuria, protein uria. \200 Urine microscopy for red morphology 9 casts ( b p. 22). \200 Amount of prote inuria variable (often <1g/day, i.e. uACR <70mg/mmol and uPCR <100mg/mmol, but may be nephrotic range). SCr, eGFR, U&E, FBC, bone pro \201 le, LFT. \200 Acute phase markers (CRP, ESR). \200 Immunological and serological ( \200\230 nephritic \200\231 ) screen ( b p. 40). \200 U SS kidneys. \200 Renal biopsy ( b p. 80). Salt and water restriction 2 It is vital to correctly assess volume status. \200 Fluid ov erload 9 pulmonary oedema often complicates oliguric GN. If present: \200 Limit salt intake <80mmol/day (<5g/day). \200 Set oral intake at 500 \200\223 1,000mL/day (adjusted according to volume status and UO). Diuretics may promote a natriuresis and provide symptomatic relief: use loop diuretic, e.g. furosemide 40 \200\223 160mg/day PO or IV, titrated agains t response and renal function. Less commonly, dehydration may be present, in which case increased oral intake or rehydration with IVI 0.9% NaCl may be needed. Review volume status and monitor weight daily, and chart input and output to plan following day \200\231 s \202 uid balance. Indwelling catheter only rarely required. Control BP \200 i BP is usually volume-related and may be signi \201 cant. Aim for targe t BP of \211 130/80mmHg. \200 Suggested treatment: Diuretic (as described in salt and water restriction). \200 Stepwise add-on therapy, usin g B -blockers 9 calcium channel blockers. ACE-I or ARB: titrate up from low dose with daily increments. ACE-I or ARB offer theoretica l advantages in the control of i BP secondary to renal disease due to their anti \201 brot ic and anti-proteinuric effects. However, their use in GN-associated with AKI may precipita te a further decline in renal function. (cid:2) Careful monitoring is essential. Other supportive measures \200 2 Prompt treatment of infection. \200 Adequate nutrition . \200 Management of the complications that may be associated with a systemic disease causing GN (e.g. lupus, vasculitis). Renal replacement therapy, according to standard indications ( b p. 172). NEPHRITIS: MANAGEMENT OVERVIEW 539 Speci \201 c therapies: immunosuppression Almost always tailored to a histological diagnos is (so a renal biopsy is often indicated as soon as is possible). See Nephritis: overview o f immune suppression ( b p. 540) and under each particular diagnosis.