Calcineurin inhibitors (CNIs) Ciclosporin and tacrolimus are widely used in transplantation , glomerular disease, and in \202 ammatory disorders. Both are associated with important n ephrotoxicity. CHAPTER 12 Drugs and the kidney 900 Acute toxicity \200 Haemodynamically mediated and reversible. \200 Often no structural damage. \200 Responds to dose adjustment or drug withdrawal. \200 Presents as an asympt omatic i SCr (even where serum level is in the desired therapeutic range). This can mimic rejection in transplant recipients, triggeri ng further investigation, e.g. a transplant biopsy ( b p. 416). Histology may be normal or reveal indicative tubular changes, such as vacuolization, tubular microcalci \201 cation, or giant mitochondria. \200 AKI is relati vely common in post-heart, lung, and bone marrow transplantation (although is not exclusively s to CNIs in this situation). CNI-induced thrombotic microangiopathy is an uncommon, but important, syndrome post-transplantation ( b p. 412). Chronic toxicity \200 Characterized by irreversible and progressive tubulointerstitial \201 brosis. \200 Fibrosis typically a \200\230 striped \200\231 pattern from the medul la to the cortical medullary rays. Degenerative afferent arteriolar changes may be present. In non-renal transplantation, CNIs are linked to the development of CKD, e.g. ESRD occurs i n 7 1 \200\223 8% of cardiac transplant recipients. Nephrotoxicity may increase with concurrent use of mTOR inhibitors, e.g. sirolimus, everolimus. Prevention: Therapeutic drug monitoring. Tacrolimus trough concentrations (C 0 ) correlate well with overall drug exposure (AUC) and are used to monitor therapy. X Debate remains surrounding the optimal way of monitoring ciclosporin levels. C 0 , C 2 (2 hours post-dose), and AUC 0 \200\223 4 (multipoint testing from 0 \200\223 4 hours) are all in clinical use. Avoid concomitant nephrotoxins. \200 Be cautious with drugs that inhibit cytochrome P450 liver microsomal enzymes and i CNI levels (e.g. ketoconazole, \202 uconazole, erythromyci n, clarithromycin, verapamil, diltiazem). Drugs that induce cytochrome P450 and d CNI levels include carbamazepine and rifampicin. DRUG-RELATED NEPHROTOXICITY 901 Herbal medicines Herbal medicines, often dispensed in an unregulated manner, are a ubiquito us part of healthcare provision in many developing countries, and their use in the develope d world has expanded considerably (see Table 12.3). The kidney is the primary route of excr etion for many such compounds, and their potential for nephrotoxicity is increasingly recog nized. The true global incidence of CKD related to the ingestion of herbal remedies is curr ently unknown but could be very signi \201 cant. When suspected, reporting is desirable. Causes of toxicity \200 Consumption of herbs known to have toxic potential. \200 Consum ption of herbs with unknown, or underappreciated, toxicity. \200 Incorrect identi \201 c ation l inadvertent ingestion of a toxic herb. \200 Deliberate or accidental contaminatio n of herbal products, e.g. NSAIDs or heavy metals (such as cadmium). Interaction with prescribed drugs. Table 12.3 Clinical syndromes and associated herbal medicines Clinical syndrome Example Securida longe pedunculata , Euphoria matabelensis , Callilepsis laureola (African medicine s) Taxus celebica (yew tree) Tung Sheuh pills (containing mefenamic acid) Aristolochia spp. ( b p. 583), Fucus vesiculosis (bladder wrack), Larrea tridentate (chapparal) Aristolochia spp. ( b p. 583), cadmium contamination d K + : Glycyrrhiza glabra (liquorice) AKI CKD Tubular dysfunction Electrolyte disturbances i K + : Medicago sativa (alfala), Taraxacum of \201 cinale (dandelion) Glycyrrhiza glabra (liquorice) Hypertension Ephedra sinica (ma-huang) Renal stone disease Vaccinium macrocarpon (cranberry l oxalate) Salix daphnoides (willow bark l salicylate) Aristolochia spp. ( b p. 583) Papillary necrosis Urothelial cancer CHAPTER 12 Drugs and the kidney 902 NSAIDs and the kidney Mechanism of action NSAIDs inhibit the cyclo-oxygenases (COX), an enz yme family critical for prostaglandin synthesis. There are at least two COX isoforms: most NSAIDs inhibit both, but COX-2 inhibitors (the \200\230 -coxib \200\231 family) are selec - tive for COX-2 ( X and 6 possibly cause fewer GI side effects). Side effects Potent anti-in \202 ammatory and analgesic properties make these drugs amongs t the most ubiquitous in the world. Adverse effects include: \200 Renal toxicity ( b see below). \200 GI side effects: dyspepsia, ulceration, and small and large bowel toxicity. Cardiovascular: i risk of CV disease and i BP ( X COX-2 > non-selective NSAIDs). Bronchospasm. \200 Liver toxicity: abnormal LFTs (although serious liver failure is rare) . \200 Antiplatelet effects ( d thromboxane A 2 production). Bene \201 cial when aspirin is given to modify CV risk but a potential adverse effect in other situations. Renal toxicity \200 2 NSAIDs should generally be avoided in the presence of either AKI or CKD, except in very select and carefully monitored situations. (cid:2) NSAIDs are a very signi \201 cant cause of hospital-based AKI. \200 NSAIDs and r enal haemodynamics: NSAIDs have only a marginal effect on renal haemodynamics when kidney function is normal. However, when renal blood \202 ow is impaired, they abolish prostacyclin- and prostaglandin E 2 -mediated compensatory afferent arteriolar vasodilation , causing reduced glomerular perfusion. Clinically relevant situations include: pre-existing CKD, CCF, sepsis, nephrotic syndrome, hypovolaemia, concomitant ACE-I/ARB use, concomitant gentamicin or other nephrotoxin use, i ncreasing age. NSAIDs also ameliorate the antagonistic effect of prostaglandins on ADH action. This antidiuretic effect can cause salt and water retention, i BP, and blunt th e action of diuretics. Many of the renal effects of NSAIDs are mediated by COX-2, so COX-2 inhibitors appear equally nephrotoxic. (cid:2) In general, always beware claims of more \200\230 renal friendly \200\231 NSAIDs, as there is limited supporting evidence. \200 Other NSAID-induced renal lesions: Important cause of acute interstitial nephritis ( b p. 580). \200 Chronic interstitial ne phritis (and 6 CKD) with long-term use. \200 Analgesic nephropathy ( b p. 584). \200 Ne phrotic syndrome: particularly minimal change disease and membranous GN ( b p. 564). \200 Papillary necrosis ( b p. 585). \200 Electrolyte disord ers d Na + , i K + , acidosis. NSAIDS AND THE KIDNEY 903 Sulfasalazines \200 Sulfasalazine is 5-aminosalicylic acid (5-ASA) coupled to a carrier sulfapyridine molecule that assists GI absorption. \200 5-ASA shares structural similarit ies with aspirin. \200 Second-generation sulfasalazines (e.g. mesalazine) were designed t o minimize troublesome hematological side effects. Such agents are effective and important treatments for in \202 ammatory bowel disease (IBD). There has been signi \201 cant historical concern regarding an association with acute interstitial nephritis. However, available data suggest this is actually relatively uncommon. Case control data fro m a UK primary care database suggested an adjusted odds ratio for renal disease of 0.86 for current 5-ASA users and 2.48 for recent users. Mesalazine and sulfasalazine appeared to ca rry comparable risks. Causality was unclear in the majority of cases. What is more important is to keep in mind that patients with IBD are at increased risk of renal disease, in general. In addition to 5-ASA toxicity, the diff erential of renal impairment in patients with IBD includes: \200 Glomerulonephritis (e.g. membranous GN). \200 Amyloidosis. \200 Oxalate stone disease. If suspected, acute interstitial nephritis usually requires a diagnostic renal biopsy for con \201 rmation. In summary, all patients with active IBD are at higher risk of renal dys- function and shou ld have their renal function and urinalysis checked intermittently. This is particularly tr ue of those treated with 5-ASA derivatives, who should have their renal function monitored every 7 3 \200\223 6-monthly. CHAPTER 12 Drugs and the kidney 904 Lithium and the kidney Introduction \200 Lithium is a very effective treatment for uni- a nd bipolar affective disorders, allowing many patients to stabilize their symptoms and enjo y an excellent quality of life. Lithium clearance mirrors that of Na + : it is freely \201 ltered at the glomerulus and predominantly reabsorbed in the proximal tubule. 7 20% is excreted unchanged in the urine. Accumulation can occur in principal cells of the collecting duct, particularly if GFR falls ( l hypovolaemia, concomitant diuretics, NSAIDs, or ACE-I). Long-term exposure can cause tubular atrophy, tubular cyst formation, progressive interstit ial \201 brosis, and, eventually, glomerulosclerosis. Lithium has a narrow therapeutic window, and therapeutic drug monitoring is mandatory. The goal should be the lowest serum concentration that maintains adequate control of affective symptoms (e.g. 0.4 \200\223 0.8mmol/L). Once-daily dosing regimens appear to have less pot ential to cause toxicity. Renal damage is related to both the average serum lithium concentration and cumulative dose. Any patient receiving lithium should have their renal function measured 6 \200\223 12-monthly. Toxic effects Renal \200 Nephrogenic diabetes insipidus ( b p. 789). Lithium causes ADH resistance ( d aquaporin-2 expression). \200 7 50% of patients have im paired urinary concentrating ability and 7 25% develop polyuria and polydipsia (although th ese do not generally require cessation of treatment). Amiloride can be used to d urine volumes in this situation, as it blocks lithium uptake thr ough the collecting duct epithelial Na + channel (ENaC). (cid:2) Thiazides may i toxicity through both volume contraction and i Na + and lithium reabsorption in the proximal tubule. Lithium use is a rare cause of hypercalcaemia (and mild hypermagnesaemia), which may further perpetuate renal damage. Chronic interstitial damage: Leads to progressive CKD. \200 Uncommon, although the true incidence is dif \201 cult to ascertain, as patients may have non-lithium-related causes of CKD. Kidney biopsies are oft en not undertaken \200\224 or reveal non-speci \201 c, non-diagnostic change only. Histological clues: microcytic change in distal tubules, with only limited interstitial in \202 ammation or vascular change. The mechanism of renal damage is unclear, but tubular cell uptake with impairment of cell proliferation appears important. LITHIUM AND THE KIDNEY 905 Once established, drug withdrawal may not stabilize renal function. \200 Diagnosis does n ot necessarily mandate lithium withdrawal. Many patients will prefer to remain on lithium, rather than risk destabilization of their s ymptoms, particularly if their GFR is declining slowly. Careful individual assessment and e xplanation are necessary. Other \200 GI disturbance. \200 Goiter and thyroid dysfunction. \200 Neurological inc luding tremor and cognitive impairment. Treatment of acute lithium intoxication \200 Complications: Common: tremor, thirst, polyuria, diarrhea, and vomiting. \200 More severe: d GCS, hypert onia, seizures, focal neurological signs, cardiac arrhythmias, d BP. Investigations: Serum lithium concentration. \200 U&E, SCr. \200 Management: Protect airway and monitor cardiac rhythm. \200 Consider gastric lavage if early presenta tion post-ingestion (1h). \200 No role for activated charcoal. \200 Fluid-resuscitate: correct hypovolaemia using 0.9% NaCl 9 0.45% NaCl (if hypernatraemic). Haemodialysis ( b p. 906): Effectively removes lithium. \200 Use high pump speed and large membrane for 4 \200\223 6h. \200 Indications for haemodialysis: \200\224 Lithium level >3.5mmol/L. \200\224 Lithium level >2mmol/L with severe symptoms 9 d GFR. \200 Rebound is common, as lithium moves from the intracellular to extracellular space. Recheck lithium concentration after 6h, and repeat dialysis treatment, as necessary. CHAPTER 12 Drugs and the kidney 906 Dialysis treatment of poisoning Introduction Although rarely necessary (0.05% of all cases) , dialysis can be an effective way to treat drug overdoses and toxicity. Standard supportiv e measures for poisoning must still always be undertaken. Indications \200 The poison (or its toxic metabolites) is removed by dialysis. Favorable characteristics: \200 Low MW (<500Da). \200 Relatively low protein binding. \200 Small volume of distribution (i.e. con \201 ned to plasma volume). \200 Water-solu ble. Severe toxicity. \200 Elimination is quicker via dialysis, or native clearance is impaire d (e.g. renal or hepatic impairment is present). Examples Methanol and ethylene glycol ( b pp. 910 \200\223912), lithium ( b p. 904), aspiri n (salicylic acid) ( b p. 908), theophylline, barbiturates, antibacterials, antivi- rals, s tar fruit poisoning ( Averrhoa carambola ). Techniques Haemodialysis \200 The goal is to remove as much of the drug/toxin as possible . Use a high ef \201 ciency dialyser with a large surface area (>1.5m 2 ). \200 High pump speeds; blood \202 ow >300mL/min. \200 Long treatment (4 \200\223 8 hours). Complications: The patient often does not have renal impairment, so \200\230 overcorrection \200\231 of electrolyte imbalances may occur. d PO 4 may occur and require correction (phosphate is not present in standard dialysate solutions). d K + . \200 Metabolic alkalosis. Haemo \201 ltration \200 Haemo \201 ltration is less effective than HD for drug and tox in elimination but is often the only technique immediately available. Haemodia \201 ltration improves clearance and is the preferred continuous technique. Peritoneal dialysis \200 PD is less ef \201 cient and rarely used in this context. DIALYSIS TREATMENT OF POISONING 907 Haemoperfusion \200 Involves circulation of blood through an extracorporeal circuit, containing an adsorbent (activated charcoal, carbon, or a polystyrene resin). Requires a similar circuit to HD, but without dialysate, and generally with the adsorbent c ontained within a cartridge. The circuit requires anticoagulation with heparin. Haemoperfusion can eliminate protein-bound and lipophilic drugs and toxins (e.g. phenytoin, digoxin, and paraquat). Complications: hypocalcaemia, hypoglycaemia, leucopenia, thrombocytopenia. Less widely available than dialysis or \201 ltration. CHAPTER 12 Drugs and the kidney 908 Salicylate poisoning Introduction Salicylate poisoning remains relatively common. In additi on to aspirin (ace- tylsalicylic acid), methyl salicylate is present (in large amounts) in oil of wintergreen preparations used topically for musculoskeletal ailments. After absorption, salicylate is rapidly converted to salicylic acid. In over- dose, absorpt ion may be delayed >4 \200\223 6h as a consequence of pyloros- pasm, delayed gastric empty ing, tablet clumping, or the ingestion of extended-release formulations. Salicylate handling Under normal circumstances it is highly protein-bound (>90%) and under- goes hepatic metabolism to salicyluric acid, which is both less toxic and more rapidly exc reted by the kidney than salicylate. Only a small amount is excreted unchanged by the kidne ys. However, in overdose, protein binding falls; liver conjugation pathways are saturated, and renal excretion (via the anion secretory pathway in the proximal tubule) becomes more i mportant. Drug t 1/2 increases from 7 2 \200\223 4h to >20h. Salicylate actions \200 Med ullary trigger zone stimulation l nausea and vomiting. \200 Medullary respiratory center stimulation l hyperventilation. \200 Cyclo-oxygenase inhibition l d prostaglandin, d pros tacyclin, and d thromboxane synthesis ( l platelet dysfunction and gastric injury). Cellular injury l disturbed metabolism (including oxidative phosphorylation) l metabolic acidosis. Acid \200\223base considerations \200 An assortment of acid \200\223 base disturbances a re possible, following salicylate overdose: \200 Direct salicylates stimulation of the respiratory center l hype rventilation l initial d pCO 2 l respiratory alkalosis. Accumulation of organic acids (including lactic acid and keto-acids) l i anion gap l metabolic acidosis. Salicylate itself has an insigni \201 cant effect on pH, as serum concentrations are relatively low. A p respiratory acidosis is unusual and indicates severe poisoning ( (cid:2) or the co-ingestion of a respiratory depressant). Most patients present with either a p respiratory alkalosis or mixed p respiratory alkalosis and p metabolic acidosis. Symptoms and signs \200 May correlate poorly with serum levels (esp. in the elderly): Nausea, vomiting, diarrhea, epigastric pain. \200 i RR. \200 Tinnitus, vertigo, blurred vision, SALICYLATE POISONING 909 Agitation, swearing, tremor, confusion, seizures, respiratory depression, coma, hyperthermia, cerebral oedema (esp. if severe acidosis l salicylate cross es the blood \200\223 brain barrier more easily if non-ionized). Non-cardiogenic pulmonary oedema ( i vascular permeability), arrhythmias. 3 Treatment of salicylate poisoning \200 Monitor in HDU setting. \200 O 2 as required. \200 Investigations: U&E ( i or d K + , d HCO 3 \200\223 ), ABG ( 2 \200\223 4-hourly ) , lactate, glucose (hypoglycaemia common), LFT, FBC (GI bleeding is rare), i INR, ECG, and CXR (pulmonary oedema). Salicylate level every 2h until falling: Therapeutic level are <300mg/L (<2.2mmol/L). \200 Moderate toxicity 500 \200\223 750mg/L (3.6 \200\223 5.4mmol/L). \200 Severe overdose >750mg/L (>5.4mmol/L). Exclude other drug ingestions ( (cid:2) paracetamol and respiratory depressants, such as benzodiazepines). Gastric lavage if presenting within 1h of ingestion. Later if delayed gastric emptying suspected. Activated charcoal (50g x 3 at 4-hourly intervals) may be effective. \200 Optimize \202 uid status: Aim for urine output >100mL/h. \200 Alkalinize the urine (salicylate is more soluble at i pH). Give NaHCO 3 1.26% IVI (e.g. 1L over 4h, repeated, as necessary, with regular clinical assessmen t of \202 uid status) until urine pH >7.5 \200\223 8.5. Metabolic alkalosis is not a contraindication to bicarbonate administration. IV glucose (e.g. 20% glucose) if any neurological signs, including confusion, even if blood glucose is normal (salicylates l neuroglycopenia). Recheck K + 2 \200\223 4-hourly . Correct hypokalaemia, if present (allows more effective urinary alkalinization). Dialysis: Effectively removes salicylate. \200 Indications: renal impairment, poor urine output, pu lmonary oedema (non-cardiogenic or volume overload), deteriorating neurological signs, cere bral oedema, progressive acidosis despite adequate medical management, salicylate level >70 0mg/L (>5.1mmol/L). Use high pump speeds and a large dialyser for 4 \200\223 6h. \200 Continue to monitor sa licylate level after dialysis (e.g. at 2h). \200 Repeat dialysis treatment may be require d if levels rebound ( s to delayed salicylate absorption). CHAPTER 12 Drugs and the kidney 910 Ethylene glycol poisoning Introduction \200 Ingestion of ethylene glycol (EG) is usually \200\230 accidental \200\231 when imbibed as an ethanol substitute. It is widely used in antifreeze and solvents. EG is rapidly absorbed and metabolized in the liver (by alcohol dehydrogenase) to glycolaldehyde, then to various acids (including glycolic, glyoxylic, and oxalic). Ingestion of just 50 \200\223 100 mL can be lethal. These acids are responsible for EG toxic effects. Glycolic acid is cleared by the kidney and is the dominant cause of the anion gap acidosis, characteristic of severe cases. Tissue calcium oxalate monohydrate crystals are the cause of cerebral oedema and renal failure. Concomitant ethanol ingestion will be protective by blocking the metabolism of glycol to toxic metabolites. Symptoms and signs (cid:2) Patients may not admit to ingestion and can present in any of th e fol- lowing stages. \200 Stage 1 (30min \200\223 12h): inebriation, although often no alcoholic fetor, nausea and vomiting, convulsions (may be focal), nystagmus, ataxia, visual disturbance, ophthalmoplegia, papilloedema, hypotonia, hypore \202 exia, myoclonic jerks, cranial nerve palsies, altered conscious level, coma. Metabolic acidosis (with i AG). Stage 2 (12 \200\223 24h): i RR, tachycardia, i BP, pulmonary oedema. \200 Stage 3 (24 \200\223 72h): \202 ank pain, renal tenderness, AKI, d Ca 2+ , crystalluria (calcium oxalate), i K + , d Mg 2+ . Investigations \200 ABG: i AG metabolic acidosis with respiratory compensation (mainly glycolic acid, but lactate may contribute). Lactate may also be spuriously high, as many an alysers report an elevated glycolate as lactate). 2 The degree of acidosis correlates with tissue injury and outcome. \200 Ethylene glycol level: may be normal if ingestion >12h pr ior to measurement. >500mg/L (8mmol/L) indicates severe toxicity. Check ethanol, methanol, and isopropyl alcohol levels if suspected co-ingestion. Other: U&E, Ca 2+ , FBC ( i i WCC). LFTs, paracetamol, and salicylate levels ( (cid:2) beware co-ingestion), urine microscopy for crystals (needle-shaped calcium oxalate monohydrate). If undertaken, a renal biopsy would show widespread tubular crystal deposition with ATN. Osmolality and anion gap: measured serum osmolality is raised, but calculated osmolality ([ 2 x Na + ] + urea + glucose) is often normal. The difference between the two is termed the osmolar gap (often >10mOsmol/kg). This develops as patients absorb glycol over the \201 r st few hours post-ingestion. Subsequently, as glycol is metabolized to acids, the osmolar g ap falls \200\224 while the anion gap increases and systemic acidosis worsens. (cid:2) Oth er toxic alcohols also raise the osmolar gap. ETHYLENE GLYCOL POISONING 911 Management \200 Gastric lavage if <1h since ingestion. \200 If within 12h of ingestion, administer fomepizole (4-methypyrazole). \200 Competes with EG for alcohol dehydrogenase , preventing rapid accumulation of toxic metabolites (8,000 x greater af \201 nity than et hanol). It is relatively easy to use. Loading: 15mg/kg IVI in 100mL normal saline over 30min. Maintenance: 12-hourly doses of 10mg/kg (increase frequency 4h if dialysis is required \200\224 fomepizole is dialysable). The dose is increased to 15mg/kg 12h after 48h treatmen t. Continue until acidosis has resolved and EG level <200mg/L (<3.2mmol/L), or preferably undetectable. \200 If fomepizole is not available, then admin ister ethanol . Ethanol is much more dif \201 cult to use: (cid:2) intoxication and respiratory depression. Give IVI as a 10% solution in 5% glucose, e.g. remove 50mL from a 500mL bag of glucose, and replace with 50mL absolute ethanol. Loading dose: 7.5mL/kg of 10% solution. \200 Maintenance: 1mL/kg/h for non-drinkers (2mL/ kg/h for drinkers). \200 Titrate to a plasma ethanol level of 7 1g/L (22mmol/L). Haemodialysis effectively removes EG and metabolites. Discuss in all cases, and refer without delay if: \200 Renal failure, oliguria, severe acidosis. \200 End-organ dysfunction, e.g. neurological signs. \200 Plasma level >500mg/L (8mmol/L). Adjunct therapies include: NaHCO 3 1.26% IVI infusion to correct acidosis. \200 Maintain high urine \202 ow rate t o minimize risk of crystal deposition. \200 Thiamine, pyridoxine, and other co-factors (e .g. as Pabrinex IV). CHAPTER 12 Drugs and the kidney 912 Methanol Present in methylated spirits, contaminated alcoholic drinks, and many varnishes. Metabolized by alcohol dehydrogenase ( l formaldehyde l formic acid). Symptoms and signs Presentation may be delayed until 24h after initial intoxication resolve s. Nausea, vomiting, confusion, headache, abdominal pain (pancreatitis), seizures ( 2 check blood sugar), d GCS and visual disturbance (retinal oedema and optic nerve demyelination l d acuity, photophobia, \200\230 snow storm \200\231 vision). Late: white matter hemorrha ge ( l parkinsonism). Investigations U&E, SCr, CK ( (cid:2) rhabdomyolysis), amylase ( i in 7 60%), glucose (hypoglycaemia common), serum osmolality, ABG. Peak methanol level >0.2g/L (6.25mmol/L) represents signi \201 cant ingestion, and >0.5g/dL (15.6mmol/L) indicates se vere intoxication. Management Supportive care, administer fomepizole or ethanol if level >0.2g/dL (6.25mmol/L) , high osmolar gap (>10mOsmol/kg), or metabolic acidosis (pH <7.3). Haemodialysis Refer if renal failure, visual impairment, metabolic acidosis, or methanol le vel >0.5g/L (>15.6mmol/L). 913 Chapter 13 Renal physiology Renal structure and function 914 The glomerulus 916 Regulation of GFR 920 Tubular function: overview 922 The proximal convoluted tubule 924 The loop of Henle 926 The loop of Henle: t he countercurrent system 928 The distal nephron 930 CHAPTER 13 Renal physiology 914 Renal structure and function Kidney structure \200 The functional unit of the kidney is t he nephron (see Fig. 13.1). \200 Each kidney contains 7 1 million nephrons. \200 There are \201 ve parts to the nephron (see Fig. 13.1): The glomerulus, which acts as the blood \200\223 kidney interface. Plasma is \201 ltered from capillaries into Bowman \200\231 s capsule before heading off down the nephron. The proximal convoluted tubule where most of the \201 ltered load is reabsorbed ( 7 60%). The loop of Henle, which is able to concentrate urine because of the high osmolality of the surrounding medullary interstitium. This high concentration of solutes is maintained by th e countercurrent multiplier system. The distal convoluted tubule, which \200\230 \201 ne-tunes \200\231 solute and water reabsorption. The collecting system is formed by the convergence of several nephrons to create a collecting duct. These progressively amalgamate, as they cross the med ulla, until opening into papillary ducts in the renal pelvis. There are two types of nephrons, those localized to the cortex and those extending into the medulla, the latter characterized by longer loops of Henle and additional metabolic activi ty. Renal blood supply: Renal artery l renal sinus l interlobar arteries (occupy the space between the renal pelvis and adjacent cortical tissue) l divide at the corticomedullary junction l branching arcuat e arteries l interlobular arteries (traverse the cortex). No arteries penetrate the medulla. \200 The kidneys are unique for possessing two capilla ry beds in series. The glomerular capillaries are maintained at the high pressure required for \201 ltration. Peritubular capillaries are low pressure. This arrangement allows for large volumes of \202 uid to be \201 ltered and reabsorbed. Functions of the kidney \200 Glomerular \201 ltration rate ( b p. 30): This refers to the \201 ltrate of plasma crossing the glomerular barrier into the urinary space per unit time across all functioning nephrons (usually expressed in mL/min). Tubular function: The renal tubules reabsorb 7 99% of the glomerular \201 ltrate, enabling them to regulate electrolyte excretion and to concentrate or dilute urine, according to physiological circu mstances. RENAL STRUCTURE AND FUNCTION 915 Production of urine \200 The production of urine is the result of three processes within the kidney: \200 Glomerular \201 ltration. \200 Selective and passive reabsorption within the renal tubules. \200 Excretion from the distal nephron into the urinary tract. Acid \200\223 base regulation ( b p. 818). The kidneys and lungs work together to maintain an arterial pH of 7.35 \200\223 7.45. The lungs excrete CO 2 . The kidneys: (i) prevent HCO 3 \200\223 loss; (ii) excrete H + ; and (iii) buffer urinary H + . Endocrine functions: Renin: produced by specialized cells within the juxtaglomerular apparatus ( b p. 456). Erythropoietin: produced by the peritubular interstitial \201 broblasts in the outer medulla and deep cortex ( b p. 218). The kidneys are also an important site of action of several hormones, e.g. aldosterone (pro motes Na + reabsorption), ANP (promotes Na + loss), and ADH (increases distal tubular perme ability, allowing urinary concentration). Autocrine function: Production of NO, endothelins, prostaglandins, natriuretic peptides. Protein and polypeptide metabolism, e.g. metabolism of insulin. Glomerular capillary Afferent arteriole Filtrate Juxtaglomerular apparatus Macula densa Distal convoluted tubule Efferent arteriole Cortical collecting duct Connecting tubule Convoluted Thick ascending limb of loop of Henle x e t r o C Proximal tubule Straight Thin ascending limb of loop of Henle a l l Thin descending limb of loop of Henle u d e M Outer meduliary collecting duct Inner meduliary collecting duct Papillary duct Fig. 13.1 The geography of the nephron. Reproduced from O \200\231Callaghan, C (2009). The Renal System at a Glance , 3rd edn. With permission from Wiley-Blackwell. CHAPTER 13 Renal physiology 916 The glomerulus Introduction The glomerulus is at the start of the nephron and provides the \201 rst step in \201 ltering the blood to form urine. The glomerulus comprises a tuft of specialized capillaries attached to the mesangium, both of which are enclosed in a pouch -like extension of the tubule called Bowman \200\231 s cap- sule. Bowman \200\231 s capsu le is a pocket of epithelial cells in continuity with the epithelial cells of the proximal convoluted tubule (PCT). Blood is \201 ltered through the capillaries of the glomerulus i nto Bowman \200\231 s capsule, and it can then start its journey down the remainder of the nephron (see Fig. 13.2). Bowman \200\231 s capsule contains: Capillaries A knot of capillaries lined by endothelial cells. Blood \202 ows in via the a ffer- ent arteriole and out via the efferent arteriole (for a capillary bed to have arterio les on both ends is unique in the circulation). Changes in afferent and efferent arteriolar tone are powerful ways of regulating blood \202 ow and pressure within the glomerulus ( b p. 920). The capillary endothelium contains large fenestrae. This renders it considerably more permeable ( 7 100 x ) than most capillary beds. A strong ionic glycocalyx helps with charge selection. The glomerular basement membrane (GBM) The GBM is a non-cellular layer, consisting mainly o f glycoproteins (esp. type IV collagen), sialoglycoproteins (e.g. laminin, \201 bronectin ), proteogly- cans (e.g. heparin sulfate). It is manufactured mainly by podocytes and is th e principal \201 ltration barrier. On electron microscopy, it consists of three layers: t he lamina interna, lamina densa, and lamina externa. Epithelial cells (podocytes) Podocytes are specialized epithelial cells that produce the co mponents of the GBM (under cytokine control). They have specially adapted foot pro- cesses (hence the name \200\230 podocyte \200\231 ) that possess a contractile apparatus. Interd igitating podocytes are separated from each other on the GBM by \200\230 slit diaphragms \200\231 , which constitute the key mechanical and signaling barrier to \201 ltration. Po docytes produce podocalyxin (a sialoglycoprotein) to form a highly anionic coating that all ows charge selectivity. Abnormal podocyte function is considered central to proteinuric nep hropathies. Mesangial cells Mesangium is the remaining structural component of the glomerulus. Mesangia l cells have an important regulatory function. Two main types have been identi \201 ed; mo st are derived from a smooth muscle lineage (and respond to similar stimuli). These are sit uated adjacent to the endothelium (within the GBM) and are active in signaling, recruitment of non-resident cells, and maintenance of vascular tone. Other mesangial cells are derived from macrophages and monocytes and possess phagocytic properties. Mesangial cells are embe dded in an extracellular matrix containing collagen IV and V, \201 bronectin, laminin, an d proteoglycans. Mesangial cell activation and proliferation occur in response to immune-me diated glomerular injury. THE GLOMERULUS 917 The glomerular \201 lter See Figs 13.3 and 13.4. The glomerular \201 lter is composed of four layers: Charged endothelial glycocalyx. \200 Endothelial fenestrations. \200 The glomerular bas ement membrane. \200 The inter-podocyte slit diaphragm. The inter-podocyte slit diaphragm offers a mesh of interlocking proteins and lipids, includ ing nephrin, podocin, CD2AP, and podocalyxin. Podocyte dysfunction (at the heart of many proteinuric nephropa- thies) impairs both the slit diaphragm and foot process adhesion. Filtration is principally determined by molecular size and, to a much lesser extent, by charge. The glomerular barrier is very permeable to water. Substances with a MW <5,000Da are freely \201 ltered (unless albumin-bound in plasma). Larger molecules are partially \201 ltered, with \201 ltration fraction depend- ing on both size and charge. Negatively charged molecules have a lower \201 ltration fraction th an similarly sized cationic molecules. Albumin (MW 61kDa) is polyanionic and scarcely \201 ltered under nor- mal circumstances. Approximately 70,000g passes through the glomeru- lus every 24h, of which just 7g (0.01%) a ppears in the \201 ltrate (and this is usually reabsorbed further down the nephron). CHAPTER 13 Renal physiology 918 Extra-glomerular matrix Mesangial cells Efferent arteriole Macula densa Afferent arteriole Glomerular basement membrane Fenestrated endothelium Podocytes Foot process Urinary space Parietal epithelium e u b u t l l a m x o r P i Fig. 13.2 Glomerular structure. Blood enters via the afferent arteriole and leaves via the efferent arteriole. The capillaries have a fenestrated endothelium. The visceral epithelium of Bowman \200\231 s capsule consists of podocytes, the foot processes of which (with the GBM) cover the capillaries and the mesangium. At the vascular pole, the visceral epitheliu m re \202 ects into the parietal epithelium, which itself becomes the proximal tubule at t he urinary pole. US, urinary space . Reproduced from Fogo, A, Kashgarian, M (2011). Diagnos tic Atlas of Renal Pathology , 2nd edn. With permission from Elsevier. THE GLOMERULUS 919 PO E MM GBM M Fig. 13.3 Schematic demonstrating the \201 ltration barrier. The glomerular capillary has a fenestrated endothelium (E). The capillary is surrounded by the GBM, which deviates to c over the mesangial cells (M). The interdigitating foot processes of the podocyte (PO), sepa rated by the slit diaphragm, cover the GBM and form the \201 nal barrier to \201 ltrati on. Reproduced with permission from Davison AMA, Cameron JS, Grunfeld J-P et al (eds) (2005 ). Oxford Textbook of Clinical Nephrology, 3rd edn. Oxford, Oxford University Press. Fig. 13.4 Scanning EM of rat glomerular capillaries. The capillary is covered by branching podocytes. The primary (P) and secondary (F) processes interdigitate, separated by slit dia phragms, and cover the entire surface of the GBM. Reproduced with permission from Davison A MA, Cameron JS, Grunfeld J-P et al (eds) (2005). Oxford Textbook of Clinical Nephrology, 3r d edn. Oxford, Oxford University Press. CHAPTER 13 Renal physiology 920 Regulation of GFR Introduction GFR is dependent on the net hydrostatic and colloid osmotic pressure gradients between glomerular plasma and the \202 uid in Bowman \200\231 s space . This will be determined by: \200 Renal blood \202 ow (RBF): Renal blood \202 ow represents 20 \200\223 25% of cardiac output (1.25L/ min). Two to three million nephrons produce an ultra \201 ltrate of plasma (125mL/min or 7 170L/day). Most water and solutes are all reabsorbed into the tubular epithelium. Glomerular structure ( \201 ltration surface area and permeability). \200 Transglomerula r capillary pressure (afferent \200\223 efferent tone). \200 Plasma oncotic pressure. Physiological regulation Autoregulation Preserves renal blood \202 ow and GFR despite var iations in systolic BP. Predominantly effected by the afferent arteriole: local stretch rec eptors quickly adjust afferent arteriolar tone via a \200\230 myogenic re \202 ex \200 \231 . Afferent and arteriolar tone Controls intra-glomerular pressure and \202 ow: \200 Incre ased afferent arteriolar tone (vasoconstriction) leads to reduced \202 ow and reduced pressure within the glomerulus. Increased efferent arteriolar tone (vasoconstriction) leads to reduced \202 ow and increased pressure within the glomerulus. Tubuloglomerular feedback TGF allows tubular \202 ow sensing to change GFR: Cl \200\223 delivery to the juxtaglomerular apparatus is sensed at the macula densa ( b p. 921). i dist al Cl \200\223 delivery l afferent arteriolar vasoconstriction l d GFR (medi- ators includ e adenosine, adenosine triphosphate, thromboxane, NO, and A2). The importance (and beauty) of this mechanism can be appreciated if large quantities of Cl \200\223 (and thus Na + ) a re pathologically delivered to the distal tubule (e.g. non-oliguric ATN). Through TGF, d re nal blood \202 ow leads to d GFR, safeguarding against profound diuresis and volume deple tion. In other words, TGF basically aims to avoid volume depletion/ overload if GFR i or d . Systemic factors \200 The sympathetic nervous system (noradrenaline/norepinephrine) is a key mediator of vasoconstriction of the afferent arteriole. Thus, in systemic hypotension ( l i sympathetic activity), renal blood \202 ow is reduced (allowing blood to be diverted to the brain and heart). Noradrenaline also stimulates production of renin and A2. A2, with its potent vasoconstrictive effects at the efferent arteriole (with much weaker vasoconstrictor effects at the afferent arteriole), will assist in the ma intenance of GFR ( (cid:2) this is why ACE-I drop REGULATION OF GFR 921 transglomerular capillary pressures). Renin also increases with sodium depletion l i A2. Vasodilator prostaglandins (PGE 1 , PGE 2 , and prostacyclin) are also important ( (cid:2) hence the need to avoid NSAIDs when renal blood \202 ow is compromised). Other factors: endothelins (esp. ET 1 ) are vasoconstrictors (efferent > afferent). ANP and BNP cause afferent dilatation. NO relaxes both the afferent and efferent arteriole and inc reases renal blood \202 ow. The juxtaglomerular apparatus \200 The juxtaglomerular apparatus has a regulatory role. I t consists of a specialized area of cells that are intimately related to the distal nephron and to the adjacent afferent and efferent arterioles and glomerulus. It comprises the macula densa, extra-glomerular mesangium, and arterioles (the last part of the afferent and the \201 rst part of the efferent). The macula densa is situated toward the end of the thick ascending limb of the loop of Henle (i.e. in the distal nephron) (see Fig. 13.1). The cells of the macula densa are closely packed with large nuclei and attached to a baseme nt membrane that is intimately related to the extra-glomerular mesangium. They contain larg e amounts of NO and cyclo-oxygenase. Modi \201 ed smooth muscle cells, called granular cells, surround the afferent arteriole. \200\230 Granular \200\231 refers to conspicuous cytoplasmic granules containing renin th at is ready for exocytosis into the surrounding interstitium. Granular cells have dense sym pathetic innervation.