of voiding and drinking, particu- larly at night, is useful information in assessing the s everity of NDI. Parents often also report problems with the attention span and mental conce ntration of an affected child, which may be partly due to the constant interruptions needed to drink and to void. With adequate treatment patients with NDI can function well. In cont rast, untreated patients typically have a persist- ent failure to thrive, as the constant i ntake of \202 uid limits their appetite. Mental retardation used to be an almost invariab le feature, probably as a result of repeated episodes of hypernatremic dehydration, but it is rarely seen in patients who have been diagnosed and treated early. Some patients develop dilatation of the lower urinary tract from the high urine \202 ow rate ( \200\230functio nal out \202 ow tract obstruction \200\231) especially if they have poor voiding habits an d they are not encouraged to \200\230double micturate \200\231 to ensure bladder emptying. Pathophysiology Blood (plasma or serum) osmolality is centrally monitored by the hypothalam us: in response to a rise in osmolality, arginine vasopressin (AVP or ADH) is secreted. In the kidney, AVP binds to a receptor (AVPR2) in the \201 nal (distal) part of the nephron, the collecting duct. The urine entering the collecting duct is dilute and has an osmolalit y that is much lower than that of plasma ( 100 vs 300 mOsm/kg), because of active solute r emoval (transportation) in the thick ascending limb (TAL) of Henle \200\231s loop. In the a bsence of circulating AVP, the collecting duct is water impermeable and the \201 nal urin e will remain dilute. However, binding of AVP to its receptor (and through a series of inte rmediate steps) leads to the insertion of water channels (aquaporin 2 or AQP2) in the lumin al (urine-facing) membrane of collecting duct (principal) cells, making them water permeabl e. Since the osmolality in the interstitium of the renal medulla is high (because of the co unter-current multiplier mecha- nism), water is reabsorbed, which concentrates the urine (t o a maximum of 1000 mOsm/kg). Thus, AVP regulates water permeability of the collect- ing d uct so that the \201 nal urine concentration can vary between the osmolality of the urine entering the collect- ing duct ( 100 mOsm/kg) and that of the interstitium ( 1000 mOsm/kg) . In NDI, the kidney \200\231s ability to respond to AVP is impaired and the urine remains maximally dilute (with an osmolality <100 mOsm/kg). Etiology Congenital This presents in the \201 rst weeks to months of life: \200 \200 \200 Acquired NDI The presenting symptom in acquired NDI is typically poly- uria and frequency, including nocturia, but the onset is usu- ally much later than in congenital NDI and there is usually no family history. X-linked recessive due to mutations in AVPR2 (90%); autosomal recessive due to mutations in AQP2 (10%); (autosomal dominant DI due to mutations in AQP2 is very rare; autosomal domina nt DI is more likely to be of the central rather than nephrogenic type). Diagnosis of DI An inappropriately dilute urine in the face of a raised plasma osmolality d e \201 nes DI. A large urine volume in a dehydrated patient should always raise the possib ility of a urinary concentrating defect. The diagnosis is easily made by obtaining plasma a nd urine biochemistries, particularly osmolalities. Acquired This presents at any age: \200 \200 obstructive uropathy ( \200\230post-obstructive diuresis \200\231); renal failure/tubular d ysfunction (e.g. nonoliguric acute kidney injury, tubulo-interstitial nephritis, renal dysp lasia, nephronophthisis, cystic kidney diseases); lithium (in 20% of patients treated with lithium); CHAPTER 5.5 Nephrogenic diabetes insipidus 221 A diagnostic algorithm for patients with hypernatremic dehydration and suspected diabetes i nsipidus (DI) with a urine output >1 mL/kg/h. Urine osmolality >800 mOsm/kg? (>500 mOsm/kg in infants)? no yes No DI DDAVP test Urine osmolality >800 mOsm/kg (>500 mOsm/kg in infants)? no yes Evidence for acquired DI? Central DI History: lithium? Biochemistry: hypokalemia? hypercalciuria? generalized tubulopathy? renal failure? Radiology: obstructive uropathy? yes no Inherited NDI Proceed to molecular genetic testing Acquired NDI Fig. 5.5.1 A diagnostic algorithm for patients with hypernatremic dehydration and suspected diabetes insipidus (DI) with a urine output > 1 ml/kg/h. Maximal urinary concentrating ability increases during the \201 rst year of life, but a u rine osmolality <500 mOsm/kg (infant) or <800 mOsm/kg (adult) in the presence of hypernatre mia indicates DI. In classic inherited NDI the urine osmolality is always <200 mOsm/kg (and typically 100 mOsm/kg). A diagnostic algorithm for a child or adult presenting with hyper natremic dehydration is given in Fig. 5.5.1. Interestingly, intravenous DDAVP at high doses (0.3 g/kg) can cause systemic side-effects : a mild decrease in blood pressure and an increase in heart rate via AVPR2. Patients with mutated AVPR2 (X-linked recessive NDI) do not experience these hemodynamic effects, while p atients with intact AVPR2, but mutated AQP2 (autosomal reces- sive and dominant NDI), do. T hus, the intravenous DDAVP test can help to discriminate between these two forms of NDI. A typical protocol for the DDAVP test is given in Table 5.5.1. A rare complication of the DDA VP test is hyponatremia. Patients with an intact thirst mechanism and who respond normally to DDAVP will stop drinking water as their plasma osmolality falls. Hyponatremia may develo p in those patients with psycho- genic polydipsia who keep on drinking, despite lowered pla sma osmolality, and in infants who continue to be fed by their parents or carer during the test. Therefore, close observation and limitation of \202 uid intake to a volume equal to the amount of urine excreted during the test period is necessary to avoid this potentially serious complication. DDAVP test interpretation (see also Fig. 5.5.1) If urine osmolality after DDAVP in the test period is: \200 \200 Diagnostic procedures DDAVP test A DDAVP test is used to discriminate central (cranial) fro m nephrogenic DI. The effects of AVP are mediated by two different receptors: \200 AVP re ceptor type 1 (AVPR1) mediates vasocon- striction; AVP receptor type 2 (AVPR2) mediates ant idiuresis. The AVP analog 1-desamino-8-D-arginine vasopressin (DDAVP) has a high speci \201 city for AVPR2 and can be used to assess the renal response, while avoiding the system ic effects mediated by AVPR1. DDAVP can be given intranasally (20 g), intramuscularly (0. 4 g if <10 kg, 2 g if >10 kg), intravenously (0.3 g/kg) or orally (200 g). While in tranasal DDAVP is less invasive, absorption is less reliable; if the result of the test is inconclusive, it may need to be repeated using injected DDAVP. DDAVP given intravenously or orally requires a shorter observation period (2 \200\2234 h) than when given by the other routes (4 \200\2236 h). <200 mOsm/kg: the diagnosis of NDI is established; >800 mOsm/kg: normal renal concentrating ability: NDI is excluded; 200 \200\223800 mOsm/kg: this is an intermediate response, arisi ng because: The test is invalid and needs to be repeated. 2 2 2 D . B O C K E N H A V E R , D . B C H E L I Table 5.5.1 Typical protocol for the DDAVP test , Time (min) Actual time (e.g. 09:00) \200\22330 \200\22315 0 10 15 20 30 40 50 60 75 90 110 130 150 A N D __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ R . U N W N dDAVP infusion I BP (mmHg) HR (beats/min) Fluid intake (mL) Urine volume (mL) Urine osmolality Urine Na+ Plasma osmolality Plasma urea, creat, Na+ CHAPTER 5.5 Nephrogenic diabetes insipidus 223 Diuretics The use of a diuretic in a polyuric disorder seems counter- intuitive, but it doe s make physiological sense. Thiazide diuretics inhibit reabsorption of sodium and chlo- rid e in the distal convoluted tubule (DCT; part of the uri- nary diluting mechanism \200\223 see above) and so increase the NaCl concentration and osmolality of the urine. The increase d loss of NaCl in the urine decreases intravas- cular volume, which increases proximal tubu lar reabsorp- tion of sodium and \202 uid (in this nephron segment). As a result, less \202 uid is delivered to the collecting duct and the urine volume decreases. An example is hydrochlorothiazide at a dose of 2 mg/kg/ day in two divided doses. The more long-acting be nd- ro \202 umethiazide (50 \200\223100 g/kg/day) can be given as a single daily dose. H ypokalemia is a complication of thiazide diuretic adminis- tration, but supplementation wit h potassium salts can increase the osmolar load and is best avoided. Combining a thiazide d iuretic with a potassium-sparing diuretic such as amiloride (0.1 \200\2230.3 mg/kg/day) is a better choice, although amiloride can cause gastrointestinal side-effects. The kidneys are immature (renal concentrating ability is diminished in infants). The patien t has partial NDI. (This is physiologic in chil- dren aged <1 year if >500 mosm/kg. It is m ore common in acquired forms of NDI, but rare in inherited forms.) Water deprivation test A water deprivation test is used to discriminate central DI from psy chogenic polydipsia. The aim of the water deprivation test is to produce mild dehydration t o challenge the kidney \200\231s concentrating ability. A simple water deprivation test can be undertaken by determining the osmolality of the first morning urine sample (ideally the second void, as there may be some car- ryover from the evening before). A concentrated uri ne excludes a diagnosis of DI. In those patients with dilute \201 rst-morning urine, and who are suspected of having psychogenic polydipsia, a formal water deprivation test may be necessary. Water is withheld until the plasma osmolality rises to just above the upper limi t of normal (>295 mOsm/kg). A water deprivation test carries the risk of hypernatremic dehy dration, especially in infants, as there may be delays in obtaining (and reacting to) labor atory results. It should only be done with close monitoring of body weight, vital signs and biochemistry. Some useful (adult) guideline values are summarized below: 1. Early morning urine: osmolality >700 mOsm/kg and Prostaglandin synthesis inhibitors Prostaglandin synthesis inhibitors can help to decrease polyuria. Indomethacin (1 \200\2233 mg/kg/day in three or four divided doses) is most widel y used. However, the long-term use of this drug risks impairing renal function, and is asso ciated with hematological and gastrointestinal side-effects, which include life-threatening hemorrhage. A histamine H2-antagonist (e.g. ranitidine 2 \200\2234 mg/kg/ dose twice daily ) and a prokinetic drug (e.g. domperidone 250 \200\223500 g/kg three to four times daily) can help with the vomiting often seen in infants with NDI, and may also help to reduce the gastrointestinal side-effects of indomethacin. A combination of a thiazide diuretic and in domethacin is useful during the \201 rst years of life, with or without amiloride. Close monitoring of a patient with NDI for side-effects and for any changes in urine output or gr owth are key compo- nents of management. [Na+] <80 mmol/L is normal. 2. Eight-hour water deprivation test: Normal response. Urine volume <1 L, and urine osmolality >700 mOsm/kg. Diabetes insipidus. Urine volume >1.5 L, urine osmo- lality <400 mOsm/kg (if urine [Na+] >100 mmol/L, there may be a salt-wasting disorder), and plasma osmolality >295 mOsm/kg. Congenital NDI Treatment in the outpatient setting Diet The importance of proper treatment of NDI is highlighted by the fact that mental retardation used to be a common complication, but can be completely prevented by early and proper treatment. Treatment should be provide d by a specialist physician and a dietician with experience of the condition, and consists mainly of osmotic load reduction. The osmotic load consists of salts and protein (urea), wh ich the kidney must excrete and can be roughly esti- mated using the following formula: Osm otic load = \2272 amount of sodium and potassium (to account for the accompanying anions) in millimoles plus protein (in grams) \2274. Since lipids and sugars are metabolized witho ut products that require renal excretion, only protein intake needs to be restricted, but i t should still meet the recommended daily allowance. A reasonable goal is a diet containing 15 mOsm/kg/day: a child with a urine osmolality of 100 mOsm/kg will need a \202 uid int ake of 150 mL/kg/day to be able to excrete this load. Future perspective: molecular chaperones The vast majority of mutations identi \201 ed in the AVPR2 gene lead to improper folding of the protein product, its entrap- ment in the end oplasmic reticulum (ER), and failure to reach the plasma membrane. Small membrane-permeable AVP-receptor antagonists ( \200\230vaptans \200\231) can induce correct folding and transp ortation the protein to the plasma membrane. Pilot studies in NDI patients have shown a sig ni \201 cant decrease in urine output when given these antagonists. Treatment in the hospital setting Patients are always prone to the development of dehydra- tion, especially if they are without free access to \202 uids (infants are at greatest ri sk) or if there are extrarenal \202 uid losses (vomiting and diarrhea). There should be a low threshold for admission to hospital for intravenous hydration to prevent dehydration. D. BOCKENHAVER, D. BICHEL, AND R. UNWIN 224 Further reading Bernier V, Morello JP, Zarruk A, et al. Pharmacologic chaperones as a poten tial treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 2006; 17: 232 \200\223243. Hypotonic \202 uids that match the osmolality of the urine, such as dextrose in water or 0.2% saline, are standard solu- tions for intravenous hydration in NDI. Hypotonic \202 ui ds should never be given in boluses, since any acute lowering of plasma sodium concentratio n risks causing cerebral edema. Fluid administration should be calculated to meet mainte- n ance requirements and to correct \202 uid de \201 cits over 48 h, while keeping in mind any ongoing losses \200\223 a tonicity balance (see below). Replacement \202 uids that h ave a higher osmolality than urine osmolality can worsen hypernatremia. For example, 0.9% n ormal or isotonic saline contains 150 mmol Na+ with an osmolality of 300 mOsm/kg; if wate r balance is maintained and the input volume is matched to the output volume of urine, 3 L of this solution will give 900 mOsm (450 mmol Na+) intravenously; if urine output is also 3 L over the same time period, but with an osmolality of 100 mOsm/kg (maximally dilute), on ly 300 mOsm (150 mmol Na+) will be excreted, result- ing in retention of 600 mOsm (or 300 m mol Na+). By contrast, if there are increased salt losses, as can occur with diarrhea, or i f hypotonic \202 uids are administered at a rate higher than urinary losses, hyponatremia may occur. Therefore, close monitoring of the patient \200\223 weight, \202 uid balance , clinical symptoms and biochemistry \200\223 is essential to avoid these complications. Bockenhauer D. Diabetes insipidus. In: Geary DF, Schaefer F (eds), Comprehensive Pediatric Nephrology. St Louis, MO: Mosby; 2008; 11: 489 \200\22398. Fujiwara TM, Bichet DG. Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol 2005; 16: 2836 \200\2232846. Nielsen S, Frokiaer J, Marples D, et al. Aquaporins in the kidney from molecules to medicine. Physiol Rev 2002; 82: 205 \200\223244. Sands JM, Bichet DG. Nephrogenic diabetes insipidus. Ann Intern Med 2006; 144: 186 \200\223194. Internet resources The Diabetes Insipidus Foundation: http://www.diabetesinsipidus.org/ The NDI Foundation: http://www.ndif.org/ See also Hypo-/hypernatremia: disorders of water balance, p. 42 Urinary tract obstruction, p. 652 Nephronophthisis, p. 600 Renal dysplasia, p. 646 225 Chapter 6 Chronic interstitial disease Chapter contents Analgesic nephropathy 226 Nonsteroidal anti-in \202 ammatory drugs and th e kidney 228 Uric acid and kidney 232 Nephrotoxic metals 236 Balkan nephropathy 238 Aristol ochic acid nephropathy ( \200\230Chinese herb nephropathy \200\231) and other rare causes o f chronic interstitial nephritis 240 H. DODEJA 226 Analgesic nephropathy Analgesic nephropathy is the commonest drug-induced chronic kidney disease. It is character ized by renal papillary necrosis and chronic tubulointerstitial nephritis. Papillary necros is is an ischemic lesion of the inner medulla secondary to a decrease in blood \202 ow, i n combination with in \202 ammation. Analgesic abuse accounts for >25% of cases of papilla ry necrosis in the USA, and 75% in Australia. Prolonged consumption of combination analgesics for migraine, low backaches and menstrual p ain is common. Renal manifestations Polyuria and nocturia (secondary to concentrating defect), and urinary acidi \201 cation defects. Low \200\223moderate grade proteinuria (<2 g/day). More severe proteinuria suggests associated focal segmental glomerulo- sclerosis and predicts a poor p rognosis. Sterile pyuria. Occasional episodes of hematuria may be due to papillary necrosis causing sloughed papilla to be shed in the urine, or due to recurrent urinary tract infect ions. Persistent hema- turia suggests the possibility of urinary tract malignancy. Papillar y necrosis may present as an acute devastating ill- ness with early mortality secondary to sepsis. It may have a protracted course extending from months to years, with recurrent urin ary tract infection and tubular dysfunction. It also may be totally asymptomatic in 75% of cases, and may be detected incidentally on IVP or CT scan. The risk of uroepithelial carci noma is 8 \200\22310%. Early cessation of analgesic abuse arrests progression of renal dysf unction in 50% of cases and leads to an improve- ment in renal function in a further 20%. I n the remaining 30%, progression to end-stage renal disease occurs. Factors that predict pr ogressive renal function deteriora- tion include severe hypertension, persistent proteinuri a, and the presence of small kidneys on presentation. Epidemiology Early recognition of analgesic abuse is important as it causes a completely pr eventable form of renal disease and renal failure. There is wide variation in the geographi c incidence, based on differences in the annual per capita consumption of phenacetin. The i ncidence is highest in Australia (20%) and Sweden, and lowest in Canada (2 \200\2235%). Pathogenesis It results from the habitual consumption of combination analgesics, particular ly those containing phenacetin, aspirin and caffeine. Dependence on these combination mixtu res is encour- aged by the caffeine component. This risk of developing renal disease is dep endent on the cumulative dose. Renal injury begins after consumption of 2 \200\2233 kg of b oth phenacetin and aspirin, and is clinically evi- dent after 5 \200\2237 kg is consumed ov er a period of 5 \200\2238 years. The principle site of damage is in the medulla, which is vulnerable due to the higher concentration of toxic metab- olites in this region. Injury is enhanced by the countercurrent mechanism and the associated low oxygen content in that are a. \200 Extra-renal manifestations Peptic ulcer disease is seen in more than one-third of the patie nts. Microcytic anemia due to chronic blood loss is more common and severe than expected fo r the level of renal dysfunction. Hypertension is seen in >70% of patients, and is severe i n 6 \200\22310%. Ischemic heart disease and renal artery stenosis are seen occasionally. Phenacetin is converted to acetaminophen, depleting the cells of glutathione, resulting in the generation of oxidative and alkylating metabolites. Aspirin and other NSAIDs decrease v asodilatory pros- taglandins, resulting in the unrestricted influence of vasoconstrictors. Caffeine is metabolized to adenosine, which further promotes vasoconstriction in the kidney . Pathology The characteristic lesions include renal papillary necrosis and chronic tubuloint erstitial nephritis. Damage starts with focal coagulative necrosis of the medulla, followed by overlying interstitial nephritis. Golden-brown lipofuchsin like pigment in the tubular cells is characteristic. The earliest changes are at the papillary tip, which is the site o f highest tissue concentration of analgesics. The classical lesion is capillary sclerosis i n the vessels of the renal pelvis and the ureteral mucosa. It is the earliest detectable pa thological lesion and can be demonstrated in 80 \200\22390% of analgesic abusers. The sever ity of the pathological lesions increases from the pelvis to the pyeloureteral transition. Initially, the kidneys are normal in size with unchanged cor- tex. With continued damage, t he patchy lesions coalesce, the entire papilla becomes necrotic, and is sequestrated and sl oughed into the urine. In combination these effects cause oxidant and ischemic injury to the medulla, which is com pounded by volume depletion. This leads to coagulative necrosis of the medulla with renal p apillary necrosis and overlying interstitial nephritis. Risk factors include increasing age , volume depletion, hypertension and recurrent urine infection. Clinical features Females are more commonly affected than males, with a ratio of 5:1. Analg esic abuse and nephropathy is more common in the middle-aged to elderly population. Median age of onset is 53 years. Affected patients have a typical psychiatric pro \201 le with a tendency to addictive behavior. CHAPTER 6.1 Analgesic nephropathy 227 This is associated with prominent tubulointerstitial nephri- tis in the cortical labyrinth over the necrotic papilla. Retraction of the affected tissue, with compensatory hypertrophy of the unaffected medullary rays, gives the classic nodular kidneys of papillary necrosis. Renal papillary necrosis may be medullary, when focal areas involving innermost medullary regions are necrotic, but the fornices and papillary tips are viable, or papillary, when th e calyceal fornices and the entire papillary tip are destroyed. Analgesic Nephropathy [IVU] Contrast tracking from fornix \200\234Egg in cup \200\235 appearance (ring sign) Normal papilla Shedding of papilla Diagnosis The lack of speci \201 c features makes the diagnosis dif \201 cult. The histor y of analgesic abuse has to be sought by asking leading questions for chronic pain (headach es, backache and menstrual pains). Intravenous urography has historically been the investig a- tion of choice. Depending on the stage of the kidney dis- ease, the changes include (Fig . 6.1.1): \200 atrophic asymmetrical kidneys; \200 clubbed calyces that result from con trast penetrating the spaces that develop following parenchymal necrosis; early cavitation and sinus formation; arc shadows that result from contrast trapping in the sinus and re \202 ect separation of the sequestrum; ring shadows that are due to the sloughed papilla ly ing in the pool of contrast; cavities that develop after the sloughing of the seques- trum. medullary cavities are round or oval, and the papil- lary cavities are triangular; hydrone phrosis may be seen following obstruction by the sloughed sequestrum; caliectasis that is s econdary to the shrinkage of the papil- lary cavities and enlarged medullary cavities; Radi o-opaque concretions due to calci \201 cation. Horns from calices \200\230Claw Sign \200\231 Wavy outlline Fig. 6.1.1 Diagrammatic representation of papillary changes in analgesic nephropathy (IVU). \200 Management Stop further exposure to analgesics. Maintain a daily urine output of >2 L. This decreases the medullary hypertonocity, and the concentration of the analgesics at the papi llary tip. Identify and treat urinary tract infection promptly. Correct anemia. Urologic in tervention for relief of ureteral obstruction due to shed papillae. Regular follow-up for d etection and control of hyperten- sion and proteinuria, according to current recommenda- ti ons for the mangement of CKD. Regular surveillance for hematuria. If it develops, a full ur o- logical work-up is usually required to identify uroepithelial malignancy. Screening may be undertaken with yearly uri- nary cytology. Ultrasound shows a classic garland pattern of papillary calci \201 cations surrounding the renal sinus. Hydronephrosis, secondary to obstruction by the sloughed papilla, may also be seen. The kidneys have an irregular outline with increased echogenicity. Noncontrast CT is the new \200\230gold standard \200\231 in patients with renal failure. It is superior to other methods in the detection of papillary calcifications. In patients with moderate renal failure (serum creatinine of 130 \200\223350 mol/l), papillary calci \201 ca- tions wer e detected with a sensitivity of 92% and a speci \201 - city of 100%. Diagnostic features include decreased renal mass with bumpy contours and papillary calci \201 cations. The dif ferential diagnosis of analgesic nephropathy will include all forms of slowly progressive k idney diseases. Renal papillary necrosis has many other etiologies including: \200 \200 \200 \200 \200 \200 Further reading De Broe ME, Elseviers MM. Analgesic nephropathy. N Engl J Med 1998; 388: 446 \200\223452. Gault MH, Barrett BJ. Analgesic nephropathy. Am J Kidney Dis 1998; 32: 351 \200\223360. Nanra RS. Analgesic nephropathy in the 1990s \200\223 an Australian perspective. Kidney Int 1990; 42: S86 \200\22392. See also NSAIDs and the kidneys, p. 228 Sickle cell disease, p. 192 Drug-induced nephropathies, p. 6 98 Tumors of the renal pelvis and ureter, p. 676 Tumors of the bladder, p. 680 diabetes mellitus; chronic pyelonephritis; sickle cell nephropathy; transplant rejection; r e \202 ux nephropathy; dehydration and hypoxia (children). H. DODEJA 228 Nonsteroidal anti-in \202 ammatory drugs and the kidney Nonsteroidal anti-in \202 ammatory drugs (NSAIDs) are one the most widely prescribed group s of drugs and in addition are available for sale over-the-counter. They can be associ- ate d with signi \201 cant gastrointestinal and renal toxicity. The therapeutic and adverse ef fect pro \201 le is mediated via inhibition of prostaglandin (PG) synthesis from arachidon ic acid by nonspeci \201 c blockade of the enzyme cyclo-oxygen- ase (COX). A variety of re nal side-effects can be observed including salt and water retention, acute tubular necrosis , acute interstitial nephritis, hyperkalemia, and chronic kidney dis- ease. NSAIDs reported to induce kidney damage include aspirin, ibuprofen, fenoprofen, indomethacin, naproxen, di clofenac and mefenamic acid. Table 6.2.1 Risk factors for NSAID- associated AKI Congestive cardiac failure Nephrotic syndrome Cirrhosis with ascites Hemorrhage Drugs, e.g. ACEIs, diuretics, calcineurin inhibitors, gentamicin Underlying renal disease Diabetes mel litus Hypertension Sepsis Anesthetic agents Renal artery stenosis Renal syndromes The spectrum of nephrotoxicities seen with NSAIDs includes: \200 \200 \200 \200 \200 \200 Pharmacokinetics The liver is the site of metabolism for most NSAIDs. Since they are protein-bound, in hypoa lbuminemic states such as liver failure and nephrotic syndrome, the free drug levels increa se and can cause nephrotoxicity. AKI/acute tubular necrosis; acute tubulointerstitial nephritis; renal papillary necrosis; s alt and water retention; hyperkalemia; hypertension. Role of prostaglandins Renal prostaglandins are autacoids that are synthesized on demand and exert their physiolog ic effects locally. PGI2 (prostacyclin) is the most abundant prostaglandin synthesized in t he renal arterioles and the glomerulus. It regulates renal blood \202 ow and GFR by causi ng vasodilata- tion of the renal vasculature and relaxation of mesangial cells. It induces a preferential increase in medullary blood \202 ow. PGE2 is found mainly in the tubules a nd medullary intersti- tial cells, where it modulates sodium and chloride trans- port in th e loop of Henle, and inhibits vasopressin-mediated water transportation in the collecting d uct. In the presence of hypovolemia prostaglandins have an important role in maintaining th e glomerular \201 ltration rate. Consumption of NSAIDs causes inhibition of prostaglandin synthesis, which permits unopposed vasoconstrictive actions of leukotrienes, angiotensin I I, vasopressin, and cat- echolamines. In salt- and water-replete subjects, this has no majo r effects. However, in states of renal hypoperfusion, this is associated with a decline in GFR, and can precipitate renal failure (Table 6.2.1). Elderly patients are more susceptible to NSAID-induced renal failure because of: \200 Acute kidney injury (AKI) NSAIDs (and aminoglycosides) are the leading causes of drug-induc ed AKI. AKI associated with NSAIDs account for 15.5% of all cases of drug-induced renal fai lure. All groups of NSAIDs are implicated, although indometh- acin is the most commonly ass ociated with AKI. Short-acting NSAIDs are more harmful than long-acting NSAIDs. Deteriorati on in renal function may be related to the dose and duration of exposure. Rechallenge with the same or any another NSAID can result in recurrence of the toxicity. Under conditions of circulatory stress, use of NSAIDs shifts the balance towards vasoconstriction, causing a d ecline in the GFR. Patients with underlying chronic kidney disease are highly susceptible, with up to 30% of them developing worsening of renal function on exposure to NSAIDs. In sev ere cases ATN may ensue. Affected individuals are usually oliguric with unremarkable urinal ysis, signi \201 cant hyperkalemia, and a fractional sodium excretion (FENa) of <1%, re \202 ecting avid sodium retention. AKI typically develops within the \201 rst week, and i s usually reversible within 24 \200\223h of stopping the offending agent. Dialysis support is rarely required. Decreased albumin levels causing decreased protein binding and increased free NSAID levels. Decreased total body water and hepatic metabolism, which increases the total concentration of the drug. Age-related decrease in GFR and RBF. Acute tubulointerstitial nephritis (AIN) This is much less common than hemodynamically medi - ated AKI, and usually develops after an average of several months of NSAID therapy. It ha s been reported with all types of NSAIDs, although it is most strongly associated with prop ionic acid derivatives, with >50% of cases occurring with fenoprofen. It is characterized b y a nephrotic presentation in 75% of cases, is often seen in an elderly population, with a Diuretics increase the dependence of renal blood \202 ow and GFR on vasodilatory prostagl andins. The use of NSAIDs in this situation may precipitate renal failure. The degree of re nal disturbance depends on the combina- tion of NSAIDs and the diuretic used. Triamterene i s the most commonly implicated. CHAPTER 6.2 Nonsteroidal anti-in \202 ammatory drugs and the kidney 229 mean age of 65 years, and after a longstanding exposure to the drug. An increased risk is s een in patients with diabetes, hyper- tension, increasing age, diuretic use, and a past his tory of interstitial nephritis. The reaction is renal-limited, with systemic features (feve r, rash, eosinophilia) present in <10% of patients. The pathogenesis of NSAID-induced AIN i s unclear. The underlying mechanism may be a hypersensitivity reaction, which is milder tha n that seen with other drugs, since the offending drug itself inhibits the in \202 ammator y reaction. A primary T-cell disorder or delayed hypersensitivity reac- tion may be respons ible. Arachidonic acid metabolism may be altered such that leu- kotrienes are preferentiall y synthesized. These are proin- \202 ammatory, they increase vascular permeability, and t hey are chemotactic, directing an in \202 ux of in \202 ammatory cells into the interstit ium. Heavy proteinuria may be due to the lymphokines pro- duced as a response to the immuno logical activity. The clinical presentation may be determined by the sever- ity of the immu ne response: a robust immune reaction pro- duces acute renal failure with less proteinuria; and a weak immune reaction permits immunocompetent cells to pro- duce lymphokines that res ult in heavier proteinuria. The lack of fever, rash or arthralgia suggests that an allergic etiology is unlikely (Table 6.2.2). The use of steroids in this situation is controversial, although they may shorten the durat ion of the illness. Papillary necrosis This is associated with a history of ingestion of an NSAID during a peri od of severe volume depletion or infection. In the presence of volume depletion, renal bloo d \202 ow is dependent on local PG production. NSAIDs, by dec reasing local PG production , cause medullary ischemic necrosis. It is limited to the distal segment of the involved py ramid. Histology reveals coagulative necrosis, consistent with infarction. The presentation can be acute with an episode of a renal colic associated with hematuria, or the passage of the slough causing obstruction, or it can be subtle with fea- tures of impaired urine conc entration. Though more commonly seen with combination analge- sics, it has also been report ed with the use of NSAIDs alone, especially propionic acid derivatives. Elderly men appear to be more susceptible. Electrolyte imbalance Sodium retention secondary to inhibition of prostaglandin- induced na triuresis is very common. It is usually transient and insigni \201 cant, except when assoc iated with diuretic resistance. The extent to which salt retention becomes clinically man- ifest depends on the degree of baseline prostaglandin pro- duction and the presence of sodi um-retaining states (e.g. heart failure). Hyperkalemia is secondary to inhibition of renin release, with secondary hypoaldosteronism. It is more often seen in patients with underlyin g renal disease and diabetes mel- litus, and in the elderly. Hyponatremia results from NSAI D-induced impairment of solute-free water excretion. This is caused by increasing both the hydro-osmotic effect of any given level of circulat- ing ADH, and the interstitial tonicity . Table 6.2.2 Comparison of clinical features of NSAID- associated tubulo-interstitial nephri tis (TIN) and typical drug-induced TIN Feature NSAID-induced Drug-induced Exposure time Days to months <1 month Nephrotic >90% <10% Eosinophilia <20% >80% Hypertension The combination of salt and water retention, with a decrease in vasodilatory p rostaglandins, causes a rise in the blood pressure, which is more pronounced in known hyper tensives. An average increase in the mean blood pressure of 6 \200\2238 mmHg is seen. Patie nts taking diuretics and -blockers, the elderly, and blacks with low-renin hypertension a re more susceptible. Eosinophiluria <5% >80% Fever and rash <10% >80% A typical presentation is with acute onset of edema, and rarely oliguria. Urinalysis shows proteinuria, microscopic hematuria, and sterile pyuria. Diagnosis requires a renal biopsy. Pathologically NSAID- associated AIN is characterized by a focal or diffuse lymphocytic inf iltrate (Fig. 6.2.1). Glomeruli typically have changes of minimal change disease (foot proc ess effacement). Other less common presentations include: \200 Subclinical renal dysfunction There have been a few reports describing subclinical renal dy sfunction in the form of functional abnormalities. Safe NSAIDs \200\223 a myth Sulindac is a prodrug requiring hepatic conversion of an inact ive sulfoxide to an active sul \201 de. This active metabo- lite is then oxidized and inac tivated in the kidney. Because of this it is suggested to be less likely to inhibit renal p rostaglandins. However, it has been associated with renal toxicity in some patients and the refore its use still needs to be closely monitored. COX-2 inhibitors are a group of drugs w hich inhibit only the damaging COX-2 enzyme, with no effect on the COX-1 enzyme. nephrotic syndrome without tubulointerstitial disease. Histology typically shows features o f minimal change dis- ease or membranous nephropathy; interstitial nephritis with non-nephr otic proteinuria which resembles a more typical allergic interstitial nephritis. Resolution of the disease on withdrawal of the drug is common. Time to recovery varies. Occ asionally dialysis support is necessary, and in this situa- tion recovery of renal function may be incomplete. H. DODEJA 230 Further reading: Ejaz P, Bhojani K, Joshi VR. NSAIDs and kidney. J Assoc Physns Ind COX-2 enzyme is constitutively expressed in the visceral epithelial cells of the glomerulus , and is upregulated by salt depletion. In a study of >5000 subjects receiving the COX-2 in hibitor, celecoxib, for >2 years, renal adverse events were more common than with a placebo , and similar in frequency to that seen with other NSAIDs. Thus, although initially theoret ically appealing, recent reports indicate that COX-2 inhibitors are not devoid of renal sid e-effects. 2004; 52: 632 \200\223640. Gault MH, Barrett BJ. Analgesic nephropathy. Am J Kidney Dis 1998; 32: 355 \200\223360. Klienknecht D. Interstitial nephritis, the nephrotic syndrome, and chronic renal failure se condary to nonsteroidal anti-in \202 amma- tory drugs. Semin Nephrol 1995; 15: 228 \200 \223235. See also Analgesic nephropathy, p. 226 Hypokalemic tubular disorders, p. 214 Minimal change disease, p. 86 Acute tubulointerstitial nephritis, p. 344 Ischemic acute kidney injury, p. 356 Drug-induced nephropathies, p. 698 Therapeutic use of NSAIDs in renal disease. The therapeutic uses of NSAIDs in renal disease are listed in Table 6.2.3. Table 6.2.3 Therapeutic use of NSAIDs in kidney disease Bartter \200\231s syndrome Characterized by hyperreninemic hyperaldosteronism with hypokale mia secondary to NaCl wasting in the loop of Henle. It is also associated with exaggerated renal prostaglandin synthesis. Several manifestations of this condition are corrected by NSAID therapy. See Chapter 5.4. Nephrotic syndrome NSAIDs reduce proteinuria by decreasing renal blood \202 ow and GFR. NSAID therapy in this setting involves a risk of irreversible renal failure. This page intentionally left blank H. DODEJA 232 Uric acid and the kidney Uric acid is a water-insoluble end-product of purine metabolism. It is a weak acid, therefo re at a physiological pH, 98% of uric acid is in the ionized form as urate. By contrast, in collecting tubules where the pH is \211 5.0, the majority is in the form of undissociated uric acid. In humans, the fractional excretion of uric acid is 10%. Net reabsorption is g reater in males (92%) than in females (88%) and children (70 \200\22385%). Gout is therefor e most common in males. Race also in \202 uences uric acid excretion: Polynesians (both ma les and females) have much higher plasma urate concen- trations than Caucasians, and theref ore a greater preva- lence of gout. Parenchymal Urate Hypertension n o i t i s o p e D s e t a r U Renal Insufficiency Tubular Uric Acid Obstruction f l a n e R o Pelvic Calculi Urinary Tract Infection Pathophysiology Renal excretion of uric acid involves four processes: filtration, reabsorpt ion, secretion, and postsecretory reabsorption. Increasing tubular \202 uid \202 ow and urine pH decreases uric acid precipitation in the collecting ducts while increasing renal blood \202 ow regulates secretion. Decreased urate clearance results from: \200 Fig. 6.3.1 Urate and renal disease.