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. intracellular nucleotides causing hyperuricemia (tumor lysis syndrome). Risk factors includ e: volume depletion, lymphoma, rapid response to chemotherapy, pre-existing renal failure, urine pH <5, and high lactate dehydrogenase (LDH) levels. Volume contraction, leading to re duced urine \202 ow and an acidic pH will decrease the solubility of the uric acid within the tubular lumen. Uric acid crystals precipitate and cause blockage of tubules and collec ting ducts. Elevated tubular pressure and decreased renal blood \202 ow cause a decline i n the GFR, and AKI. Uptake of uric acid crystals by tubular epithelial cells leads to tubul ar necrosis and in \202 ammation. Gross overproduction of urate with hyperuricemia is also seen in Lesch \200\223Nyhan syndrome (HGPRT (hypoxanthine guanine phosphoribosyl transfera se) de \201 ciency, an X-linked disorder), rhabdomyolysis, phencyclidine toxicity, and met abolic muscle disorders. In this setting serum urate levels are usually very high (in the r ange of 900 \200\2233000 mol/L (15 \200\22350 mg/dL)). There is pro- gressive renal impai rment with a disproportionate rise in the serum phosphate and LDH levels. A random urine ur ic acid:creatinine ratio of >0.7 (for mmol/L, or >1 for mg/dL) is highly suggestive of acut e uric acid nephropathy. Ultrasound typically demonstrates large echogenic kidneys. Birefri ngent needle-shaped uric acid crystals may be identi- \201 ed on urine microscopy. Drugs (ciclosporin, NSAIDs, pyrazinamide, and vasocon- strictors such as adrenaline, noradr enaline, and angi- otensin). Overproduction of lactate (starvation and status epilepticus). Plasma volume contraction (inadequate salt and water intake, loss of \202 uid from diarr hea, or diuretics). Increased urate clearance is seen with: \200 \200 Circulatory volume expansion (e.g. in pregnancy). Drugs (probenicid and sulphinpyrazone, wa rfarin, corti- costeroids, and X-ray contrast media) (Table 6.3.1). Table 6.3.1 Factors affecting renal handling of urates Decreased clearance Increased clearance Volume contraction Volume expansion Pregnancy Renal vasoconstrictors Increased lactate Drugs (e.g. probenicid, sulphinpyrazone, warfarin, steroids) X-ray contrast Chronic lead toxicity Drugs (e.g. pyrazinamide) Renal deposition of urate causes three types of kidney injury: \200 \200 \200 Acute uric acid nephropathy. Chronic urate nephropathy. Uric acid nephrolithiasis. Treatment Volume expansion and diuresis to maintain a high urine \202 ow rate is the corn erstone of prevention and treatment of acute urate nephropathy. Alkalinization of the urine increases the solubility of uric acid. The urine pH should be maintained at >7.0, until th e hyperuricemia has resolved. Allopurinol inhibits the conversion of xanthine and hypox- an thine to uric acid, thereby reducing both the serum uric acid concentration and the urinary excretion of urate (Fig. 6.3.2). It may, however, induce acute xanthine nephropathy, since xanthine is more insoluble than uric acid. These disorders all result from excess uric acid or urate deposition, although the clinical features may vary (Fig. 6.3.1). Acute uric acid nephropathy Renal tubular obstruction by urate and uric acid crystals resul ts in acute oligoanuric renal failure. It usually occurs in a setting of rapid cell turnove r and lysis, as seen in leukemia and lymphoma (usually after treatment). There is release o f large quantities of CHAPTER 6.3 Uric acid and the kidney 233 The dose of allopurinol has to be adjusted according to the creatinine clearance. If dialys is support is required, hemodialysis is preferable because urate is less ef \201 ciently c leared by peritoneal dialysis. Rasburicase (US Food and Drug Administration- and European M edicines Agency-approved drug for tumor lysis syndrome (only pediatric cases in USA)) is re combinant urate oxidase, which converts uric acid to the non-nephro- toxic product, allanto in. The dose used in children and adults is 0.15 \200\2230.2 mg/kg/day IV for 5 days. Adenine Deaminase Hypoxanthine Adenosine Xanthine Oxidase Guanine Deaminase Xanthine Guanine Chronic urate nephropathy Chronic kidney disease (CKD) has been associated with persistentl y high uric acid levels, as seen in patients with longstanding gout. Sodium urate deposits in the renal medullary interstitium and induces a foreign body reaction. The typical pathol ogical appearance is of central accu- mulation of crystalloid monosodium urate surrounded b y an in \202 ammatory in \201 ltrate that includes in \202 ammatory giant cells. Within this lesion neutrophil activation releases oxidants and protease enzymes that activate plat elets and the coagulation cascade, which leads to chronic in \202 ammation, and ultimately interstitial \201 brosis and tubular atrophy. Hyperuricemia can also induce hypertension which may cause or promote the subsequent development of albu- minuria and progressive CKD . Lesch \200\223Nyhan syndrome causes chronic uric acid overpro- duction with hyperuricemia , uricosuria and CKD. Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal do minant disease characterized by hyperuri- cemia (due to underexcretion), with gout and CKD. Mutation of the uromodullin gene is seen in the majority of Japanese families with FJHN. T here is now increased recognition of subclinical lead intoxication in the renal disease ass ociated with hyperuri- cemia and tubulointerstitial nephritis. Lead probably has both a dir ect toxic effect on renal epithelia, and an effect of increasing tubular uric acid reabsorp tion. The renal biopsy features of chronic urate nephropathy are tubulointerstitial \201 brosis, arteriosclerosis and glomerulo- sclerosis. Uric acid crystals may be seen in the tu bules and the interstitium. The functional associations include mild tubular dysfunc- tion causing minimal proteinuria and renal impairment. A disproportionate increase in the serum uric acid con- centration relative to the degree of the renal dysfunction is seen. The resp onse to allopurinol is variable. Early administra- tion may prevent the progression of the disease, but it is ineffective when renal insuf \201 ciency is established. Allopurinol Xanthine Oxidase Oxypurinol Uric Acid Fig. 6.3.2 The purine degradation pathway and the role of allopurinol. dissociated acid concentration six-fold and promotes the solubilization of anionic urate. A cidic pH oversaturates the urine with undissociated uric acid and promotes the formation an d precipitation of crys- tals in the collecting system. The male to female ratio is 4:1. Ri sk factors for uric acid nephrolithiasis are: gout, acute diarrheal states with acidic urin e, purine-rich diets (meat, \201 sh (particularly salmon and tuna), vegetables such as ca uli \202 ower, beans and spinach), and drugs like aspirin and probenicid. In addition a va riety of disorders involving genetic disorders of purine metabolism, defective renal handli ng, and altered urinary pH predispose to uric acid stone formation. Idiopathic These patients will have normal serum urate levels, but a consistently low urine pH keeps the urine saturated with uric acid. Cases may be sporadic or familial. Sporadic d is- ease begins in middle age, and may be due to low urine pH secondary to decreased ammoni um excretion. They recur until the underlying disorder is treated. Familial forms are autos omal dominant, with an ethnic pre- dilection for Jews and Italians. Hyperuricemic In patients with gout, 22% will develop uric acid nephro- lithiasis. It is d ue to the overproduction of endogenous purines. Lesch \200\223Nyhan syndrome causes gout an d uric acid calculi in childhood. Acute leukemia in childhood and myeloprolif- erative dise ases in adults increase uric acid excretion, caus- ing precipitation and obstruction of the urinary tract. Gastrointestinal diseases Salt, water and bicarbonate loss from the GI tract results in red uced urine volumes and decreased urine pH which both promote uric acid stone formation. Uric acid nephrolithiasis Uric acid stones account for 5 \200\22310% of all renal calculi i n the USA and UK, and 75% in Israel. It may manifest as crys- talluria, stone formation or urinary tract obstruction. Stone formation is promoted by increased serum urate levels, and increased urate excretion in the urine. However, the risk of stone formation is affected m ore by the urine pH than by the daily excreted load of uric acid. For example, a urine pH c hange from 5 to 6 increases the Clinical features Patients present with \202 ank pain and hematuria. Recurrent pyelonephr itis is common. Acute ureteral obstruction sec- ondary to uric acid sludge may occur as a p art of tumor lysis syndrome. H. DODEJA 234 Further reading Conger JD. Acute uric acid nephropathy. Med Clin North Am 1990; Uric acid stones are radiolucent, and have a characteristic yellow-cream appearance, and cr ush with great dif \201 culty. They may be identi \201 ed by a positive response to urica se and by chemical analysis using high-performance liquid chromatography, or mass spectrome try. 74: 859 \200\223871. Kudo E, Kamatani N, Tezuka O, et al. Familial juvenile hyperuricemic nephropathy: detection of mutations in the Uromodullin gene in \201 ve Japanese families. Kidney Int 2004; 65: 1589 \200\2231597. Treatment The goals include regression in the size of preformed stones, and prevention of n ew stone formation. The urine volume should be increased to 3 L per day. Urine pH should be maintained at 6.0 \200\2236.5 with the use of urinary alkalinizers like citrate (1 meq/kg/ day in divided doses), or a nocturnal dose of acetazolamide (250 mg). Decreasing animal pro tein in the diet helps to reduce the excreted load of uric acid. Allopurinol may be used in resistant cases with urinary uric acid levels of >60 mmol/day (1000 mg/day), or in cases w ith gout. It is used prior to chemotherapy to prevent increased serum uric acid levels, and in the dissolution of large nonobstructive stones in the pelvis. Nickeleit V Mihatsch MJ. Uric acid nephropathy and end stage renal disease \200\223 a revi ew of a non disease. Nephrol Dial Transplant 1997; 12: 1832 \200\2231838. Internet resources Lesch \200\223Nyhan Disease Registry: http://www.lndinfo.org/ See also Medical management of stone disease, p. 270 Surgical management of stone disease, p. 274 Renal and urinary tract stone disease in children, p. 282 Cancer and the kidney, p. 196 Inherited disorders of purine metabolism and transportation, p. 636 This page intentionally left blank H. DODEJA 236 Nephrotoxic metals The toxic effects of chronic exposure to heavy metals are far more common than acute poison ing. Many Chinese and Ayurvedic herbal products contain lead, mercury and arsenic that are considered to have medicinal properties themselves. Metals cause injury by combining with s ulfhydryl groups in proteins, thereby altering structure and function (e.g. enzy- matic act ivity). Children are more susceptible to the toxic effects of metals. Acute metal toxicity causes acute tubular necrosis due to selective damage to the proximal tubule, while low dos e chronic exposure leads to chronic tubulointerstitial nephri- tis which may be confused wi th changes caused by aging and other disorders, e.g. hypertension. Urinary biomarkers used to characterize the early stages of toxic renal injury are classi \201 ed as follows: \200 Pathophysiology Lead exposure can occur in occupational and environmen- tal settings, and w hen engaged in hobbies. Absorption is via the skin, gut and lungs, and is indirectly propor tional to the particle size. It is increased with iron and calcium de \201 ciency, and low calorie and high fat diets. Children are more susceptible to lead toxicity. Absorbed lead binds to the red blood cells with a half-life of 30 days, diffuses into soft tissues, and i s later deposited in bone. Low socioeconomic status is a risk factor for both lead exposure and the coexisting conditions that increase the susceptibility to lead toxicity. In suscep tible populations such as those with hypertension, diabetes and chronic kid- ney disease (C KD), lead can contribute to nephrotoxicity at blood levels as low as 5 g/dl. Mean blood l ead levels are decreasing in the developed nations. NHANES III reported a drop in the mean blood lead level to 0.075 mol/L (1.56 g/dL), compared to 0.63 mol/L (13.1 g/dL) in NHANES II. However, blood lead levels are higher in developing nations due to the con- tinu ed use of leaded gasoline and paints. proximal tubular injury: low molecular weight proteins and intracellular enzymes; distal tu bular injury: Tamm \200\223Horsfall glycoprotein and kallikrein; increased glomerular perme ability: high molecular weight proteinuria; vascular injury: eicosanoids. Laboratory features Anemia with basophilic stippling in red blood cells, reduced erythrocyt e aminolevulinic acid dehydratase (ALAD) activity, Fanconi syndrome, hypophosphatemia, rais ed urea and creatinine, and hyperuricemia. The specificity of tubular injury tends to disappear once signi \201 cant renal damage has occurred. These uri- nary markers should be determined in freshly voided spot samples and expressed relative to the creatinine con centration. They should ideally be collected at 08 :00, when both GFR and biomarker excretion are highest (Table 6.4.1). Blood lead levels They re \202 ect acute poisoning, and are a very insensitive indicator f or assessing the cumulative lead stores in the body. They tend to fall rapidly once acute e xposure is completed. Blood lead levels >3.9 mol/L (80 g/dL) in adults and >1.95 mol/ L (40 g/dL) in children are considered high. Sustained levels of >0.48 mol/L (10 g/dL ) may be associ- ated with lead-induced nephropathy. Table 6.4.1 Urinary biomarkers in toxic nephropathies Metal Markers Lead TXB2 , NAG Cadmium HIAP, NAG, RBP Mercury HIAP, THG EDTA test Chronic lead load is estimated using a lead mobilization test. This is performed by parenteral administration of two doses of 1 g of calcium disodium edetate, 12 h apart in adults (20 \200\22330 mg/kg in children) with subsequent collec- tion of 24 h urine sample s. In the presence of renal failure, the collection should be done for \211 3 days. Normal adults excrete <650 g of lead chelate in urine. Bone lead content is a cumulative dose m easure of endog- enous exposure. Lead in trabecular bone is more bioavail- able with a shor ter half-life than lead in the cortical bone, which has a half-life of >10 \200\22330 years . Perchloroethylene TNAP TXB2, thromboxane B2; NAG, N-acetyl-D-glucosaminidase; HIAP, human intestinal alkaline phos phatase; RBP, retinol binding protein; THG, Tamm \200\223 Horsfall glycoprotein; TNAP, tota l nonspeci \201 c alkaline phosphatase. Lead Early reports were from Queensland in Australia, where lead nephropathy was seen in yo ung adults following expo- sure to lead-based paint in childhood, and from the south- easte rn USA where Moonshiners drank contaminated illicit liquor. The different patterns of renal toxicity seen with lead include: \200 Tibial K X-ray \202 uorescence (XRF) Diagnostic monitoring of body lead burden is done by a new noninvasive technique using XRF. K-line XRF permits detection of lead molecules from the full thickness of bones, and allows accurate assessment of the lead:calcium ratio. acute lead poisoning from sudden massive exposure associated with Fanconi syndrome; chronic progressive interstitial nephritis associated with hypertension and gout; lead-induced hyp ertension without renal failure. Acute lead nephropathy Children are predisposed by their habits like pica, and adults are p rone to high dose respiratory exposure. Acute toxicity causes multisystem involvement with symptoms