Analgesic nephropathy was first recognised as a clinical entity as early as the 1950s in Swiss watch factory workers, who were habitually taking large amounts of over-the-counter analgesics, particularly combination analgesics containing phenacetin. Shortly thereafter analgesic nephropathy was recognised as an important cause of ESRD, especially in certain areas of Europe and Australia. In two Australian States, Queensland and New South Wales, as many as 25 % of patients with ESRD in the 1970s had analgesic nephropathy identified as the primary disease, and in the 1980s in Belgium the prevalence was nearly 20 % [31]. In contrast, analgesic nephropathy was substantially less frequently diagnosed in the USA, which presumably related to a lesser clinical awareness of the entity as well as the lower availability of compound analgesic mixtures, particularly those containing phenacetin.

The eventual recognition of compound analgesic mixtures particularly those containing phenacetin as a risk factor for renal disease importantly led to the prohibition of such compounds in a number of countries. Whereas the restriction of compound analgesic sales in Scandinavian countries Finland, Canada, and the UK led to variable effects on the incidence of ESRD, in Australia a very significant decline in the incidence of ESRD related to analgesic nephropathy was observed [32]. Following the introduction of the legislation, the number of new patients commencing dialysis fell significantly from 1980 (Fig. 24.3). Controversy has continued as to whether the reduction in incidence related to the banning of the compounds rather than the elimination of phenacetin from the mixtures [33].

The decline in patients requiring dialysis was most pronounced for those between the ages of 40 and 49 years. In the early 1990s, the percentage of hemodialysis patients with analgesic nephropathy as an incident disease was 9 % in Australia, 3 % in Europe and 0.8 % in the USA [31]. Analgesic nephropathy as a presenting cause of ESRD in Australia accounts currently for only 2.8 % of cases [24] (Fig. 24.3).

So in summary, the withdrawal of phenacetin was not associated with a complete eradication of analgesic nephropathy, but it was associated with a marked diminution in the incidence of ESRD attributed to analgesic nephropathy. Considerable evidence (experimental, pharmacologic and epidemiologic) [34, 35] evolved, suggesting that succeeding analgesic mixtures not containing phenacetin but containing compounds such as acetaminophen, pyrazolones and even aspirin [36] were capable of producing the typical kidney pathology lesions (see below).

The clinical syndrome of classical analgesic nephropathy resulted from the prolonged misuse or abuse of compound analgesics containing aspirin or antipyrine, combined with phenacetin, acetaminophen (paracetamol) or salicylamide, and caffeine or codeine. Lately, it has been suggested that a similar lesion can be induced with chronic nonsteroidal anti-inflammatory agent (NSAID) use. NSAIDs reported to induce analgesic nephropathy include alclofenac, antipyrine, benoxaprofen, fenoprofen, ibuprofen, indometacin (indomethacin), mefenamic acid and naproxen; there are also reports suggesting aspirin and acetaminophen may have contributory roles. While the role of non-phenacetin compounds in causing analgesic nephropathy remains controversial [31], there is some evidence that the chronic use of aspirin or acetaminophen may accelerate renal progression of any aetiology [37]. In this regard, it is important to recognise that agents that block intrarenal prostaglandin synthesis, such as NSAIDs, can be acutely nephrotoxic and can cause an acute but not always reversible decline in glomerular filtration rate (GFR) or acute tubular necrosis, especially in the setting of volume depletion, in the elderly and in diabetics [38–41]. Acute papillary necrosis may also occur particularly if large doses are ingested, and acute renal papillary necrosis induced by NSAIDS has certainly been demonstrated in animal studies [42]. NSAIDs may also be idiosyncratically associated with a minimal change-like lesion glomerular with acute presumably allergic TIN.

Establishing a link between NSAIDS and chronic kidney lesions is problematic. The data is scarce and epidemiological in nature. The studies have been criticised for poor study design, and the odds ratio for risk of end-stage renal disease varies from decreased risk (RR = 0.6) to markedly increased (RR = 10) depending on duration of exposure to NSAIDS [43, 44], age and gender and adjustment for other analgesics.

Because of the uncertainties surrounding toxicologic data and pathogenesis, it follows that it is difficult to establish the critical amounts and periods of intakes of the various analgesic agents required to produce analgesic nephropathy. Epidemiologic studies generally show a dose-dependent risk for developing analgesic nephropathy with compound analgesics, especially with those containing phenacetin, and it has been estimated that there is a 15- to 20-fold increased relative risk for the development of chronic renal disease when the total consumption of phenacetin exceeds 1,000 g [45]. For NSAIDS, an association was demonstrated between prolonged exposure (up to 26,000 doses) and the demonstration of renal papillary necrosis on imaging [46] but with only modest effects on kidney function.

Limitations of study design and of diagnosis have made the interpretation of case–control and other epidemiological studies [43, 47–49] highly problematic [50]. At the current time, it has not been possible either to establish a clear link between prolonged analgesic exposure and progression of underlying chronic kidney disease of any aetiology or to reach a clear understanding of the risk of end-stage kidney disease associated with analgesic use. Interestingly, despite the widespread perception that analgesic use may promote progressive CKD, a recent analysis from the Danish National Registry of over 6,600 ESRD patients reported that over one-third received NSAIDS for a median of 40 days in the 3 years before starting dialysis [51].

The principal site of renal injury with chronic analgesic abuse is in the medulla and papillae, sites that are vulnerable because of the concentration of toxic metabolites built up by the countercurrent mechanism and because of the low oxygen tension present in these anatomical regions. The injury may relate to the net effects of several metabolites [52]. Phenacetin, for example, is converted to acetaminophen, which can deplete cells of glutathione and result in the generation of oxidative and alkylating metabolites. Aspirin [53, 54] and NSAIDs [55, 56] can result in the reduction of vasodilatory prostaglandins; caffeine may be metabolised to adenosine, with vasoconstrictive effects within the kidney. Collectively, these substances may lead to oxidant and ischemic injury to the medulla and papillae, an effect that is exacerbated in the setting of volume depletion [57]. Renal papillary necrosis with features of an ischemic infarct may develop, with atrophy of the overlying cortex leading to chronic interstitial changes.

The quintessential pathologic lesion of analgesic nephropathy is renal papillary necrosis [58], a coagulative necrosis involving the medulla, including the loops of Henle, the vasa recta, the medullary interstitial cells and the collecting ducts. The cortical changes of chronic interstitial nephritis overlying the necrotic papilla are secondary and comprise tubular atrophy, interstitial fibrosis and a mononuclear cellular infiltrate. The presence of a golden-brown lipofuscin-like pigment in tubular cells, and the characteristic analgesic microangiopathy or capillary sclerosis, is highly indicative of an analgesic aetiology. Glomerular changes of focal glomerular sclerosis and hyalinosis associated with proteinuria are similar to those described in reflux-associated nephropathy and tend to be late features.

The vast majority of patients are female [59] and have a history of chronic pain syndromes and other somatic complaints or symptoms suggestive of a broader analgesic syndrome [60]. An addictive and dependent personality trait characterised by introversion, psychoneurosis and an external locus of control has been reported, and an association with cigarette smoking has been noted. Peptic ulcer disease and gastrointestinal symptoms are also present in many patients. Denial of analgesic abuse is common.

The renal function abnormalities of analgesic nephropathy (other than a slowly progressive impairment of GFR) include impaired urine-concentrating ability (often an early defect possibly associated with polyuria), urinary acidification defects and impaired sodium conservation [54]. The urinalysis frequently shows pyuria with or without urinary tract infection, micro- or macrohaematuria may be present, and non-nephrotic range proteinuria. Proteinuria occurs in at least half of the patients [61] and increases progressively as GFR decreases with advanced disease. The proteinuria is of both tubular and glomerular origin, the latter as a consequence of secondary glomerular sclerosis that develops as renal function deteriorates. Hypertension is a very common clinical feature [54].

Although patients with any form of chronic kidney disease are at greatly increased risk of cardiovascular mortality, cardiovascular disease, fatal or nonfatal myocardial infarction, heart failure or stroke, patients with analgesic nephropathy may be at even greater risk for premature atherosclerosis [62]. Atheromatous renal artery stenosis is also more common in analgesic abusers. The increased atherogenic tendency probably relates to multiple factors, including hypertension, smoking and hyperlipidemia, and perhaps the formation of atherogenic oxidised low-density lipoproteins under the oxidative influence of phenacetin [63].

An important association of analgesic nephropathy is the increased risk of transitional cell carcinoma of the uroepithelium (renal pelvis, ureter, bladder and proximal urethra) [64]. This should be especially considered in patients with gross haematuria.

The disease is suggested by a history of analgesic abuse coupled with urographic, sonographic and/or tomographic findings showing papillary calcifications and bilateral atrophic but often asymmetric kidneys with irregular contours (“bumpy”). The imaging findings are not always easily distinguishable from those of reflux-associated nephropathy. Papillary calcification is a very helpful diagnostic feature and may be best detected by a noncontrast CT scan [65]. The differential diagnosis of papillary necrosis, the key underlying pathology in analgesic nephropathy, includes diabetic nephropathy, sickle-cell nephropathy and, very rarely, obstructive uropathy and reflux-associated nephropathy. Papillary deposits of calcium can also be seen in medullary sponge kidney and all forms of nephrocalcinosis.

Management consists of avoiding phenacetin-containing analgesic mixtures (which are largely not available now) and reducing or ideally completely stopping ingestion of other analgesic medications [66, 67] as no specific treatments are available. Management is essentially similar to that for all patients with chronic kidney disease, including careful monitoring of blood pressure and the use of renoprotective agents such as ACE inhibitors for those with impaired kidney function (stage 3 CKD with an eGFR <60 mL/min/1.73 m²). Because of the increased incidence of uroepithelial tumours, long-term follow-up is necessary. A cause of flank pain may be obstruction due to detached (necrotic) papillae lodging in the ureter. In the presence of infection, this complication can be a life-threatening clinical scenario.

Lithium ingestion is associated with the development of resistance to vasopressin (antidiuretic hormone), resulting in polyuria (usually defined as a urine volume exceeding 3,000 mL/24 h) and polydipsia in up to 40 % of patients. Lithium is the most common cause of iatrogenic diabetes insipidus [69–74]. Lithium accumulates in the collecting tubule cells after entering these cells through sodium channels in the luminal membrane. It then interferes with the ability of vasopressin to increase water reabsorption [75] by inhibiting adenylate cyclase and hence cyclic AMP (cAMP) production and also by decreasing the apical membrane expression of aquaporin 2 [76], the collecting tubule water channel. Although this common side effect is widely regarded as reversible, lithium-induced impairment of urine-concentrating ability was shown in some patients to persist many months after cessation of lithium therapy. Interestingly, lithium is also less commonly a cause of hypercalcemia. This complication is a consequence of an increased release of parathyroid hormone (PTH) and is associated with local (parathyroid) cAMP production. Persistent hypercalcemia could potentially exaggerate the tubular concentrating defect and contribute to the development of chronic interstitial nephritis in lithium-treated patients (see section “Hypercalcemic Nephropathy”).

A lithium-induced impairment in distal urinary acidification [type 1 (distal) RTA] may be seen in parallel with nephrogenic diabetes insipidus with lithium therapy. A lithium-induced impairment in distal urinary acidification [type 1 (distal) RTA] is a partial functional defect that is rarely of clinical importance. A lithium-induced decrease in the activity of the H+ ATPase pump in the distal nephron (collecting ducts) may be the main cause of this defect.

Acute impairment of GFR and tubular injury (acute tubular necrosis) associated with episodes of acute lithium intoxication have for many years been recognised potential complications of lithium therapy. The risk is greatly increased in the presence of volume depletion [77].

Histologically, the most distinctive change associated with lithium occurs in the distal convoluted tubules where there is ballooning, swelling and vacuolation of the cell cytoplasm, accompanied by strands and granules of periodic acid-Schiff (PAS)-positive staining material (glycogen). This lesion is not only acute but also quite reversible [78, 79].

A new observation in the 1970s was the recognition that, in lithium-treated patients, the polyuria (and polydipsia) was not always reversible [80–86].

A large number of studies subsequently demonstrated a correlation between the duration of lithium therapy and persistent impairment of urine-concentrating ability [68] (Fig. 24.4). Biopsies in these patients subsequently revealed primarily a focal chronic interstitial nephropathy with interstitial fibrosis and tubular atrophy, and more recently the degree of associated glomerular sclerosis has been recognised [87].

Another characteristic finding is the presence of microcystic changes in the distal tubule. More recently, these cystic changes have been well demonstrated using MR imaging [88]. Patients at particular risk seemed to be those with severely impaired urine-concentrating defects and those with a history of repeated episodes of acute lithium intoxication.

Interestingly, most patients with chronic lithium nephropathy have a relatively well-preserved GFR [73, 89–92] in relation to the distal tubular defect(s). Although a small number of patients have chronic kidney disease with renal impairment, in most studies there is no correlation between GFR and the duration of lithium therapy (unlike with the concentrating defect). At least in one study, the slow rate of deterioration of renal function and final creatinine clearance was related to duration of therapy [93]. In patients taking lithium who do not have repeated episodes of acute lithium intoxication, the role of lithium in chronic interstitial disease remains controversial. Nonetheless, the number of reported cases of either serious renal insufficiency or chronic kidney disease continues to cause concern as there are clearly cases of elevated serum creatinine (>177 μmol/L or >2.0 mg/dL) with no obvious cause other than the long-term ingestion of lithium. In Lepkifker et al.’s review [94], it was estimated that 20 % of patients on long-term lithium develop renal insufficiency [70, 94–96]. Controversy also persists because although differences in urinary concentrating ability between patients on lithium and patients not on lithium are apparent, patients with affective disorders do not concentrate urine normally [97] (Fig. 24.5). Furthermore, other similar degrees of functional change [97, 98] and chronic interstitial change, including interstitial fibrosis, have been noted in patients with affective disorders not being treated with lithium [99], although the characteristic microcystic dilatation of the distal tubules is generally absent. The role of other psychotropic medication in this setting is unknown. If chronic TIN does occur in association with long-term stable maintenance therapy with lithium, it probably requires many years of therapy [93, 100, 101] and the consequent degree of renal insufficiency, as indicated above, is likely to be relatively mild. Perhaps the most important factor in preservation of renal function and histology is prevention of episodes of acute intoxication.

Proteinuria is not a particular feature of lithium-associated nephropathy, but proteinuria has certainly been reported in association with lithium-induced minimal lesion nephrotic syndrome and focal glomerular sclerosis [102, 103].

After eliminating other possible causes of polyuria and polydipsia [104], especially psychogenic polydipsia (or potomania), one should first consider reducing the dose of lithium, aiming for therapeutic concentrations (12-h serum lithium concentrations) of 0.4–0.6 mmol/L (0.28–0.42 mg/dL) or converting to a single daily dose [105] aiming for a lower trough serum lithium concentrations. For prophylaxis, levels of 0.4–0.6 mmol/L (12 h standard trough serum lithium concentrations) may be sub-therapeutic in a proportion of patients [106], compared to recommended levels of at least 0.5–0.8 mmol/L (identical in patients with bipolar and unipolar illness) [107], but also likely to be associated with fewer side effects. Values of 0.8–1.0 mmol/L are likely to have marked efficacy but many side effects. The potassium-sparing diuretic amiloride can also reduce the urine output by up to 50 % and has the added advantage of blocking lithium uptake through the sodium channels in the collecting duct [108]. Amiloride is most effective when the concentrating defect is mild and potentially reversible and has generally been disappointing in patients with severe defects in urine-concentrating ability. Although thiazide diuretics are effective in treating lithium-induced polyuria, they should be avoided as they pose risks for the induction of acute lithium intoxication because the resultant volume contraction causes an increase in sodium and lithium reabsorption in the proximal tubule. Avoidance of NSAIDs if possible is also recommended.

A practical approach to the patient on long-term lithium treatment should include a regular (at least yearly) estimation of renal function measured as serum creatinine (or estimated GFR), estimation of spot urine albumin/creatinine ratio and measurement of 24-h urine volume [95, 107, 109, 110]. Because progressive renal injury with a reduced GFR (or raised serum creatinine) in a patient without prior acute lithium intoxication is relatively unusual, a raised serum creatinine should probably in the first instance be treated with dose reduction. For persistently elevated serum creatinine estimations, a renal biopsy could be considered, although the result would not often lead to a recommendation to cease lithium entirely. At all times, the risk of discontinuation of lithium in a patient with a severe unipolar or bipolar affective disorder needs to be measured against the minimal risk of progressive renal injury. As for analgesic nephropathy, the management of lithium-associated nephropathy with chronic kidney disease is similar to that for all patients with chronic kidney disease and includes careful monitoring of blood pressure and the use of renoprotective agents such as ACE inhibitors for those with impaired kidney function (stage 3 CKD with an eGFR <60 mL/min/1.73 m²). Care is required when introducing any new agent to a patient taking lithium to check serum lithium estimations because of the potential of some agents to acutely alter GFR and/or renal clearance of lithium.

Also, a range of other therapies exist for bipolar and unipolar affective disorders including anticonvulsants such as carbamazepine, valproate and lamotrigine, which may be alternative medications in cases of severe lithium-induced renal symptoms or renal insufficiency.

Acute lead intoxication is rare but may present with abdominal pain, encephalopathy, haemolytic anaemia, peripheral neuropathy [111, 112] and proximal tubular dysfunction (as manifested by either a proximal RTA or Fanconi’s syndrome) [113]. In contrast, chronic lead intoxication, which may develop insidiously and even follow decades after acute lead poisoning [114], is much more subtle with impaired renal function, episodic gout (“saturnine”) and hypertension being the main manifestations [115]. Occasionally, patients may exhibit other signs of chronic lead intoxication including peripheral motor neuropathies, anaemia with “basophilic” stippling and perivascular cerebellar calcifications [116]. Individuals known to be at risk from lead intoxication include children exposed to lead-based paints, adults drinking “moonshine” and residents living close to lead-smelting factories and other industries expelling lead into the environment [117, 118].

Tubular functional disturbances are usually the earliest manifestations of chronic lead nephropathy leading to hyperuricaemia (resulting from diminished urate secretion), aminoaciduria or renal glycosuria. Chronic exposure can ultimately lead to a chronic interstitial nephritis. The pathogenesis of the renal disease may be related to the proximal tubule reabsorption of filtered lead, with subsequent accumulation in the proximal tubular cells. Histologically, proximal tubular injury, with intranuclear inclusion bodies composed of a lead–protein complex, may be observed initially but with prolonged lead exposure the major histologic features of chronic interstitial nephropathy: progressive tubular atrophy and interstitial fibrosis associated with chronic renal insufficiency occur in the presence of a relatively normal urinalysis, but associated with hypertension, and gout [119]. Populations with high rates of diabetes, hypertension and/or chronic kidney disease appear to be at greater risk of developing adverse renal effects from lead [118]. Ideally, all patients with significant hyperuricaemia and renal insufficiency should have a history of occupational lead exposure excluded [120], as confusion may occur with chronic urate nephropathy in which urate deposits (tophi) may form in the renal interstitium.

Several epidemiologic studies in the general population have also suggested that low-level lead exposure may be associated with chronic kidney disease with renal impairment and/or hypertension. In these studies, an increase in lead burden has been shown, but no causal association has been established [121–123], leading to some investigators to question whether chronic lead exposure truly promotes renal failure in recent years [124].

Diagnosis of chronic lead intoxication can be made by the calcium disodium edetate (CaNa₂ EDTA) lead chelation test or K X-ray fluorescence [125, 126].

In the industrial and occupational settings including foundry workers and individuals working with lead-based paints and glazes, preventative measures to minimise exposure and low-level absorption are essential. In established cases, removal of the source of lead is obviously important. Otherwise, treatment involves the use of infusions of CaNa₂ EDTA. The likelihood of a satisfactory response to CaNa₂ EDTA chelation will be influenced by the degree of already established interstitial fibrosis.

Cadmium is a metal used in a variety of industries, especially in the manufacturing of alloys and electrical equipment. Historically, a major outbreak of cadmium toxicity including nephrotoxicity occurred in Japan as a result of industrial contamination of the Jinzu River in the Toyama prefecture, leading to contamination of rice crops. The disease, named itai-itai [127, 128] or “ouch-ouch”, primarily affected older women and was characterised by proximal tubular dysfunction [129], anaemia, severe osteomalacia and, rarely, progressive chronic interstitial disease [130]. Functional changes accompanying cadmium nephropathy include proteinuria, enzymuria, aminoaciduria, glycosuria, polyuria, hypercalciuria and increased urinary uric acid and of course urinary cadmium [131]. Cadmium workers also have a higher incidence of hypertension and renal calculi (the latter caused by hypercalciuria). Cadmium accumulates in renal tubular lining cells [132] bound to a small (30 % cystine) protein metallothionein, which actually protects against nephrotoxicity by binding cadmium in a nontoxic form. Chronic interstitial fibrosis and renal functional abnormalities have been reported to occur when cadmium levels in the renal cortex exceed a concentration of ~200 μg/g [133].

Prevention is the only known effective treatment. Interestingly, exposure to cadmium industrially has been associated with an increased relative risk of developing lung cancer [134] and also renal cell carcinoma [135].

Arsenic, present in insecticides, weed killers, wallpaper and paints, rarely causes renal disease. Chronic arsenic toxicity manifests most commonly as sensory and motor neuropathies, distal extremity hyperkeratosis, palmar desquamation, diarrhoea and nausea, Aldrich–Mees lines (linear white bands on the nails) and anaemia. However, both proximal tubular dysfunction [renal tubular acidosis (RTA)] and eventually chronic interstitial fibrosis may occur [136]. The diagnosis is established by demonstrating elevated urinary arsenic levels.

Balkan (endemic) nephropathy is a slowly progressive form of chronic TIN found almost exclusively in some well-defined areas in Croatia, Serbia, Bosnia, Bulgaria and Romania [144]. Balkan nephropathy is further geographically localised to a few areas along the Danube’s tributaries in topographical regions characterised by plains and low hills that have generally a high humidity and high rainfall. Although described originally, more than 50 years ago [145], the precise aetiology of Balkan nephropathy has never been established. A variety of factors have been either considered or implicated, including genetic factors, environmental agents (such as trace elements [146] and fungal and plant toxins) and immune disturbances.

It has been argued that the inheritance of Balkan nephropathy, the familial nature of which has also been recognised for many years, is more likely to be polygenic and that the environment might markedly influence the manifestations of the genotype. In the endemic areas, likely affected individuals are villagers, but several members of one family (or household) across one or more generations may be affected with many unaffected households being present in the same area. An early Bulgarian genetic study favoured an autosomal dominant form of inheritance [147]. Later chromosomal breakage and spontaneous aberration studies demonstrated linkage to the 3q25 band on chromosome 3 [148–150], in both affected individuals and in healthy relatives of individuals with Balkan nephropathy considered to be at high risk.