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Analgesic Abuse Nephropathy
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Essentials of Diagnosis
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- The most common cause of CIN.
- Long-term ingestion of phenacetin, acetaminophen, aspirin, and caffeine or combinations of such.
- Most common in women in their 60s or 70s with a history of chronic low back pain, chronic or recurrent headaches, and chronic joint pains.
- Hypertension is common.
- Imaging studies: Papillary necrosis on IVP, papillary calcifications and bumpy renal contours on CT scan, and small echogenic appearing kidneys on ultrasonography.
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General Considerations
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Analgesic abuse nephropathy (AAN) is the most common cause of CTIN. There has been a positive correlation between the incidence of renal disease secondary to analgesic nephropathy and the daily consumption of analgesics, in particular phenacetin and other analgesic mixtures.
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In the past, it was believed that only phenacetin-containing analgesics were responsible for the disease, but it has been reported on numerous occasions that all analgesics, including acetaminophen, and aspirin can actually cause the same disease process.
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Nonsteroidal anti-inflammatory drugs (NSAIDs) are another common cause of CIN. This is discussed in detail in Chapter 15.
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The main site of renal injury in analgesic nephropathy is the renal medulla (area of the medullary loops of Henle, the vasa recta, and collecting ducts), primarily because of its inherent low oxygen tension. This is also the region in which toxic metabolites of various analgesic compounds build up as a result of the countercurrent mechanism. As the vasoconstrictive effects on the renal medulla predominate, ischemic injury continues, leading to cortical atrophy and eventual interstitial changes.
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AAN is most commonly seen in females in their 60s or 70s who have chronic pain syndromes, eg, headaches, joint pains or back pains. Ingestion of 1 g of analgesic preparations daily for more than 2 years is considered the minimum dosage and time required to produce clinical analgesic nephropathy. Peptic ulcer disease and gastrointestinal symptoms are a common occurrence.
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Renal dysfunction is manifested by isosthenuria (impaired urinary concentration) as well as impaired sodium conservation that may predispose to intravascular volume depletion. Renal tubular acidification defects are also seen. Urinalysis may show evidence of sterile pyuria, urinary tract infection, microscopic or macroscopic hematuria, and mild proteinuria.
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Occasionally, patients can present with flank pain or gross hematuria associated with papillary necrosis. Such papillae can slough off and cause obstructive manifestations. These are usually demonstrated on IVP or ultrasonography. Papillary calcification and characteristic “bumpy” renal contours are usually demonstrated on CT. In some instances, the kidneys can appear bilaterally atrophic or asymmetric in size.
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Patients with analgesic nephropathy are also at increased risk for transitional cell carcinoma of the uroepithelium.
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The oxidative effects of phenacetin are believed to be responsible for the increased formation of atherogenic low-density lipoprotein (LDL), thereby predisposing patients to an increased risk of premature atherosclerosis with attendant cardiovascular morbidity and mortality.
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Management is primarily supportive, including discontinuation of the culprit analgesic agent. Even after cessation of the analgesic, close monitoring, especially for the development of new symptoms such as gross hematuria, is recommended due to increased risk of uroepithelial tumors.
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Lithium-Induced Renal Disease
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Essentials of Diagnosis
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- CIN is the most common pathologic finding in those with chronic lithium nephropathy.
- Polydipsia and polyuria are presenting symptoms of nephrogenic diabetes insipidus (NDI).
- Incomplete distal renal tubular acidosis (RTA) in up to 50% of patients.
- Pathology: Cystic dilation of the distal tubules leads to the formation of “microcysts.”
- Increased incidence of uroepithelial tumors.
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General Considerations
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Lithium has been commonly used in patients treated for bipolar disorders. Chronic lithium ingestion is a known cause of NDI. Lithium enters the collecting tubule cells via the sodium channels; by inhibiting adenylate cyclase and subsequent cyclic AMP (cAMP) production it interferes with the ability of antidiuretic hormone (ADH) to increase water reabsorption. Likewise, it decreases the expression of the water channels (aquaporin 2) in the collecting tubules. A positive correlation has been described between the length of duration of treatment (average 6.5–10 years) with lithium and such impairment of urinary concentrating ability manifested by polyuria (and polydipsia). An incomplete distal (type 1) RTA, secondary to lithium-induced decreased H ATPase pump activity in the distal tubule, has been described.
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Lithium has also been associated with hypercalcemia. It has been suggested that it induces morphologic changes in the parathyroid glands, resulting in increased parathyroid volume and parathyroid hormone secretion (hyperparathyroidism), which consequently promote bone resorption and subsequent release of calcium into the bloodstream, leading to hypercalcemia.
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Pathologically, lithium-induced nephropathy is characterized by the formation of “microcysts” (cortical and medullary tubular cysts) in the distal convoluted tubules and collecting ducts (Figure 37–2). Such distal tubular involvement clinically correlates with NDI, manifested by polyuria and polydipsia.
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Typically, renal dysfunction secondary to chronic lithium use is mild to moderate. However, patients with serum creatinine levels greater than 2.5 mg/dL at the time of presentation progress to end-stage renal disease (ESRD) even after cessation of lithium. However, in patients with less severe renal dysfunction, such discontinuation of lithium usually leads to stabilization of kidney function.
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Amiloride, a potassium-sparing diuretic, has been shown to reduce polyuria and to block lithium uptake in the sodium channels of the collecting duct. In contrast, although thiazide diuretics can reduce lithium-induced polyuria, they can also cause intravascular volume depletion, which can lead to increased sodium and lithium reabsorption in the proximal tubule, thereby aggravating acute lithium toxicity.
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For those patients on chronic maintenance therapy with lithium, a regular follow-up of serum creatinine, estimated glomerular filtration rate (GFR), and 24-hour urine volume is recommended. Elevations in creatinine should lead to either appropriate dose reduction or complete withdrawal of the drug.
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The average latent period between initiation of lithium therapy and onset of ESRD was 20 years.
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Calcineurin Inhibitor Induced
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Essentials of Diagnosis
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- Commonly seen in recipients of solid organ (kidney, pancreas, heart) transplants, with histopathologic features similar to those seen in chronic rejection.
- Electrolyte abnormalities are common, in particular hyperkalemia and hypomagnesemia.
- Pathology: “Striped” pattern of patchy interstitial fibrosis and tubular atrophy.
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General Considerations
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Cyclosporine and tacrolimus, which belong to a class of immunosuppressive agents primarily called calcineurin inhibitors, are commonly used in solid organ transplantation. Cyclosporine has also been commonly used in the treatment of various autoimmune diseases. These agents also cause acute and chronic renal failure. The pathogenesis can be attributed to the drugs' predominantly vasoconstrictive effect on the afferent arteriole, thereby causing glomerular ischemia.
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Pathologically, the tubulointerstitial damage occurs in a band-like pattern, referred to as “striped interstitial fibrosis,” involving the cortex and medulla. Tubular injury secondary to calcineurin inhibitors can lead to hyperkalemia and a non-anion gap metabolic acidosis. Other electrolyte abnormalities include hypomagnesemia, hypophosphatemia, and hyperuricemia.
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Treatment of renal dysfunction requires a significant reduction in the dose of the offending agent, which often translates to an improvement in GFR. Mycophenolate mofetil and rapamycin are alternative immunosuppressive agents commonly used in transplant recipients.
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Interestingly, calcineurin inhibitor-induced nephropathy is rare in bone marrow transplant recipients due to the shorter duration and lower doses of the usual treatment regimens.
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Aristolochic Acid Nephropathy or Chinese Herb Nephropathy
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Essentials of Diagnosis
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- Aristolochic acid nephropathy is commonly seen among users of Chinese herbal medications for weight reduction.
- Nephrotoxicity is usually attributed to “aristolochic acid.”
- Pathology: Hypocellular interstitial fibrosis with marked tubular atrophy.
- Increased incidence of uroepithelial tumors.
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General Considerations
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Typical changes of CIN have been described in mostly middle-aged women in Belgium who were using Chinese herb pills as part of a weight losing diet regimen in 1992. The culprit active ingredient was discovered to be aristolochic acid, which was not only nephrotoxic, but carcinogenic as well.
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Interestingly, affected patients have normal blood pressure readings. There is a positive correlation between the total dose of aristolochic acid and the decline in GFR.
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If untreated, patients usually rapidly progress to ESRD. Histopathologically, a hypocellular interstitial fibrosis with marked tubular atrophy is seen. A short course of oral steroids has been shown to slow progression of renal failure.
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Changes in CIN have been associated with chemotherapeutic agents, especially those with predominant renal routes of excretion. Cisplatin-induced CIN appears to be mediated by increased production of tumor necrosis factor (TNF)-α. Pentoxyphyllin (a known TNF-α inhibitor) has been shown to prevent such cisplatin-induced injury. Damage to the tubulointerstitial areas leads to salt wasting, which may be complicated by orthostatic hypotension, as well as hypomagnesemia and hypocalcemia. Other CIN lesion-producing chemotherapeutic agents include ifosfamide and carmustine. Findings of interstitial fibrosis and chronic inflammatory changes are quite common.
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Treatment entails discontinuing the culprit agent and avoiding coadministration of other agents with potential nephrotoxicities.
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Acute Phosphate Nephropathy
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Acute phosphate nephropathy is a newly described entity commonly seen in patients after exposure to oral sodium phosphate solutions (OSPS) used as bowel cleansers in preparation for colonoscopy. This is characterized by low-grade proteinuria as well as hyperphosphatemia. Histopathologically, there is evidence of acute and chronic tubular injury with interstitial edema, accompanied by tubular atrophy and interstitial fibrosis. The distinctive feature of this entity is the presence of abundant calcium phosphate deposits in the distal tubules and collecting ducts. The following factors predispose patients to acute renal failure: Volume depletion, advanced age, hypertension, concurrent treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), diuretics and NSAIDs, baseline creatinine elevation, or inappropriate use of OSPS in those with underlying chronic kidney disease (CKD).
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Preventive measures include adequate hydration and possibly withholding ACEIs, ARBs, diuretics, and NSAIDs on the day prior to and on the day of colonoscopy. OSPS should be used cautiously in elderly individuals.