Kidney Disease Caused by Therapeutic Agents

Radiocontrast Agents

Contrast-associated AKI (CA-AKI) is a relatively common cause of hospital-acquired AKI. It is defined by an absolute or percentage rise in serum creatinine from the baseline within 48 to 72 hours of exposure. In general, serum creatinine begins to rise within the first 24 hours of administration, peaks between 2 and 5 days, and returns to baseline by 7 to 14 days. The incidence of CA-AKI depends on the definition used and the population studied, ranging from 5% to 40%, and the course varies depending on the overall patient risk profile. The increased number of imaging studies and percutaneous procedures with radiocontrast throughout the past decade and the ever-enlarging population of patients with underlying CKD have resulted in a rise in the incidence. Patients with CKD stage 4 or greater have the highest risk of CA-AKI.

Radiocontrast media may injure the kidney via several mechanisms. First, vasoactive substances such as adenosine and endothelin mediate vasoconstriction of the afferent arterioles, thereby reducing kidney blood flow and promoting kidney medullary ischemia. Second, kidney epithelial cell necrosis also occurs with isoosmolar radiocontrast agents because their high viscosity causes sluggish blood flow through the peritubular capillaries and promotes hypoxic kidney injury. Lastly, radiocontrast causes direct renal tubular toxicity through hyperosmolar injury, which results in vacuolization of proximal tubular cells, and oxidative stress from free oxygen radicals with associated tubular cell apoptosis and necrosis.

The level of kidney function at the time of exposure is one of the most important determinants of the risk for CA-AKI. In addition, patient-specific risk factors include older age, volume depletion, congestive heart failure, diabetic kidney disease, both hypertension and hypotension, and anemia. Intraaortic balloon pumps are associated with increased AKI risk primarily because they are a surrogate for severe cardiac disease, tenuous cardiac output, and kidney hypoperfusion. Emergent procedures increase risk because of reduced use of contrast prophylaxis and increased severity of patient illness. The type, volume, and route of contrast administration also affect CA-AKI risk. With regard to radiocontrast type, osmolality and viscosity are the two most important characteristics. The osmolality of a solution varies significantly from high-osmolar contrast media (HOCM) to low-osmolar media (LOCM) to isoosmolar media (IOCM). Viscosity, another contrast property, varies from one product to the next, does not correlate with osmolality, and may be associated with CA-AKI. For example, IOCM solutions are about twice as viscous as LOCM products despite having a lower osmolality.

The incidence of CA-AKI is higher with HOCM than with LOCM, and the relative risk is doubled in CKD patients. As a result, LOCM and IOCM agents have replaced HOCM. A meta-analysis of 16 randomized, controlled trials suggested a benefit of using IOCM instead of LOCM, with the relative risk reduction of CA-AKI greatest in CKD patients. The maximum increase in serum creatinine was less in CKD patients given IOCM compared with LOCM. However, a randomized trial comparing IOCM with LOCM noted no significant difference in CA-AKI incidence. Thus, the benefits of low osmolality may be counterbalanced by the detrimental properties of high viscosity, making these agents equal in their risk for CA-AKI. A larger volume of contrast increases CA-AKI, with a recommended upper limit of 150 mL for patients with a serum creatinine 1.5 to 3.4 mg/dL and maximum dose of 100 mL recommended for patients with a creatinine greater than 3.4 mg/dL. The smallest contrast volume required to perform the procedure should be used. Risk of CA-AKI is highest with intraarterial injection, with the intravenous (IV) route presenting a much lower risk. Coronary angiography has an even higher CA-AKI risk than other arterial studies, likely due to the underlying comorbidities of the patient. CKD outpatients have a low CA-AKI risk with nonemergent computed tomography (CT) scans. In fact, an eGFR greater than 30 mL/min per 1.73 m ² is not considered a substantial risk for CA-AKI in patients dosed by the IV route.

Measures to reduce kidney injury should be undertaken in patients at higher risk for CA-AKI. In addition to limiting the contrast load and using either IOCM or nonionic LOCM, the most important intervention is IV fluid administration. Studies have uniformly demonstrated the benefit of prophylactic isotonic fluids administered both before and after radiocontrast administration. Because urinary alkalinization is hypothesized to reduce kidney oxidative stress, IV sodium bicarbonate has been studied and initially showed promise. The PRESERVE study, a randomized, controlled trial of IV sodium bicarbonate versus isotonic saline prophylaxis in 4993 relatively high-risk patients exposed to intraarterial contrast, showed no difference in outcomes between the two forms of volume repletion (sodium bicarbonate, 4.4% vs. isotonic saline, 4.7%). Thus, isotonic saline is preferable for radiocontrast prophylaxis due to its low cost and avoidance of the need for pharmacy compounding. For outpatient studies, oral fluids with salt tablets before exposure may provide adequate volume expansion to prevent CA-AKI in CKD, but this approach has not been extensively examined.

N-acetylcysteine (NAC) is an antioxidant that has been used for CA-AKI prevention. However, the Acetylcysteine for Contrast-Induced Nephropathy Trial showed no benefit with NAC in 2308 patients randomized to NAC vs. placebo (the proportion developing CA-AKI was 12.7 among both NAC and placebo recipients). The PRESERVE trial also showed no benefit with NAC prophylaxis (NAC, 4.6% vs. placebo, 4.5%), confirming NAC offers no protection against CA-AKI. In regard to other medications, it is reasonable to avoid nonsteroidal antiinflammatory drugs (NSAIDs) and other potential nephrotoxins before radiocontrast exposure. Regarding renin-angiotensin-aldosterone system (RAAS) blockers, some studies note increased CA-AKI risk, whereas others show nephroprotection. An individualized approach is required for the RAAS blockers prior to contrast exposure.

Based on its size, lack of protein binding, and small volume of distribution, radiocontrast is efficiently removed with hemodialysis (HD). In fact, approximately 80% is removed over 4 hours with a high-flux dialyzer. HD following radiocontrast exposure to prevent CA-AKI, especially in patients with advanced CKD, has been examined in several studies. Although all HD studies have been negative, one small study demonstrated that prophylactic HD in CKD stage 5 patients reduced the need for an acute and chronic dialysis requirement after discharge. Hemofiltration performed 4 to 6 hours before and 18 to 24 hours after contrast reduced the incidence of CA-AKI, in-hospital events, need for acute dialysis, and both in-hospital and 1-year mortality. In contrast, the hemofiltration postprocedure alone offered no benefit beyond standard prophylaxis. A systematic review of 11 studies with 1010 patients concluded that one or more sessions of HD, hemofiltration, or hemodiafiltration performed after contrast administration did not reduce the incidence of CA-AKI or the need for acute or chronic dialysis. Examination of HD and hemofiltration/hemodiafiltration separately shows that HD is associated with increased CA-AKI risk, whereas hemofiltration/hemodiafiltration did not affect the occurrence of CA-AKI but did reduce the receipt of acute dialysis. Therefore, HD and hemodiafiltration are not recommended as a prophylactic measure for CA-AKI.

Gadolinium-Based Contrast Agents

Gadolinium-based contrast agents (GBCAs) were considered a safe and effective diagnostic agent, revolutionizing the world of imaging. However, over time, it became clear that GBCAs were not risk free. Rare reports of AKI surfaced, primarily in patients with underlying kidney disease who received large doses via direct arterial injection. However, GBCA-induced AKI is rare and typically of minor severity, likely caused by the small volume of contrast required for imaging.

GBCAs began to be used widely for imaging patients with kidney disease in the early to mid-1990s as an alternative to radiocontrast. However, nephrogenic systemic fibrosis (NSF), a severe and largely irreversible sclerosing condition of skin, joints, eyes, and internal organs, was first noted as a complication of GBCAs in 2006. Two factors were required for the development of NSF: GBCA exposure and underlying kidney disease. Certain linear GBCAs (gadodiamide, gadoversetamide, gadopentetate), which were considered unstable, were the primary agents associated with NSF. Other factors that likely further increased the risk for NSF included infection, inflammation, vascular disease, hypercoagulability, hypercalcemia, hyperphosphatemia, erythropoiesis-stimulating agent (ESA), and iron therapy.

The GBCAs were recently categorized into three groups (group I: gadodiamide, gadoversetamide, gadopentetate dimeglumine; group II: gadoterate meglumine, gadobutrol, gadoteridol, gadobenate dimeglumine; and group III: gadoxetate disodium) by the American College of Radiology. Group I GBCAs have the highest risk and have been essentially eliminated from clinical use in the United States. The group II GBCAs, which have been shown to be a safer GBCA option, are now employed. In a 2019 systematic review and meta-analysis of 4931 group II GBCA administrations in patients with CKD stage 4 or 5 (eGFR <30 mL/min/1.73 m ² ), the risk of NSF was 0% (0 cases in 4931 subjects). Importantly, 732 CKD stage 5 and 1849 CKD stage 5D patients were included in this study. While these data are reassuring, it is premature to assume no risk.

The best approach to preventing NSF is as follows. High-risk patients should be considered for imaging options such as non-GBCA MR imaging, CT scan, ultrasonography, and other techniques that will provide equivalent diagnostic results. When a GBCA is necessary to make the diagnosis, a group II GBCA with the lowest dose required to obtain a diagnostic image should be used. It is also helpful to extend the time between GBCA studies. In AKI and ESKD patients on hemodialysis, schedule dialysis to follow the GBCA exposure.

Analgesics

NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, are widely used to treat pain, fever, and inflammation, and are available by prescription or over the counter. Annually, more than 50 million patients in the United States ingest these drugs on an intermittent basis, whereas 15 to 25 million people use NSAIDs daily.

NSAIDs and selective COX-2 inhibitors are associated with various clinical kidney syndromes ( Box 34.1 ). It has been estimated that 1% to 5% of patients who ingest NSAIDs develop some form of nephrotoxicity, perhaps representing as many as 500,000 persons in the United States alone. These adverse effects are caused primarily by prostaglandin (PG) inhibition; however, other effects are idiosyncratic. PGs are produced by COX enzyme metabolism and are secreted locally in the kidney to modulate the effects of various systemic and local substances. For example, PGs enhance afferent arteriolar vasodilatation in the presence of vasoconstrictors such as angiotensin-II, norepinephrine, vasopressin, and endothelin, thereby providing critical counterbalance to the vasoconstriction that predominates in hypovolemic states. Patients with decreased true or effective circulating volume are at highest risk to develop renal vasoconstriction and reduced GFR. Because CKD is a PG-dependent state, these patients are also at higher risk for NSAID-induced kidney injury. In fact, exposure to NSAIDs doubles the risk of hospitalization for AKI in patients with CKD. Similar rates of AKI with NSAID exposure are noted in the elderly, those with cardiac disease, and patients receiving angiotensin-converting enzyme (ACE) inhibitors. As noted in a nested case-control study, the adjusted relative risks of AKI were 4.1 and 3.2 in current NSAID users versus nonusers in the general population, respectively. Patients with hypertension, heart failure, and diuretic therapy had an adjusted relative risk of 11.6 with addition of NSAIDs.

In addition to increasing arteriolar blood flow, PGs also enhance kidney sodium, potassium, and water excretion. PGs modulate kidney potassium excretion through stimulation of the RAAS. Inhibition of PGs can result in hyperkalemia when coexistent conditions such as AKI, CKD, diabetes mellitus, and therapy with certain medications (RAAS blockers, potassium-sparing diuretics) are also present. The classic syndrome of hyporeninemic hypoaldosteronism with hyperkalemic metabolic acidosis (type IV renal tubular acidosis) can be observed with NSAID therapy. Inhibition of PGs is associated with decreased kidney sodium excretion, and all NSAIDs cause some degree of sodium retention. This is especially common in patients with hypertension, heart disease, and other salt-retentive disease states (e.g., cirrhosis, nephrotic syndrome, AKI, and CKD) who are at highest risk for developing edema, hypertension, or heart failure. Hypertension is a particularly important complication, as small changes in blood pressure are associated with increased cardiovascular events. Hyponatremia from impaired water excretion also complicates therapy as PGs act to antagonize water reabsorption in the distal nephron, an effect that is lost with NSAIDs. Reduced GFR also contributes to water retention and hyponatremia.

Idiosyncratic effects of selective and nonselective NSAIDs include proteinuric glomerular diseases. Minimal change disease (MCD) is most common, whereas membranous nephropathy is a relatively rare complication of these drugs. Nephrotic-range proteinuria or full-blown nephrotic syndrome is the typical clinical presentation, sometimes accompanied by AKI. NSAID-induced AIN can occur alone or along with these glomerular diseases.

Antiangiogenesis Drugs

Antiangiogenesis drugs target vascular endothelial growth factor (VEGF) or its tyrosine kinase receptor (VEGF-R). VEGF signaling is critical to tumor angiogenesis, and disruption of the signaling pathways provides novel treatment options for aggressive malignancies. However, VEGF function is also essential to renal microvasculature, peritubular, and glomerular integrity. Podocytes provide local VEGF to glomerular endothelial cells, preserving the integrity of the fenestrated endothelium. Loss of VEGF promotes endothelial dysfunction and injury. A reduction in podocyte-synthesized VEGF by pharmacologic VEGF inhibition or genetic ablation decreases local inhibitory complement factor H and other complement regulators in the glomerulus, increasing susceptibility to complement activation and development of thrombotic microangiopathy (TMA). In animals, pharmacologic reduction in VEGF production or effect causes proteinuria, hypertension, and TMA by damaging the renal microvasculature, in particular, the glomerular endothelium. A similar clinical syndrome marked by proteinuria (rarely nephrotic) and hypertension occurs in patients treated with antiangiogenesis agents such as bevacizumab and the tyrosine kinase inhibitors. TMA is the most common pathologic lesion noted in patients taking these medications who undergo kidney biopsy for AKI ( Fig. 34.1 ). Importantly, nearly 50% of the reported cases of anti-VEGF therapy-related TMA is kidney limited with no systemic findings.

Interferon

Interferon (α, β, γ) is described as causing glomerular injury and proteinuria. Early reported cases showed minimal change lesions, but more recent reports describe collapsing and noncollapsing focal segmental glomerulosclerosis (FSGS) on biopsy. Patients tend to present with nephrotic-range proteinuria and/or AKI within weeks of commencing interferon therapy. The time to clinical presentation is shorter for interferon-α as compared to other subtypes. Although proteinuria declines with cessation of interferon therapy, complete reversal is uncommon. The mechanism underlying interferon-associated glomerular injury is not entirely clear, but it may include direct binding to podocyte receptors and alteration of normal cellular proliferation. Other postulated effects include macrophage activation and skewing of the cytokine profile toward IL-6 and IL-13, which are purported permeability factors in MCD and FSGS.

Bisphosphonates

The bisphosphonates are effective treatments for malignancy-related bone disorders such as multiple myeloma, hypercalcemia of malignancy, and osteolytic metastases. They are also commonly used in Paget disease and osteoporosis. One of their major adverse effects is nephrotoxicity, seen primarily with pamidronate and zoledronate. Nephrotoxicity is more common with high-dose IV formulations than the oral or low-dose IV preparations used in osteoporosis treatment. Depending on the particular bisphosphonate, glomerular and/or tubular injury may result. Pamidronate-induced kidney injury is dose related, where high dosage and long duration increase risk. Nephrotoxic manifestations include nephrotic-range proteinuria or nephrotic syndrome associated with collapsing FSGS or MCD, consistent with a toxic podocytopathy. Acute tubular necrosis (ATN) may also accompany collapsing FSGS. Nephrotoxicity is sometimes reversible, but progressive CKD and end-stage kidney disease (ESKD) requiring chronic dialysis may develop. IV zoledronate is more commonly associated with AKI from ATN, although rare cases of FSGS are described. Current evidence suggests that ibandronate has the least nephrotoxicity. Because bisphosphonates undergo kidney excretion, prevention of nephrotoxicity hinges on dose reduction in patients with reduced GFR, with clinical guidelines recommending discontinuation of therapy when estimated GFR falls to less than 30 mL/min.

Gemcitabine

Gemcitabine is an effective antineoplastic agent that is associated with AKI from TMA. This lesion is a rare complication with an incidence of 0.015%–0.31%. However, development of TMA with this drug is associated with a high mortality rate (40%–90%). TMA develops when the median cumulative gemcitabine dose exceeds 20,000 mg/m ² , but may occur at lower doses when combined with mitomycin. In general, most patients develop TMA within 1–2 months of the last gemcitabine infusion. Treatment includes drug discontinuation and supportive care. Plasma exchange is not beneficial, but case reports/series suggest that complement inhibition may be useful for gemcitabine-associated TMA. Correction of hematologic abnormalities and kidney function improvement were observed with eculizumab in some patients who failed drug withdrawal and plasmapheresis.