Nonsteroidal antiinflammatory drugs (NSAIDs)
Angiotensin-converting enzyme (ACE) and angiotensin-receptor blocker (ARB)
Pamidronate and zoledronate
Proton pump inhibitors (PPIs)
Checkpoint inhibitors (CPI) chemotherapy
Intravenous immune globulin (IVIG)
Vancomycin + piperacillin/tazobactam
1. What classic syndromes involving the kidneys are associated with NSAIDs?
NSAIDs are well described to cause a number of clinical syndromes involving the kidneys many which are related to decrease in prostaglandin production by the kidneys. Whereas others are idiosyncratic, those associated with NSAIDs include:
Acute kidney injury (AKI)
Edema/congestive heart failure (CHF)
Acute interstitial nephritis (AIN)
Minimal change/membranous nephropathy
Acute papillary necrosis
The following factors increase the risk for APN:
Concomittant diuretic or ACE-I use
2. What are the clinical scenarios where ACE inhibitors and ARBS are likely to cause AKI?
Any clinical circumstance where perfusion to the kidney is impaired will cause a decline in glomerular filtration rate (GFR) and AKI by inducing efferent arteriolar vasodilatation through blockade of angiotensin II production or receptor binding. Clinical scenarios include:
Disease states associated with hypotension
Decreased blood volume (i.e., diuretics, diarrhea, vomiting, etc.)
Decreased effective circulating blood volume (i.e., CHF, cirrhosis, nephrotic syndrome, etc.)
Critical renal artery stenosis
Treatment with medications such as NSAIDs, calcineurin inhibitors (CNIs), and vasoconstrictors
The typical scenario is that the GFR continues to decline with ACE inhibitor/ARB therapy and does not stabilize until drug withdrawal or correction of the underlying disease process. Stabilization of kidney function, without hyperkalemia or hypotension, with continued ACEi/ARB therapy is likely associated with beneficial effects on both the heart and the kidneys.
3. What are the major adverse effects on the kidney of ACE inhibitors and ARBs?
ACE inhibitors and ARBs are associated with AKI and hyperkalemia. These effects are due to inhibition of angiotensin II production by ACE inhibitors or competitive antagonism of the angiotensin II receptor by ARBs. This results in loss of angiotensin II–induced efferent arteriolar tone, leading to a drop in glomerular filtration fraction and GFR. The efferent arteriolal vasodilation reduces intraglomerular hypertension (and pressure-related injury) and maintains perfusion (and oxygenation) of the peritubular capillaries. Hyperkalemia occurs due to reduced adrenal aldosterone synthesis from decreased angiotensin II production/receptor binding. AIN is a rare complication of ACE inhibitors.
4. What are risk factors for the development of acute phosphate nephropathy (APN)?
Oral sodium phosphate-containing purgatives used for colonoscopy preparation can cause both acute and chronic kidney disease (CKD). The acute form is called APN. The following factors increase risk for development of APN. It is notable that two-thirds of patients that developed APN had three or more of these risk factors. APN may resolve or progress to CKD.
5. What are the histopathologic lesions associated with APN?
The hallmark of APN is abundant tubular and less prominent interstitial calcium phosphate deposits. Greater than 30 calcifications and sometimes greater than 100 calcifications per tubular profile may be seen. The calcifications form basophilic rounded concretions, are mainly confined to the distal tubules and collecting ducts, and are prominent in the kidney cortex. The calcifications do not polarize and have a strong histochemical reaction with the von Kossa stain, indicating that they are composed of calcium phosphate. Acute tubular degenerative changes and interstitial edema are seen with early lesions. Biopsies performed more than 3 weeks after exposure to sodium phosphate exhibit chronicity (tubular atrophy/interstitial fibrosis). Acute and/or chronic tubulointerstitial nephropathy, reminiscent of changes seen in nonresolving acute tubular necrosis (ATN), may be present. There may also be an association between PPI’s and hyponatremia via SIADH. But due to the paucity of data and the many confounding variables, causation has not been demonstrated.
6. What lesions in the kidneys can be caused by pamidronate and zoledronate?
The bisphosphonates have been described to cause a couple of lesions involving the kidneys. High-dose pamidronate causes collapsing focal and segmental glomerulosclerosis (FSGS) and minimal change lesion, along with some tubular injury. In contrast, high-dose zoledronate causes a pure tubular injury pattern with severe ATN. These agents target epithelial cells, visceral epithelial cells with pamidronate, and tubular epithelial cells with zoledronate.
7. What syndromes involving the kidneys are associated with PPIs?
PPIs, regardless of class, can cause AIN. Hyponatremia, likely the result of SIADH, is less common. Most PPIs are metabolized predominantly by hepatic CYP450 enzymes, in particular CYP3A4 and CYP2C19. PPIs can cause CNI toxicity due to their effects to reduce CNI metabolism by these 2 CYP450 enzymes. Hypomagnesemia is another complication of PPIs. This is due to reduced GI absorption rather than magnesium loss via the kidneys. A reduction in TRPM-6/7 function, which are magnesium pores in apical membranes of gastrointestinal (GI) epithelial cells, lead to this effect. Discontinuation of the PPI generally reverses GI magnesium wasting.
8. Are PPIs associated with CKD?
PPIs are widely used and maintain a fairly good safety profile; however, recent observational evidence has described an association of PPI use with a variety of risks, including hip fractures, cardiovascular events, pneumonia, Clostridium difficile infection, and most recently CKD and end-stage kidney disease (ESKD). Higher-dose PPI use was associated with a greater incident risk of CKD, an association that remained significant with a time-varying model. The duration of PPI use was also significantly associated with incident CKD and ESKD. One can hypothesize that CKD and ESKD occurring in the setting of chronic PPI use is due to unrecognized (and untreated) AIN, which then transitions into chronic interstitial nephritis. However, little is known beyond the epidemiological observation of association. Therefore the precise mechanism as well as whether PPI therapy itself is causative is unclear.
9. Are CPIs associated with AKI?
The immune system has the capacity to differentiate self from foreign invaders by the use of “checkpoints,” which allow cellular communication via cell surface receptors on T cells. Cancer cells use tumor products acting via checkpoints to deactivate T cells. Ipilimumab, a CTLA-4 antibody, was the first CPI approved by the Food and Drug Administration (FDA). Thereafter, immune-related adverse events were observed in many organ systems. Kidney toxicity from ipilimumab is rare but has been associated with granulomatous AIN. This was attributed to a steroid responsive autoimmune mechanism. The CPIs, nivolumab and pembrolizumab, which are antiprogrammed cell death protein 1 (PD1) antibodies, have also been associated with AIN. Nephritogenic drugs (NSAIDs, PPIs) may prime drug-specific effector T-cells and then the drug-induced inhibition of the PD-1 pathway, resulting in a loss of tolerance and AIN. An alternate hypothesis is that PD-1 inhibition causes a loss of T-cell self-tolerance, resulting in a general autoimmune disease in the kidney.
10. What adverse effects on the kidneys can be caused by antiangiogenesis drugs such as bevacizumab, sorafenib, and sunitinib?
Drugs that target the angiogenesis pathway are important in treatment of certain malignancies. However, a number of adverse effects involving the kidneys have been described. The two most common are hypertension and proteinuria, which appear to be the result of vascular endothelial growth factor (VEGF) deficiency. In the vasculature, VEGF maintains vasodilatation through the nitric oxide pathway. Hypertension results when the antiangiogenesis drugs disrupt this pathway. VEGF has a role in maintaining healthy glomerular endothelial cell function as well. Thus a common adverse event is the development of proteinuria. Rarely, if microvascular injury is significant and is not repaired, thrombotic microangiopathy (TMA) can develop. AIN have also been described with sorafenib and sunitinib. Tyrosine kinase inhibitors (sorafenib, sunitinib, axitinib, etc.) have been associated with direct podocyte toxicity, leading to minimal change disease/collapsing FSGS lesions, which contrasts the TMA lesion observed with anti-VEGF drugs (bevacizumab, aflibercept). This direct podocyte injury is thought to result from an upregulation of c-mip (c-maf-inducing protein), which disrupts intracellular signaling in podocytes.
11. How does cisplatin cause AKI and proximal tubule injury?
Cisplatin is a platinum-based agent whose nephrotoxicity is thought related to the chloride in the cis position. Cisplatin gains entry into tubular cells via uptake by the OCT-2 system on the basolateral membrane of proximal tubular cells.
Cellular apoptosis/necrosis develops due to endoplasmic reticulum-induced stress, mitochondrial injury pathways, and a death receptor pathway.
Normal cell-cycle regulation is disrupted by cisplatin, leading to tubular apoptosis and kidney injury.
Cisplatin-induced DNA damage activates p53, which through various intracellular signals promotes cell apoptosis.
Cisplatin stimulates production of reactive oxygen species and oxidative stress by depleting and inactivating glutathione and other related antioxidants.
Cisplatin induces both inflammation and vascular injury, which further promotes kidney injury.
In addition to AKI, cisplatin causes proximal tubulopathy, salt wasting, loss of urinary concentrating ability, and magnesium wasting.
12. Do braf (V-RAF murine sarcoma viral oncogene homolog B) inhibitors cause AKI?
BRAF is a protooncogene involved in cell signaling that, when mutated, has been associated with development of a number of other malignancies. Vemurafenib is associated with ATN, which can be associated with proteinuria (~500 g/day), and usually resolves with drug discontinuation. Reintroduction with dose reduction may cause recurrent AKI. Vemurafenib-induced nephrotoxicity may also include Fanconi syndrome and Sweet syndrome (also called acute febrile neutrophilic dermatosis; it is an uncommon skin condition characterized by fever and inflamed or blistered skin and mucosal lesions). Dabrafenib is associated with a lower incidence of AKI, although when combined with trametinib, an mitogen-activated protein kinase kinase (MEK) inhibitor, AKI incidence increases. The manifestations involving the kidneys are more commonly seen with dabrafenib are hyponatremia, hypokalemia, and hypophosphatemia. BRAF inhibitor–induced AKI causes both tubular and interstitial damage.
13. How do IVIG and intravenous (IV) hydroxyethyl starch (HES) cause AKI?
IVIG preparations are stabilized with sucrose (vs. maltose and glucose), which can cause “osmotic nephropathy.” Similarly, the plasma expander HES also causes “osmotic nephropathy.” In fact, large prospective sepsis trials comparing HES with other plasma expanders demonstrate that HES use was associated with excess AKI, increased renal replacement therapy, and mortality. Sucrose and HES are both filtered by the glomerulus and then endocytosed by proximal tubular cells. Once inside the cells, they are transported to lysosomes and can not be degraded. The cells become swollen with enlarged lysosomes, which can cause tubular obstruction. Also, as the cells are injured, they detach from the basement membrane and are released into the tubular lumens. Risk factors include kidney impairment and high doses.
14. How is tenofovir (TDF) excreted by the kidneys, and how is it related to the drug’s nephrotoxicity?
TDF causes AKI and Fanconi syndrome. TDF damages the proximal tubule. It enters the proximal tubular cells via the basolateral circulation and is then transported into the intracellular space via the human organic anion transporter (OAT). It is subsequently secreted into the urinary space via efflux transporters such as multidrug-resistant protein-2 (MRP-2). Endogenous substances and drugs compete for the MRP-2 efflux transporter, impairing TDF excretion and leading to higher intracellular concentrations. A single nucleotide polymorphism of the MRP-2 gene (loss-of-function mutation) increases the risk for Fanconi syndrome. Mitochondrial injury is the major cause of the proximal tubulopathy associated with high intracellular TDF concentrations.
15. Do vancomycin and piperacillin-tazobactam cause AKI?
Vancomycin is an antibiotic that inhibits cell wall synthesis in gram-positive bacteria. The incidence of vancomycin-induced nephrotoxicity is highly variable, ranging from <1% to >40%, depending on the population studied, dosing regimens, event under/overreporting, and the definitions employed. Risk factors for vancomycin-induced AKI include increased exposure of the kidneys to vancomycin from higher doses or higher trough levels (>20 mg/L) and underlying CKD. Piperacillin-tazobactam is an antibiotic combination containing an extended-spectrum beta lactam with β-lactamase inhibitor. Retrospective studies demonstrate a significant increase in serum creatinine (incidence ∼30%), with the combination of vancomycin and piperacillin-tazobactam. This may reflect pseudo-nephrotoxicity, a situation where piperacillin competes with creatinine for uptake by the OAT in the proximal tubule. This effect would raise serum creatinine and lead to a diagnosis of AKI. True AKI may also result from either AKI or AIN.
16. What are risk factors for ciprofloxacin-associated crystalline nephropathy?
While AIN is the most common cause of AKI with ciprofloxacin, crystalluria does occur. The drug is insoluble at alkaline pH. Ciprofloxacin causes crystalluria when the urine pH is greater than 7.3, especially with higher drug doses. AKI develops within 2 days to 2 weeks of exposure and urinalysis reveals crystals, which are strongly birefringent and show a wide array of appearances, including needles, sheaves, stars, fans, butterflies, and other unusual shapes. Needle-shaped birefringent crystals are seen within the tubules on biopsy. Ciprofloxacin crystalline nephropathy should be considered as a cause of AKI in elderly patients with impaired kidney function, volume depletion, and urine pH > 6.0. Prevention includes dose adjustment for GFR and volume repletion.
17. What is the adverse effect of topiramate on the kidney and what is the underlying pathomechanism?
Topiramate is an antiseizure drug that is also used to prevent migraine headaches. Nephrolithiasis was noted at a higher-than-expected rate in patients treated with this medication, raising the possibility of a drug-related complication. It was subsequently shown that topiramate acts as a carbonic anhydrase inhibitor and causes a defect in hydrogen secretion in both the proximal tubule and collecting duct. This is a drug-induced type 1 and type 2 renal tubular acidosis (RTA). These abnormalities produce an alkaline urine and promotes the formation of calcium phosphate stones.
18. What other drugs cause crystalline-induced nephropathy?
AKI from drug-induced crystalline nephropathy requires the presence of a significant amount of drug crystal within tubular lumens that favor crystal insolubility in a low urinary flow state. This is accomplished by supersaturation of constituent molecules, low or high urine pH (depending on the drug), volume depletion, and the absence of urinary inhibitors of crystallization. Sulfadiazine causes crystalline nephropathy or nephroliths in the setting of hypoalbuminemia, volume depletion, acid urine, and high drug doses. Prevention and/or treatment are directed at correcting hypovolemia and alkalizing the urine. Acyclovir can precipitate in the setting of hypovolemia, rapid IV bolus administration, and with excessive dosing. IV fluids and slower IV administration are employed to prevent/reduce the occurrence. IV methotrexate and its metabolites can precipitate within the tubules when given in high doses, with acid urine, and in the setting of hypovolemia. Prevention includes aggressive alkaline IV fluids and induction of high urine flow rates. When AKI develops, in addition to leucovorin rescue, drug removal can be achieved with prolonged high-flux hemodialysis (HD) or drug metabolism with carboxypeptidase G.
19. What is the risk of lactic acidosis with metformin therapy in patients with acute or CKD?
Metformin can be rarely associated with lactic acidosis, with an incidence of 3 to 10 per 100,000 person-years. Metformin binds to complex I of the mitochondrial respiratory chain, inhibiting oxidative phosphorylation and thereby increasing the proportion of uncoupled respirations. This leads to increased glycolysis and glucose uptake and shuts off gluconeogenesis in the liver. Because oxidative phosphorylation is inhibited, pyruvate is shunted to lactate instead of acetyl CoA in order to restore the NAD+ needed for glycolysis. If metformin levels get too high, the lactate can increase to clinically significant levels and cause metformin associated lactic acidosis (MALA). The greatest risk factor for MALA is impaired kidney function. The FDA recently relaxed use in certain patients with diminished kidney function based on its favorable safety profile. The prior contraindication of a serum creatinine ≥1.5mg/dL in males and ≥1.4mg/dL in females was updated to a genderless, GFR-based definition of <30mL/min. The FDA does not recommend starting metformin in patients with an eGFR of 30 to 45 mL/min, but does support continuing metformin if drug was started at an eGFR >45 mL/min and the patient’s kidney function gradually declines to an eGFR 30 to 45 mL/min. However, kidney function should be monitored frequently. MALA is reversible with drug discontinuation and improvement of kidney function, but has been associated with fatalities. In cases of overdose, HD should be considered to remove metformin and correct the underlying acidosis.
20. Are bath salts and spice associated with AKI?
Bath salts, which are cathinones, contain 3,4-methylenedioxypyrovalerone and 4-methylcathinone (mephedrone), which give users a feeling of euphoria, alertness, and increased sexual arousal. AKI is reported with bath salts, most often due to pigment-associated ATN in the setting of rhabdomyolysis. It is unclear whether AKI results from a direct nephrotoxic drug effect, pigment-related tubular injury, or an ischemic tubular insult. Spice is a synthetic cannabinoid with clinical presentations ranging from euphoria to psychosis. The active ingredient, δ THC, binds to the cannabinoid receptor 1 in the central nervous system, modulating GABAergic and glutaminergic transmission. While there is variability in the type of AKI syndromes, the majority is due to ATN. Nearly 25% of AKI patients may need temporary dialysis. Urine metabolites may damage kidney tubules and cause AKI.
21. What factors determine if a drug is effectively removed by extracorporeal therapies?
There are clinical situations where an overdose or intoxication with certain drugs warrants removal with an extracorporeal therapy such as hemodialysis (HD) or continuous venovenous hemofiltration (CVH). Efficient drug removal by extracorporeal therapies is determined primarily by:
Drug characteristics associated with efficient removal
Small molecular weight (<10,000 Da)
Limited protein binding (<50%)
Small volume of distribution (<1.0 L/kg, which suggests the drug is limited to the plasma space or extracellular space)
Water versus lipid solubility
Dialyzer characteristics associated with efficient clearance
Large surface membrane
Large pore size
High blood flow rates
High dialysate flow rates
Examples of drugs efficiently removed by HD include the toxic alcohols, lithium, metformin, theophylline, and salicylates. CVVH is inferior to HD due to its low drug clearance, which is primarily determined by the lower blood flow rates and dialysate flow rates employed with this extracorporeal modality. CVVH does have a role to treat drug rebound following HD for drugs such as lithium, metformin, and methotrexate.
22. What is the risk for development of AKI following exposure to IV and intraarterial contrast agents?
Refer to Chapter 14 on Contrast-Induced Nephropathy