Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and ...hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6–7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.
Cisplatin is a platinum containing drug first approved as an antineoplastic agent in 1978. It remains an important and effective therapy in many forms of cancer today. Cisplatin mediates its ...tumorcidal effects via a number of different cytotoxic mechanisms. Although it is best known for DNA damage, cisplatin also causes cytoplasmic organelle dysfunction particularly with the endoplasmic reticulum and mitochondria. It also activates apoptotic pathways and inflicts cellular damage via oxidative stress and inflammation. One of its dose limiting toxicities is its effects on the kidney. This includes acute kidney injury as well as tubular injury resulting in electrolyte wasting. Extensive research has found that cisplatin entry into a cell is facilitated by a number of cellular transporters including human copper transport protein 1 (Ctr1) and the organic cation transporter 2 (OCT2) which are expressed on renal tubular cells. The interactions between the mechanisms of cytotoxicity and cellular transport play an important role in the nephrotoxicity. Better understanding of these interactions could one day help devise better renoprotection that would not reduce its anti-tumor effects.
Background Acute interstitial nephritis (AIN) is an important cause of acute kidney injury, especially in hospitalized patients. The cause and outcome of AIN, particularly that due to drugs, is ...changing with prevalent medication use. The effectiveness of steroids for treatment of AIN is debated. Study Design Case series. Setting & Participants 133 patients with biopsy-proven AIN from 1993 through 2011 at a single center. Outcomes Recovery of kidney function by 6 months, either complete, partial, or none. Complete recovery was defined as improvement in serum creatinine level to within 25% of baseline (or <1.4 mg/dL), and partial recovery, as a ≥50% decrease in serum creatinine level from its peak value but not reaching within 25% of its baseline value. Results Causes of AIN included drugs (70%), autoimmune diseases (20%), and infections (4%). Drug-induced AIN was due to antibiotics in 49%, proton pump inhibitors (PPIs) in 14%, and nonsteroidal anti-inflammatory drugs (NSAIDs) in 11%. Overall, the top 3 drug causes were omeprazole (12%), amoxicillin (8%), and ciprofloxacin (8%). Patients with drug-induced compared to non-drug-induced AIN were older and had higher baseline kidney function, but more severe acute kidney injury. Patients with PPI-induced AIN were older, were less symptomatic, and had longer durations of drug exposure and longer delays in getting kidney biopsy and steroids than for antibiotic-induced or NSAID-induced AIN. At 6 months postbiopsy, 49% of patients with drug-induced AIN treated with steroids achieved complete recovery; 39%, partial recovery; and 12%, no recovery. Correlates of poor recovery included a longer duration of drug exposure (15 vs 30 vs 130 days for complete, partial, and no recovery, respectively; P = 0.04) and longer delay in starting steroid therapy (8 vs 11 vs 35 days, respectively; P = 0.05). Limitations Retrospective study, selection bias in patients who had kidney biopsy, single-center experience. Conclusions The cause of AIN may be shifting; PPIs are emerging as an important contributor to this disease. Delays in discontinuation of the culprit drug and in initiating steroid treatment adversely affect recovery of kidney function.
IgG4-related kidney disease (IgG4-RKD) is a comprehensive term for renal lesions associated with IgG4-related disease, which is a recently recognized clinical entity characterized by a dense ...lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells with fibrosis affecting several organs. Tubulointerstitial nephritis with increased IgG4-positive plasma cells and fibrosis is the most dominant feature of IgG4-RKD and may cause acute or chronic renal dysfunction, although some glomerular lesions such as membranous nephropathy are sometimes evident. Radiologically, several characteristic abnormalities are often demonstrated, sometimes mimicking malignancies. IgG4-RKD predominantly affects middle-aged to elderly men, and most patients have accompanying IgG4-related extrarenal lesions such as sialadenitis, lymphadenopathy, or type 1 autoimmune pancreatitis. Serology usually demonstrates high levels of serum total IgG and IgG4, and high levels of serum IgE and hypocomplementemia are also frequent features. Corticosteroid therapy is usually quite effective, leading to amelioration of the renal dysfunction and radiological and serological abnormalities. However, as any delay in treatment may result in irreversible renal failure, early diagnosis and appropriate therapy are very important. Despite these distinctive clinicopathological features of IgG4-RKD, its pathogenesis remains poorly understood. Awareness of this condition and accumulation of more cases worldwide are necessary.
Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant ...treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug‐drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3‐fold increase in dose‐normalized tacrolimus concentrations while receiving 2000‐2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA‐approved CBD product. Larger studies are needed to better understand the impact of this drug‐drug interaction in solid organ transplant recipients.
A case of a clinically significant drug interaction with a pharmaceutical‐grade cannabidiol product and tacrolimus suggests caution when using the combination.
Drug-Induced Acute Interstitial Nephritis Moledina, Dennis G; Perazella, Mark A
Clinical journal of the American Society of Nephrology,
12/2017, Letnik:
12, Številka:
12
Journal Article
Acute interstitial nephritis (AIN) represents a frequent cause of acute kidney injury, accounting for 15–27% of renal biopsies performed because of this condition. By and large, drug-induced AIN is ...currently the commonest etiology of AIN, with antimicrobials and nonsteroidal anti-inflammatory drugs being the most frequent offending agents. Pathogenesis is based on an immunologic reaction against endogenous nephritogenic antigens or exogenous antigens processed by tubular cells, with cell-mediated immunity having a major pathogenic role. The characteristic interstitial infiltrates, mostly composed of lymphocytes, macrophages, eosinophils, and plasma cells, experience a rapid transformation into areas of interstitial fibrosis. A significant proportion of AIN has nowadays an oligosymptomatic presentation, although the presence of specific extrarenal symptoms such as fever, skin rash, arthralgias, and peripheral eosinophilia has an important role to orientate clinical diagnosis. Identification and removal of the offending drug are the mainstay of the treatment, but recent studies strongly suggest that early steroid administration (within 7 days after diagnosis) improves the recovery of renal function, decreasing the risk of chronic renal impairment. Delayed steroid treatment, when interstitial fibrosis has taken place, would have a less pronounced or nule therapeutic benefit.
The approved therapeutic indication for immune checkpoint inhibitors (CPIs) are rapidly expanding including treatment in the adjuvant setting, the immune related toxicities associated with CPI can ...limit the efficacy of these agents. The literature on the nephrotoxicity of CPI is limited. Here, we present cases of biopsy proven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potential mechanisms of these adverse effects.
We retrospectively reviewed all cancer patients from 2008 to 2018 who were treated with a CPI and subsequently underwent a kidney biopsy at The University of Texas MD Anderson Cancer Center.
We identified 16 cases diagnosed with advanced solid or hematologic malignancy; 12 patients were male, and the median age was 64 (range 38 to 77 years). The median time to developing acute kidney injury (AKI) from starting CPIs was 14 weeks (range 6-56 weeks). The average time from AKI diagnosis to obtaining renal biopsy was 16 days (range from 1 to 46 days). Fifteen cases occurred post anti-PD-1based therapy. ATIN was the most common pathologic finding on biopsy (14 of 16) and presented in almost all cases as either the major microscopic finding or as a mild form of interstitial inflammation in association with other glomerular pathologies (pauci-immune glomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A (IgA) nephropathy, or amyloid A (AA) amyloidosis). CPIs were discontinued in 15 out of 16 cases. Steroids and further immunosuppression were used in most cases as indicated for treatment of ATIN and glomerulonephritis (14 of 16), with the majority achieving complete to partial renal recovery.
Our data demonstrate that CPI related AKI occurs relatively late after CPI therapy. Our biopsy data demonstrate that ATIN is the most common pathological finding; however it can frequently co-occur with other glomerular pathologies, which may require immune suppressive therapy beyond corticosteroids. In the lack of predictive blood or urine biomarker, we recommend obtaining kidney biopsy for CPI related AKI.
The roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that (
) ...asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; (
) UA crystal granulomas may form due to pre-existing CKD; and (
) proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression.
MALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD.
Asymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UA crystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosine attenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective.
Asymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UA crystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.
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