Article

Proton Pump Inhibitors and Acute Interstitial Nephritis

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Abstract

Proton pump inhibitors (PPIs) are a widely prescribed class of drugs, and their usage worldwide is increasing. Although well-tolerated, there have been case reports and a recent case series implicating these drugs in acute interstitial nephritis (AIN) and progression to acute renal failure (ARF). The aim of this study was to investigate how widespread this complication is in Australia, to identify which PPIs are implicated, and to establish whether PPI-induced AIN is a class effect. We undertook a retrospective case review of potential cases at 2 teaching hospitals and a review of registry data from the Therapeutic Goods Administration of Australia (TGA). Parameters sought included the drug implicated, concurrent medications, symptoms, signs, serum creatinine, and time of onset after prescription. We identified 18 cases of biopsy-proven PPI-induced AIN causing ARF in the retrospective case review, which is the largest hospital-based case series to date. The TGA registry data identified an additional 31 cases of "biopsy proven interstitial nephritis." An additional 10 cases of "suspected interstitial nephritis," 20 cases of "unclassified acute renal failure," and 26 cases of "renal impairment" were also identified. All 5 commercially available PPIs were implicated in these cases. With the ever more widespread use of this class of medications, PPI-induced AIN is likely to become more frequent. There is now evidence to incriminate all the commercially available PPIs, suggesting there is a class effect. Failure to recognize this entity might have catastrophic long-term consequences including chronic kidney disease. Increased awareness might facilitate more rapid diagnosis and management of this potentially reversible condition.

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... La nefritis tubulointersticial aguda (NTIA) asociada a fármacos se ha convertido en una causa cada vez más frecuente de daño renal agudo potencialmente reversible 1 . La generalización de la prescripción de inhibidores de la bomba de protones (IBP) ha propiciado un aumento de las NTIA inducida por estos fármacos, siendo responsables del 18-64% de los casos [2][3][4] . ...
... La presentación clínica de la NTIA es variada e inespecífica. La clínica no se ajusta a las manifestaciones sistémicas alérgicas descritas con otros fármacos; la triada clásica de fiebre, rash y eosinofilia aparece en menos del 10% 4 , los síntomas más comunes fueron astenia (39%) y pérdida de peso (22%). En nuestra paciente, los síntomas fueron inespecíficos, si bien la fiebre y el eritema cutáneo al inicio del tratamiento con rabeprazol orientaron hacia una etiología inmunoalérgica. ...
... La eosinofilia está presente en aproximadamente un tercio de pacientes 7 . La anemia y el aumento de la proteína C reactiva han sido descritos hasta en el 89 y 78% de casos, respectivamente 4,9 . La detección de hematuria, proteinuria, leucocituria y eosinofiluria podrían apoyar el diagnóstico, siendo detectadas en más de la mitad de los pacientes con NTIA asociada a IBP 7 . ...
Article
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La nefritis tubulointersticial aguda (NTIA) asociada a fármacos es una causa cada vez más frecuente de daño renal agudo. Su incidencia es variable y difícil de cuantificar con precisión por el intervalo de tiempo entre la toma del fármaco y la detección de la lesión renal. Los inhibidores de la bomba de protones (IBP) se consideran uno de los principales fármacos responsables de esta entidad tras los antibióticos. Una mayor conciencia acerca de la NTIA por IBP podría facilitar un diagnóstico y manejo más rápidos de esta lesión renal potencialmente reversible y evitar así la progresión a enfermedad renal crónica.
... A precise understanding of factors contributing to recovery of kidney function after AIN can guide clinicians and patients in making informed management decisions and help researchers enroll appropriate patients in therapeutic trials for AIN. Several studies have evaluated prognostic factors in druginduced AIN and have identified degree of interstitial fibrosis, delay in starting corticosteroid therapy and duration of exposure to culprit drugs as potential factors associated with poor prognosis [11][12][13]. However, these studies did not evaluate blood or urine biomarkers to determine kidney prognosis after AIN. ...
... We found that higher urine IL-9 levels were associated with lower 6 m-eGFR only in those who did not receive corticosteroid therapy. Treatment with 28 (13,47) FIGURE 1: eGFR at various time-points around AIN diagnosis. Baseline eGFR was obtained 62 (47-115) days before biopsy. ...
... corticosteroids was associated with higher 6 m-eGFR in those with higher IL-9 and higher baseline eGFR. An episode of AIN usually leads to permanent kidney damage and loss of kidney function [13] and only a minority of patients achieve complete recovery of kidney function [11,12,23,24]. Epidemiological studies noted a higher risk of CKD and end stage kidney disease (ESKD) in users of proton pump inhibitors, a known cause of AIN [25][26][27][28][29][30][31][32][33]. ...
Article
Background: We previously demonstrated that urine interleukin (IL)-9 and tumor necrosis factor (TNF)-α can distinguish acute interstitial nephritis (AIN) from other causes of acute kidney injury. Here we evaluated the role of these biomarkers to prognosticate kidney function in patients with AIN. Methods: In a cohort of participants with biopsy-proven, adjudicated AIN, we tested the association of histological features and urine biomarkers (IL-9 and TNF-α) with estimated glomerular filtration rate measured 6 months after diagnosis (6 m-eGFR) controlling for eGFR before AIN and albuminuria. We also evaluated subgroups in whom corticosteroid use was associated with 6 m-eGFR. Results: In the 51 (93%) of the 55 participants with complete data, median (interquartile range) eGFR before and 6 m after AIN were 41 (27-69) and 28 (13-47) mL/min/1.73 m2, respectively. Patients with higher severity of interstitial fibrosis had lower 6 m-eGFR, whereas those with higher tubulointerstitial infiltrate had higher 6 m-eGFR. IL-9 levels were associated with lower 6 m-eGFR only in the subset of patients who did not receive corticosteroids [6m-eGFR per doubling of IL-9, -6.0 (-9.4 to -2.6) mL/min/1.73 m2]. Corticosteroid use was associated with higher 6 m-eGFR [20.9 (0.2, 41.6) mL/min/1.73 m2] only in those with urine IL-9 above the median (>0.66 ng/g) but not in others. Conclusions: Urine IL-9 was associated with lower 6 m-eGFR only in participants not treated with corticosteroids. Corticosteroid use was associated with higher 6 m-eGFR in those with high urine IL-9. These findings provide a framework for IL-9-guided clinical trials to test efficacy of immunosuppressive therapy in patients with AIN.
... For example, fewer than half of the cases have fever, <10% develop a rash, about one-third manifest hypereosinophilia, and only 5% to 10% present with typical symptoms of a hypersensitivity reaction. [28] Because it can take several weeks or even months to confirm a diagnosis of AIN after the development of symptoms, some patients inevitably develop chronic renal interstitial fibrosis before treatment can be initiated. [28,29] It has been reported that renal function does not recover to the baseline in a substantial proportion of patients with PPI-induced AIN despite discontinuation of the causative drug and treatment with steroids. ...
... [28] Because it can take several weeks or even months to confirm a diagnosis of AIN after the development of symptoms, some patients inevitably develop chronic renal interstitial fibrosis before treatment can be initiated. [28,29] It has been reported that renal function does not recover to the baseline in a substantial proportion of patients with PPI-induced AIN despite discontinuation of the causative drug and treatment with steroids. [7] Furthermore, long-term administration of PPIs may increase the risk of chronic renal injury. ...
... PPIs are over-the-counter drugs that are widely used without prescription. [28] Many clinicians have expressed concerns about the safety implications of the misuse of PPIs due to widespread availability of these drugs and a lack of regulation. [20,39,40] PPIs are more frequently used by the elderly population than by the young people, which may contribute to a higher prevalence of AIN and CKD as well as a higher proportion of patients in need of dialysis. ...
Article
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Introduction: Proton pump inhibitors (PPIs) are widely prescribed and generally well tolerated but can rarely cause severe allergic reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS). We report a case of DRESS and renal injury induced by PPIs, and describe the therapeutic process. Patient concerns: The patient was a 66-year-old female who complained of fever, pruritus, desquamation, erythema multiforme, and anuria caused by omeprazole taken for 2 weeks to treat abdominal distention. Diagnosis: The clinical history revealed a similar episode of PPI-induced fever, eosinophilia, and acute kidney injury more than 1 year ago. The present laboratory tests revealed eosinophilia and oliguric renal failure. The renal biopsy was performed subsequently and proved the diagnosis of PPI-induced DRESS. Interventions: After the suspected diagnosis of PPI-induced DRESS, omeprazole was discontinued and methylprednisolone infusion (40 mg qd) was initiated. Because of oliguric renal failure, the patient received intermittent hemodialysis. Outcomes: The patient initially responded to omeprazole discontinuation, hemodialysis, and glucocorticoids but later died from severe infection during the tapering of glucocorticoid therapy. Conclusion: Clinicians should remain on high alert for potential life-threatening complications when prescribing PPIs. If unexplained renal injury develops in a patient taking a PPI, renal biopsy may help in identifying the pathogenesis and might facilitate timely intervention.
... Присутствие в инфильтратах CD4+ и CD8+ лимфоцитов является подтверждением клеточноопосредованной реакции гиперчувствительности. На начальных этапах воспалительного процесса часто выявляются полиморфноядерные гранулоциты -преимущественно эозинофилы [83,84,[86][87][88][89]. При этом обычно отсутствует вовлечение в патологический процесс клубочкового аппарата и почечных сосудов. ...
... В базе данных НЛР Всемирной организации здравоохранения (ВОЗ) имеется несколько сотен сообщений о развитии ОИН на фоне приема ИПП [99]. Распространенность ИПП-ассоциированного ОИН составляет 8 случаев на 10 000 человеко-лет [26,83,84,85,87,121]. ...
Article
Among the causes of acute interstitial nephritis, drug-induced acute interstitial nephritis accounts for 50 to 78 % of all cases. Th e review summarizes the literature data on drugs that cause acute interstitial nephritis. Search in eLibrary databases.RU, PubMed®, MEDLINE, EMBASE, manuals and guidelines, materials of adverse drug reactions databases, instructions for the medical use of drugs. it was held until October 2020. Th e most probable mechanisms of its development are considered. Most attention is paid to non-steroidal anti-infl ammatory drugs, anticoagulants, antibiotics, antitumor drugs (immune checkpoint inhibitors), which are widely used in clinical practice. Th e symptoms of drug-induced acute interstitial nephritis are variable and oft en non-specific; therefore, a kidney biopsy is required for an accurate diagnosis. The main direction of treatment of drug-induced acute interstitial nephritis is the cancellation of nephrotoxic drugs, if this condition is not feasible and/or the duration of acute interstitial nephritis is less than 3 weeks, the biopsy has minimal interstitial fibrosis and there are no serious contraindications, then the possibility of using it should be considered.
... Recently, accumulating evidence has aroused the strong association of acute kidney injury (AKI) following PPI regimens (14)(15)(16)(17)(18)(19), with a shallow incidence rate of around 12 per 100,000 person-years (19). Acute interstitial nephritis (AIN) is the manifest form evidenced in PPI-associated AKI (19)(20)(21). The long-term PPI usage may result in chronic kidney disease (CKD) through AIN, recurrent AKI or inconspicuous clinical course (16,17,(22)(23)(24), and lead to an increased mortality rate (25,26). ...
... year-period since 1993, biopsy-proven AINs from various PPIs have been deducted in two Australian hospitals as a potential cause of AKI in patients without an apparent cause of kidney dysfunction (21). Recent clinical cohorts (15)(16)(17)28), case-control studies (14,19), and metaanalysis (18,29) have revealed the increased AKI incidence in PPI receivers. ...
Article
1.Abstract Backgrounds Recent evidence has concerned acute kidney injury (AKI) after the proton pump inhibitor (PPI) application. There are few real‐world studies to compare the occurrences, clinical features, and prognosis of AKI related to various PPI regimens. Methods Disproportionality analysis and Bayesian analysis were used in data‐mining to screen the suspected AKI after different PPIs based on the FDA's Adverse Event Reporting System (FAERS) from January 2004 to December 2019. The times to onset, fatality, and hospitalization rates of PPI‐associated AKI were also investigated. Results We identified 19,522 PPI‐associated AKIs, which appeared to influence more middle‐aged patients than elderly ones (53.04% vs. 33.94%). Women were more affected than men (55.42% vs. 44.58%). Lansoprazole appeared a stronger AKI association than other PPIs, based on the highest reporting odds ratio (ROR=20.8, 95%CI=20.16‐21.46), proportional reporting ratio (PRR=15.55, χ2=73899.68), and empirical Bayes geometric mean (EBGM=15.15, 95%CI=14.76). The median time to AKI onset was 446 (IQR 16‐2176) days after PPI administrations. PPIs showed a significant difference in average time to AKI onset (p <0.001), with the shortest of 9 (IQR 3‐25) days for rabeprazole, and the longest of 1221 (IQR 96.5‐2620) days for esomeprazole. PPI‐associated AKI generally led to a 5.69% fatality rate and an 8.94% hospitalization rate. The highest death rate occurred in rabeprazole (15.35%). Conclusion Based on the FAERS database, we profiled AKI related to various PPIs with more details in occurrences, clinical characteristics, and prognosis. Concern should be paid for PPIs when applied to patients with a tendency for AKI.
... Eventually, the consequences of changing this physiology were understood as physicians began to recognize complications associated with prolonged acid suppression. [14][15][16][17][18][19][20][21][22][23][24][25][26][27] At the same time, surgical innovators began to push the envelope from minimal incision surgery to no incision surgery through what has become known as natural orifice surgery. 28 An obvious target of natural orifice surgery would be the gastroesophageal junction and its repair, thus treating reflux disease surgically again. ...
... Studies indicate progression of the disease during the prolonged use of PPI therapy. [14][15][16][17][18][19][20][21][22][23][24][25][26][27] Additionally, an increase in the incidence of esophageal adenocarcinoma has been identified during this period of PPI use. 110 Based on the studies discussed, TIF 2.0 is a viable alternative to chronic medical therapy in patients who fail to resolve their reflux symptoms after 6 months of medical therapy. ...
Article
Full-text available
Transoral incisionless fundoplication (TIF) was introduced in 2006 as a concerted effort to produce a natural orifice procedure for reflux. Since that time, the device, as well as the procedure technique, has evolved. Significant research has been published during each stage of the evolution, and this has led to considerable confusion and a co-mingling of outcomes, which obscures the results of the current device and procedure. This report is intended to review the identified stages and literature associated with each stage to date and to review the current state of treatment outcomes.
... Hemolytic anemia and AIN are considered rare side effects of PPI with only few case reports described patients with PPI-induced hemolytic anemia and a few others reported patients with PPI-induced AIN. 2,4 Drug-induced autoimmune hemolytic anemia is commonly associated with the use of antibiotics. Drug-induced AIHA is believed to be significantly underestimated likely due to underdiagnosis. ...
... AIN developed at a mean of 11 weeks following initiation of PPI. 4 The presentation of PPI-induced AIN is variable. While 10% of reported cases in literature have classical hypersensitivity triad of fever, rash, and eosinophilia, the majority of patients, however, had nonspecific complaints including weakness, fatigue, nausea, and vomiting as in our patient. ...
Article
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Proton pump inhibitors (PPI)—induced acute interstitial nephritis and autoimmune hemolytic anemia can occur concomitantly, which should prompt discontinuation of PPI. PPI should wisely be prescribed and discontinued when no longer needed. Proton pump inhibitors (PPI)—induced acute interstitial nephritis and autoimmune hemolytic anemia can occur concomitantly, which should prompt discontinuation of PPI. PPI should wisely be prescribed and discontinued when no longer needed.
... Evidence suggests that around 30-70% of patients affected by the drug-induced AIN fail to return to their baseline renal function probably due to the swift conversion of interstitial cellular infiltrates into large areas of fibrosis [17]. It was evident from the findings of an Australian study that used a retrospective study design to determine the incidence of PPI-induced AIN [18]. The study detected 18 cases of biopsy-proven PPI-induced AIN that led to the development of acute kidney injury (AIN). ...
... Although all patients affected with PPI-induced AIN improved their renal function, yet their mean calculated creatinine clearance was reported to be 15.9 ml/min/ 1.73 m2 and 11.5 ml/min/1.73 m2 that remained lower than baseline at three and six months respectively [18]. An observational study conducted in Auckland, New Zealand that was aimed to assess reports of patients diagnosed with AIN and renal failure from PPI use over a period of three years reported AIN incidence of 8 per 100,000 patient years (95% confidence level 2.6-18.7) ...
Article
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Background Proton pump inhibitors (PPIs) are used worldwide for the treatment of gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD). Although considered to be widely safe, PPIs have been associated with the potential risk of adverse effects such as infections including pneumonia and Clostridium difficile, malabsorption of vitamins and minerals, dementia and more recently with chronic kidney disease (CKD). Evidence including large cohort studies suggests that there is a greater risk of developing CKD in chronic users of PPIs. However, the association of CKD with PPI use reported in these studies is weak and does not establish a clear causality. This review aims to further investigate the association of CKD with PPI use by including studies with various study designs. Methods A literature search of published articles with no start date restrictions was undertaken in May 2018 in three electronic databases (PubMed, ScienceDirect, Google Scholar). Search terms included ‘Proton Pump Inhibitors’, ‘chronic kidney disease’, and ‘association’. Both observational and randomised controlled trials (RCTs) investigating the association of CKD with PPI use were eligible for inclusion. Results Ten observational studies with 1,005,899 patients contributed to the review. No experimental study was available for inclusion in the review. Of the included studies, six used a retrospective study design, while the rest were prospective (two) or a case-controlled studies (two). A large prospective cohort study with 144,032 patients conducted in the USA reported that PPI use compared to no PPI use was associated with an increased risk of CKD Hazard ratio [HR] 1.28; 95% Confidence Interval [CI] 1.22–1.34. However, the observational study design of this study together with other studies included in the review suggests that the strength of evidence associating PPI use with CKD is weak and does not establish true causality. Conclusions The current evidence related to the potential association of CKD with PPI use remains inconclusive in establishing true causality. Further prospective studies including randomised controlled trials and cohort studies would be required to confirm the findings reported in this review and to draw any conclusions.
... Moreover, four of our patients refer a previous PPIs administration, which is regarded as an additional risk factor for the development of tubulointerstitial kidney inflammation. This class of drugs is believed to incite the proliferation and partial activation of T-cells populations, with specificity for antigenic epitopes expressed on tubular epithelium [27,28]. Two main theories have emerged to explain their immunomodulatory activity: the first is based on the concept of molecular mimicry, suggesting that PPIs constituents share structural similarities with tubular epithelial antigens and, as a result, drug exposure leads to the activation of drug-specific lymphocytic clones, which can also recognize epitopes expressed on kidney tubules. ...
Article
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We present a series of twelve patients, bearing a wide range of solid malignancies, who received either PD-L1 or a combination of PD-L1 and CTLA-4 inhibitors. Following immunotherapy administration, they exhibited the clinical signs indicative of renal toxicity, including increased serum creatinine levels, proteinuria, nephrotic syndrome and/or hematuria. All patients underwent renal biopsy. Results: All cases demonstrated some degree of interstitial inflammation and tubular injury, while in five patients, glomerular alterations consistent with a specific glomerulopathy were also observed: secondary “lupus-like” membranous glomerulopathy in two cases and membranoproliferative glomerulonephritis, IgA glomerulonephritis and secondary AA amyloidosis in each of the remaining three patients. The two patients with “lupus-like” nephritis and the one with amyloidosis experienced nephrotic syndrome, while their creatinine was within normal range. In the remaining nine cases, deterioration of renal function was the main manifestation. Conclusion: Our findings harmonize with bibliographical data that identify tubulointerstitial nephritis as the most frequent histological lesion related to ICIs administration. The preferential involvement of tubulointerstitial tissue could be associated with the reported higher expression levels of PD-L1 on tubular epithelial cells, compared to glomeruli. On the other hand, glomerular involvement is probably a consequence of a systemic immune system reconstruction, induced by immune-checkpoints inhibition.
... RBC lifespan durations in CKD stages 1-5 were 122±50, 112±26, 90±32, 88±28, and 60±24 days, respectively [39]. Although patients with autosomal dominant polycystic kidney disease could maintain their Hb levels up to CKD stages 3-4 [40], in patients with chronic interstitial nephritis [41,42] or diabetic nephropathy [43], anemia tends to occur at an earlier stage. Treatment of anemia in patients with CKD using iron replacement therapy resulting in lowering of the A1c values secondary to the formation of new erythrocytes in the bloodstream, causing a change of proportion of young to old cells, and also from an alteration in the RBC glycation rates [44,45]. ...
Article
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Background Previous studies reported that low levels of glycated hemoglobin A1c (HbA1c) were associated with increased mortality. We investigated rates and risks of all-cause and cardiovascular mortality in association with mean HbA1c levels with stratification of anemia and chronic kidney disease (CKD) stages, major causes of low HbA1c. Methods 47,145 patients with prescription of antidiabetic agents >6 months in the outpatient visits (2003–2018) were linked to Taiwan’s National Death Registry to identify all-cause and cardiovascular mortality. Poisson assumption was used to estimate the mortality rates, and the Cox proportional hazard regression model was used to evaluate the relative hazards of respective mortality in relation to mean HbA1c in different statuses of anemia and CKD stages. Results All-cause and cardiovascular mortality rates were the lowest in non-anemic stages 1–2 CKD patients, and the highest in anemic stages 3–5 CKD patients. In stages 1–2 CKD, excessive HRs observed in those with mean HbA1c <6.0% (Hazard Ratio [HR]) 1.58; 95% Confidence Interval [CI] 1.18–2.12) became inconsequential after adjustment of medications and laboratory results (HR: 1.26; 95% CI 0.89–1.79). The similar patterns were observed in anemic stages 1–2 CKD, anemic or non-anemic stages 3–5 CKD. Low HbA1c was not related to cardiovascular mortality in any anemia status or CKD staging. Conclusions Higher risks associated with low mean HbA1c and all-cause mortality were attenuated by adjustment of medications and comorbidities. It is imperative for the diabetologists to consider confounding effects of underlying illness before concluding low HbA1c associated higher mortality.
... In a retrospective analysis of community-acquired acute kidney injury (AKI), reported from an advanced care center in north India, AIN was found to be the usual routine cause of AKI in patients who underwent renal biopsy [19]. Proton pump inhibitors, commonly available in our population as an over-the-counter drug have also been speculated as a causative agent of AIN [20]. ...
Article
Introduction: Diabetic kidney disease (DKD) is the commonest cause of chronic kidney disease and end-stage kidney disease worldwide, consequently it has become an important productive implication to the healthcare system. This study was conducted to assess the prevalence of non-DKD (NDKD) in diabetic patients from south India. Objective: To assess the prevalence of NDKD in type 2 diabetes mellitus patients presenting to a tertiary care hospital from south India and also to analyze clinical clues to establish a diagnosis of NDKD. Patient and methods: It is a retrospective observational study of analyzing patient characteristics and renal biopsies. All Diabetic patients with a clinical suspicion of non-diabetic kidney disease who underwent renal biopsy during the study period between January 2012 and June 2017 were included. Based on the biopsy findings, the patients were classified into three groups (isolated diabetic nephropathy, isolated NDKD, and NDKD with underlying diabetic nephropathy) and patients' characteristics were compared between the groups for analysis. Results: A total of 236 renal biopsies were analyzed for the study. Of that, 114 had features of DKD, 78 NDKD with diabetic nephropathy (DN) and 44 had isolated NDKD. Acute interstitial nephritis was the most common cause of NDKD. Conclusion: From the current study, the long duration of diabetes mellitus beyond five years and hypertension beyond two years reasonably predict DKD.
... The kidney is a vital organ of the body. Some medications and toxic chemicals may exert several poisonous effects, leading to severe kidney malfunctioning like tubular proteinuria, lowering urine concentration capacity, lysosomal enzymuria, decreased glomerular filtration rate, and reduced ammonium secretion [88]. It has been reported that aloin and its metabolites are found to be distributed or/and accumulated in kidney, liver, and intestinal tract after oral administration of 14C aloe-emodin (AE) in rats, showing the highest accumulation of aloin in kidney and liver as compared to plasma, resulting in nephrotoxicity [89]. ...
Article
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Background Aloe vera (Aloe barbadensis Miller), commonly known as Ghritkumari/Gwarpatha, is a member of the Liliaceae family, used in the traditional medicine system for ages. Aloe vera has made its importance as a therapeutic agent, acting as a cure for various diseases such as skin problems, lungs, and heart disorders, diabetes, ulcers, various microbial infections, and asthma. Despite its tremendous health benefits, the dark side of the plant is a reason of concern as there are several active compounds present in the plant, raising questions on its safe oral consumption and application. Methods and Results The literature review was compiled from information resourced from various national and international journals available at Google Scholar and curated with Mendeley. The data mining was carried out during the period of January to May 2021. This study explored and summarized the dark side of Aloe vera, subjected to various secondary metabolites present in it. Aloin, the most active compound of Aloe vera, is a type of anthraquinone metabolized by human gut microflora, resulting in the formation of aloe-emodin anthraquinone, later being associated with several harmful effects such as carcinogenicity, genotoxicity, nephrotoxicity, and purgative. Besides this, several alkaloids and polysaccharides present in the plant are reported to cause hepatotoxicity and male infertility, respectively. Conclusions The harmful effects of the plants are not adequately discovered yet; hence there is a need to come up with some mechanism to understand and suppress the formation of such toxic compounds completely. This review examined the botany, active compounds, and adverse clinical effects in the range of metabolites associated with this herb – “Aloe vera”.
... The mean time of development of AIN after initiation of PPIs was 11 weeks. [9] The most likely pathogenesis was described as hypersensitivity immune reaction to the drug or one of its metabolites. [6] With this background, the current study was aimed at evaluating association between PPI use and DN. ...
Article
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Introduction: Proton pump inhibitors (PPIs) are liberally used over the counter medication and is largely considered safe. Off late, there are many reports that suggest increased incidence of chronic kidney disease with long-term PPI use. PPIs are often prescribed in patients with diabetes mellitus (DM) and one of the well-known complications of DM is diabetic nephropathy (DN). Thus, the aim of our study was to evaluate association between PPI use and DN. Methods: It was a case-control study conducted over a 2-year period (April 2017-March 2019). Cases were outpatients with type II DM and associated DN. Controls were age and sex-matched type II DM without DN. Results: A total of 200 participants, 100 each in the case and control group, were recruited. The proportion of participants using PPI was 62% in the cases and 42% in the controls (P = 0.005). The most common PPI used was pantoprazole. Increased duration of PPI use was significantly associated with DN [adjusted odds ratio: 1.171; 95% confidence interval: 1.022, 1.341; P = 0.023]. Conclusion: There is a significant association between the use of PPIs and DN in patients with type II DM. Since PPIs have other beneficial effects in patients with DM such as glycaemic control and relief from gastro-oesophageal symptoms, need for risk benefit assessment for long-term use of PPIs in DM is warranted.
... We acknowledge that our patient was receiving medications with known associations with AIN occurrence. For example, she was treated with proton pump inhibitors (PPIs) that may be associated with the idiosyncratic development of AIN in the long term [22] . However, our patients began the PPI therapy a long time before initiating the PD-1 inhibitor therapy. ...
Article
Recently, a number of innovative anticancer agents such us the programmed death 1 (PD-1) immune checkpoint inhibitors have been developed. Nevertheless, this type of immunotherapy may be associated with immune-related adverse events whose pathophysiology is considered similar to those found in autoimmune diseases such as nephritis. We report the case of a 71-year-old female with metastatic renal carcinoma who underwent nephrectomy. After three lines of other chemotherapies (VEGF and mTOR inhibitors), the patient was treated by nivolumab (3 mg/kg) for 4 months and developed acute kidney injury 16 weeks after initiating this immunotherapy. Kidney biopsy displayed a diffuse extensive interstitial inflammation associated with moderate interstitial edema. The discontinuation of nivolumab and the administration of prednisone (at 1 mg/kg and tapered over 3 months) was an effective treatment of the interstitial edema and led to the recovery of the kidney function.
... Coadministration of two or more drugs can make it difficult to identify the culpable agent, but NSAIDs clearly represent the main cause for drug-induced TIN in our study, followed by antibiotics (21% of druginduced cases). Although proton-pump inhibitors (PPIs) are a widely prescribed class of drugs and have been considered a relevant cause of acute TIN since the first published report of PPIinduced TIN in 1992, [22][23][24][25] no case of PPI-induced TIN was found in our cohort. ...
Article
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Background Acute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN. Patients, design and setting We collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate. Results Thirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54% female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31% and drug-induced TIN in 30% (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28% of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/min/1.73 m ² 3–6 months later (p<0.001). After 3–6 months, eGFR normalised in 41% of patients (eGFR ≥90 mL/min/1.73 m ² ), with only 3% having severe or end-stage impairment of renal function (<30 mL/min/1.73 m ² ). 80% of patients received corticosteroid therapy. Median eGFR after 3–6 months did not differ between steroid-treated and steroid-untreated patients. Other immunosuppressants were used in 18% (n=31) of patients, 21 of whom received mycophenolate mofetil. Conclusions Despite different aetiologies, acute paediatric TIN had a favourable outcome overall with 88% of patients showing no or mild impairment of eGFR after 3–6 months. Prospective randomised controlled trials are needed to evaluate the efficacy of glucocorticoid treatment in paediatric patients with acute TIN.
... The first report of omeprazole induced AIN was reported in 1992 while that of pantoprazole and lansoprazole were reported on 2004, simultaneously similar reports of all PPI are coming. 10 The risk of PPI treatment in hemodialysis patients remains unexplored. 11 The aim of the study was to evaluate drug utilization of PPI in patient undergoing haemodialysis procedure. ...
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Background: Proton pump inhibitors (PPI) are generally thought to be safer drug with fewer adverse effects. Though this class of the drug is thought to be well tolerated, a detail study about actual use of these agents in nephrology department is still awaited in many parts of India. There had been case reports and case series which were reporting PPIs producing acute interstitial nephritis progressing to acute renal failure. The risk of PPI treatment in haemodialysis patients remains unexplored. The aim of the study was to evaluate a drug utilization of PPI in patient undergoing haemodialysis procedure.Methods: In this study every day visit to the dialysis units of the hospitals was carried out. After taking consent from the patients, the information from the case-report form was noted like; age, sex, diagnosis, laboratory reports and drug prescried. No personally identifiable information about patient or physician was collected. After this an interview of patients was taken.Results: In this study, out of 126 patients 76.6% were male and 23.4% were female. Out of these 126 patients 88.89% patients were on PPI. Nearly 54% were using PPI for more than six months. Nearly 29% patients were using PPI for more than 12 months.Conclusions: As many case-reports and studies are suggesting, there is co-relation of PPI and acute interstitial nephritis from this study we suggest that especially in nephrology unit patients’, more caution must be exercised while using PPI.
... H i g h e r f r e q u e n c y i n t h e ( 5 4 , 5 5 ) elderly , increased risk of incomplete (15,17,30,56) recovery of renal function and progression (57) t o c h r o n i c i t y e v e n w i t h p r o m p t ( 5 4 ) corticosteroid treatment instituted after biopsy confirmation, are cited. Eosinophilia is quite common , but the other specific (58) manifestations of ATIN are inconsistent , (59) and many cases are therefore classified as ARI of unknown cause until the biopsy result is obtained. In some non-Caucasian races, a genetic predisposition for ADATIN to PPI has been described . ...
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Acute drug-allergic tubulointerstitial nephrites are increasingly common conditions in current practice due to increased patient access to a variety of drugs. The clinical-biological panel associates acute renal injury with hypersensitivity phenomena. Considered classically reversible after the cessation of the incriminated drug, drug-allergic tubulointerstitial nephrites have changed their evolutionary characteristics in recent decades, even under treatment. This article presents the clinical-biological, therapeutic and evolutionary characteristics of drug-allergic tubulointerstitial nephrites.
... 98 Newer PPIs, such as esomeprazole and pantoprazole, have most recently been implicated in causing AIN. [99][100][101][102] Because PPIs are metabolized in the liver by cytochrome P450 enzymes, interactions between PPIs and other drugs, or variations in metabolism of PPIs due to genetic polymorphisms, may lead to higher levels of these medications in some patients and increase their susceptibility to adverse reactions, such as AIN. 103 ...
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Context.—Many new therapies have emerged within the last 5 to 10 years to treat a variety of conditions. Several of these have direct or indirect renal toxicities that may go undiagnosed without careful attention of the pathologist to a patient's clinical history, particularly the addition of new medications or treatments. Objective.—To discuss patterns of renal injury resulting from medications or therapeutic regimens that have been introduced within the last 10 years. Recognition of these patterns may allow the pathologist to alert the attending clinician to a possible drug-induced renal injury and prevent further deterioration of renal function and possible chronic kidney disease. Data Sources.—A review of recent literature and unpublished observations of case-derived material. Conclusions.—A number of newer therapies have emerged as agents of renal toxicity, producing a variety of pathologic changes in the kidney. The outcome can be acute or chronic glomerular, tubular, interstitial, and/or vascular injury. Some drugs will result in irreversible changes and end-stage renal disease, whereas many of the alterations can be reversed with removal of the offending agent, avoiding potential long-term kidney injury.
... It is cited higher incidence in the (54,55) elderly , increased risk of incomplete (15,17,30,56) recovery of renal function and progression (57) t o c h r o n i c i t y , e v e n w i t h p r o m p t ( 5 4 ) corticosteroid treatment applied after biopsy confirmation. Eosinophilia is usually seen , but other (58) s p e c i fi c m a n i f e s t a t i o n s o f AT I N a re inconsistent , so many cases are classified as (59) AKI of unknown cause until a biopsy is obtained. In some non-Caucasian races, a genetic predisposition for PPIs-induced ATIN has been described ; because PPIs are (60) metabolized by the cytochrome P450 enzyme system, patients with CYT P450 genetic polymorphism appear to be at risk for ATIN due to the interstitial accumulation of PPIs and/or their metabolites where they elicit an immune-mediated inflammatory response . ...
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Nowadays, incidence of drug-induced acute tubulointerstitial nephritis is on the rise due to increased access of the patients to a variety of both prescribed and over-the-counter drugs. Acute kidney injury and hypersensitivity manifestations are the main features of acute tubulointerstitial nephritis. Classically considered reversible after prompt withdrawal of the offending medication, recent decades revealed potential for evolution to chronic kidney disease. This article presents the challenges in the diagnosis and treatment and also evolutive features of allergic acute tubulointerstitial nephritis induced by drugs.
... It was first reported in 1992 that PPI use could cause acute interstitial nephritis (AIN) [58] and more than a decade later PPI-induced AIN became recognized as a clinical entity [59]. Due to their widespread use, PPIs are now considered to be among the most common causes of drug-induced AIN worldwide [60]. ...
Article
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Proton pump inhibitors (PPIs) have been increasingly used over the last decades and there are concerns about overuse and the numerous reported side-effects. It is uncertain whether associations between PPI use and potential side effects are causal. However, important evidence from experimental and mechanistic studies that could support a causal relationship may have been underestimated by epidemiologists and meta-analysists. In the current manuscript we review the combined epidemiological and mechanistic evidence of the adverse effects of PPI use.
... systemic lupus erythematosus [28,29], Sjö gren's syndrome, sarcoidosis [30], immunoglobulin G4-related disease) play a key role in the pathogenesis of this disease. Among the drugs triggering AIN, there has been increasing awareness about the role of proton pump inhibitors (PPIs) [3,14,21,22,31,32] in addition to non-steroidal anti-inflammatory drugs (NSAIDs) [3] and antibiotics [13] as causative agents and even inducers of chronic kidney disease (CKD) [33]. ...
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Background: Acute interstitial nephritis (AIN) is a renal injury causing renal function deterioration and requiring renal replacement therapy (RRT) in a substantial number of cases. Therapy is based on withdrawal of suspicious causative drugs or the underlying diseases and/or steroid application if renal function is not restored after cessation of the underlying condition. Hard clinical evidence for augmenting steroid therapy is not available. Methods: We reviewed the course and diagnosis for >20 years among all 1126 biopsied samples of our tertiary renal centre. Results: 49 (4.4%) were diagnosed with primary AIN, corresponding to an annual incidence of 1/100 000 population; 17 out of 49 biopsy-proven AIN patients required short-term or long-term (n = 5) RRT. According to a combined outcome criterion of coming off dialysis and/or reaching serum creatinine <200 µmol/L, 19 patients reached recovery whereas 20 did not. Among 39 patients with a comprehensive clinical and histopathological data set, presence of cortical scars, AIN histological activity (acute leucocyte infiltrates) and proteinuria were baseline parameters discriminating significantly between groups with or without recovery. No associations with the presence of specific drugs were found. Therapeutic use of steroids was associated with a lower probability of recovery (P = 0.008), presumably due to inclusion bias. Conclusions: Following our basic finding of the importance of histopathological parameters of acuity associated with recovery, we argue for the inauguration of grading measures to characterize this issue quantitatively and make it usable for future controlled investigations. Finally, we provide a suggestion for a therapeutic algorithm in the management of AIN.
... Acute inflammation may progress to chronic form with interstitial fibrosis and tubular atrophy. Retrospective review of all cases of biopsy proven AIN in two Australian teaching hospitals for a period of 10 years showed 28 cases of AIN of which 18 were due to PPIs [8]. ...
... In 1992, the first single case was published by Ruffenach and his colleagues [6] , followed by many reported cases of AIN after pantoprazole and omeprazole exposure [7][8][9] . Most of the published studies described and discussed the PPIs induced AIN clinically and statistically [10][11][12] . ...
... 10 ATIN caused by PPIs occurs mainly in elderly subjects and predominantly involves non-specific symptoms, as observed in this case. 1,10,11,13 Manifestations of hypersensitivity (fever, rash, and eosinophilia) are infrequent. 10,11 The diagnosis of ATIN due to PPIs may be difficult because of the variability in drug exposure times and the predominance of nonspecific manifestations. ...
Article
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Proton pump inhibitors (PPIs) are among the most frequent implicated drugs in acute tubulointerstitial nephritis (ATIN), nevertheless it is important to report cases with atypical profiles. A 80-year-old female, exposed during 34 months to omeprazole, presented with polyclonal hypergammaglobulinaemia and renal failure. After stopping omeprazole there was a partial improvement in serum creatinine and IgG. Renal biopsy revealed ATIN; immunohistochemistry for IgG4 was negative. Treatment with steroids and mycophenolate sodium improved renal function and normalized immunoglobulins. The lack of data of other entities and the patient’s evolution strongly point omeprazole as the culprit. After 27 months of follow-up, she remains clinical and analytically stable. ATIN caused by PPIs may appear after a long period of exposure and may be accompanied by analytical anomalies that simulate a systemic disease.
... The mechanisms of the associations between PPI use and acute kidney injury (AKI) could be through acute interstitial nephritis (AIN). Most AKI events were identified specifically in the form of AIN, which has been suggested by multiple studies as having an association with PPI exposure [14][15][16][17][40][41][42] and might be a cell-mediated idiosyncratic immune response [43], a class effect, as all PPIs could cause AIN. Several studies have attempted to estimate the incidence rate and relative hazards of the development of CKD, both in survivors of AKI and compared in populations without AKI. ...
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Background: Proton Pump Inhibitors (PPIs) have been associated with chronic kidney disease (CKD). Our objective was to quantify the association between PPI use and incident CKD in a population-based cohort. Methods and findings: We used a population-based retrospective cohort, including people aged 15 years or over, between January 1, 2005 and December 31, 2012. PPI use was measured in a follow-up session by recording prescriptions. Incident CKD was defined as an estimated glomerular filtration rate < 60 ml/ min/1.73 m2 and/or urinary albumin level to creatinine level ≥ 30 mg/g, in two or more determinations over a period of at least 3 months of the follow-up. Proton Pump Inhibitor use was associated with incident CKD in analysis adjusted for different clinical variables (Hazard Ratio (HR) 1.18; 95% CI 1.04-1.51) in individuals who used PPI in the basal visit (HR 1.37; 95% CI 1.25-1.50) and in those who started to use PPI during the follow-up. High doses of PPI increased the risk of incident CKD (HR 1.92; 95%CI 1.00-6.19) for any type of exposure to PPIs (HR 2.40; 95%CI 1.65-3.46) and for individuals who used high doses throughout the follow-up. This risk of incident CKD increased after three months' exposure to PPIs, (HR1.78; 95% CI 1.39-2.25) between the third and sixth months and (HR 1.30; 95%CI 1.07-1.72) after the sixth month. Conclusions: PPI use is associated with a higher risk of incident CKD. This association is greater for high doses and becomes apparent after three months' exposure.
... El uso prolongado de los fármacos IBP es otro de los aspectos importantes que sugieren el fracaso de la terapia convencional de la ERGE debido a las reacciones adversas (Sifrim y Zerbib, 2012) que se presentan como la hipomagnesemia e hipomagnesuria (Hoorn et al, 2010;Thongon et al, 2011), el desarrollo de adenocarcinomas a causa del incremento de la gastrina (hipergastrinemia) infecciones entéricas por clostridiumdifficile relacionadas con la supresión de ácido (Orlando et al, 2007;Garcia-Rodriguez et al, 2007), la ocurrencia de fracturas (Yang et al, 2006), complicaciones renales y respiratorias (Geevasinga et al 2006), así como la disminución de la biodisponibilidad de drogas dependientes del ácido gástrico (Silver-Matula et al, 2009). En este contexto, el reforzamiento con el uso de sustancias antioxidantes y citoprotectores gástricos, también han atenuado la esofagitis inducida por reflujo (Song et al, 2016). ...
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The increased incidence of esophageal adenocarcinomas is a complication of duodenal reflux oesophagitis. D-002 has an oesophageal-protective effect demonstrated in different experimental models of acute and chronic esophagitis. In order to evaluate the influence of D-002 in esophageal adenocarcinomas formation induced by experimental duodenal esophageal reflux (DER) in rats, male SD rats were used. The animals were divided into five experimental groups, one control without DER, and four with DER induction by surgical procedure and receiving treatment with D-002, indomethacin and omeprazol at doses of 2, 20 y 200 mg/Kg, respectively, over a period of 16 weeks. At the end of treatments, the esophagus macroscopically was evaluated and the ILE was determined. Subsequently, the esophageal tissue was preserved in formaldehyde for histological analysis. The results showed that D-002, indomethacin and omeprazole treatments, significantly reduced (40, 35 and 50 %, respectively) ILE; therefore, there were no significant histologic changes compared to positive control (DER). We concluded that oral administration of D-002 may be used as long-term treatment of duodenal reflux esophagitis, although not reverse the esophageal histological changes induced by duodenal reflux.
... The underlying mechanism of pantoprazole-induced acute kidney injury is complex. Sensitivity to pantoprazole is the primary reason for the onset of acute kidney injury and may only be confirmed by renal pathology (27). The standard diagnostic method for pantoprazole-induced acute kidney injury is monitoring the response to prednisone treatment (26). ...
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The present study reports a case of pantoprazole-induced acute kidney disease. The patient was diagnosed with acute kidney injury with wide interstitial inflammation and eosinophil infiltration. Following 1 month of glucocorticoid therapy, the patient's serum creatinine and urea nitrogen decreased to within normal ranges. The presentation, clinical course, diagnosis and prognosis of pantoprazole-induced acute kidney injury are discussed herein to highlight the importance of early and correct diagnosis for good prognosis. Disease characteristics include short-term increased serum creatinine levels that respond to glucocorticoid treatment. The patient had no history of chronic kidney disease or proteinuria and presented with increased serum creatinine following treatment with pantoprazole. Following the end of pantoprazole treatment, short-term RRT and long-term prednisolone was administered, then serum creatinine returned to normal. Pantoprazole-induced acute kidney injury is commonly misdiagnosed and late diagnosis results in poor patient prognoses. Misdiagnosis leads to the administration of treatments that may exacerbate the condition, so appropriate diagnosis and treatment for pantoprazole-induced acute kidney injury is necessary.
Article
Proton pump inhibitors are widely used in the treatment of various acid-related diseases and are among the most commonly used drugs. Studies estimate that 25-70% of proton pump inhibitors are prescribed for inappropriate treatments, doses, and indications, where the benefits of proton pump inhibitor use may be less than the risk of adverse drug reactions for many patients. Acute interstitial nephritis is an immune-mediated atypical kidney injury in the long-term use of proton pump inhibitors that causes problems for clinicians and patients. In this review, we summarize the current knowledge of proton pump inhibitors inducing acute interstitial nephritis, chronic kidney disease, and even end-stage renal disease in terms of incidence, pathogenesis, factors, clinical features, and diagnosis. We discuss how these factors change under conditions of acute interstitial nephritis, chronic kidney disease, and end-stage renal disease. The purpose of this review is to assess the current evidence to help clinicians and patients interpret the potential causal relationship between proton pump inhibitor intake and nephrotoxicity. This prompts clinicians to consider the appropriate dose and duration of proton pump inhibitor therapy to avoid inappropriate use.
Chapter
Acute tubulointerstitial nephritis (ATIN) is a heterogenous kidney disease and outcomes depend upon many factors including patient characteristics, clinical presentation and histopathological features on kidney biopsy. When considering short-term kidney outcomes, about 20% of adult patients with ATIN will require transient acute dialysis, although many will fully or partially recover without need for maintenance dialysis. However, current evidence suggests that long-term kidney outcomes are far less favorable than originally thought. When adult patients are followed for 1-3 years after an episode of ATIN, about 50% will experience full renal recovery, 40% will develop chronic kidney disease (CKD) and 10% end-stage-kidney disease (ESKD) requiring renal replacement therapy. Risk factors for adverse renal outcomes include patient characteristics (e.g., older age, hypertension), a higher degree of proteinuria, recurrent ATIN-episodes and signs of disease chronicity or granulomatous interstitial nephritis on kidney biopsy. Whether the use of corticosteroids improves long-term kidney outcomes in ATIN remains controversial. Pediatric patients have a better long-term prognosis, although a significant proportion of patients will develop CKD as well. Outcomes are also influenced by the underlying disease etiology. In general, drug-induced ATIN has a better prognosis when compared to auto-immune etiologies, certainly if the inciting drug is discontinued early in the disease course and re-exposure is avoided. Most frequently implicated drugs are antibiotics, proton pump inhibitors (PPIs) and non-steroidal anti-inflammatory drugs (NSAIDs), although the incidence of ATIN related to immune checkpoint inhibitors (ICPIs) is increasing. Auto-immune etiologies frequently cause CKD, partially because they are associated with recurrent ATIN-episodes. Finally, long-term kidney outcomes of ATIN related to Hantavirus-infection, Leptospirosis and Y. pseudotuberculosis are generally very good with high rates of complete recovery, although a significant proportion may require transient dialysis in the acute setting.
Chapter
Acute tubulointerstitial nephritis (ATIN) is an emerging cause of acute kidney disease, and drugs represent the most common etiology. In the majority of cases, symptoms associated with ATIN are non-specific, although the classical triad comprising fever, rash and eosinophilia, while rare, is observed more frequently in drug-related ATIN, particularly when beta-lactam antibiotics are involved. The identification of the causative drug is often challenging, especially in patients exposed to polypharmacy. Antibiotics are frequently involved in ATIN, although nonsteroidal anti-inflammatory drugs represent the most common etiology. When this latter group of drugs are implicated, fewer extra-renal manifestations and longer latency periods from the time of exposure are peculiar characteristics. Proton-pump inhibitors are another emerging group of drugs responsible for ATIN while advances in anticancer agents have also brought an increased incidence in drug-related side effects, including ATIN. Immune checkpoint inhibitors may induce ATIN in an interval between 1 and 24 months, and up to 25% of the patients in which these agents are rechallenged may develop recurrent acute kidney injury. Several other drugs have also been associated with the development of ATIN, which may represent a challenge for clinicians. This chapter aims to provide an update on the different etiologies underlying drug-induced ATIN.KeywordsAcute tubulointerstitial nephritisAntibioticsDrugsProton pump inhibitorsImmune checkpoint inhibitorsNonsteroidal anti-inflammatory drugsAcute kidney injuryChronic kidney disease
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Proton pump inhibitors (PPIs) are a group of medications effectively used to inhibit gastric acid secretion and to treat many acid-related disorders, including gastroesophageal reflux disease and other gastric disorders. Recent studies recommended that they may be associated with the risk of chronic kidney disease and liver disease. Therefore, the current study aimed to investigate the effect of long-term treatment with PPIs on kidney and liver function in laboratory rats. Fifteen female albino white rats (Rattusnorvigicus) were randomly assigned to three groups of five animals. The control group was fed regular pellet, group PPI-2 received standard pellet diet and was given esomeprazole (10 mg/kg b.w.) via daily oral gavage in mornings for two weeks, and group PPI-3 was fed standard pellet diet and was given esomeprazole (10 mg/kg b.w.) via daily oral gavage in mornings for three months. Blood samples were taken after 2 weeks and 3 months by cardiac puncture for measuring serum creatinine, urea, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). In addition, kidney and liver tissues were histopathologically evaluated. Serum creatinine, urea, ALT, total bilirubin, and ALP significantly increased in group PPI-3, compared to other groups. Histopathological study of the kidneys and liver revealed normal histology structure in the control group and the rats of the PPI-2 group, while some histological changes were observed in the liver and kidney of the animals in the PPI-3 group. The histological changes included the widening of Bowman's space and shrunken glomeruli, whereas the renal tubules had congested tubular cells. Furthermore, congestion in the blood vessels and hepatic cells degradation were observed in the liver. These data indicate that the long-term administration of PPIs has adverse effects on the structure and function of the kidney and liver.
Article
Zusammenfassung Protonenpumpenhemmer werden seit etwa 30 Jahren erfolgreich gegen magensäureassoziierte Erkrankungen, wie peptische Ulzera oder Refluxerkrankungen, eingesetzt. Durch ihre kovalente Bindung an die Protonenpumpen in den Parietalzellen des Magens kann die Magensäureproduktion effektiv reduziert und die therapeutische Wirkung der Protonenpumpenhemmer entfaltet werden. Auf diese Weise wird aber auch ein wichtiger Bestandteil der unspezifischen Immunabwehr ausgeschaltet, der den Körper – und vor allem das Darmmikrobiom – vor mit der Nahrung aufgenommenen Pathogenen oder eingeschwemmten Mundkeimen schützt. Daraus ergeben sich Veränderungen des Darmmikrobioms, wie eine Reduktion der Diversität des Mikrobioms oder eine Fehlbesiedelung des Dünndarms, die mit verschiedenen Nebenwirkungen der Protonenpumpen-(Langzeit-)Therapie, wie einem erhöhten Risiko für Clostridium-difficile-Infektionen oder gastrointestinalen Beschwerden, assoziiert sind. Bei Menschen mit Leberzirrhose bspw. ist die Einwanderung von oralen Bakterien in den Darm mit intestinaler Inflammation und Permeabilität verbunden und kann als Biomarker für das 3-Jahres-Überleben herangezogen werden. Mikrobiomassoziierte Nebenwirkungen sollten daher in den Diskurs über die Risiken von Langzeittherapien mit Protonenpumpenhemmern und dem Abwägen von Alternativen miteinbezogen werden.
Chapter
Gastroesophageal reflux disease (GERD) is defined as the objective pathologic sequelae of retrograde movement of gastric contents into the esophagus as it leads to troublesome symptoms or complications. Patients with cerebral palsy (CP) are at increased risk for GERD due to a number of contributing factors such as anatomy, altered gastrointestinal motility, posture, and other comorbidities. There is no gold standard diagnostic tool for the diagnosis of GERD. The diagnosis is often made clinically, based on signs and symptoms. There are different testing methods that can be used to document the presence of pathologic reflux and complications. One should have a high index of suspicion for GERD in children with CP in order for timely diagnosis and management. Treatment includes lifestyle modifications, pharmacotherapy, and surgical options. Suboptimal treatment of GERD can lead to complications such as erosive esophagitis and Barrett esophagus.
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RESUMEN En el presente artículo se efectúa una revisión bibliográfica sistemática sobre el manejo del sín-drome de Rendu-Osler-Weber en odontología y cirugía oral. Además se describe el tratamiento realizado en un paciente de 55 años de edad diagnosticado de dicha enfermedad y que fue sometido exitosamente a un tratamiento odontológico a nivel ambulatorio. PALABRA CLAVE Rendu, Osler, Weber, telangiectasia, hereditaria, hemorragica, dental, cirugía, oral, manejo, trata-miento. INTRODUCCIÓN La THH es un trastorno autosómico dominan-te con penetrancia y expresividad variable1. La pre-valencia se estima en 1 de cada 5000-10000 perso-nas 1-3. Existen al menos, 3 genes implicados: la THH tipo 1, por mutaciones en el gen endoglina (ENG), del brazo largo del cromosoma 9; la THH tipo 2 por mutaciones en el gen ACVRL1 (ALK-1) del brazo largo del cromosoma 12; el gen SMAD4 se ha asociado a la THH con poliposis juvenil 3-4. El diagnóstico se basa en los criterios de Curaçao (2000): 1) telangiecta-sias múltiples (cara, manos, nariz o cavidad oral); 2) epistaxis recurrentes; 3) malformaciones arteriove-nosas (MAVS) de afectación visceral y 4) anteceden-tes de familiar de primer grado con dicha enferme-dad. El diagnóstico se confirma con al menos tres de los 4 criterios 2,4,5. DESCRIPCIÓN DEL CASO Paciente de 55 años de edad, sin alergias me-dicamentosas conocidas. En tratamiento con lor-metazepam, sertralina, diazepam, espironolactona, atorvastatina y paracetamol. Diagnosticado de THH en el año 1993, con estudio genético (2009) que de-mostró el tipo THH-1 por delección en el exón 10 del gen ENG (endoglina). En seguimiento hospita-lario a cargo de los servicios de medicina interna, hematología, neumología y neurología. Múltiples ingresos hospitalarios desde la infancia por epista-xis de repetición de difícil control. Diagnosticado de MAVS encefálicas tratadas mediante radiocirugía; múltiples MAVS pulmonares tratadas por emboliza-ción con coils endovasculares. Ectasias vasculares de gran tamaño en hígado, médula espinal y recto. Insuficiencia respiratoria de origen mixto (cardíaco y pulmonar), requiriendo de la administración de oxígeno domiciliario con gafas nasales y CPAP noc-turna. Disnea a moderados o leves esfuerzos, pero no en reposo. El paciente se hallaba clínicamente estable desde hacía varios meses, sin complicacio-nes recientes sobreañadidas. Analítica sanguínea sin hallazgos de interés. En la consulta de odontología se aprecia gin-givitis con sarro supragingival, caries cervicales en 1.3, 1.4, 4.3 y 4.4 susceptibles de tratamiento con-servador con obturaciones, y caries extensas y des-trucción en el 4.7 y el 3.8, sin posibilidad de recons-trucción. Telangiectasias en la mucosa vestibular del labio inferior, porción anterior lingual y mucosa yugal. Dilataciones vasculares discretas en cuello, brazos y pabellón auricular.
Article
Purpose: Proton pump inhibitors (PPIs) are commonly used medications and are historically well tolerated. Recent studies have linked PPI use to the development of chronic kidney disease (CKD) and end-stage renal disease. This study investigated the impact of discontinuing PPIs on renal function in patients with CKD. Methods: We conducted a retrospective chart review of patients with established CKD, defined as 2 eGFR (estimated glomerular filtration rate) measurements of less than 60 mL/min/1.73 m ² at least 90 days apart, who were on a PPI from January 1, 2014 to December 31, 2014, with a medication possession ratio greater than or equal to 70%. We compared baseline eGFR to a final eGFR after at least 6 months of discontinuation or continuation of a PPI. After power analysis, we targeted an enrollment of 200 patients (100 in each group) to achieve a power of 0.80 and an alpha of 0.05. Summary: A total of 100 patients in the PPI discontinuation group and 97 patients in the PPI continuation group met the study inclusion criteria. Baseline eGFR in the PPI continuation group was 47.9 mL/min/1.73 m ² and 50.7 mL/min/1.73 m ² in the discontinuation group. Final eGFR in the PPI continuation group was significantly higher than baseline at 51.1 mL/min/1.73 m ² (+3.25 ± 12.8, P = .01). Final eGFR in the PPI discontinuation group was 51.8 mL/min/1.73 m ² (+1.09 ± 12.8, P = .3). The average time between baseline and final eGFRs was 270 days in the PPI continuation group and 301 days in the discontinuation group. There was no statistically significant difference in the change in eGFRs between groups (95% confidence interval [CI] = −5.48-2.03, P = .37). Conclusions: Proton pump inhibitor discontinuation after prolonged continuous use in patients with CKD was not associated with a significant change in renal function after 1 year.
Article
Purpose of review: The purpose of this review is to describe the most common causes of acute interstitial nephritis (AIN), the diagnostic work-up and the therapeutic management. Recent findings: Several case series and registries have found an increasing incidence of AIN, especially among older patients. Drug-induced AIN still represents the most common cause. Early withdrawal of the culprit drug together with corticosteroid therapy remain the mainstay of treatment, although recent studies have shown that prolonged treatment beyond 8 weeks does not further improve kidney function recovery. Summary: AIN is a common cause of acute kidney injury, and therefore, physicians should suspect this entity especially in patients exposed to multiple medications. While immune-allergic reaction to numerous drugs is the most common cause of AIN, other underlying systemic diseases may also be involved, and therefore, every patient should undergo a complete diagnostic evaluation. Kidney biopsy provides the definitive diagnosis of AIN, and certain histologic features may help to identify the underlying condition. In drug-induced AIN, an early discontinuation of the culprit drug is the mainstay of therapy, and unless a rapid recovery of kidney function is observed, a course of glucocorticoid therapy should be initiated.
Article
A substantial volume of literature exists linking proton pump inhibitor (PPI) use with a multitude of serious adverse events. There is uncertainty, however, over whether these associations are clinically important. Excessive concern about PPI-related adverse events may leave patients at risk of harm by leaving acid-related upper gastrointestinal disease untreated. Conversely, the risk of treatments may outweigh the benefits if any of the purported adverse events are directly caused by PPI use; this is of particular concern where indications for PPI use are not present. In this paper, we review the studies which have reported associations between adverse events and PPI use, discuss the proposed mechanisms of action, grade the confidence in whether these associations are truly causal, and provide advice regarding balancing the benefits of PPI use against their possible harms.
Article
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Background Acute tubulointerstitial nephritis (ATIN) is an important cause of acute kidney injury and often a potentially reversible disease. However, the role of steroids in ATIN remains controversial and the underlying mechanisms remain unresolved. Methods A total of 113 adult patients with biopsy-proven ATIN were recruited from three tertiary referral centers. Of 102 patients with idiopathic or drug-induced ATIN, outcomes such as renal recovery, end-stage renal disease, and all-cause mortality were compared between the steroid-treated and non-treated groups. Plasma and urine inflammatory cytokine levels at the time of biopsy were analyzed in patients (n = 33) using a bead-based multiplex assay and compared with those of healthy individuals (n = 40). Results Steroids were used in 92 (81.4%) of the total patients and in 82 (80.3%) patients with idiopathic or drug-induced ATIN. The rate of renal recovery and the risks of end-stage renal disease and mortality were not different between the steroid-treated and non-treated groups. Despite using a propensity score matching method (n = 20 in each group), none of the outcomes were different between the two groups. Several cytokines, such as monocyte chemotactic protein-1, interferon-α, and interleukin-6 and interleukin-8 levels, were markedly elevated in plasma and urine of patients compared with those in healthy individuals. However, cytokines related to Th2 response, such as IL-10, IL-33, were not different between the two groups. Conclusions Steroid use does not affect the overall outcome of ATIN. Based on the fact that targeting therapy should be investigated to improve outcomes, the present cytokine results will be helpful for developing a novel therapy for ATIN. Electronic supplementary material The online version of this article (10.1186/s12882-019-1277-2) contains supplementary material, which is available to authorized users.
Article
Objectives/Hypothesis To describe the trends in proton pump inhibitor (PPI) prescription rates and durations and compare them to those of H2‐receptor antagonists (H2RAs) between 2013 and 2016 in otolaryngology, gastroenterology, and family practice, following the increasing publications on PPI adverse effects and inappropriate prescribing. Study Design Retrospective review of publicly available Medicare Part D prescribing data. Methods PPI and H2RA prescription and beneficiary data were obtained through the Centers for Medicare and Medicaid Services website. For prescription rates, 30‐day fill counts were analyzed nationally and regionally per 10,000 Medicare members. Days supply per beneficiary was examined to show average prescription durations. Results were compared between otolaryngology, gastroenterology, and family practice. Medication‐related economic burden per year was calculated based on reported drug cost. Results From 2013 to 2016, PPI 30‐day fill counts remained stable, whereas H2RA prescription rates increased by up to 62% per 10,000 Medicare beneficiaries. The South consistently prescribed two to three times as much antireflux medication as the lowest prescribing region over time and across all three specialties. The days supply per beneficiary remained stable and ranged from an average of 128 to 203 days depending on the specialty. Antireflux medication‐related healthcare cost decreased steadily. Conclusions Despite numerous publications describing a multitude of adverse events and inappropriate prescribing patterns of PPIs in the past decade, prescription rates and durations per beneficiary have remained stable in the fields of otolaryngology, gastroenterology, and family practice. Additionally, H2RA prescriptions have increased from 2013 to 2016. Level of Evidence NA Laryngoscope, 2019
Article
More than 250 drugs carry a small but important dose-independent risk of initiating a delayed-type hypersensitivity reaction that leads to acute tubulointerstitial nephritis (TIN). Clinical manifestations are often non-specific, making epidemiological studies challenging. In severe cases, if cessation of the offending drug is not followed by a prompt improvement in renal function, corticosteroid therapy appears to enhance renal recovery rates. Other drugs, classified as potential nephrotoxins, may induce dose-dependent acute tubular necrosis. Studies over the past decade have identified a unique form of tubular cell death called “necroptosis” that is accompanied by a specific and significant interstitial inflammatory response to certain insults, including some nephrotoxins. Insights into the molecular basis of this necroinflammatory pathway have emerged. There is still a paucity of pediatric data on these two distinct types of drug-induced TIN. Early recognition is essential to minimize the risk of chronic kidney damage.
Chapter
This chapter outlines general considerations regarding the physiology and structure of the ageing kidney, epidemiological data regarding chronic kidney disease (CKD) in the elderly and management aspects of CKD and end-stage renal disease (ESRD) in an older population. The first section discusses the physiological and structural changes that occur in an ageing kidney which impact on its function and may contribute towards a declining glomerular filtration rate (GFR). As a consequence of this and new guidelines defining CKD, many elderly people are being classed as having CKD, although this may not reflect true pathology. Challenges in determining which individuals have true kidney pathology and which have normal age-related decline are discussed, including pitfalls in the usage of creatinine-based equations for calculating GFR. The second section outlines management aspects of CKD and ESRD. Treatment of CKD in the elderly should be individualised and maintain a geriatric perspective, which may prioritise quality of life over prolonging life. Strategies are aimed at preventing progression of CKD through blood pressure and metabolic control and minimising sequelae from complications of CKD such as anaemia and renal bone disease. However, treatment and objectives may need to be adjusted if initial therapy causes adverse effects or significantly reduces quality of life. Current practice for ESRD includes three potential pathways – dialysis, transplantation and a supportive (conservative) care pathway. In many older people, dialysis is poorly tolerated, particularly in the presence of comorbidities or frailty. The pros, cons and management aspects, including considerations specific to the elderly, of these pathways are outlined. Progression of CKD can be variable, and many patients with ESRD value early discussion and open communication regarding the course of their disease, treatments and early advanced care planning.
Chapter
Drug-induced acute kidney injury (AKI) is a relatively common problem. Prescribed medications, over-the-counter drugs/substances, and diagnostic agents may alter kidney function. As the kidney filters, secretes, reabsorbs, biotransforms, and excretes many drugs, it is not surprising that acute kidney injury is an adverse effect. Drugs and their metabolites can lead to injury within all compartments of the kidney including the vasculature, glomerulus, tubules, and interstitium. Common forms of drug-induced AKI affecting the various renal compartments include thrombotic microangiopathy, membranous and minimal change/focal segmental glomerulosclerosis, acute tubular injury/necrosis, osmotic nephropathy, crystalline-induced AKI, and acute interstitial nephritis. Recognizing AKI syndromes that are associated with various agents can lead to early identification of potentially harmful drugs and therapeutic agents, reducing exposure in at-risk patients. Once identified, the medication or agent can be withheld or dose-reduced, thereby significantly impacting and potentially reducing the duration and severity of kidney injury.
Article
Introduction: Proton pump inhibitors (PPIs) have become the first choice medical treatment of acid-related disease and, as with any pharmacological agent, they have been reported to be associated with some adverse events mainly linked to their chronic use. The most important postulated harms are represented by serum electrolyte alterations, vitamin B12 and iron deficiency, gastric tumors, enteric infections, spontaneous bacterial peritonitis, pneumonia, ischemic heart attacks, bone fractures, chronic kidney disease, dementia, and Alzheimer disease. Specific pathophysiological mechanisms have been identified for some of them and not for other manifestations. Areas covered: However, studies on PPIs safety have generally important limitations because of their frequent retrospective design and other methodological drawbacks, such as patients' selection and residual confounders. Expert opinion: Obviously, in the vast majority of the cases, adverse drug reactions cannot be assessed by means of randomized clinical trials due to the high costs, ethical reasons, and difficulties in performing prospective observational studies. So far, assessment of retrospective observational investigations remains the only method to evaluate adverse events with any drug in general and, although the weaknesses of these studies are evident, the awareness of the reported associations with the medications analyzed is important for physicians in order to manage adequately their individual patients.
Article
Proton pump inhibitors (PPIs) are among the most commonly prescribed medicines and are the mainstay of treatment for gastroesophageal reflux disease. Recently, there has been an increase in the use of these medicines for unclear and inappropriate indications. Although generally well tolerated and considered to be safe, several observational studies have linked PPI use with a variety of conditions such as pneumonia, Clostridium difficile infection, fractures, hypomagnesemia, and dementia. The well-established association between PPIs and acute interstitial nephritis has raised questions about whether they may also cause acute kidney injury and chronic kidney disease. Observational studies have evaluated these possible associations. This paper reviews the currently available literature about these associations and considers their possible underlying pathophysiological mechanisms. The level of evidence-linking PPI use with acute kidney injury and chronic kidney disease is weak and does not establish causality. More research is required to explore these possible associations further. The PPIs should be used in the lowest effective dose and inappropriate use should be avoided.
Article
Background and Aim More concerns had been raised about the risk of kidney disease (KD) associated with acid‐suppressive drugs (ASDs). But whether they could directly increase such risk remained unclear. Meta‐analysis was conducted to comprehensively investigate this relationship. Methods PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and three Chinese databases were searched until April 2017 for observational studies investigating the associations between ASDs and KD. Pooled log (odds ratios, ORs) or log (hazard ratios, HRs) with standard errors for KD risk were calculated using the generic inverse variance method and random‐effect model. Results Ten studies involving 128,020 KD patients were included. Proton pump inhibitor (PPI) therapy was associated with higher risks of acute interstitial nephritis (AIN) (OR, 2.78; 95% confidence interval (CI), 1.25‐6.17), acute kidney injury (AKI) (HR, 1.85; 95% CI, 1.33‐2.59), chronic kidney disease (CKD) (HR, 1.47; 95% CI, 1.03‐2.09), and end‐stage renal disease (ESRD) (HR, 1.61; 95% CI, 1.26‐2.04) than non‐PPI therapy. Additionally, PPI significantly increased the risks of AKI (HR, 1.32; 95% CI, 1.16‐1.51), CKD (HR, 1.28; 95% CI, 1.24‐1.33) and ESRD (HR, 1.96; 95% CI, 1.21‐3.17) compared to histamine 2 receptor antagonist (H2RA). Relationship between H2RA therapy and AKI (OR, 0.98; 95% CI, 0.90‐1.07) or CKD (OR, 1.00; 95% CI, 0.89‐1.11) was not found. Conclusions PPI therapy significantly increased the risks of AIN, AKI, CKD and ESRD. Similar risks were not identified for H2RA therapy. More clinical trials are needed to confirm our findings.
Article
Full-text available
A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
Article
Full-text available
A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
Article
Full-text available
Advances in cellular and molecular immunology over the past decade have revolutionized the way we think about interactions between the immune system and parenchymal tissues. The availability of well characterized experimental models of organ-specific or systemic autoimmunity has allowed advances in basic immunology to be incorporated into understanding the basis for deviant immune responses resulting in host injury, as well as the mechanisms of tolerance to organ-specific antigens [1–5]. This review outlines a framework analysis for understanding how the immune system interacts with the interstitial compartment of the kidney. This framework is comprised of four sections. The first details requirements for the induction of immune responses, including antigen expression in the kidney and how such antigen is presented to the immune system. The second section summarizes work from both experimental models and human studies which have characterized cell-mediated immune responses in interstitial disease [6]. The third section is an update of the antibody response to interstitial antigens, as well as the role of antibody in the effector limb of the immune response, an area which has been previously reviewed extensively [3,4]. The final section discusses how immune responses to interstitial antigens are typically regulated, either by the host or through external manipulations, such that tolerance to organ-specific antigens is maintained [7–9].
Article
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We present the case of a 77-year-old woman who initially presented with pyrexia of unknown origin, anaemia and mild renal impairment. When her omeprazole was stopped she improved rapidly. When omeprazole was re-started she developed fever and acute renal failure, which again settled quickly on discontinuation of omeprazole. This case demonstrates how drugs can cause severe multisystem disorders that may appear to be infective or inflammatory.
Article
Full-text available
Acute interstitial nephritis is an uncommon renal dis- order, causing 2-3% of episodes of acute renal failure Results (1,2). There are no specific clinical features, and a high index of suspicion together with a readiness to perform The register contained information on 7161 renal renal biopsy in all cases of unexplained renal failure is biopsies in adult patients, 5347 in patients aged
Article
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Dyspepsia drug costs account for nearly 0.5% of the National Health Service budget. We hypothesised that improved management of dyspepsia would lead to reduced drug costs. To determine whether a multifaceted educational strategy for general practitioners aimed at improving quality of dyspepsia management can control dyspepsia costs without increasing demand for endoscopy. A multifaceted educational intervention was delivered to general practitioners in West Gloucestershire but not to those in the east of the county. Dyspepsia drug costs, the primary outcome measure, were obtained from the Prescription Pricing Authority and compared between the two sides of the county. Referral rates for endoscopy, admission to the gastrointestinal bleed unit, and delayed diagnosis of gastric cancer were secondary measures recorded in West Gloucestershire only. Following the intervention, drug costs declined and then stabilised in West Gloucestershire. Drug costs peaked in the control group 15 months after those in the intervention group. Using an autoregressive integrated moving average model it was estimated the overall costs in the intervention group reduced by 57.9 pence per head of population per half year (95% confidence interval 45.8-69.9 pence/half year; p<0.0001) in comparison with the control group. This difference was maintained for three consecutive years resulting in a cumulative saving of pound1.13 million. Referral rates for upper gastrointestinal endoscopy remained stable during the study period. A multifaceted educational intervention for general practitioners designed to improve the quality of care of patients with dyspepsia is an effective means of controlling dyspepsia drug costs without increasing demand for endoscopy.
Article
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To describe what is believed, as of November 4, 2003, to be the first case published in the literature of acute interstitial nephritis (AIN) due to pantoprazole. A 77-year-old white woman presented to the hospital with elevated serum creatinine, oliguria for the past 24 hours, arthralgia, fatigue, fever, and bilateral flank pain. The patient had initiated treatment with oral pantoprazole 40 mg/d for gastroesophageal reflux 2 months prior to admission. After 5 weeks of therapy, she stopped taking pantoprazole due to general malaise. Upon admission, all home medications, including pantoprazole, were reinitiated based on the patient's medication list. Serum creatinine increased to 6.1 mg/dL on day 4 of admission from a baseline of 1.0 mg/dL. Pantoprazole therapy was promptly discontinued, and prednisone 40 mg/d was initiated. Urinalysis revealed eosinophils, and a subsequent renal biopsy confirmed a diagnosis of AIN. The serum creatinine level gradually declined over 2 weeks, and the patient was discharged home with a serum creatinine level of 1.6 mg/dL. The Naranjo probability scale suggests a highly probable relationship between AIN and pantoprazole therapy in this patient. Drug hypersensitivity reactions are the most common cause of AIN. There have been several reported cases of omeprazole-induced AIN. Although there are very few prospective data on the efficacy of treatment of drug-induced AIN, corticosteroids may have a role in recovery of renal function. Prednisone doses of 1 mg/kg/d have been suggested. Physicians should be aware that drug-induced AIN can be associated with proton-pump inhibitors. Early detection of this rare adverse reaction may prevent acute renal insufficiency.
Book
Comprehensive Clinical Nephrology provides you with all the tools you need to manage all forms of kidney disease. Drs. Jürgen Floege, Richard J. Johnson, John Feehally and a team of international experts have updated this fourth edition to include hot topics such as treatment of hypertensive emergencies, herbal and over-the-counter medicines and the kidney, neurologic complications of the kidney, and more. In print and online at www.expertconsult.com, this essential resource gives you quick access to today's best knowledge on every clinical condition in nephrology. Make efficient, informed decisions with just the right amount of basic science and practical clinical guidance for every disorder.Diagnose effectively and treat confidently thanks to more than 1100 illustrations, abundant algorithms, and tables that highlight key topics and detail pathogenesis for a full range of kidney conditions and clinical management.Access the fully searchable text online at www.expertconsult.com, along with a downloadable image gallery.Get coverage of the latest developments in the field with 18 new chapters on the Management of the Diabetic Patient with Chronic Kidney Disease, Treatment of Hypertensive Emergencies, Principles of Drug Dosing and Prescribing of Chronic Kidney Disease, Herbal and Over-the-Counter Medicines and the Kidney, Neurologic Complications of the Kidney, and more.Tap into the experience and expertise of the world's leading authorities in the field of nephrology.Floege, Johnson, and Feehally give you the information you need to make quick and correct clinical decisions.
Article
We report renal biopsy findings in 109 patients with unexplained renal impairment (serum creatinine greater than 0.15 mmol/l) and normal-sized non-obstructed kidneys. The most common histological lesions were interstitial nephritis, rapidly progressive glomerulonephritis and a variety of other types of glomerulonephritis. The groups could not be distinguished by the presence or absence of hypertension, haematuria, proteinuria, or features of systemic disease. However interstitial nephritis was found more frequently in patients presenting with one or none of these features and rapidly progressive glomerulonephritis in patients presenting with three or more. All four patients with none of these features had interstitial lesions. Fifty-two per cent of patients with interstitial nephritis improved and 60 per cent of the patients with rapidly progressive glomerulonephritis who received immunosuppressive treatment improved or remained stable with treatment. The benefits of a biopsy diagnosis were almost wholly confined to these two groups. Complications were recorded in nine patients - prolonged macroscopic haematuria in six and symptomatic perirenal haematomata in three. Six required blood transfusion. One required nephrectomy to control haemorrhage and subsequently died. Percutaneous renal biopsy is not without risk in patients with renal impairment but the benefits of diagnosing interstitial nephritis and rapidly progressive glomerulonephritis outweigh the disadvantages.
Article
Pantoprazole is an irreversible proton pump inhibitor which, at the therapeutic dose of 40mg, effectively reduces gastric acid secretion. In controlled clinical trials, pantoprazole (40mg once daily) has proved superior to ranitidine (300mg once daily or 150mg twice daily) and equivalent to omeprazole (20mg once daily) in the short term (< or = 8 weeks) treatment of acute peptic ulcer and reflux oesophagitis. Gastric and duodenal ulcer healing proceeded significantly faster with pantoprazole than with ranitidine, and at similar rates with pantoprazole and omeprazole. The time course of gastric ulcer pain relief was similar with pantoprazole, ranitidine and omeprazole, whereas duodenal ulcer pain was alleviated more rapidly with pantoprazole than ranitidine. Pantoprazole (40mg once daily) showed superior efficacy to famotidine (40mg once daily) in ulcer healing and pain relief after 2 weeks in patients with duodenal ulcer in a large multicentre nonblinded study. In mild to moderate acute reflux oesophagitis, significantly greater healing was obtained with pantoprazole than with ranitidine and famotidine, whereas similar healing rates were seen with pantoprazole and omeprazole. Pantoprazole showed a significant advantage over ranitidine in relieving symptoms of heartburn and acid regurgitation. Reflux symptoms were similarly alleviated by pantoprazole and omeprazole. Preliminary results indicate that triple therapy with pantoprazole, clarithromycin and either metronidazole or tinidazole is effective in the treatment of Helicobacter pylori-associated disease; however, these findings require confirmation in large well-controlled studies. Pantoprazole appears to be well tolerated during short term oral administration, with diarrhoea (1.5%), headache (1.3%), dizziness (0.7%), pruritus (0.5%) and skin rash (0.4%) representing the most frequent adverse events. The drug has lower affinity than omeprazole or lansoprazole for hepatic cytochrome P450 and shows no clinically relevant pharmacokinetic or pharmacodynamic interactions at therapeutic doses with a wide range of drug substrates for this isoenzyme system. In conclusion, pantoprazole is superior to ranitidine and as effective as omeprazole in the short term treatment of peptic ulcer and reflux oesophagitis, has shown efficacy when combined with antibacterial agents in H. pylori eradication, is apparently well tolerated and offers the potential advantage of minimal risk of drug interaction.
Article
Omeprazole is a proton pump inhibitor widely used for the treatment of peptic ulcer disease. We report a patient presenting nonoliguric acute renal failure following omeprazole treatment. Both eosinophilia and eosinophiluria were observed, and the patient was diagnosed as having drug-induced acute interstitial nephritis. Renal failure spontaneously resolved when omeprazole was discontinued.
Article
Immediately after the introduction of the proton pump inhibitor lansoprazole, a 2-year follow-up study was started to evaluate patterns of use, safety and effectiveness of this drug in naturally occurring groups of patients in the Netherlands. Medical data were recorded by participating physicians while medication listing were provided by pharmacists. The study was designed according to the Safety Assessment of Marketed Medicines guidelines. The only inclusion criterion was the use of lansoprazole prior to entry into the study. A total of 5669 lansoprazole users was included by 374 general practitioners and 117 specialists. Lansoprazole was mostly prescribed in patients with reflux oesophagitis (55.1%), 'gastritis' (26.8%) and duodenal ulcers (11.4%), sometimes as part of a Helicobacter pylori eradication therapy (8.5%). For their complaints most patients (91.1%) had previously used acid-related drugs. Improvement or disappearance of complaints was achieved in 88.9% and 90.5% of patients after 4 and 8 weeks of treatment, respectively. Diarrhoea (4.1%), headache (2.9%) and nausea (2.6%) were the most frequently reported adverse events. The patterns of use of lansoprazole in daily practice deviated from the recommendations in the information leaflet. Nevertheless, lansoprazole was found to be safe in this naturally occurring group of users. Effectiveness appeared to be comparable to results found in clinical trials of the registered indications for lansoprazole.
Article
Acute renal impairment secondary to interstitial nephritis is a rare complication of omeprazole. We describe a 50-year-old woman who took 20 mg omeprazole twice daily for endoscopically proved ulcerative esophagitis. At the same time, Duke's C colonic cancer was diagnosed and completely resected. Five fluorouracil/folinic acid adjuvant chemotherapy was tolerated without diarrhea or mouth ulceration. Renal function was normal before her first monthly cycle but markedly deteriorated immediately before the second cycle was due. The patient was symptomatic with lethargy, nausea, and mild vomiting, but she was clinically normotensive and only mildly dehydrated. Her serum creatinine concentration increased despite prolonged intravenous hydration, peaking at 4.4 mg/dl 1 week later. Results of a renal ultrasound were normal, and urinary microscopic findings were unremarkable. Renal biopsy showed interstitial nephritis, and renal function improved on cessation of omeprazole, eventually returning to normal. We describe the 12 cases of omeprazole-induced interstitial nephritis reported previously.
Article
A 69-year-old male who had a long history of ocular myasthenia was treated with omeprazole for 3 months. Progressive renal insufficiency was discovered fortuitously. There were no clinical or laboratory manifestations of immunoallergy. Renal biopsy revealed severe granulomatous interstitial nephritis, tubular injury and fibrosis. Histology of a liver nodule disclosed hepatic granulomatous involvement. Withdrawal of omeprazole and a short course of corticosteroids were followed by improvement but not normalization of renal function. This is the eighth report of omeprazole-induced interstitial nephritis. In the present case as in 2 others in the literature, the patients had been followed up for an autoimmune disease previously, which suggests that in patients with such a background, patients should be examined regularly for renal functional impairment during treatment with omeprazole.
Article
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
Article
The adverse effect profile of proton-pump inhibitors is presented. The proton-pump inhibitors are a well-tolerated class of drugs. The most common adverse events of headache, diarrhea, and nausea have been reported in fewer than 5% of patients treated with lansoprazole or omeprazole. The frequency of these adverse events with the two proton-pump inhibitors is comparable to that of placebo and histamine H2-receptor antagonists. Few clinically important interactions have been observed between proton-pump inhibitors and other drugs metabolized by the cytochrome P-450 system. The interaction potential should be considered when drugs with a narrow therapeutic window, such as phenytoin, warfarin, and theophylline, are used concomitantly with proton-pump inhibitors. Theoretical concerns about the consequences of chronic administration of proton-pump inhibitors, such as the impact of sustained hypergastrinemia on gastric morphology and the development of atrophic gastritis, have been dismissed. While increased gastrin levels are observed among patients taking proton-pump inhibitors, for the majority they remain within the normal range. After long-term use of the drugs, patients do not appear to be at increased risk of atrophic gastritis or gastric cancer. Helicobacter pylori infection, rather than acid suppression, may be the more important factor for the development of atrophic gastritis. Bacterial overgrowth and altered nutrient absorption resulting from sustained hypochlorhydria induced by chronic administration of proton-pump inhibitors have not been realized as clinical concerns. Not only are proton-pump inhibitors well tolerated during short-term administration, but there also do not appear to be clinically important adverse sequelae associated with their long-term use.
Article
To review the comparative efficacy and safety of the proton pump inhibitors (PPIs)--omeprazole, lansoprazole, pantoprazole, and rabeprazole--in the management of acid-related diseases. English-language journal articles retrieved from a MEDLINE search from 1990 to the present using these index terms: proton pump inhibitors, omeprazole, lansoprazole, pantoprazole, rebeprazole, and each of the acid-related diseases. Clinical trials and pertinent review articles that discussed the pharmacology, pharmacokinetics, efficacy, and safety of PPIs in the management of acid-related disease. By the authors. PPIs are substituted benzimidazoles that inhibit gastric acid secretion by covalently binding to the proton pump (H+/K+ ATPase). All undergo extensive hepatic metabolism and conjugation. The four agents differ in their metabolism by and effects on specific hepatic enzymes and thus in their ability to interact with other medications. PPIs are important agents used for eradicating Helicobacter pylori, in treating peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison syndrome, and upper gastrointestinal bleeding, and for preventing acid aspiration. Short-term side effects of the four agents are similar. The long-term safety of pantoprazole and rabeprazole appears similar to that of omeprazole and lansoprazole. Pantoprazole, which is in the final stages of approval for marketing in the United States, will be available in both an oral and injectable formulation. Based on superior efficacy profiles, PPIs are the drugs of choice in managing patients with peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. The decision to select one PPI versus another is most likely to be based on the agents' acquisition costs, formulations, FDA-labeled indications, and overall safety profiles. Intravenous or parenteral pantoprazole may become the preferred antisecretory agent for patients unable to take oral medications (e.g., critically ill patients and those with Zollinger-Ellison syndrome).
Article
Omeprazole is a proton pump inhibitor widely used in the treatment of gastro-esophageal reflux disease and peptic ulcer disease. In a 73-year-old man we describe renal failure due to acute interstitial nephritis after use of omeprazol during 4 months. Unexpected renal failure without signs of hydronephrosis should always provoke awareness of drug reaction, omeprazole being one of the possible drugs.
Article
There have been concerns raised about the potential adverse effects of proton pump inhibitors, especially with long-term use. In particular, their potent action can suppress the features and delay the diagnosis of gastric cancer, while prolonged exposure may hasten the development of gastric carcinoids. To examine the use of proton pump inhibitors in patients at the major teaching hospital in Tasmania, Australia, principally to determine the appropriateness of the therapy according to published guidelines. A retrospective review of the medical records of all patients prescribed any of the proton pump inhibitors at the hospital over a 7-month period, was performed. An extensive range of demographic and clinical variables was recorded for each patient. The patients were also asked a series of questions during their hospitalization to extract some of the relevant information - in particular, if and when they had undergone endoscopy. The 200 patients (52% males) had a mean age of 69 +/- 16.4 years. The most common indications for using proton pump inhibitors were acute gastrointestinal bleeding (20.9%), severe refractory ulcerating oesophagitis (17.3%), mild/moderate oesophageal reflux (17.3%) and refractory peptic ulcer (11.7%). A large number of patients were using a proton pump inhibitor for 'other' indications (39.6%). The prescribing of proton pump inhibitors satisfied the approved indications, as outlined in the Australian Schedule of Pharmaceutical Benefits, in only 37.1% of cases. Endoscopy had been performed in 54.1% of patients prior to commencing therapy with a proton pump inhibitor and within the next 7 days in another 12.8% of patients. Only 59% of patients had previously been treated with an H2-receptor antagonist before commencing therapy with a proton pump inhibitor. Even worse, only 58.5% of patients had used an H2-receptor antagonist before a proton pump inhibitor for mild/moderate oesophagitis. The median duration of proton pump inhibitor therapy for patients admitted to the hospital and already receiving one of the drugs was 450 days. Over half of the patients were being concurrently treated with other drugs which are known to cause or exacerbate gastro-oesophageal disease, and 18% were smokers. Whereas the proton pump inhibitors are undoubtedly effective agents, studies of their prescribing in practice consistently suggest over-use prior to endoscopy, use in patients who do not fit the approved criteria, and prescribing for indications in which 'less powerful' agents should have been sufficiently effective for the patient's symptoms. This poses economic and safety concerns, particularly in light of the suggestion that these drugs could delay the diagnosis of gastric cancer.
Article
Omeprazole is a proton pump inhibitor that is used commonly in the treatment of acid-peptic disorders. Although omeprazole is generally well tolerated, serious adverse effects such as renal failure have been reported. Thus far, 17 cases of acute interstitial nephritis (AIN) secondary to omeprazole have been described. Another case of AIN is described in a 36-yr-old woman presenting with nausea, vomiting, weight loss, and a rising serum creatinine concentration. Omeprazole therapy had ceased 2 wk before admission. AIN was diagnosed by renal biopsy and corticosteroid therapy was initiated. After 4 wk of therapy the serum creatinine concentration had normalized. Among the reported cases in the literature, AIN was diagnosed after an average of 2.7 months of therapy with 20-40 mg of omeprazole daily. Recurrence was universal on rechallenge. Common symptoms included fatigue, fever, anorexia, and nausea. The classic triad of fever, rash, and eosinophilia was uncommon. Typical laboratory features included hematuria, proteinuria, pyuria, eosinophilia, and anemia. Management consisted of withdrawal of omeprazole and corticosteroid therapy in some patients. All but one patient recovered normal renal function. Corticosteroid therapy was well tolerated and may have been beneficial.
Article
The pharmacology, pharmacodynamics, pharmacokinetics, clinical efficacy, and adverse effects of esomeprazole are reviewed. Esomeprazole, a proton-pump inhibitor (PPI), is the S-isomer of omeprazole. Esomeprazole has FDA-approved labeling for use in the treatment of symptomatic gastroesophageal reflux disease (GERD), including healing and maintenance of healing of erosive esophagitis and as part of a triple-drug regimen for Helicobocter pylori infection. Esomeprazole is structurally similar to other PPIs but is the first PPI to include only the active isomer, which may lead to improved pharmacokinetic and pharmacodynamic characteristics. Esomeprazole maintains intragastric pH at a higher level and above 4 for a longer period than other PPIs. Clinical studies have shown that esomeprazole is at least equivalent in safety and efficacy to other drugs in the class. Esomeprazole has demonstrated efficacy in the treatment of erosive esophagitis, the maintenance of healing of erosive esophagitis, and the treatment of signs and symptoms of GERD. Effective dosages are 20 or 40 mg orally every day or as needed. Esomeprazole magnesium 40 mg once daily in combination with amoxicillin and clarithromycin is effective in eradicating H. pylori infection. The potential for interacting with other drugs is limited and is similar to that of omeprazole. The most common adverse effects are headache, respiratory infection, and abdominal symptoms. Esomeprazole has pharmacokinetic properties that may make it more effective than omeprazole in some patients.
Article
Acute interstitial nephritis is an important cause of acute renal failure resulting from immune-mediated tubulointerstitial injury, initiated by medications, infection, and other causes. Acute interstitial nephritis may be implicated in up to 15 percent of patients hospitalized for acute renal failure. Clinical features are essentially those of acute renal failure from any cause, and apart from a history of new illness or medication exposure, there are no specific history, physical examination, or laboratory findings that distinguish acute interstitial nephritis from other causes of acute renal failure. Classic findings of fever, rash, and arthralgias may be absent in up to two thirds of patients. Diagnostic studies such as urine eosinophils and renal gallium 67 scanning provide suggestive evidence, but they are unable to reliably confirm or exclude the diagnosis of acute interstitial nephritis. Renal biopsy remains the gold standard for diagnosis, but it may not be required in mild cases or when clinical improvement is rapid after removal of an offending agent or medication. The time until removal of such agents, and renal biopsy findings, provide the best prognostic information for return to baseline renal function. Corticosteroids appear to provide some benefit in terms of clinical improvement and return of renal function, but no controlled clinical trials have been conducted to confirm this.
Article
Pantoprazole is a proton-pump inhibitor (PPI) that is commonly prescribed for the treatment of gastroesophageal reflux-related disorders. There are many documented side effects of PPIs. Here we report a case of acute interstitial nephritis, which developed after 6 weeks of treatment with pantoprazole. A 23-year-old man presented with acute renal failure requiring renal replacement therapy. Acute interstitial nephritis was diagnosed by renal biopsy and was successfully treated with corticosteroids and withdrawal of pantoprazole. Drug-induced acute interstitial nephritis can occur with PPIs such as pantoprazole and vigilance needs to be maintained.
Article
Acute tubulo-interstitial nephritis (TIN) is an important cause of acute renal failure, and is often caused by hypersensitivity to drugs. The aim of this study was to determine the aetiology of interstitial nephritis among an unselected cohort of patients, and to identify those drugs commonly implicated. A single-centre retrospective analysis was carried out of renal biopsy results from 296 consecutive patients between 1995 and 1999. Acute TIN was identified in 24 (8.1%) biopsies. Eight out of 14 cases with presumed drug-related TIN could be attributed to the proton pump inhibitors omeprazole and lansoprazole. The two cases of lansoprazole-associated TIN are the first to be reported with this drug. The presentation and favourable response to treatment of these patients are described. Drugs are the most common cause of interstitial nephritis in the population studied. Those drugs most commonly associated with interstitial nephritis were the proton pump inhibitors omeprazole and lansoprazole.
Omeprazole related acute interstitial nephritis (AIN) with renal failure (abstract)
  • J H Gronich
  • E R Snipes
  • H D Stein
Gronich JH, Snipes ER, Stein HD, et al. Omeprazole related acute interstitial nephritis (AIN) with renal failure (abstract). J Am Soc Nephrol 1994;5:394.
Adverse Drug Reactions Advisory Committee. Omeprazole, musculoskeletal problems and interstitial nephritis
Adverse Drug Reactions Advisory Committee. Omeprazole, musculoskeletal problems and interstitial nephritis. Aust Adverse Drug React Bull 1995;14:14 -15.
Acute interstitial nephritis in the elderly
  • Davison