A Novel Form of Renal Tubular Acidosis Associated With Immune Checkpoint Inhibitors.
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ABSTRACT:
SUBMITTER: Shah CV
PROVIDER: S-EPMC9831939 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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A Novel Form of Renal Tubular Acidosis Associated With Immune Checkpoint Inhibitors.
Shah Chintan V CV Lee Hyun-Wook HW Clapp William L WL Weiner I David ID
Kidney international reports 20221026 1
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Project description:The main manifestation of acute interstitial nephritis (AIN) due to immune checkpoint inhibitors is acute kidney injury. We report here a biopsy-proven AIN revealed by tubular acidosis. This case highlights that immune checkpoint inhibitor prescribers must be aware of electrolytic disorders since tubular dysfunction can precede serum creatinine increase and reveal renal toxicity.
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Project description:The main cause of acute kidney injury in patients receiving immune checkpoint inhibitors (ICIs) is acute interstitial nephritis. However, as their use continues to increase, other kidney manifestations are being described. We report 3 cases of patients treated with ICIs who developed predominantly electrolyte disorders secondary to renal tubular acidosis as an immune-related adverse event and discuss the potential mechanism. Nongap acidosis in combination with hypokalemia should raise suspicion for distal renal tubular acidosis in patients treated with ICIs.
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Project description:This report describes the oral manifestations of renal tubular acidosis (RTA) associated with secondary rickets and discusses the biological plausibility of these findings. The characteristic electrolyte changes during RTA or genetic mutations that trigger RTA may be responsible for impaired amelogenesis, dental malocclusion, impacted teeth, and absent lamina dura. This report reinforces the possibility of an association between RTA and the oral manifestations described.
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Project description:Background. Fanconi-Bickel syndrome (FBS) is an autosomal recessive disorder caused by defects in facilitative glucose transporter 2 (GLUT2 or SLC2A2) gene mapped on chromosome 3q26.1-26.3, that codes for the glucose transporter protein 2. Methods. Two unrelated Egyptian families having suspected cases of FBS were enrolled after taking a written informed consent; both had positive consanguinity, and index cases had evidences of proximal renal tubular defects with hepatomegaly; they were subjected to history taking, signs of rickets as well as anthropometric measurements. Laboratory workup included urinalysis, renal and liver function tests including fasting and postprandial blood sugar; serum calcium, phosphorus, alkaline phosphatase, sodium and potassium, lipid profile, and detailed blood gas. Imaging including bone survey and abdominal ultrasound, and liver biopsy were done to confirm diagnosis. Molecular analysis of the GLUT2 gene was done for DNA samples extracted from peripheral blood leukocyte. All coding sequences, including flanking introns in GLUT2 gene, were amplified using PCR followed by direct sequencing. Results. Two new mutations had been detected, one in each family, in exon 3 two bases (GA) were deleted (c.253 254delGA) and in exon 6 in the second family, G-to-C substitution at position-1 of the splicing acceptor site (c.776-1G>C or IVS5-1G>A). Conclusion. FBS is a rare disease due to mutation in GLUT2 gene; many mutations were reported, about half were novel mutations; yet none of these mutations is more frequent. A more extensive survey for the most frequent mutations among FBS has to be contemplated to allow for use of molecular screening tests like ARMS.
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Project description:The immune system has long been known to play a critical role in the body's defence against cancer, and there have been multiple attempts to harness it for therapeutic gain. Renal cancer was, historically, one of a small number of tumour types where immune manipulation had been shown to be effective. The current generation of immune checkpoint inhibitors are rapidly entering into routine clinical practice in the management of a number of tumour types, including renal cancer, where one drug, nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody (mAb), is licensed for patients who have progressed on prior systemic treatment. Ongoing trials aim to maximize the benefits that can be gained from this new class of drug by exploring optimal timing in the natural course of the disease as well as combinations with other checkpoint inhibitors and drugs from different classes.
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Project description:Renal tubular acidosis (RTA) is a condition characterized by normal anion gap metabolic acidosis. Type 1 and type 2 RTA are the most common, and are caused by defective secretion of hydrogen ions and impaired absorption of bicarbonate, respectively. Long-standing uncorrected acidosis can lead to metabolic bone disease (MBD). Rickets and osteomalacia remain the commonest manifestations of uncorrected RTA. In addition, there can be a myriad of other skeletal manifestations like fractures, pseudofractures, secondary osteoporosis and even sclerotic bone disease. The postulated mechanism for bone involvement includes acidosis-mediated exaggerated osteoclastic bone resorption. Other contributory factors include abnormal renal handling of phosphate leading to hypophosphataemia in proximal RTA, and impaired vitamin D metabolism and action. In distal RTA, hypercalciuria and secondary hyperparathyroidism may play a key role for bone involvement. Recognizing the disease in its early course is important to prevent permanent sequelae of skeletal involvement. Most of these patients may, in fact, undergo orthopaedic interventions without primary correction of acidosis. We describe five cases who presented with MBD in varied forms. While evaluating the aetiology of MBD, they were diagnosed with RTA. Subsequently, we attempted to analyse the causes of RTA. Although the common causes were ruled out, genetic aetiology could not be ascertained due to resource constraints. RTA remains an important differential diagnosis of MBD. More awareness is required to diagnose the disease early and to treat it adequately. Our case series is an attempt to provide the clinical, biochemical and skeletal spectrum of RTA. In addition, we have attempted to provide algorithms for the approach and evaluation of RTA along with their varied causes.
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Project description:The aim of this study was to identify the causative mutation in a family with an unusual presentation of autosomal dominant osteopetrosis (OPT), proximal renal tubular acidosis (RTA), renal stones, epilepsy, and blindness, a combination of features not previously reported. We undertook exome sequencing of one affected and one unaffected family member, followed by targeted analysis of known candidate genes to identify the causative mutation. This identified a missense mutation (c.643G>A; p.Gly215Arg) in the gene encoding the chloride/proton antiporter 7 (gene CLCN7, protein CLC-7), which was confirmed by amplification refractory mutation system (ARMS)-PCR, and to be present in the three available patients. CLC-7 mutations are known to cause autosomal dominant OPT type 2, also called Albers-Schonberg disease, which is characterized by osteosclerosis, predominantly of the spine, pelvis and skull base, resulting in bone fragility and fractures. Albers-Schonberg disease is not reported to be associated with RTA, but autosomal recessive OPT type 3 (OPTB3) with RTA is associated with carbonic anhydrase type 2 (CA2) mutations. No mutations were detected in CA2 or any other genes known to cause proximal RTA. Neither CLCN7 nor CA2 mutations have previously been reported to be associated with renal stones or epilepsy. Thus, we identified a CLCN7 mutation in a family with autosomal dominant osteopetrosis, RTA, renal stones, epilepsy, and blindness. © 2016 Wiley Periodicals, Inc.
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Project description:Large population-based studies examining differences in ICI-associated cardiotoxicity across cancer types and agents are limited. Data of 5518 cancer patients who received at least one cycle of ICIs were extracted from a large network of health care organizations. ICI treatment groups were classified by the first ICI agent(s) (ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, or durvalumab) or its class (PD-1 inhibitors, PD-L1 inhibitors, CTLA4-inhibitors, or their combination (ipilimumab + nivolumab)). Time to first cardiac adverse event (CAE) (arrhythmia, acute myocardial infarction, myocarditis, cardiomyopathy, or pericarditis) developed within one year after ICI initiation was analyzed using a competing-risks regression model adjusting for ICI treatment groups, patient demographic and clinical characteristics, and cancer sites. By month 12, 12.5% developed cardiotoxicity. The most common cardiotoxicity was arrhythmia (9.3%) and 2.1% developed myocarditis. After adjusting for patient characteristics and cancer sites, patients who initiated on monotherapy with ipilimumab (adjusted Hazard Ratio (aHR): 2.00; 95% CI: 1.49-2.70; p < 0.001) or pembrolizumab (aHR: 1.21; 95% CI: 1.01-1.46; p = 0.040) had a higher risk of developing CAEs within one year compared to nivolumab monotherapy. Ipilimumab and pembrolizumab use may increase the risk of cardiotoxicity compared to other agents. Avelumab also estimated a highly elevated risk (aHR: 1.92; 95% CI: 0.85-4.34; p = 0.117) compared to nivolumab and other PD-L1 agents, although the estimate did not reach statistical significance, warranting future studies.
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Project description:Hyperchloremic acidosis is frequent in critically ill patients. Renal tubular acidosis (RTA) may contribute to acidemia in the state of hyperchloremic acidosis, but the prevalence of RTA has never been studied in critically ill patients. Therefore, we aimed to investigate the prevalence, type, and possible risk factors of RTA in critically ill patients using a physical-chemical approach.This prospective, observational trial was conducted in a medical ICU of a university hospital. One hundred consecutive critically ill patients at the age ?18, expected to stay in the ICU for ?24 h, with the clinical necessity for a urinary catheter and the absence of anuria were included. Base excess (BE) subset calculation based on a physical-chemical approach on the first 7 days after ICU admission was used to compare the effects of free water, chloride, albumin, and unmeasured anions on the standard base excess. Calculation of the urine osmolal gap (UOG)--as an approximate measure of the unmeasured urine cation NH4(+)--served as determinate between renal and extrarenal bicarbonate loss in the state of hyperchloremic acidosis.During the first week of ICU stay 43 of the patients presented with hyperchloremic acidosis on one or more days represented as pronounced negative BEChloride. In 31 patients hyperchloremic acidosis was associated with RTA characterized by a UOG ?150 mosmol/kg in combination with preserved renal function. However, in 26 of the 31 patients with RTA metabolic acidosis was neutralized by other acid-base disturbances leading to a normal arterial pH.RTA is highly prevalent in critically ill patients with hyperchloremic acidosis, whereas it is often neutralized by the simultaneous occurrence of other acid-base disturbances.Clinicaltrials.gov NCT02392091. Registered 17 March 2015.
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Project description:Autosomal recessive distal renal tubular acidosis is usually a severe disease of childhood, often presenting as failure to thrive in infancy. It is often, but not always, accompanied by sensorineural hearing loss, the clinical severity and age of onset of which may be different from the other clinical features. Mutations in either ATP6V1B1 or ATP6V0A4 are the chief causes of primary distal renal tubular acidosis with or without hearing loss, although the loss is often milder in the latter. We describe a kindred with compound heterozygous alterations in ATP6V0A4, where hearing loss was formally diagnosed late in both siblings such that they missed early opportunities for hearing support. This kindred highlights the importance of routine audiologic assessments of all children with distal renal tubular acidosis, irrespective either of age at diagnosis or of which gene is mutated. In addition, when diagnostic genetic testing is undertaken, both genes should be screened irrespective of current hearing status. A strategy for this is outlined.
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