Immunological mechanisms underlying clinical phenotypes and noninvasive diagnosis of immune checkpoint inhibitor-induced kidney disease.

Immune checkpoint inhibitors (ICIs) have become a mainstay of cancer therapy, with over 80 FDA-approved indications. Used in a variety of settings and in combination with each other and with traditional chemotherapies, the hyperactive immune response induced by ICIs can often lead to immune-related adverse events in bystander normal tissues such as the kidneys, lungs, and the heart. In the kidneys, this immune-related adverse event manifests as acute interstitial nephritis (ICI-AIN). In the era of widespread ICI use, it becomes vital to understand the clinical manifestations of ICI-AIN and the importance of prompt diagnosis and management of these complications. In this review, we delve into the clinical phenotypes of ICI-AIN and how they differ from traditional drug-induced AIN. We also detail what is known about the mechanistic underpinnings of ICI-AIN and the important diagnostic and therapeutic implications behind harnessing those mechanisms to further our understanding of these events and to formulate effective treatment plans to manage ICI-AIN.

Facing the Challenge of Drug-Induced Acute Interstitial Nephritis.

BACKGROUND: Acute interstitial nephritis (AIN) is one of the chief causes of acute kidney injury (AKI). AIN might be produced by drugs, infections, autoimmune diseases, or can be idiopathic. Among these etiologies, drug-induced AIN (DI-AIN) is the dominant one in many countries. Even when DI-AIN is suspected, identification of the putative drug is challenging. SUMMARY: DI-AIN is an increasingly common cause of AKI. Diagnosis continues to pose a challenge for physicians due to nonspecific clinical symptoms, and the fact that it can be triggered by a wide variety of medications. Furthermore, the gold standard for the diagnosis is kidney biopsy. All these aspects render the diagnosis more difficult. The withdrawal of the causative drug of DI-AIN is the centerpiece of the treatment, and if early restoration of original kidney function is not obtained, several studies support the treatment with steroids especially when they are started quickly. KEY MESSAGES: Almost all drugs have the potential to produce drug-induced acute interstitial nephritis (DI-AIN); however, antibiotics, nonsteroidal anti-inflammatory agents, and proton pump inhibitors account for the majority of the reported cases. DI-AIN is produced by an idiosyncratic delayed type IV hypersensitivity reaction, but the precise pathophysiological mechanism remains to be elucidated. DI-AIN symptoms are nonspecific, and most of the patients will present mild symptoms including malaise, nausea, and vomiting. The classical triad, associating fever, rash, and eosinophilia, is seldom present. Nonoliguric acute kidney injury is the main renal manifestation of DI-AIN. Tubular nonnephrotic range proteinuria is usually present. Diagnosis of DI-AIN relies on maintaining a high index of suspicion in those patients at greater risk, but kidney biopsy is required to confirm diagnosis. Histologically, AIN is characterized by the presence of an extensive interstitial infiltrate, mainly composed of lymphocytes and monocytes, but eosinophils, plasma cells, histiocytes, and polymorphonuclear cells can also be found. The withdrawal of the presumed causative drug of DI-AIN is the mainstay of the treatment. When there is no evidence of kidney function recovery after an interval of 5-7 days since interrupting the treatment with the suspected drug, several studies support the treatment with steroids, especially when they are promptly started. Early corticosteroids would decrease the inflammatory infiltrates of the kidney interstitium, thus preventing the risk of subsequent fibrosis.

[Acute interstitial nephritis: clinical presentation and diagnosis]. / Néphrite interstitielle aiguë : quand la suspecter et quelle prise en charge ?

Acute interstitial nephritis is characterized by renal inflammation and interstitial edema. The clinical presentation is pauci-symptomatic and often non-specific. Acute interstitial nephritis typically presents with acute renal failure, alone or with fever, eosinophilia, hematuria, sterile pyuria and small range proteinuria. An early diagnosis is crucial to prevent the morbidity and mortality associated with renal function decline. The most frequent etiology of this disease is drug-induced. A kidney biopsy is not systematically required to establish the diagnosis. It should be considered in the absence of renal function improvement 5 to 7 days after withdrawal of the causal agent. Although the benefits of glucocorticoid treatment have not been proven to date, its use may be associated with a better kidney function recovery.

La néphrite interstitielle aiguë est caractérisée par une inflammation dans le compartiment interstitiel rénal. La présentation clinique est paucisymptomatique. Elle se présente généralement par une insuffisance rénale aiguë qui peut être accompagnée de fièvre, d'éosinophilie, d'hématurie, de leucocyturie stérile et de protéinurie non néphrotique. Son diagnostic précoce est crucial pour prévenir la morbi-mortalité liée au déclin de la fonction rénale. L'étiologie la plus fréquente est médicamenteuse. Le diagnostic par la ponction-biopsie rénale n'est pas systématique, mais doit être considéré en l'absence d'amélioration de la fonction rénale 5 à 7 jours après l'arrêt de la substance incriminée. Le principal traitement consiste en l'interruption du médicament incriminé et à l'administration de corticostéroïdes.

Brief Communication PD1-related Nephrotoxicity: Optimizing Its Clinical Management Through Histopathologic Features.

Immune-related nephrotoxicity (ir-N) is a rare adverse event of immune-checkpoint(s) inhibitors (ICI) therapy and its clinical management is still debated. Among 501 consecutive ICI-treated patients at our Institution, 6 who developed an ir-N with clinical signs suggestive for an acute kidney injury underwent kidney biopsy. Histology showed an acute tubule-interstitial nephritis, simulating the scenario of acute T-cell-mediated kidney transplant rejection. Thus, the management of allograft kidney rejection routinely utilized at our clinic was implemented, leading to rapid renal function improvement. Histologic features supporting the definition of an immune-mediated acute kidney injury in ICI-treated patients may help optimizing the clinical management of ir-N.

Immune Checkpoint Inhibitor-Associated AKI: Debates in Diagnosis, Management, and Rechallenge.

Immune checkpoint inhibitors (ICIs) are now established treatments for advanced cancer and their use is now ubiquitous. The high upside of ICIs is tempered by their toxicity profile affecting almost every organ, including the kidneys. Although acute interstitial nephritis is the major kidney-related adverse effect of checkpoint inhibitors, other manifestations such as electrolyte abnormalities and renal tubular acidosis have been described. With increasing awareness and recognition of these events, the focus has shifted to non-invasive identification of ICI-acute interstitial nephritis, with sophisticated approaches involving biomarkers and immunologic signatures being studied. Although the management of immune-related adverse events with corticosteroids is straightforward, there now are more data to help guide immunosuppressive regimens, ICI rechallenge, and delineate risk and efficacy in special populations such as individuals on dialysis or those who have received a transplant.

Successful Treatment of Nephrotic Syndrome Due to Collapsing Focal Segmental Glomerulosclerosis Accompanied by Acute Interstitial Nephritis.

A 39-year-old woman was hospitalized for nephrotic syndrome. Laboratory test results showed increased serum creatinine levels and urinary excretions of beta-2-microglobulin, and N-acetyl-beta-D-glucosaminidase. A renal biopsy revealed collapsing focal segmental glomerulosclerosis (FSGS) and acute interstitial nephritis. Despite treatment with pulse steroid followed by oral high-dose glucocorticoids and cyclosporines, heavy proteinuria persisted. After low-density lipoprotein apheresis (LDL-A) therapy was initiated, her proteinuria gradually decreased, leading to complete remission. A repeat renal biopsy after treatment revealed no collapsing glomeruli. Immediate LDL-A should be performed to treat cases of collapsing FSGS poorly responding to other treatments.

Renal replacement therapy-requiring acute kidney injury due to tubulointerstitial nephritis and uveitis syndrome: case report.

BACKGROUND: Acute kidney injury is a major challenge for today's healthcare systems around the globe. Renal replacement therapy has been shown to be beneficial in acute kidney injury, but treatment highly depends on the cause of the acute kidney injury. One less common cause is tubulointerstitial nephritis, which comes in different entities. A very rare type of tubulointerstitial nephritis is tubulointerstitial nephritis and uveitis syndrome, in which the patient presents with additional uveitis. CASE PRESENTATION: A 19-year-old caucasian male presented with mild dyspnea, lack of appetite, weight loss, and moderate itchiness. Lab results showed an acute kidney injury with marked increase of serum creatinine. The patient was started on prednisolone immediately after admission. As the patient in this case showed symptoms of uremia on admission, we decided to establish renal replacement therapy, which is unusual in tubulointerstitial nephritis and uveitis syndrome. During his course of dialysis, the patient developed symptoms of sepsis probably due to a catheter-related infection requiring intensive care and antibiotic treatment, which had to be terminated early as the patient developed a rash. Intensified immunosuppression, combined with antibiotics, significantly resolved excretory kidney dysfunction. CONCLUSIONS: Since both the primary inflammatory process and the secondary infectious complication significantly impaired excretory kidney function, kidney function of younger individuals with new-onset anterior uveitis should be monitored over time and during follow-up.

Prognosis of severe drug-induced acute interstitial nephritis requiring renal replacement therapy.

OBJECTIVE: Drug-induced acute interstitial nephritis (DAIN) is often associated with improved outcomes, whereas some patients may still progress to chronic kidney disease (CKD). The aim of this study was to evaluate the prognosis of patients with severe DAIN requiring renal replacement therapy (RRT) at baseline, and to explore the risk factors of progression to CKD. METHODS: We performed a retrospective study of patients with severe DAIN confirmed by renal biopsies in our center over a 10 years period, all the patients received RRT at presentation. The clinical and pathological characteristics at baseline were recorded, and the outcomes (renal function recovered or progressed to CKD) during follow-ups were also evaluated. Univariate and multivariate logistic regression analysis were performed to identify the independent risk factors of progression to CKD. RESULTS: Seventy-two patients who met the inclusion criteria were enrolled, 13 patients (18.0%) progressed to CKD (GFR < 60 ml/min/1.73 m2) after at least 6 months of follow-up, the remaining 59 patients achieved a favorable renal function recovery. Compared with patients who achieved renal function recovery (recovery group), the patients progressed to CKD (progression group) were older and had longer interval from symptom onset to treatment with steroids. The peak serum cystatin C concentration was higher in progression group than recovery group. Higher score of interstitial fibrosis/tubular atrophy (IFTA) and more interstitial inflammatory cells infiltration were detected in renal tissue in progression group. According to multivariable analysis, higher peak cystatin C concentration (OR = 2.443, 95% CI 1.257, 4.746, p = 0.008), longer interval to treatment with corticosteroids (OR = 1.183, 95% CI 1.035, 1.352, p = 0.014) were independent risk factors of progression to CKD. The cutoff value of cystatin C concentration was 4.34 mg/L, at which the sensitivity and specificity were 76.9% and 89.3%, respectively; the cutoff value of interval to treatment with corticosteroids was 22.5 days, at which the sensitivity and specificity were 81.8% and 79.5%, respectively. CONCLUSION: Renal function was reversible in majority of patients with severe DAIN requiring RRT when early identification and treatment. Higher peak cystatin C concentration and longer interval to treatment with corticosteroids associated with worse renal prognosis.

Acute Tubulointerstitial Nephritis in Clinical Oncology: A Comprehensive Review.

Acute kidney injury in patients who suffer a malignancy is a common complication. Due to its high prevalence and effective treatment, one of the most frequent causes that both oncologists and nephrologists must be aware of is acute tubulointerstitial nephritis (ATIN). ATIN is an immunomediated condition and the hallmark of the disease, with the presence of a tubulointerstitial inflammatory infiltrate in the renal parenchyma. This infiltrate is composed mainly of T lymphocytes that can be accompanied by macrophages, neutrophils, or eosinophils among other cells. One of the major causes is drug-related ATIN, and some antineoplastic treatments have been related to this condition. Worthy of note are the novel immunotherapy treatments aimed at enhancing natural immunity in order to defeat cancer cells. In the context of the immunosuppression status affecting ATIN patients, some pathogen antigens can trigger the development of the disease. Finally, hematological malignancies can also manifest in the kidney leading to ATIN, even at the debut of the disease. In this review, we aim to comprehensively examine differential diagnosis of ATIN in the setting of a neoplastic patient.

Acute interstitial nephritis and nephrogenic diabetes insipidus following treatment with sulfamethoxazole-trimethoprim and temozolomide.

We report a case of acute interstitial nephritis with associated nephrogenic diabetes insipidus in a patient treated with temozolomide and sulfamethoxazole-trimethoprim for glioblastoma multiforme. Kidney biopsy demonstrated focal tubulointerstitial change with tubular dilatation, epithelial change and interstitial inflammation. The patient's kidney function improved with cessation of sulfamethoxazole-trimethoprim and treatment with hydrochlorothiazide for nephrogenic diabetes insipidus. Recommencement of temozolomide did not result in further deterioration in kidney function. In this case report, we discuss the novel association between sulfamethoxazole-trimethoprim-induced acute interstitial nephritis and nephrogenic diabetes insipidus, and suggest possible mechanisms involved.

A rare case of cephalexin-induced acute interstitial nephritis with hypokalemic periodic paralysis.

Drug-induced acute interstitial nephritis (AIN) is often encountered in clinical practice. Cephalexin is a first-generation cephalosporin with antimicrobial sensitivity ranging from Gram-positive to Gram-negative organisms. Cephalexin-induced AIN presenting with hypokalemic periodic paralysis (HPP) has been rarely reported. A 34-year-old female with recent history of oral cephalexin intake presented with acute onset paraplegia with deranged renal parameters and hypokalemia. She was treated conservatively with mechanical ventilator support. HPP could be a rare clinical presentation for cephalexin-induced AIN.

Toll-like 4 receptor (TLR4) expression on peripheral blood mononuclear cells in renal transplant recipients with pre-transplant chronic interstitial nephritis indicates patients at risk of graft deterioration.

Data binding the expression of Toll-like 4 receptor (TLR4ex), transplanted kidney function, and the cause of pre-transplant end-stage renal disease are scarcely available. OBJECTIVE: To investigate the relationship between pre-transplant chronic interstitial nephritis (CIN), TLR4ex and transplanted kidney function. MATERIALS AND METHODS: TLR4ex was measured in peripheral blood mononuclear cells of 43 CIN kidney transplant recipients. We compared TLR4ex among 33 patients with pre-transplant chronic non-infectious interstitial nephritis (NIN) and 10 patients with pre-transplant chronic pyelonephritis (Py). At the beginning (Day-0) TLR4ex, as well as concentrations of cyclosporin A (CyA) and tacrolimus (TAC) were determined. Both CIN and NIN patients were divided according to the respective median of TLR4ex into groups of low-TLR4 expression (L-TLR4ex) and high-TLR4 expression (H-TLR4ex). Serum creatinine/glomerular filtration rate (sCr/EGFR) was assessed on Day-0 and after the follow-up (F-up). The magnitudes of sCr/EGFR change (ΔsCr/ΔEGFR) were evaluated. The treatment was maintained stable along the F-up period (median 11.9 months). RESULTS: Day-0: in CIN with L-TLR4ex TAC was lower but sCr/EGFR were not different from H-TLR4ex; in Py TLR4ex and TAC were lower than in NIN with no difference in sCR/eGFR. After F-up: in CIN with L-TLR4ex sCR/EGFR and ΔsCr/ΔEGFR were worse than in H-TLR4ex; in Py sCR/EGFR and ΔsCr/ΔEGFR were worse than in NIN. The regression analysis points out prospective impact of Py and TLR4ex on sCR/eGFR and ΔsCr/ΔeGFR. CONCLUSION: In CIN, both TLR4ex and Tac appear to be a useful positive predictor of the effectiveness of immunosuppression. Chronic pyelonephritis indirectly promotes faster progression of chronic transplanted kidney disease.

The Association of Mesalamine With Kidney Disease.

The package inserts for products containing 5-aminosalicylic acid, or mesalamine, include the following language regarding the risk of adverse kidney effects: "renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and rarely renal failure, has been reported in patients given products such as mesalamine delayed-release tablets that contain mesalamine or are converted to mesalamine." In this article, we review the data regarding this nephrotoxicity and the recommendations regarding appropriate monitoring. Chronic interstitial nephritis is a rare occurrence in patients treated with these drugs for Crohn disease and ulcerative colitis. Patients often present with asymptomatic reductions in glomerular filtration rate, without accompanying pyuria, skin lesions, or eosinophilia, unlike cases of acute interstitial nephritis. Drug cessation is usually associated with improved kidney function. However, if left undetected, more prolonged exposure to the drug can lead to irreversible kidney failure and end-stage kidney disease. No convincing studies demonstrate efficacy of treatment with corticosteroids. Frequent monitoring of serum creatinine, especially in the first years after initiation of therapy, is recommended.

Case report: a 58 -year -old man with small kidneys and elevated liver enzymes.

BACKGROUND: The conjunction of hepatitis and renal disease can be seen in several clinical context, including karyomegalic nephritis (KIN). Karyomegalic nephritis (KIN) is a rare genetic disease, with less than 50 cases reported, which incidence is probably underestimated. We report here an unusual case presentation of KIN with obtention of several organ biopsies and a novel mutation leading to the disease. CASE PRESENTATION: A 58 year old Caucasian without relevant family history presents with advanced chronic kidney disease, elevated liver enzymes and recurrent pulmonary infection. Familial history was negative. Renal biopsy revealed a chronic tubulo-intertsitial nephritis with enlarged and irregular hyperchromatic nuclei. Karyomegalic nephritis (KIN) was confirmed by genetic testing with a non-sense mutation and a deletion in the Fanconi anemia associated nuclease 1 (FAN1) gene. CONCLUSIONS: KIN is rare disease to be suspected in the presence of renal disease, biological hepatitis and recurrent pulmonary infections, even without a familial history. Diagnosis of this condition is crucial to perform family screening, avoid progression factors, and adapt post transplantation immunosuppression. Finally, avoiding familial heterozygote donors appears of major importance in this condition.

Bilateral decompression retinopathy after deep sclerectomy with mitomycin C in a child with tubulointerstitial nephritis and uveitis syndrome.

INTRODUCTION: To report the first case of bilateral ocular decompression retinopathy after uneventful non-perforating deep sclerectomy with mitomycin C in a child with tubulointerstitial nephritis and uveitis syndrome. CASE DESCRIPTION: An 8-year-old girl affected by tubulointerstitial nephritis and uveitis syndrome developed ocular hypertension (45 mmHg in the right eye and 42 mmHg in the left eye) associated with recurrent episodes of uveitis and chronic use of steroids despite maximum hypotensive medical treatment. Bilateral non-perforating deep sclerectomy with mitomycin C (0.2 mg/mL, 1 min) was performed under general anesthesia without complications. The first postoperative day, the visual acuity was reduced to 0.6 in the right eye and 0.05 in the left eye and the intraocular pressure was 3 mmHg in both eyes. Fundoscopy revealed bilateral optic nerve swelling and diffuse retinal hemorrhages, some of them with scattered-white centers. About 2 months after surgery, the visual acuity was normal and the fundus examination showed complete resolution. CONCLUSION: The ocular decompression retinopathy is an uncommon complication after non-perforating deep sclerectomy. This is the first case of bilateral ocular decompression retinopathy reported after non-perforating deep sclerectomy in a child with ocular hypertension secondary to recurrent uveitis and chronic use of steroids associated with tubulointerstitial nephritis and uveitis syndrome.

Acute tubulointerstitial nephritis with germinal centers in antineutrophil cytoplasmic antibody-associated vasculitis: A case report and literature review.

RATIONALE: Occasionally, tubulointerstitial lesions can be found in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, significantly isolated tubulointerstitial nephritis (TIN) with germinal centers is rare. PATIENT CONCERNS: A 17-year-old Chinese Han patient showed rapidly progressive glomerulonephritis, anuria, and serum creatinine of 19.4 mg/dL. DIAGNOSIS: He had positive ANCA targeting myeloperoxidase (55.0 RU/mL). The renal biopsy showed crescent formation in 100% of glomeruli. Of special note, the glomerular crescents were surrounded by granulomatous inflammation, extensive tubular destruction or disappearance, and massive interstitial infiltration. A diagnosis of AAV was thus made with the involved organ restricted to the kidney. INTERVENTIONS: The patient underwent 7 rounds of plasmapheresis, 3 pulses of methylprednisolone therapy (500 mg per pulse), and oral prednisolone (50 mg/d). Rituximab (500 mg) was used after the plasma exchange treatment. OUTCOMES: ANCA was negative, while anti-modified C-reactive protein (anti-mCRP) antibodies remained positive. The patient was dependent on hemodialysis. We found anti-mCRP antibody in the serum of the patient, with the major epitope on amino acids 35 to 47 of mCRP. LESSONS: We proposed that the anti-mCRP antibody might play an important role in this case of acute TIN in AAV.