A case report of atypical anti-glomerular basement membrane nephritis associated with Mycobacterium Avium.

We present the case of a woman with atypical anti-glomerular basement membrane (anti-GBM) nephritis associated with concurrent pulmonary infection with Mycobacterium avium. A kidney biopsy showed crescentic glomerulonephritis with 50% active crescents and linear IgG staining, but no circulating anti-GBM antibodies were detected, and the patient did not have pulmonary hemorrhage. Despite treatment with a triple-regimen of antibiotics, corticosteroids, and plasmapheresis, the patient did not regain kidney function. One year later she is on maintenance dialysis and has still not cleared the infection with M. avium.

Design and methodology of the PRIMETIME 1 cohort study: PRecIsion MEdicine based on kidney TIssue Molecular interrogation in diabetic nEphropathy.

Background: Clinical features of diabetic kidney disease alone cannot differentiate between the histopathology that defines diabetic nephropathy (DN) and non-diabetic nephropathy (NDN). A kidney biopsy is necessary to make the definitive diagnosis of DN. However, there is no consensus on when to perform a kidney biopsy in individuals with diabetes and kidney disease. Furthermore, the implications of NDN versus DN for management, morbidity and kidney prognosis are unclear. To address the gap in knowledge, we aimed to create a national retrospective cohort of people with diabetes and a performed kidney biopsy. Methods: Adults diagnosed with diabetes in Denmark between 1996 and 2020 who had a kidney biopsy performed were included. The cohort was established by linking a nationwide diabetes registry with the Danish Pathology Registry. Data from 11 national registries and databases were compiled. The type of kidney disease was classified using a three-step analysis of Systematized Nomenclature of Medicine codes reported in relation to the histopathological examinations of kidney tissue. The final cohort and classification of kidney disease was as follows: out of 485 989 individuals with diabetes 2586 were included, 2259 of whom had type 2 diabetes. We were able to classify 599 (26.5%) with DN, 703 (31.1%) with NDN and 165 (7.3%) with mixed disease in individuals with type 2 diabetes. In individuals with type 1 diabetes, 132 (40.4%) had DN, 73 (22.3%) NDN and 39 (11.9%) mixed disease. The remaining could not be classified or had normal histology. The overall median (Q1-Q3) follow-up time was 3.8 (1.6-7.2) years. Conclusions: This cohort is a novel platform based on high-quality registry data for important longitudinal studies of the impact of kidney disease diagnosis on prognosis. With regular updates of data from the Danish registries, the presented follow-up will increase over time and is only limited by emigration or death.

Rationale and design of a prospective, clinical study of kidney biopsies in people with type 2 diabetes and severely increased albuminuria (the PRIMETIME 2 study).

INTRODUCTION: Diabetic kidney disease is a severe complication of diabetes. The diagnosis is based on clinical characteristics such as persistently elevated albuminuria, hypertension and decline in kidney function, although this definition is not specific to kidney disease caused by diabetes. The only way to establish an accurate diagnosis-diabetic nephropathy-is by performing a kidney biopsy. The histological presentation of diabetic nephropathy can be associated with a heterogeneous range of histological features with many pathophysiological factors involved demonstrating the complexity of the condition. Current treatment strategies aim to slow disease progression and are not specific to the underlying pathological processes.This study will investigate the prevalence of diabetic nephropathy in individuals with type 2 diabetes (T2D) and severely elevated albuminuria. The deep molecular characterisation of the kidney biopsy and biological specimens may pave the way for improved diagnostic accuracy and a better understanding of the pathological processes involved and may also reveal new targets for individualised treatment. METHODS AND ANALYSIS: In the PRecIsion MEdicine based on kidney TIssue Molecular interrogation in diabetic nEphropathy 2 study, research kidney biopsies will be performed in 300 participants with T2D, urine albumin/creatinine ratio ≥700 mg/g and estimated glomerular filtration ratio >30 mL/min/1.73 m2. Cutting-edge molecular technologies will be applied to the kidney, blood, urine, faeces and saliva samples for comprehensive multi-omics profiling. The associated disease course and clinical outcomes will be assessed by annual follow-up for 20 years. ETHICS AND DISSEMINATION: The Danish Regional Committee on Health Research Ethics and the Knowledge Center on Data Protection (in the Capital Region of Denmark) have granted approval for the study. The results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04916132.

Combination therapy with immune check point inhibitors and acute kidney injury.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of metastatic renal cell carcinoma and malignant melanoma but are also associated with a risk of severe side effects. Nephrotoxicity is an immune checkpoint inhibitor-related adverse effect, but acute kidney injury (AKI) can also be caused by other more common conditions. This study aimed to describe the incidence and causes of AKI in patients treated with combination therapy of immune checkpoint inhibitors. MATERIAL AND METHODS: This retrospective cohort study included 200 patients receiving ipilimumab and nivolumab for either metastatic renal cell carcinoma or malignant melanoma at the Department of Oncology at Copenhagen University Hospital, Herlev between 1 January 2019 and 31 December 2020. The incidence and cause of AKI within 6 months after treatment was determined. RESULTS: In the 96 patients treated for malignant melanoma 15 patients (16%) had an episode of AKI. Two of these patients had potential immune checkpoint inhibitor-related AKI both of which received treatment with a proton pump inhibitor (PPI). Of the 104 included patients with metastatic renal cell carcinoma 26 patients (25%) developed AKI. Five of these patients had potential immune checkpoint inhibitor-related AKI. Treatment with PPI before the development of AKI occurred in 4 out of these 5 patients. CONCLUSION: Patients receiving combination therapy with checkpoint inhibitors are at high risk of AKI, but different causes of AKI should always be considered. Use of PPI concurrently with ICIs is likely to increase the risk of AKI.

Reduced vitamin D-induced cathelicidin production and killing of Mycobacterium tuberculosis in macrophages from a patient with a non-functional vitamin D receptor: A case report.

Tuberculosis (TB) presents a serious health problem with approximately a quarter of the world's population infected with Mycobacterium tuberculosis (M. tuberculosis) in an asymptomatic latent state of which 5-10% develops active TB at some point in their lives. The antimicrobial protein cathelicidin has broad antimicrobial activity towards viruses and bacteria including M. tuberculosis. Vitamin D increases the expression of cathelicidin in many cell types including macrophages, and it has been suggested that the vitamin D-mediated antimicrobial activity against M. tuberculosis is dependent on the induction of cathelicidin. However, unraveling the immunoregulatory effects of vitamin D in humans is hampered by the lack of suitable experimental models. We have previously described a family in which members suffer from hereditary vitamin D-resistant rickets (HVDRR). The family carry a mutation in the DNA-binding domain of the vitamin D receptor (VDR). This mutation leads to a non-functional VDR, meaning that vitamin D cannot exert its effect in family members homozygous for the mutation. Studies of HVDRR patients open unique possibilities to gain insight in the immunoregulatory roles of vitamin D in humans. Here we describe the impaired ability of macrophages to produce cathelicidin in a HVDRR patient, who in her adolescence suffered from extrapulmonary TB. The present case is a rare experiment of nature, which illustrates the importance of vitamin D in the pathophysiology of combating M. tuberculosis.

Klotho and activin A in kidney injury: plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in the contralateral kidney.

In a new paradigm of etiology related to chronic kidney disease-mineral and bone disorder (CKD-MBD), kidney injury may cause induction of factors in the injured kidney that are released into the circulation and thereby initiate and maintain renal fibrosis and CKD-MBD. Klotho is believed to ameliorate renal fibrosis and CKD-MBD, while activin A might have detrimental effects. The unilateral ureter obstruction (UUO) model is used here to examine this concept by investigating early changes related to renal fibrosis in the obstructed kidney, untouched contralateral kidney, and vasculature which might be affected by secreted factors from the obstructed kidney, and comparing with unilateral nephrectomized controls (UNX). Obstructed kidneys showed early Klotho gene and protein depletion, whereas plasma Klotho increased in both UUO and UNX rats, indicating an altered metabolism of Klotho. Contralateral kidneys had no compensatory upregulation of Klotho and maintained normal expression of the examined fibrosis-related genes, as did remnant UNX kidneys. UUO caused upregulation of transforming growth factor-ß and induction of periostin and activin A in obstructed kidneys without changes in the contralateral kidneys. Plasma activin A doubled in UUO rats after 10 days while no changes were seen in UNX rats, suggesting secretion of activin A from the obstructed kidney with potentially systemic effects on CKD-MBD. As such, increased aortic sclerostin was observed in UUO rats compared with UNX and normal controls. The present results are in line with the new paradigm and show very early vascular effects of unilateral kidney fibrosis, supporting the existence of a new kidney-vasculature axis.

High dose intravenous iron, mineral homeostasis and intact FGF23 in normal and uremic rats.

BACKGROUND: High iron load might have a number of toxic effects in the organism. Recently intravenous (iv) iron has been proposed to induce elevation of fibroblast growth factor 23 (FGF23), hypophosphatemia and osteomalacia in iron deficient subjects. High levels of FGF23 are associated with increased mortality in the chronic kidney disease (CKD) population. CKD patients are often treated with iv iron therapy in order to maintain iron stores and erythropoietin responsiveness, also in the case of not being iron depleted. Therefore, the effect of a single high iv dose of two different iron preparations, iron isomaltoside 1000 (IIM) and ferric carboxymaltose (FCM), on plasma levels of FGF23 and phosphate was examined in normal and uremic iron repleted rats. METHODS: Iron was administered iv as a single high dose of 80 mg/kg bodyweight and the effects on plasma levels of iFGF23, phosphate, Ca2+, PTH, transferrin, ferritin and iron were examined in short and long term experiments (n = 99). Blood samples were obtained at time 0, 30, 60, 180 minutes, 24 and 48 hours and in a separate study after 1 week. Uremia was induced by 5/6-nephrectomy. RESULTS: Nephrectomized rats had significant uremia, hyperparathyroidism and elevated FGF23. Iron administration resulted in significant increases in plasma ferritin levels. No significant differences were seen in plasma levels of iFGF23, phosphate and PTH between the experimental groups at any time point within 48 hours or at 1 week after infusion of the iron compounds compared to vehicle. CONCLUSIONS: In non-iron depleted normal and uremic rats a single high dose of either of two intravenous iron preparations, iron isomaltoside 1000, and ferric carboxymaltose, had no effect on plasma levels of iFGF23 and phosphate for up to seven days.