Anti-Glomerular Basement Membrane Disease: Recent Updates.

Anti-glomerular basement membrane disease is a small-vessel vasculitis involving the kidneys (∼90%) and the lungs (∼60%). Antibodies against the glomerular basement membrane are directly pathogenic in anti-glomerular basement membrane disease; however, recent research has highlighted the critical role of T cells. Novel autoantigens within the glomerular basement membrane are also now recognized. Atypical forms of the disease are reported along with preceding triggers, such as immune checkpoint inhibitors, immunomodulatory drugs, and vaccines. Kidney outcomes in anti-glomerular basement membrane disease remain poor despite significant improvement in patient survival in the last 2 to 3 decades. Treatment typically relies on combined plasmapheresis with intensive immunosuppression. Dialysis dependency at presentation is a dominant predictor of kidney outcome. Histologically, a low (<10%) percentage of normal glomeruli, 100% crescents, together with dialysis dependency at presentation, is associated with poor kidney outcomes. In such cases, an individualized approach weighing the risks and benefits of treatment is recommended. There is a need for better ways to stop the toxic inflammatory activity associated with this disease. In this narrative review, we discuss recent updates on the pathogenesis and management of anti-glomerular basement membrane disease relevant to patients of all ages.

MicroRNA193a: An Emerging Mediator of Glomerular Diseases.

MicroRNAs (miRNAs) are noncoding small RNAs that regulate the protein expression of coding messenger RNAs. They are used as biomarkers to aid in diagnosing, prognosticating, and surveillance of diseases, especially solid cancers. MiR-193a was shown to be directly pathogenic in an experimental mouse model of focal segmental glomerulosclerosis (FSGS) during the last decade. Its specific binding and downregulation of Wilm's tumor-1 (WT-1), a transcription factor regulating podocyte phenotype, is documented. Also, miR-193a is a regulator switch causing the transdifferentiation of glomerular parietal epithelial cells to a podocyte phenotype in in vitro study. Interaction between miR-193a and apolipoprotein 1 (APOL1) mRNA in glomeruli (filtration units of kidneys) is potentially involved in the pathogenesis of common glomerular diseases. Since the last decade, there has been an increasing interest in the role of miR-193a in glomerular diseases, including diabetic nephropathy and membranous nephropathy, besides FSGS. Considering the lack of biomarkers to manage FSGS and diabetic nephropathy clinically, it is worthwhile to invest in evaluating miR-193a in the pathogenesis of these diseases. What causes the upregulation of miR-193a in FSGS and how the mechanism is different in different glomerular disorders still need to be elucidated. This narrative review highlights the pathogenic mechanisms of miR-193a elevation in various glomerular diseases and its potential use in clinical management.

Kidney dysfunction due to AA amyloidosis in a morbidly obese female.

Kidneys are commonly involved in systemic amyloidosis. Systemic AA amyloidosis is known to be associated with states of chronic inflammation such as autoimmune conditions, chronic infections, and malignancies. Obesity is increasingly recognized to be a risk factor for low-grade, chronic inflammation. We report a 48-year-old female with morbid obesity who presented with unexplained persistent mild kidney dysfunction and low-grade proteinuria. Attempt at evaluating the cause of kidney dysfunction included performing kidney biopsy despite technical challenges. Kidney biopsy showed AA amyloidosis with predominant vascular deposition, explaining the absence of nephrotic-range proteinuria. Evaluation for secondary causes of systemic AA amyloidosis was negative. While our patient was treated with sleeve gastrectomy for morbid obesity with reasonable response, it is likely that ongoing chronic inflammation, reflected by her laboratory markers, resulted in AA amyloidosis. Treatment with anakinra, an interleukin-1 antagonist, led to improvement in the laboratory markers in the next 6 months, and her kidney function remained stable. This report highlights an important cause of kidney dysfunction in morbid obesity, an atypical presentation of AA amyloidosis, and emphasizes the value of kidney biopsy in such patients.

Atypical Anti-Glomerular Basement Membrane Disease.

Atypical anti-glomerular basement membrane (anti-GBM) disease is characterized by linear immunoglobulin G (IgG) deposition along the GBM without circulating IgG anti-GBM antibodies. Compared to classic anti-GBM disease, atypical anti-GBM disease tends to be milder with a more indolent course in certain cases. Moreover, pathologic disease pattern is much more heterogenous in atypical anti-GBM disease than in the classic type, which is uniformly characterized by diffuse crescentic and necrotizing glomerulonephritis. Although there is no single well-established target antigen in atypical anti-GBM disease, the target antigen (within the GBM) and the autoantibody type are hypothesized to be different from the classic type. Some patients have the same antigen as the Goodpasture antigen that are detected only by a highly sensitive technique (biosensor analysis). Some cases of atypical anti-GBM disease have autoantibodies of a different subclass restriction like IgG4, or of monoclonal nature. Antibodies targeting antigen/epitope structure other than the Goodpasture antigen can be detected using modified assays in some cases. Patients with IgA- and IgM-mediated anti-GBM disease are known to have negative circulating antibodies because conventional assays do not detect these classes of antibodies. A significant proportion of cases with atypical anti-GBM disease do not have any identifiable antibodies despite extensive evaluation. Nevertheless, extensive evaluation of atypical autoantibodies using modified assays and sensitive techniques should be attempted, if feasible. This review summarizes the recent literature on atypical anti-GBM disease.

Kidney and urinary tract involvement in systemic mastocytosis.

Systemic mastocytosis (SM) is a disorder of excessive mast cell accumulation in tissues due to a somatic gain-of-function mutation, commonly in the KIT gene, which prevents apoptosis of mast cells. Whereas bone marrow, skin, lymph nodes, spleen and gastrointestinal tract are commonly involved, kidneys are rarely involved directly by SM. However, there are increasing reports of indirect kidney involvement in patients with SM. Novel anti-neoplastic agents to treat advanced forms of SM include non-specific tyrosine kinase inhibitors, which are reported to be associated with kidney dysfunction in some patients. SM is also associated with immune-mediated glomerulonephritis (GN) such as mesangioproliferative GN, membranous nephropathy and diffuse proliferative GN. Kidney injury, in the form of monoclonal deposition disease and primary light chain amyloidosis, is reported in SM associated with plasma cell dyscrasia. In this narrative review we discuss the various ways kidneys (and the urinary tract) are involved in patients with SM.

Parietal Epithelial Cell Behavior and Its Modulation by microRNA-193a.

Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, activated PECs are speculated to be pathogenic and comprise extracapillary proliferation in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CrescGN). The reparative and pathogenic roles of PECs seem to represent two sides of PEC behavior directed by the local milieu and mediators. Recent studies suggest microRNA-193a (miR193a) is involved in the pathogenesis of FSGS and CrescGN. In a mouse model of primary FSGS, the induction of miR193a caused the downregulation of Wilms' tumor protein, leading to the dedifferentiation of podocytes. On the other hand, the inhibition of miR193a resulted in reduced crescent lesions in a mouse model of CrescGN. Interestingly, in vitro studies report that the downregulation of miR193a induces trans-differentiation of PECs into a podocyte phenotype. This narrative review highlights the critical role of PEC behavior in health and during disease and its modulation by miR193a.

AA amyloidosis associated with cancers.

Systemic AA amyloidosis is associated with systemic inflammatory processes such as autoimmune disorders or chronic infections. In addition, AA amyloidosis can develop in a localized or systemic form in patients with malignant neoplastic disorders, and usually involves kidneys impacting renal function. Among solid tumors, renal cell carcinoma (RCC) appears to be responsible for one-quarter to half of all cancers associated with amyloidosis. Among other solid cancers, various clinical presentations and pathological types of lung cancer and basal cell carcinoma skin were reported with AA amyloidosis more often than isolated case reports on other cancers with AA amyloidosis. Symptoms from kidney involvement rather than from the tumor per se were the presenting manifestations in cases of RCC associated with AA amyloidosis. Among hematological malignancies, clonal B cell/plasma cell dyscrasias such as monoclonal gammopathy and lymphoma were noted to be associated with AA amyloidosis. In addition, AA amyloidosis was reported in a substantial number of cases treated with immune checkpoint inhibitors such as pembrolizumab and nivolumab. The mechanism of association of cancer and AA amyloidosis seems to be mediated by the immune response exacerbated from the tumor and its microenvironment or immune therapy. The mainstay of treatment consists of therapy directed against the underlying malignancy or careful withdrawal of the offending agent. This review will discuss this rare but highly morbid clinical condition.

Long-term complications in patients with childhood-onset nephrotic syndrome.

BACKGROUND: Reports on long-term complications of childhood-onset nephrotic syndrome (NS), such as obesity, osteoporosis, growth failure, and hypertension, are mostly from developed countries not representing South Asian ethnicities. Furthermore, data on cardiovascular health among patients with childhood-onset NS are limited. METHODS: This was an observational study involving patients attending a tertiary care center. Patients aged 15 years and older were examined for long-term complications and remission of NS at their visit in December 2021. Childhood-onset NS meant onset of NS before 10 years of age. Long-term complications included obesity, growth failure, low bone mineral density (BMD) Z score, hypertension, and increased carotid intima-media thickness (cIMT). Long-term remission was defined as no relapse for the last [Formula: see text] 3 consecutive years without immunosuppressive medication to maintain remission. RESULTS: Of 101 patients studied (~ 80% with frequent relapsing (FR)/steroid-dependent (SD) NS), the mean age was 17.6 (± 2.4) years at the time of study. Long-term complications were noted in 89.1% of patients which included one or more of the following: obesity (22.7%), growth failure (31.7%), low BMD Z score (53.5%), hypertension (31.7%), and high cIMT (50.5%). Thirty-nine patients (38.6%) were in long-term remission at the time of the study. Growth failure and low BMD Z scores were less frequent in patients with long-term remission compared to those without long-term remission. CONCLUSIONS: In patients with childhood-onset NS (predominantly FR/SDNS) who were studied at [Formula: see text] 15 years of age, ~ 90% had long-term complications which included high cIMT in 50%. Only ~ 40% were in long-term remission. A higher resolution version of the Graphical abstract is available as Supplementary information.

Diagnosis, Prevention, and Treatment of Infections in Kidney Transplantation.

Kidney transplant often is complicated by infections in the recipient from therapy-related and patient-related risk factors. Infections in kidney transplant recipients are associated with increased morbidity, mortality, and allograft dysfunction. There is a predictable timeline after kidney transplant regarding the types of pathogens causing infections, reflecting the net state of immunosuppression. In the early post-transplant period, bacterial infections comprise two thirds of all infections, followed by viral and fungal infections. Infections occurring early after kidney transplantation are generally the result of postoperative complications. In most cases, opportunistic infections occur within 6 months after kidney transplantation. They may be caused by a new infection, a donor-derived infection, or reactivation of a latent infection. Community-acquired pneumonia, upper respiratory tract infections, urinary tract infections, and gastrointestinal infections are the most common infections in the late period after transplantation when the net immunosuppression is minimal. It is crucial to seek information on the time after transplant, reflecting the net state of immunosuppression, previous history of exposure/infections, geography, and seasonal outbreaks. It is imperative that we develop regionally specific guidelines on screening, prevention, and management of infections after kidney transplantation.

The environment and kidney health: challenges and opportunities.

The accelerating environmental degradation as a result of modernisation and climate change is an urgent threat to human health. Environment change can impact kidney health in a variety of ways such as water scarcity, global heating and changing biodiversity. Ever increasing industrialization of health care has a large carbon footprint, with dialysis being a major contributor. There have been calls for all stakeholders to adopt a 'one health approach' and develop mitigation and adaptation strategies to combat this challenge. Because of its exquisite sensitivity to various elements of environment change, kidney health can be a risk marker and a therapeutic target for such interventions. In this narrative review, we discuss the various mechanisms through which environmental change is linked to kidney health and the ways that the global kidney health communities can respond to environmental change.

IgA Nephropathy with Posterior Reversible Encephalopathy with Spinal Cord Involvement in a Young Male: A Case Report.

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological phenomenon commonly associated with kidney diseases, especially chronic kidney disease. A consequence of endothelial dysfunction, PRES is usually associated with uncontrolled blood pressures and can rarely have atypical radiological findings involving the brain stem and spinal cord, called posterior reversible encephalopathy with spinal cord involvement (PRES-SCI). These atypical features may be confused with other etiologies causing a delay in diagnosis and management. We describe a young male patient who presented with neurological symptoms suggestive of PRES; however, the atypical radiological findings along with concomitant rapidly progressive glomerulonephritis led to a diagnostic dilemma. Repeat neuro-imaging after appropriate blood pressure control showed disappearance of the lesions confirming the diagnosis of PRES-SCI, and kidney biopsy showed advanced IgA nephropathy. Knowledge of atypical features of PRES is crucial amongst nephrologists as it is a common association with kidney disease and prompt identification and management avoid irreversible sequelae and unnecessary investigations.