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.

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.

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.

Management of Lupus Nephritis: An Update.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, and lupus nephritis (LN) is associated with increased morbidity and mortality. Renal biopsy is essential and the gold standard to diagnose LN. Extra-glomerular involvement is seen in up to 60% of patients with LN and is associated with poor outcomes. The revised International Society of Nephrology/Renal Pathology Society classification for LN has changed the parameters for activity index scoring, redefined crescent and highlighted the significance of extra-glomerular involvement. Repeat renal biopsy is done for resistant disease or during a flare, usually when atypical features are present or when the baseline biopsy showed non-proliferative histology. Protocol repeat biopsy may prove to be valuable as a monitoring tool in patients with LN. Newer modalities of therapy like multitargeted therapy and biological agents may pave a way for better outcomes with minimal adverse effects to the patients.

Long-Term Follow-Up of Cyclical Cyclophosphamide and Steroids Versus Tacrolimus and Steroids in Primary Membranous Nephropathy.

INTRODUCTION: Kidney Disease: Improving Global Outcomes (KDIGO) 2012 recommends cyclical cyclophosphamide plus glucocorticoids (GC) (modified Ponticelli regimen) or calcineurin inhibitors (CNIs) such as tacrolimus (TAC) or cyclosporine as the first-line agents for the management of primary membranous nephropathy (PMN) that is resistant to antiproteinuric therapy with renin-angiotensin system blockers. However, the long-term outcome of patients treated with CNIs is not known. METHODS: We report the outcomes of 70 patients randomized 1:1 to receive modified Ponticelli regimen or TAC/GC for renin-angiotensin system-resistant PMN who were prospectively followed for 6 years. Patients were followed monthly for 12 months, then quarterly for 12 months, and then every 6 months through the end of 6 years. RESULTS: At the end of 6 years, 21 (61.76%) and 9 (28.12%) patients maintained relapse-free remission in modified Ponticelli regimen and TAC/GC groups, respectively (relative risk [RR]: 2.19, 95% confidence interval [CI]: 1.23 to 4.15), and 30 (88.23%) and 17 (53.12%) patients were in remission (including relapses) in modified Ponticelli regimen and TAC/GC groups (RR: 1.66; 95% CI: 1.21 to 2.45), respectively. There was no significant difference in the proportion of patients who had a 40% decline in the estimated glomerular filtration rate (eGFR), death, or end-stage kidney disease between the groups. None of the patients treated with modified Ponticelli regimen reported a solid organ or hematological malignancy. CONCLUSIONS: To conclude, in the long-term, modified Ponticelli regimen is superior to TAC/GC as first-line therapy for the management of antiproteinuric-resistant PMN.

Anti-Nuclear Antibody-Negative Lupus Nephritis or Post-Infectious Glomerulonephritis: Diagnostic Dilemma in a Young Male.

Proliferative lupus nephritis (LN) is histologically characterized by endocapillary hypercellularity and large immune deposits on light microscopy. Immunofluorescence shows almost all immunoglobulins and complement staining. The presence of antinuclear antibodies (ANA) is important for diagnosing systemic lupus erythematosus (SLE). Absence of ANA rules out the possibility of SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for SLE. We report a young boy with fever, nephrotic-nephritic syndrome and pancytopenia consistent with hemophagocytic lymphohistiocytosis. Renal biopsy was consistent with LN; however, his initial ANA was negative. In view of pathological features of LN and persistent pancytopenia, high dose steroid therapy was started. Repeat ANA, done during the illness, turned positive. In this report, we describe the relevance of pathological patterns and the uncertainties of ANA positivity in making a diagnosis of SLE.

Complete Remission of Lupus Nephritis Following Chemoradiotherapy of Carcinoma Cervix: An Association.

Systemic lupus erythematosus (SLE) is associated with a higher incidence of solid organ malignancies, including cervical carcinoma, creating a paradox in their management in the context of autoimmunity. We present a case of 45-year-old female presented with mucocutaneous, musculoskeletal symptoms of SLE. Renal biopsy showed class IV lupus nephritis (LN); modified NIH activity score: 8/24, chronicity score: 6/12. Post NIH regimen induction, she achieved partial remission; further developed proteinuric relapse which was re-induced with mycophenolate mofetil (MMF) to which she failed to respond. Subsequently diagnosed with carcinoma cervix stage IIB, she received four cycles of concurrent cisplatin-based chemoradiotherapy. MMF was stopped; low dose steroids continued. Following this, the patient achieved complete remission (CR) of LN and is in remission for 5 years. This is an unexpected association between chemoradiotherapy of cervical carcinoma and CR of class IV LN, allowing long-term discontinuation of immunosuppression.

Hematopoietic stem cell donor with IgA nephropathy: Challenges and management algorithm.

Donor safety is of prime importance in allogeneic hematopoietic cell transplantation. The Worldwide Network for Blood and Marrow Transplantation (WBMT) standing committee on donor issues has issued a consensus statement regarding suitability criteria for related adult donors. This committee recommends that donors with a history of immune-mediated glomerulonephritis and abnormal urine tests should preferably undergo bone marrow harvest, to avoid the theoretical risk of granulocyte colony-stimulating factor (G-CSF) induced immune flare-up. We discuss here a unique situation where a related donor with a history of IgA nephropathy (IgAN) insisted on a peripheral blood stem cell harvest. We propose a management plan for this situation, which posed challenges about donor suitability.

Contribution of Clinically Indicated Repeat Renal Biopsy in Indian Patients with Lupus Nephritis.

BACKGROUND: Repeat renal biopsy is usually done for lupus nephritis (LN) flare or resistant disease. We analyzed the changes between first and repeat biopsy and the contribution of repeat biopsy on renal outcome in LN patients. METHODS: This was a retrospective study carried out at a tertiary care center in India. Sixty-two LN patients who underwent repeat biopsy for clinical indications, between January 2012 to December 2016, were included. Clinical and histological parameters at first and second biopsies were compared. Logistic regression analysis was done to determine parameters on repeat biopsy predicting response at last visit. RESULTS: Repeat biopsy was done for relapse in 56% and for resistant disease in 44% patients. Seven (13.7%) out of 51 patients with baseline proliferative histology converted to non-proliferative lesion on second biopsy, while 2 (18.2%) out of 11 with baseline non-proliferative lesion converted to proliferative lesion on second biopsy. On repeat biopsy, the presence of endocapillary proliferation decreased, whereas glomerulosclerosis, interstitial fibrosis/tubular atrophy (IFTA), and glomerular basement membrane thickening increased. At the last visit (median follow-up of 38.6 months after first biopsy and 13.8 months after second biopsy), 79% of patients were in remission and 6.5% needed renal replacement therapy. The presence of IFTA >30% and thrombotic microangiopathy (TMA) on second biopsy independently predicted response at last visit. CONCLUSION: In Indian patients with LN, chronicity markers and superimposed membranous pattern increased on repeat biopsy done for clinical indications. The presence of IFTA and TMA on second biopsy predicted response at last visit.

C-Terminal Fibroblast Growth Factor-23 Levels in Non-Nutritional Hypophosphatemic Rickets.

Fibroblast growth factor-23 (FGF23) is central to phosphate homeostasis. The author examined if blood levels of FGF23 allow discrimination of classic hypophosphatemic rickets from other causes of non-nutritional rickets with hypophosphatemia. Forty-two children (median age: 102 mo) with non-nutritional rickets and hypophosphatemia were clinically classified as having distal renal tubular acidosis (RTA, n = 12), Fanconi syndrome (n = 8), classic hypophosphatemic rickets (n = 11), vitamin D dependent rickets (n = 7) and Dent disease (n = 4). Median blood FGF23 (measured by C-terminal ELISA) concentrations were similar in all groups (P = 0.24). These levels did not correlate with phosphate, tubular maximum for phosphate, calcium, 25-hydroxyvitamin D, creatinine, and parathormone levels. Patients with distal RTA showed variable degree of proximal tubular dysfunction that resolved following alkali supplements. Blood FGF23 levels did not satisfactorily differentiate classic hypophosphatemic rickets from other causes of hypophosphatemic rickets.

18F-FDG PET/CT Demonstrates Renal Cell Cancer in a Transplant With Synchronous Intestinal Infection.

We present a case of a 22-year-old man with history of allogenic renal transplantation on immunosuppression, who underwent F-FDG-PET/CT to characterize a lesion in the transplanted kidney on ultrasonogram and contrast-enhanced computed tomography imaging. PET/CT revealed FDG avid lesion in the transplanted kidney and mural thickening involving the distal ileum, ileocecal junction, and ileocolic lymph nodes. Subsequent histopathological examination from the renal lesion revealed renal cell carcinoma in the transplanted kidney. Additionally, endoscopic biopsy from the ileal thickening revealed granulomatous inflammation, suggesting tuberculosis, which was missed on both ultrasonogram and contrast-enhanced CT imaging.

Persistent CD-19 depletion by rituximab is cost-effective in maintaining remission in calcineurin-inhibitor dependent podocytopathy.

AIM: A significant proportion of patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are either steroid dependent or steroid resistant, requiring long-term calcineurin inhibitors (CNI) use. Rituximab has more favourable safety profile. The present study was undertaken to evaluate the efficacy and safety of rituximab in CNI-dependent patients. METHODS: This was a prospective observational study conducted from July 2014 to February 2018. Steroid-dependent nephrotic syndrome or steroid-resistant nephrotic syndrome (biopsy proven MCD/FSGS), who were CNI dependent were enrolled. Mean age at enrolment was 22.77 ± 7.45 years. All patients received rituximab at a dose of 375 mg/m2 at entry in the study. CD-19 levels were monitored monthly and patients having CD-19 levels >5/µL and/or > 1% received additional low-dose (100 mg) of rituximab. RESULTS: A total of 24 patients were followed up for 12 months. At the end of 6 and 12 months, 87.5% and 79.16% of the patients achieved remission, respectively. Eight (33.33%) patients developed relapse. The mean dose of rituximab in the first year was 791 mg. The average cost of rituximab in the first year was 487.17$. Rituximab was well-tolerated, with mild infusion reactions, respiratory tract infection and oral candidiasis in 5 (20.83%), 5 (20.83%) and 1 (4.17%) patient, respectively. CONCLUSIONS: CD-19 targeted rituximab is a safe and cost-effective agent in remission maintenance in adults with CNI dependent. Over three-fourths of the patients with CNI-dependent podocytopathy maintain clinical remission with CD-19 targeted rituximab therapy.

Membranous nephropathy with light chain restricted deposits.

The literature on membranous nephropathy (MN) with monoclonal deposits on immunofluorescence (IF) and their outcome is very scarce. We report our experience of managing five patients with this clinical entity. The mean age of the patients was 33.2 ± 6.55 years. The mean proteinuria, serum albumin and serum creatinine was 5.73 ± 2.17 g/day, 2.86 ± 0.51 g/dL and 1.34 ± 1.19 mg/dL, respectively. None of the patients had a lymphoproliferative disorder. Only one patient had an elevated free light chain ratio. Four (80%) patients were M-type phospholipase A2 receptor (PLA2R) negative (tissue and serum), and one (20%) was PLA2R related. Three (60%) cases had monoclonal IgG3/k, one IgG3/λ, whereas one patient with PLA2R positivity had an IgG3/IgG4k subtype. Two (67%) patients treated with cyclical cyclophosphamide and steroids (cCYC/GC) achieved complete remission and one patient (33%) with elevated baseline creatinine had a reduction in serum creatinine with persistent proteinuria at the end of the 12th month of follow-up. One patient with PLA2R positive MN was treated with Rituximab and is in complete remission. The patient with an elevated free light chain at baseline was treated with Bortezomib/Thalidomide/Dexamethasone, had complete remission at 12 months, however, had a progressive rise in creatinine over the next 40 months of follow-up. The current series, though limited by numbers, documents the efficacy of conventional therapies in non-malignant associated MN with monoclonal deposits on IF.

Calcinosis in juvenile dermatomyositis mimicking cold abscess.

We report a case of dystrophic calcification presenting as soft cystic swelling in a patient with juvenile dermatomyositis. A 15-year-old boy with lumbosacral cystic swelling, which was considered a cold abscess clinically, was evaluated for nonresponse to antitubercular therapy. The cystic swelling had liquefied calcium with a well circumscribed calcified wall on imaging, which was subsequently excised.