Ibuprofen-associated minimal change disease and acute interstitial nephritis with possibly linked membranous glomerulonephritis.

Non-steroidal anti-inflammatory drugs are not only potent analgesics and antipyretics but also nephrotoxins, and may cause electrolyte disarray. In addition to the commonly expected effects, including hyperkalemia, hyponatremia, acute renal injury, renal cortical necrosis, and volume retention, glomerular disease with or without nephrotic syndrome or nephritis can occur as well including after years of seemingly safe administration. Minimal change disease, secondary membranous glomerulonephritis, and acute interstitial nephritis are all reported glomerular lesions seen with non-steroidal anti-inflammatory use. We report a patient who used non-steroidal anti-inflammatory drugs for years without diabetes, chronic kidney disease, or proteinuria; he then developed severe nephrotic range proteinuria with 7 g of daily urinary protein excretion. Renal biopsy showed minimal change nephropathy, a likely secondary membranous glomerulonephritis, and acute interstitial nephritis present simultaneously in one biopsy. Cessation of non-steroidal anti-inflammatory drug use along with steroid treatment resulted in a moderate improvement in renal function, though residual impairment remained. Urine heavy metal screen returned with elevated levels of urine copper, but with normal ceruloplasmin level. Workup suggested that the elevated copper levels were due to cirrhosis from non-alcoholic fatty liver disease. The membranous glomerulonephritis is possibly linked to non-steroidal anti-inflammatory drug exposure, and possibly to heavy metal exposure, and is clinically and pathologically much less likely to be a primary membranous glomerulonephritis with negative serological markers.

Complement-Mediated Thrombotic Microangiopathy Associated with Lupus Nephritis Treated with Eculizumab: A Case Report.

Thrombotic microangiopathies (TMAs) involve multiple organ systems due to the presence of microangiopathic hemolysis. One such condition, atypical hemolytic uremic syndrome (aHUS), is a complement-mediated process that is part of a spectrum of disorders that have underlying complement dysfunction of the alternative pathway due to overactivity or decreased self-nonself discrimination by innate immunity. Complement-amplifying conditions such as pregnancy may unmask a diagnosis of aHUS. We present an important case of a pregnant 23-year-old Hispanic female who presented in mid-gestation (21 weeks) with an initial diagnosis of systemic lupus erythematosus (SLE) complicated by aHUS. She met clinical criteria for aHUS on presentation and was found to have a pathogenic CFHR1-3 homozygous deletion. She has been treated with intravenous and oral steroids, cyclophosphamide, subsequently also with plasma exchange, and finally with eculizumab with partial improvement in renal function. This case adds to the emerging literature showing that SLE and aHUS (or complement-mediated TMA) can be successfully treated with C5 blockade.

The consequences of altered microbiota in immune-related chronic kidney disease.

The normal gut microbiome modulates host enterocyte metabolism and shapes local and systemic immunity. Accumulation of urea and other waste products in chronic kidney disease induces gut dysbiosis and intestinal wall inflammation (leaky gut). There are decreased numbers of bacteria that generate short-chain fatty acids, which are an important nutrient source for host enterocytes and also contribute to regulation of the host immune system. Anaerobic proteolytic bacteria that express urease, uricase and indole and p-cresol enzymes, such as Enterobacteria and Enterococci, are increased. Microbial-derived uremic toxins such as indoxyl sulfate and trimethylamine N-oxide contribute to the pathophysiology of immune-related kidney diseases such as diabetic nephropathy, lupus nephritis and immunoglobulin A (IgA) nephropathy. Animal and clinical studies suggest potential benefits of dietary and probiotic interventions in slowing the progression of immune-related kidney diseases.

A Case of Novel Coronavirus Disease 19 in a Chronic Hemodialysis Patient Presenting with Gastroenteritis and Developing Severe Pulmonary Disease.

Novel coronavirus disease 2019 (COVID-19) is a highly infectious, rapidly spreading viral disease with an alarming case fatality rate up to 5%. The risk factors for severe presentations are concentrated in patients with chronic kidney disease, particularly patients with end-stage renal disease (ESRD) who are dialysis dependent. We report the first US case of a 56-year-old nondiabetic male with ESRD secondary to IgA nephropathy undergoing thrice-weekly maintenance hemodialysis for 3 years, who developed COVID-19 infection. He has hypertension controlled with angiotensin receptor blocker losartan 100 mg/day and coronary artery disease status-post stent placement. During the first 5 days of his febrile disease, he presented to an urgent care, 3 emergency rooms, 1 cardiology clinic, and 2 dialysis centers in California and Utah. During this interval, he reported nausea, vomiting, diarrhea, and low-grade fevers but was not suspected of COVID-19 infection until he developed respiratory symptoms and was admitted to the hospital. Imaging studies upon admission were consistent with bilateral interstitial pneumonia. He was placed in droplet-eye precautions while awaiting COVID-19 test results. Within the first 24 h, he deteriorated quickly and developed acute respiratory distress syndrome (ARDS), requiring intubation and increasing respiratory support. Losartan was withheld due to hypotension and septic shock. COVID-19 was reported positive on hospital day 3. He remained in critical condition being treated with hydroxychloroquine and tocilizumab in addition to the standard medical management for septic shock and ARDS. Our case is unique in its atypical initial presentation and highlights the importance of early testing.

Hemodynamic and Laboratory Changes during Incremental Transition from Twice to Thrice-Weekly Hemodialysis.

OBJECTIVE: Incremental hemodialysis (HD) is a strategy utilized to gradually intensify dialysis among patients with incident end-stage renal disease. However, there are scarce data about which patients' clinic status changes by increasing treatment frequency. METHODS: We retrospectively examined statistically de-identified data from 569 patients who successfully transitioned from twice- to thrice-weekly HD (2007-2011) and compared the differences in monthly-averaged values of hemodynamic and laboratory indices during the 3 months before and after the transition with the values at 1 month prior to transition serving as the reference. RESULTS: At 3 months after transitioning from twice- to thrice-weekly HD, ultrafiltration volume decreased by 0.5 (95% CI 0.3-0.6) L/session among 189 patients (33%) with weekly interdialytic weight gain (IDWG) ≥5.4 kg/week, and increased by 0.4 (95% CI 0.3-0.5) L/session among 186 patients (33%) with weekly IDWG <3.3 kg/week. Weekly IDWG consistently increased after the transition irrespective of baseline values (1.7 [95% CI 1.5-1.9] kg/week). Pre-HD systolic blood pressure (SBP) decreased by 12 (95% CI 9-14) mm Hg among 177 patients (31%) with baseline pre-HD SBP ≥160 mm Hg, which coincided with a decreasing trend in post-HD body weight (1.3 [95% CI 0.8-1.7] kg). DISCUSSION: In conclusion, patients who increased HD frequency from twice to thrice weekly treatment experienced increased weekly IDWG and better pre-HD SBP control with lower post-HD body weight.

Survival Advantage of African American Dialysis Patients with End-Stage Renal Disease Causes Related to APOL1.

BACKGROUND: Observational studies show that African American (AA) dialysis patients have longer survival than European Americans. We hypothesized that apolipoprotein L1 (APOL1) genetic variation, associated with nephropathy in AAs, contributes to the survival advantage in AA dialysis patients. METHODS: We examined the association between race and mortality among 37,097 adult dialysis patients, including 54% AAs and 46% European Americans from a large dialysis organization (entry period from July 2001 to June 2006, follow-up through June 2007), within each cause of end-stage renal disease (ESRD) category associated with APOL1 renal risk variants using Cox proportional hazard models. RESULTS: AA dialysis patients had numerically lower mortality than their European American counterparts for all causes of ESRD. The mortality reduction among AAs compared to European Americans was statistically significant in patients with ESRD attributed to diabetes mellitus, hypertension, and APOL1-enriched glomerulonephritis (GN) (HR [95% CI]: 0.69 [0.66-0.72], 0.73 [0.68-0.79], and 0.89 [0.79-0.99], respectively); these are conditions in which APOL1 variants promote kidney disease. By contrast, the significant survival advantage of AA dialysis patients was not observed in patients with ESRD attributed to other kidney disease (including polycystic kidney disease, interstitial nephritis, and pyelonephritis) and other GN, which are not associated with APOL1 variants. CONCLUSIONS: These data suggest the hypothesis that the relative survival advantage of AA dialysis patients may be related to APOL1 variation. Further large population-based genetic studies are required to test this hypothesis.

There's no place like home: 35-year patient survival on home hemodialysis.

The vast majority of maintenance dialysis patients suffer from poor long-term survival rates and lower levels of health-related quality of life. However, home hemodialysis is a historically significant dialysis modality that has been associated with favorable outcomes as well as greater patient autonomy and control, yet only represents a small minority of the total dialysis performed in the United States. Some potential disadvantages of home hemodialysis include vascular access complications, infection-related hospitalizations, patient fatigue, and attrition. In addition, current barriers and challenges in expanding the utilization of this modality include limited patient and provider education and technical expertise. Here we report a 65-year old male with end-stage renal disease due to Alport's syndrome who has undergone 35 years of uninterrupted thrice-weekly home hemodialysis (ie, every Sunday, Tuesday, and Thursday evening, each session lasting 3 to 3» hours in length) using a conventional hemodialysis machine who has maintained a high functional status allowing him to work 6-8 hours per day. The patient has been able to liberalize his dietary and fluid intake while only requiring 3-4 liters of ultrafiltration per treatment, despite having absence of residual kidney function. Through this case of extraordinary longevity and outcomes after 35 years of dialysis and a review of the literature, we illustrate the history of home hemodialysis, its significant clinical and psychosocial advantages, as well as the barriers that hinder its widespread adaptation.

Pharmacologic Blockade of αvß1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo.

Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells in vivo is poorly understood. PDGF receptor ß (PDGFRß) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFRß promoter-driven Cre system to delete αv integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFRß-Cre line to isolate and study renal fibroblasts ex vivo We found that renal fibroblasts express three αv integrins, namely αvß1, αvß3, and αvß5. Blockade of αvß1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-ß1 and prevented activation of the latent TGF-ß complex. Continuous administration of a recently described potent small molecule inhibitor of αvß1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of αvß1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.

Successful Peritoneal Dialysis Catheter Placement in a New End-Stage Renal Disease Patient with Combined Antiphospholipid Syndrome and Factor XI Deficiency.

Coagulopathies and bleeding disorders can affect dialysis outcomes by increasing the thrombosis risk at the arteriovenous access or by causing prolonged bleeding at access or catheter sites. We present the case of a 68-year-old woman with combined antiphospholipid syndrome and factor XI deficiency, with chronic prolongation of activated partial thromboplastin time that was not correctable with fresh-frozen plasma (FFP).The patient had a history of stroke, but was not on antiplatelet therapy because of mucocutaneous bleeding events. She had progressive renal failure attributed to her autoimmune disease, and a decision was made to pursue peritoneal dialysis (PD) when she reached end-stage kidney disease. She was admitted to the hospital the day before her planned PD catheter placement and was transfused with FFP and platelets before placement of a temporary hemodialysis catheter. One session of hemodialysis was performed to minimize uremic platelet dysfunction. The patient was given additional FFP and platelets at the time of PD catheter placement; desmopressin was not used. No thrombotic or bleeding complications occurred, and at 8 months out, the patient has been doing well on PD.In summary, careful perioperative planning led to successful PD initiation in a patient with combined bleeding and clotting disorders.

The role of low protein diet in ameliorating proteinuria and deferring dialysis initiation: what is old and what is new.

In the management of patients with chronic kidney diseases (CKD), a low-protein diet usually refers to a diet with protein intake of 0.6 to 0.8 grams per kilogram of body weight per day (g/kg/day) and should include at least 50% high-biologic-value protein. It may be supplemented with essential acids or nitrogen-free ketoanalogues if <0.6 g/kg/d. Low-protein diet can reduce proteinuria especially in non-diabetic CKD patients. In hypoalbuminemic patients it may lead to an increase in serum albumin level. By lowering proteinuria, decreasing nitrogen waste products, ameliorating metabolic burden, mitigating oxidative stress and acidosis, and lowering phosphorus burden, a low-protein diet can help delay dialysis start in advanced CKD. Low-protein diet is safe, since most CKD patients can maintain nitrogen balance by mechanisms of decreasing amino acid oxidation and protein degradation in addition to increased utilization of amino acids for protein synthesis. We suggest a dietary protein intake below 1.0 g/kg/day when estimated glomerular filtration rate (eGFR) falls below 60 mL/min/1.73 m2 or when there is solitary kidney or proteinuria at any level of GFR. Protein intake should be reduced progressively based on severity and progression of CKD and patient's nutritional status with a target of 0.6-0.8 g/kg/d in most patients with eGFR <45 mL/min/1.73 m2. The risk of protein-energy wasting can be overcome by careful attention to quantity and quality of the ingested proteins, sufficient energy intake of 30-35 Kcal/kg/d, and use of dietary supplements. Long-term observations and individualized approaches are needed to further demonstrate the benefits and safety of low-protein diet.

α-Smooth muscle actin is an inconsistent marker of fibroblasts responsible for force-dependent TGFß activation or collagen production across multiple models of organ fibrosis.

Fibrosis is a common pathological sequela of tissue injury or inflammation, and is a major cause of organ failure. Subsets of fibroblasts contribute to tissue fibrosis in multiple ways, including generating contractile force to activate integrin-bound, latent TGFß and secreting excess amounts of collagens and other extracellular matrix proteins (ECM) that make up pathologic scar. However, the precise fibroblast subsets that drive fibrosis have been poorly understood. In the absence of well-characterized markers, α-smooth muscle actin (αSMA) is often used to identify pathologic fibroblasts, and some authors have equated αSMA(+) cells with contractile myofibroblasts and proposed that these cells are the major source of ECM. Here, we investigated how well αSMA expression describes fibroblast subsets responsible for TGFß activation and collagen production in three commonly used models of organ fibrosis that we previously reported could be inhibited by loss of αv integrins on all fibroblasts (using PDGFRß-Cre). Interestingly, αSMA-directed deletion of αv integrins protected mice from CCl4-induced hepatic fibrosis, but not bleomycin-induced pulmonary or unilateral ureteral obstruction-induced renal fibrosis. Using Col-EGFP/αSMA-RFP dual reporter mice, we found that only a minority of collagen-producing cells coexpress αSMA in the fibrotic lung and kidney. Notably, Col-EGFP(+)αSMA-RFP(-) cells isolated from the fibrotic lung and kidney were equally capable of activating TGFß as were Col-EGFP(+)αSMA-RFP(+) cells from the same organ, and this TGFß activation was blocked by a TGFß-blocking antibody and an inhibitor of nonmuscle myosin, respectively. Taken together, our results suggest that αSMA is an inconsistent marker of contractile and collagen-producing fibroblasts in murine experimental models of organ fibrosis.

A Case of Hypercalcemia and Overexpression of CYP27B1 in Skeletal Muscle Lesions in a Patient with HIV Infection After Cosmetic Injections with Polymethylmethacrylate (PMMA) for Wasting.

Foreign body-induced granuloma is an uncommon yet clinically significant cause of hypercalcemia. The molecular mechanisms are uncertain, although extrarenal calcitriol production has been proposed. We describe severe hypercalcemia associated with increased levels of plasma calcitriol in a patient with HIV and local granulomatous reaction 5 years after injection of polymethylmethacrylate (PMMA) as dermal filler for cosmetic body sculpting. Extensive evaluation revealed no identifiable cause of increased calcitriol levels. Nuclear imaging was remarkable for diffuse uptake in the subcutaneous tissues of the buttocks. Subsequent muscle biopsy and immunohistochemical staining showed strong local expression of CYP27B1 within histiocytes surrounding globules of PMMA. This case highlights an unfortunate complication of dermal fillers and shows that inflammatory cells can express high levels of CYP27B1 even without frank granulomas. The growing trend of body contour enhancement using injectable fillers should raise suspicion for this cause of hypercalcemia in clinical practice. Patients with HIV who receive this treatment for lipodystrophy or other cosmetic purposes may have increased susceptibility to hypercalcemia in the setting of underlying chronic inflammation. This may be a concern when changing anti-retroviral therapy, since alterations in levels of HIV viremia may initiate or contribute to worsening hypercalcemia.

Reversible posterior leukoencephalopathy syndrome associated with concurrent bevacizumab, gemcitabine, and oxaliplatin for cholangiocarcinoma.

INTRODUCTION: Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare disorder characterized by altered mental status, seizure, hypertension, and symmetrical white matter edema (leukoencephalopathy) typically in the posterior cerebral hemispheres on brain imaging. It is often linked to certain medication use, in particular, chemotherapeutic agents. Here, we present a case of chemotherapy-related RPLS and review the current literature on this topic. CASE REPORT: We report a case of RPLS associated with concurrent bevacizumab (Avastin), gemcitabine, and oxaliplatin use for unresectable intrahepatic cholangiocarcinoma. CONCLUSION: This is the first reported case of RPLS associated with bevacizumab, gemcitabine, and oxaliplatin combination chemotherapy. Concurrent use of multiple agents could significantly increase the risk of RPLS, a potentially fatal disease. Our case suggests that gradual progression of hypertension and proteinuria may be early warning signs before the onset of RPLS that should alarm clinicians.

Tetraspanin CD81 is required for the alpha v beta5-integrin-dependent particle-binding step of RPE phagocytosis.

Retinal pigment epithelial (RPE) cells are among the most active phagocytes in the body. Every morning, circadian shedding of outer segment fragments by photoreceptor cells activates a synchronized phagocytic response by RPE cells that is critical for vision. RPE cells require alpha v beta5 integrin receptors for particle binding that triggers engulfment. Here, we show that tetraspanins CD81 and CD9 reside in a complex specifically with alpha v beta5 integrin but not the engulfment receptors Mer tyrosine kinase and CD36 at the apical, phagocytic surface of RPE cells. Function blocking and RNA silencing of CD81 but not of CD9 specifically diminish particle binding. CD81 but not CD9 overexpression is sufficient to increase particle binding and surface levels of alpha v beta5 integrin. Wild-type and mutant RPE cells defective in particle engulfment equally reduce and increase particle binding in response to CD81 inhibition and CD81 overexpression, respectively. By striking contrast, neither CD81 inhibition nor CD81 overexpression has any effect on particle binding by RPE lacking alpha v beta5 integrin. These results identify a novel and important role for CD81 in phagocytosis. CD81 does not function as a binding receptor by itself but promotes outer segment particle binding through functional interaction specifically with alpha v beta5 integrin.