Nephrotic Range Research Articles

A novel mouse model of phospholipase A2 receptor 1-associated membranous nephropathy mimics podocyte injury in patients

The phospholipase A2 receptor 1 (PLA2R1) is the major autoantigen in patients suffering from membranous nephropathy. To date, the lack of endogenous glomerular expression of PLA2R1 in mice and rats has impeded the establishment of PLA2R1-dependent animal models of this disease. Here, we generated a transgenic mouse line expressing murine full-length PLA2R1 in podocytes. Furthermore, expression of murine PLA2R1 did not result in any morphological disturbance as high-resolution confocal microscopy demonstrated an intact nephrin distribution with normal foot processes. Transfer of rabbit anti-mPLA2R1 antibodies to these mice induced nephrotic range proteinuria, hypercholesterolemia, and histomorphological signs of membranous nephropathy. Immunohistochemical and immunofluorescence analyses revealed enhanced staining for murine PLA2R1 in the presence of unaffected staining for murine thrombospondin type-1 domain-containing 7A in the diseased mice, resembling what is classically found in patients with PLA2R1-associated membranous nephropathy Thus, our mouse model of membranous nephropathy will allow investigation of PLA2R1-specific pathomechanisms and may help to develop and assess antigen-specific treatments invivo.

Clinical and genetic analysis of Dent disease with nephrotic range albuminuria in Shaanxi, China.

Clinical and genetic analysis of Dent disease with nephrotic range albuminuria in Shaanxi, China.

Serum Levels of BAFF and APRIL Predict Clinical Response in Anti-PLA2R-Positive Primary Membranous Nephropathy.

Primary membranous nephropathy (PMN) is a renal-specific autoimmune disease caused by circulating autoantibodies that target glomerular podocyte antigens (PLA2R/THSD7A). However, very little is known on the molecular mechanisms controlling B cell response in this nephropathy. The present study was aimed at correlating the serum levels of B cell activators BAFF/BLyS and APRIL with the presence of anti-PLA2R antibodies in PMN patients and with long-term clinical outcome. To this aim, 51 patients with anti-PLA2R-positive biopsy-proven PMN and nephrotic range proteinuria (>3.5 g/24 hours) were enrolled between January 2009 and December 2015 and treated with conventional 6-month immunosuppressive therapy. After 6 months, 29 patients (56.9%) cleared circulating anti-PLA2R, while in remaining 22 (43.1%), they persisted. Intriguingly, in the first group, baseline serum levels of BAFF/BLyS and APRIL were significantly lower than those in the second one. Moreover, after 6 months of immunosuppressive therapy, an overall reduction in both cytokine serum levels was observed. However, in PMN patients with anti-PLA2R clearance, this reduction was more prominent, as compared with those with anti-PLA2R persistence. When related to clinical outcome, lower baseline BAFF/BLyS (<6.05 ng/mL) and APRIL (<4.20 ng/mL) serum levels were associated with significantly higher probability to achieve complete or partial remission after 24-month follow-up. After dividing the entire study cohort into three groups depending on both cytokine baseline serum levels, patients with both BAFF/BLyS and APRIL below the cut-off showed a significantly higher rate of complete or partial remission as compared with patients with only one cytokine above the cut-off, while the composite endpoint was achieved in a very low rate of patients with both cytokines above the cut-off. Taken together, these results provide new insights into the role of BAFF/BLyS and APRIL in both the pathogenesis of anti-PLA2R-positive PMN and the response to immunosuppressive therapy.

2110 A Case of IgA Vasculitis in Crohn’s Disease and Recurrent Clostridioides difficile Infection

INTRODUCTION: IgA vasculitis (IgAV) is an immune-mediated systemic vasculitis characterized by palpable purpura, arthralgias, abdominal pain, and renal disease. Approximately 90% of cases occur in children; however, adults are at increased risk for more severe disease. The pathogenesis of IgAV is associated with inflammatory, infectious, autoimmune, and medication triggers, including tumor necrosis factor (TNF) alpha inhibitors. We describe a case of a man with Crohn’s disease (CD) who developed IgAV in the setting of a perirectal abscess, recurrent Clostridioides difficile infection (CDI), and anti-TNF therapy. CASE DESCRIPTION/METHODS: A 20 year old man with ileocolonic Crohn’s disease and perianal involvement, inflammatory arthropathy, and recurrent CDI presented to an outside ED with increased abdominal pain and rash on the extremities, trunk, and soft palate. Medications included etanercept, vedolizumab, and prednisolone. In the ED, the patient was hypotensive and tachycardic. CT abdomen/pelvis noted multifocal active inflammatory disease and a 3.2 cm abscess in the left ischiorectal fossa. He was initiated on broad spectrum antibiotics for septic shock and underwent emergent perirectal drain placement; post-operatively, his shock resolved. He was transferred to our institution for further management. Upon arrival, the patient was hemodynamically stable and remained on broad spectrum antibiotics and high dose prednisolone. Review of systems was notable for worsening abdominal pain and hematuria. Biopsy of the rash demonstrated IgA vasculitis. C. difficile toxin PCR was positive. Repeat urinalysis demonstrated nephrotic range proteinuria and hematuria, consistent with IgA nephropathy. ACE-inhibitor therapy was initiated, and skin lesions gradually improved with topical triamcinolone. DISCUSSION: We report a case of a patient with ileocolonic and perianal Crohn’s disease on TNF-alpha inhibitor therapy who developed IgA vasculitis in the setting of septic shock secondary to perirectal abscess and recurrent CDI. This case highlights anti-TNF therapy, infection and inflammatory bowel diseases as potential causes of systemic vasculitis. A high clinical suspicion is needed in order to obtain an early histopathologic diagnosis for IgAV and prompt evaluation of other organ system involvement.

2309 Vasculitic Mononeuritis Multiplex Mimicking Bilateral Carpal Tunnel Syndrome: A Diagnostic Challenge

INTRODUCTION: Cryoglobulinemic vasculitis(CV) can have variety of presentations including palpable purpura, arthralgias, glomerulonephritis, peripheral neuropathy, lymphadenopathy, hepatosplenomegaly, and hypocomplementemia. We present a patient with bilateral hand mononeuritis multiplex secondary to hepatitis C related CV. CASE DESCRIPTION/METHODS: A 52-year-old man with untreated hepatitis C (Viral load 520388, Genotype 1b), diabetes mellitus type II, hypertension and chronic kidney disease, presented with two months of bilateral hand pain. He also complained of numbness and tingling over the palmar aspects of the medial three digits of his hands, in addition to his medial left foot. He had no rash, arthritis, fevers, or weight loss. Physical exam was significant for positive Tinel's sign bilaterally, with weakness on finger extension, flexion and decreased power of interossei. Fundoscopy demonstrated non proliferative diabetic retinopathy (NPDR).Laboratory work-up revealed negative ANA, C-ANCA, MPO/PR3, HIV and RPR. Vitamin B12 and TSH levels were normal. However, serum cryoglobulins were positive with low C3, C4 and nephrotic range proteinuria Electromyography showed non-length-dependent neuropathy, which was more suggestive of mononeuritis multiplex rather than carpal tunnel syndrome (CTS). Sural nerve biopsy was performed and revealed vasculopathic changes consistent with vasculitis. He was diagnosed with mononeuritis multiplex secondary to hepatitis C related cryoglobulinemia. Immunosuppresive treatment was withheld because the patient tested positive for latent Tuberculosis (TB). He is currently undergoing treatment for the latent TB. DISCUSSION: CV is a small-to-medium-vessel vasculitis that occurs in 10 to 15 percent of patients chronically infected with hepatitis C virus (HCV). The two competing diagnosis for our patient’s neurological symptoms were diabetic neuropathy and CV secondary to untreated Hepatitis C. NPDR favored the microvascular complications of diabetes but the rapid onset of symptoms, positive cryoglobulins in the setting of HCV infection and sural nerve biopsy helped to establish the diagnosis of CV. This case is especially unique because it’s a very rare extrahepatic manifestation of HCV infection .Management of HCV cryoglobulinemic vasculitis involves administration of immunosuppressive therapy such as rituximab and antivirals but all patients should be tested and treated for latent TB prior to treatment initiation.

2427 A Case of Hepatitis B Virus-Related Membranous Nephropathy in an Adult With Low Hepatitis B Viral Load

INTRODUCTION: Hepatitis B virus (HBV) infection is an important etiologic factor for secondary membranous nephropathy (MN), especially in regions with endemic HBV infection. Though an uncommon occurrence, it is crucial to recognize HBV-related MN as it may progress to renal failure in untreated adults. In patients with HBV infection, it is critical to exclude other secondary causes of MN. This case describes a case of HBV-related MN in a HBeAg-negative patient with low HBV viral load. CASE DESCRIPTION/METHODS: Mr C is a 64 year old gentleman who has underlying chronic HBV infection and Stage 3b chronic kidney disease. He presented with bilateral lower limb swelling. He was found to have hypoalbuminemia and nephrotic range proteinuria associated with microscopic hematuria. He was in “inactive chronic HBV carrier infection” phase with negative hepatitis B e antigen (HBeAg), positive anti-HBe and low HBV viral load 2.68 log IU/ml with positive antinuclear antibody and low complement C3. Other workup for secondary causes of membranous nephropathy was unyielding. Renal biopsy showed membranous nephropathy with focal proliferative glomerulonephritis. Immunofluorescence was not suggestive of lupus nephritis and staining for antiphospholipase A2 receptor was negative. He was diagnosed as HBV-related MN and he was treated with Tenofovir Alafenamide. Six months after HBV treatment, his proteinuria has improved with stable renal function. HBV viral load was suppressed to less than 1.3 log IU/ml but he still had high titer of HBsAg (7000 IU/ml) as expected. DISCUSSION: In HBV-related MN, HBV treatment is recommended as previous studies showed that HBV treatment and HBeAg clearance are associated with remission of MN. However, treatment endpoint remains unclear. The pathogenesis of HBV-related glomerular disease is due to the deposition of HBV antigens immune complexes in the glomerulus, especially to HBeAg. Therefore, MN can occur in patients with low HBV viral load. In HBeAg-positive patients, it may be reasonable to consider stopping antiviral following clearance of HBeAg. In HBeAg-negative patients, HBsAg immune complexes may contribute to MN. As in this case, it may be prudent to continue with HBV therapy as he has persistently high HBsAg titer. Future research is needed to find reliable HBV markers to guide management and define clinical end points for patients with HBV-related MN.

3172 A Rare Complication of Hepatic Cirrhosis: Nephrotic Syndrome in IgA Nephropathy

INTRODUCTION: There have been many documented cases of cirrhosis and associated Parenchymal renal disease (Ig-A nephropathy, glomerulonephritis). We discuss here rare case of hepatorenal syndrome type 2, in-patient with no clinically and imaging finding indicative of portal hypertension. Also, further interesting finding is to have nephrotic range proteinuria in nephritic syndrome. CASE DESCRIPTION/METHODS: 56-Year-old Indian male with no past medical or surgical history presented with complaints of generalized weakness and occasional abdominal discomfort. He denied significant family history and alcohol, tobacco or illicit drug use. Ultrasonography (USG) abdomen showed cirrhotic changes. All work up including autoimmune panel negative, hence diagnosed with idiopathic liver cirrhosis. Patient managed with conservative approach, as there were no changes indicative of portal hypertension including Esophagogastroduodenoscopy. After about a year, on routine follow up he found to have his serum creatinine (Cr) progressed from 0.8 to 3.8 mg/dl. Repeat USG abdomen showed diffuse liver parenchymal disease with mild ascites and normal size of kidney with cortical thickness. Urine Microscopy revealed proteinuria and hematuria with 24 hour measured urinary protein 5 gm. Renal biopsy was performed and showed diffuse proliferative glomerulonephritis-Ig A Nephropathy (nephritic syndrome with nephrotic range proteinuria). Autoimmune profile was negative. Hospital course was complicated by septic shock and hemorrhagic cystitis. Patient was treated with inotropes, Pulse dose of intravenous methylprednisolone, albumin and other supportive approach. Decision was made not to continue cyclophosphamide due to hemorrhagic cystitis. Patient Cr later stabilized after peak of 4.3 mg/dl. Presently, is on diuretics and prednisone with Cr is stable around 1.3 mg/dl. DISCUSSION: Hepatorenal syndrome is divesting complication of liver cirrhosis, which can occur due to various mechanism one of which is described as in our case. Literature has focused mainly on mechanism of Ig-A nephropathy in portal hypertension. Our aim for this case report is to focus on monitoring renal function in cirrhotic patient even without no evidence of portal hypertension as there is no firm correlation between degree of portal hypertension and severity of IG A nephropathy. Thus, further studies can effect future era of hepatic transplant by more effectively understanding complex mechanism and managing complications.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a nephrologist perspective.

Proliferative glomerulonephritis (GN) with monoclonal immunoglobulin deposits (PGNMIDs) is a recently described entity among the spectrum of monoclonal gammopathy of renal significance (MGRS). The disease is renal limited and manifests with chronic glomerular disease, altered renal function and albuminuria, sometimes in the nephrotic range. Acute nephritic syndrome is rare. PGNMID occurs mostly in the sixth decade, but it may affect young adults. Histologically, PGNMID is characterized predominantly by membranoproliferative GN and less frequently by diffuse endocapillary GN, mesangioproliferative GN or atypical membranous GN. Immunofluorescence and electron microscopic studies are the cornerstone of diagnosis, showing granular deposits involving glomeruli only, and composed of monotypic immunoglobulin G (IgG), with a single heavy chain subclass (most commonly IgG3) and light chain (LC) restriction (usually κ), admixed with complement deposits. PGNMID variants with monotypic LC-only, IgA or IgM deposits are uncommon. Ultrastructurally, deposits are amorphous with predominant subendothelial and mesangial distribution. PGNMID should be distinguished from type 1 cryoglobulinemic GN and immunotactoid GN, which share some common pathological features. Contrary to other MGRS lesions, the rate of detection of the nephrotoxic monoclonal Ig in the serum or urine, and of an abnormal bone marrow B-cell clone, is only ∼30%. Renal prognosis is poor, with progression to end-stage renal disease in 25% of patients within 30 months and frequent early recurrence on the renal allograft. The pathophysiology of PGNMID is unclear and its treatment remains challenging. However, recent studies indicate that clone-targeted chemotherapy may significantly improve renal outcomes, opening future perspectives for the management of this rare disease.

CYP3A5 and CYP3A7 genetic polymorphisms affect tacrolimus concentration in pediatric patients with nephrotic range proteinuria.

The purpose of this study was to investigate the potential impact of CYP3A4, CYP3A5, and CYP3A7 polymorphisms on the concentration and efficacy of tacrolimus in a cohort of pediatric patients with nephrotic range proteinuria. Genetic variants including CYP3A5*3 (rs776746), CYP3A4*1G (rs2242480), rs4646437, and CYP3A7 rs2257401 and rs10211 were detected in 70 pediatric patients with nephrotic range proteinuria. The relationships of dose-adjusted trough concentration (C0) of tacrolimus with corresponding genotypes were investigated. The tacrolimus concentration in patients without CYP3A5*3 A allele was 94% higher than those with A allele (90.7 vs 54.2, P = 0.00006). The CYP3A7 rs2257401 was also associated with the concentration of tacrolimus. The C allele carriers had an obviously lower C0 than the non-carriers (62.4 vs 90.7, P = 0.001). In addition, there were significant differences in tacrolimus concentration among CYP3A7 rs10211 G carriers and non-carriers; the latter had an almost twofold C0 of the former (101.8 vs 59.6, P = 0.0004). Our study demonstrated the associations between CYP3A5*3, CYP3A7 rs2257401 and rs10211, and tacrolimus concentration in pediatric patients with nephrotic range proteinuria. Children with CYP3A5*3 A, CYP3A7 rs2257401 C, and rs10211 G alleles might need a higher dose of tacrolimus.

Minimal change disease associated with balsalazide therapy for ulcerative colitis

Introduction: 5-aminosalicylic acid (5-ASA) compounds have been used in the management of ulcerative colitis for decades. Nephrotoxicity has been previously described in patients treated with 5-ASA compounds and usually manifests as interstitial nephritis, however a few cases of nephrotic syndrome have been reported. Balsalazide is a pro-drug composed of 5-ASA linked to an inert carrier. Case Presentation: Here we report the case of a 74-year-old man with a history of ulcerative proctosigmoiditis treated with balsalazide who presented to our clinic with bilateral lower extremity edema three months after initiation of balsalazide. Laboratory workup showed nephrotic range proteinuria without an apparent secondary etiology. Given worsening proteinuria and renal function despite cessation of balsalazide, the patient underwent renal biopsy that revealed minimal change disease. High dose steroids were started and complete remission of proteinuria was achieved one month into therapy which was slowly tapered over the next five months. Eventual resolution of edema and return of creatinine back to patient’s baseline level was achieved. Conclusion: To our knowledge, this is the first report of nephrotic syndrome manifesting soon after initiation of balsalazide therapy. Our work highlights the importance of maintaining a high clinical suspicion for nephrotoxicity when using balsalazide.

Late-Onset De Novo Minimal Change Disease Presenting With Nephrotic Range Proteinuria More Than 1 Year After Combined Heart-Kidney Transplant: A Case Report

We present a case of de novo minimal change disease occurring more than 1 year after transplant in a combined heart-kidney transplant recipient. A 68-year-old white man with past medical history of nonischemic cardiomyopathy with left-ventricular assist device and end-stage renal disease due to type 2 diabetes mellitus and cardiorenal syndrome underwent a combined heart-kidney transplant in a sequential manner in August 2016. He was induced with rabbit antithymocyte globulin and methylprednisolone; he was maintained on mycophenolate mofetil, tacrolimus, and a protocolized tapering dose of prednisone. More than 1 year after transplant, in December 2017, he had about 2.3 g of proteinuria. Kidney function remained stable with a creatinine of 1.2 mg/dL. Serologic and infectious workup was nonrevealing. Proteinuria peaked at 4.5 g in January 2018, and kidney biopsy results were consistent with minimal change disease. After the biopsy, his prednisone dosage was escalated to 80.0 mg daily and slowly tapered to 2.5 mg (including most recent follow-up data from May 2019) daily, in alignment with improvement in his proteinuria and creatinine. Proteinuria decreased to 130.0 mg/g. To our knowledge, this is the first reported case of its kind in a combined heart-kidney transplant patient.

MON-013 A CASE OF MEMBRANOUS NEPHROPATHY THAT DEVELOPPED AFTER USE OF NIVOLUMAB

Immune checkpoint inhibitors (ICIs) are novel medicines for cancer immunotherapy that have increasingly been used in recent years.Nivolumab is a human anti-programmed cell death 1(PD-1) monoclonal antibody that serves as an ICI. It activates anti-tumor immunity by interfering with the interaction between PD-1 and PD-1 ligand. However, by activating the immune system, ICIs also cause unique side effects, termed immune-related adverse events (irAE). Although renal irAEs are considered less common, case reports related to renal irAEs are becoming more frequent with the increasing use of ICIs. Most renal irAEs involve acute interstitial nephropathy, and glomerulonephritis is rarely reported. Here, we present the first case of membranous nephropathy (MN) that developed after use of nivolumab. ［HPI］ A 69-year-old man was referred to our hospital with nephrotic syndrome. Sixteen months previously, he commenced chemotherapy with docetaxel for stage IV non-small cell lung carcinoma. However, docetaxel was discontinued because of drug-induced lung injury and immunotherapy with nivolumab was initiated 5 months previously. He subsequently developed leg edema and increasing proteinuria. Despite discontinuation of nivolumab after the seventh course, his symptoms did not improve. He was admitted and underwent renal biopsy. ［Investigations］ His urine protein/creatinine ratio was 19 g/g Cre and serum albumin was 2.3 g/dL. Light microscopic examination of the biopsy specimen, which contained 19 glomeruli, showed global sclerosis in one of the glomeruli. The remaining glomeruli demonstrated diffuse thickening and spikes in the glomerular basement membrane. There was no evidence of acute interstitial nephritis. Immunofluorescence staining showed IgG and C3 deposition on the capillary walls. IgA, IgM, C4, and Ciq were not stained. These observations led to the diagnosis of MN. Staining for IgG subclasses and phospholipase A2 receptor (PLA2R), a membrane protein expressed on podocytes, indicated only IgG1 deposition on the capillary wall. ［In-hospital course］ Glucocorticoid therapy was started with 50 mg/day prednisolone as the standard treatment for irAEs, with recovery of proteinuria from the nephrotic range in 4 weeks. During tapering of glucocorticoids, proteinuria decreased and he attained incomplete remission in 7 months. Thereafter, chemotherapy was resumed with pemetrexed, anantimetabolic drug, which maintained the lung carcinoma at a steady disease state. ［Discussion］ It is well-documented that about 10% of MN cases are associated with malignancy. In previous studies, the absence of IgG4 and PLA2R deposition was a common finding in malignancy-associated MN (M-MN) and was useful for distinguishing M-MN from idiopathic MN. Our case was considered as M-MN because of the staining pattern. Although previous reports show that M-MN improves after successful treatment of malignancy, our patient’s proteinuria increased even though his lung carcinoma remained stable during chemotherapy with nivolumab. This suggests that his M-MN was induced by immune activation caused by nivolumab. Additionally, the favorable response to glucocorticoid therapy supports the association between nivolumab and MN. With the increasing use of ICIs, renal irAEs will likely increase. Our case report demonstrates that ICIs can cause M-MN, which can be successfully treated with glucocorticoids.

Changing Protein Permeability with Nephron Loss: Evidence for a Human Remnant Nephron Effect

Background: If loss of functioning nephrons predisposes to glomerular barotrauma (a “remnant nephron” effect), then glomerular permeability should increase as glomerular filtration rate (GFR) falls, as is observed in animal models of nephron loss. Methods: Changes in net renal protein permeability, defined as proteinuria or albuminuria per mL/min of GFR, were measured in the setting of nephron loss due to kidney donation (Assessing Long Term Outcomes in Living Kidney Donors cohort) or progressive chronic kidney disease (CKD; Modification of Diet in Renal Disease [MDRD], African American Study of Kidney Disease [AASK], and Chronic Renal insufficiency Cohort [CRIC] studies). Results: Following kidney donation, renal albumin permeability increased by 31% from predonation levels (p < 0.001). With progression of CKD, a 50% loss of residual GFR was accompanied by increases in proteinuria per mL/min GFR of 1.8-, 2.1-, and 1.6-fold in the MDRD, AASK, and CRIC cohorts, respectively (p < 0.001 for all), independent of changes in systolic blood pressure and ACEi/ARB use. A 70% reduction in GFR was associated with permeability increases of 3.1-, 4.4-, and 2.6-fold in the same cohorts. Among MDRD participants with progression of nonglomerular primary disease, the 75th percentile of final permeability was 141 mg/24 h proteinuria per mL/min GFR. This degree of permeability would have resulted in nephrotic range proteinuria had it been present at the baseline mean GFR of 40 mL/min, implying the development of de novo glomerular pathology as GFR fell. Increasing permeability also accompanied CKD progression in participants with nephrotic syndrome at baseline. Consequently, these participants had little improvement in 24 h proteinuria or serum albumin, despite substantial loss of functioning nephron mass across which the protein leak occurred. In the absence of a fall in GFR, there was no increase in permeability in any cohort. Conclusion: Nephron loss is accompanied by an increase in renal protein permeability, even in the absence of a primary glomerular disease. This is consistent with a remnant nephron effect in human CKD.

SUN-034 Liposorber® LA-15 system for LDL apheresis in drug resistant primary focal segmental glomerulosclerosis patients: Interim results from a prospective, multicenter, single-arm intervention study

Focal segmental glomerulosclerosis (FSGS) is the major cause of end stage renal disease (ESRD) in the United States and worldwide. Primary FSGS carries poor prognosis as spontaneous remission is rare and more rapidly progress to ESRD within 2-8 years in nephrotic range proteinuria patients. Management of FSGS patients refractory to standard treatments or resistant to steroids remains a major challenge. Low-density lipoprotein apheresis (LDL apheresis) is a novel therapy for drug resistant (corticosteroids and/or calcineurin inhibitors) primary FSGS and post-renal transplant primary FSGS recurrence.

A LONG FORGOTTEN DIAGNOSIS – A CASE OF MALIGNANT HYPERTENSION

Objective: Malignant hypertension is a severe form of hypertension (HTN) classified as a hypertensive emergency, whose occurrence is rather rare given compared to the time it entered the medical lexicon, given the nowadays ample blood pressure (BP) lowering therapeutic arsenal. We present the case of a patient with acutely decompensated heart failure due to malignant HTN. Design and method: A 66 years old diabetic, chronic renal disease, obese, female patient presented to the emergency department for a five days onset of hallucinations and confusion. She described dyspnea on mild-moderate efforts, headache and vertigo for the past six months, lacking BP control for the past two years on a four-drug regimen including perindopril, amlodipine, bisoprolol, and furosemide. Clinical evaluation found no signs of stroke, but significant systemic and pulmonary congestion, BP levels 250/160 mmHg (equal both arms), and bilateral flame haemorrhages and papilloedema on fundoscopy. CT scan was positive for cerebral edema and echocardiography showed left ventricle hypertrophy with an ejection fraction of 40%, diffuse hypokinesis, with no significant valvulopathy. Upon admission the patient received urapidil during the first 24 h, on top of high dose loop diuretic and a six-drug regimen including an ACE inhibitor, calcium channel blocker, spironolactone, betablocker and two central acting antihypertensives. 24 h and 72 h control CT scan did not reveal any changes; nephrotic range proteinuria (17 g/24 h) was also noted along with a moderate increase in creatinine levels once BP control was obtained. Results: Congestion and neurological symptoms were significantly improved during the two-week course of above mentioned therapy and patient was discharged. Control at one month revealed an asymptomatic patient with good BP control at 110/90 mmHg and improved cardiac function, persistent but lower proteinuria, however with significantly increased serum creatinine levels. This led to a step-down in antihypertensive therapy aiming for a systolic BP of 130–139 mmHg. Conclusions: This is a case of refractory hypertension aggravated by inertia to seek medical advice and secondary poor BP control. This led to a severe form of malignant hypertension in which adequate control was obtained with difficulty and over a long period of time.

Hearing Status in Children with Idiopathic Nephrotic Syndrome

Background The nephrotic syndrome is a glomerular disease, in which the glomerular capillary wall becomes no longer impermeable to proteins. It is characterized by nephrotic range proteinuria and the clinical findings associated with large urinary losses of protein: hypoalbuminemia, edema, and hyperlipidemia. The organs of the inner ear bear a physiological similarity to the kidney, both being concerned with maintaining the electrolyte concentration gradient. There is an association between renal and inner ear disorders, either genetically determined as in Alport syndrome and branchio-oto-renal syndrome or acquired as in acute kidney injury and chronic kidney disease. Aim of the Work To evaluate hearing status in children with idiopathic nephrotic syndrome. Patients and Methods This case-control study was conducted on 80 patients with nephrotic syndrome (for at least 12 months’ duration) following up at Pediatric Nephrology Clinic, Children’s Hospital, Ain Shams University and 20 (age and sex-matched) apparently healthy children as a control group Patients included were in remission or relapse and none had known ear disease or secondary nephrotic syndrome. Patients were subjected to thorough history taking and clinical examination. Corrected s. calcium, s. albumin and s. sodium was measured in all patients. Pure tone audiometry for all patients and controls was done to assess hearing status. Results We found that patients with hearing impairment had lower serum albumin and serum calcium. Presence of proteinuria and the use of cyclophosphamide was significantly more in patients with hearing impairment. We also found that sensorineural hearing loss group had lower serum calcium and as well as serum sodium compared to conductive hearing loss group, with no significant difference in serum albumin between the 2 subgroups. No significant difference was noted in hearing status among patients in remission and those in relapse Conclusion Biochemical changes in idiopathic nephrotic syndrome, especially electrolytes, may play a role in hearing impairment in those patients. Drugs- (maybe) perhaps through immunosuppression (and) as well as increasing infection incidence;may also contribute to hearing impairment especially conductive hearing loss.

Renal tubular P-glycoprotein expression is reduced in plasma cell disorders.

BackgroundP-glycoprotein (P-gp) transports many chemicals that vary greatly in their structure and function. It is normally expressed in renal proximal tubular cells. We hypothesized that P-gp expression influences light chain excretion. Therefore, we investigated whether renal tubular P-gp expression is altered in patients with plasma cell disorders.MethodsWe evaluated renal biopsy specimens from patients with plasma cell disorders (n = 16) and primary focal segmental glomerulosclerosis (the control group, n = 17). Biopsies were stained with an anti-P-gp antibody. Loss of P-gp expression was determined semi-quantitatively. Groups were compared for loss of P-gp expression, and clinical variables.ResultsP-gp expression loss was more severe in patients with plasma cell disorders than it was in those with glomerulonephritis (P = 0.021). In contrast, clinical and histological parameters including serum creatinine, level of urinary protein excretion, and interstitial fibrosis/tubular atrophy grade were not significantly different between the groups. P-gp expression loss increased with age in patients with plasma cell disorders (P = 0.071). This expression loss was not associated with serum creatinine, the level of urinary protein excretion or the interstitial fibrosis/tubular atrophy grade. There was no significant association between the severity of P-gp expression loss with the types and serum levels of light chains, isotypes and serum immunoglobulin levels.ConclusionRenal tubular P-gp expression is significantly down-regulated in patients with plasma cell disorders characterized by nephrotic range proteinuria. Additional studies are needed to determine whether reintroduction of renal tubular P-gp expression would mitigate the proximal tubular injury that is caused by free-light chains.

PB2138 LIGHT CHAIN (AL) AMYLOIDOSIS: A SINGLE CENTRE EXPERIENCE AND THE EFFECTIVENESS OF BORTEZOMIB BASED THERAPY AS FIRST LINE THERAPY

Background:Amyloidosis is a heterogenous disease characterised by deposition of amyloid fibrils in soft tissue. Light chain (AL) amyloidosis is the most common form of systemic amyloidosis and is a complication of plasma cell dyscrasia. It can affect a wide range of organs including kidneys, heart, nervous system, liver, gastrointestinal tract and spleen which make the diagnosis difficult. Kidneys are the most commonly affected organ in AL amyloidosis and most patients present with nephrotic range proteinuria.In light chain amyloidosis, clonal plasma cells use proteasome to cope with misfolded light chain induced proteotoxicity, and the proteasome inhibitor bortezomib is a potential targeted therapy. Studies have demonstrated that Cyclophosphamide, Bortezomib, Dexamethasone (CyBorD) is a useful, highly effective upfront option.Aims:A retrospective study to evaluate the experience of a single centre, Waitemata District Health Board on the source of referral, biopsy source and the effectiveness of Bortezomib‐based therapy with long term follow up.MethodsDatabase at Waitemata District Health Board was searched for newly diagnosed patients with amyloidosis between 2001 and 2018. 55 out of 70 cases reported to New Zealand Cancer Registry were included. The source of referral, light chain subtype, disease association and biopsy source were analysed.43 patients who received Bortezomib based therapy as first line had been identified. The haematological response was assessed according to the International Society of Amyloidosis criteria. The duration to complete remission and relapse rates were also analysed.Results:55 patients were diagnosed with AL amyloidosis between 2001 and 2018. Half of the patients were referred by renal service (49%) and 11/55 (20%) were from cardiology service. Two third (38/55) of the patients had lambda light chains. Vast majority (87%) had either MGUS or smouldering myeloma.Half of the patients were diagnosed from renal biopsy. Other sites of diagnostic biopsy sample include bone marrow, lymph node, cardiac, GI tract, liver and tongue. Congo red stain was done on 39/50 bone marrow trephine samples and 16 of them (41%) were positive (8 muscular layer, 1 cortical bone, 7 marrow interstitium). Rectal biopsies were done on 10 patients with 7 positive result (70%).Of the 43 patients who received Bortezomib based therapy as first line treatment, 14 (32.6%) achieved complete response within 30 days of commencing treatment. Three patients (21.4%) relapsed with median time to relapse of 3.6 years. 15 patients (34.9%) achieved complete response after 30 days of commencing therapy and 5 patients (33.3%) relapsed with median time of 2 years. Five patients achieved very good partial response (VGPR), six patients with limited or no response.Summary/Conclusion:Renal disease is the most common presentation of AL amyloidosis followed by cardiac involvement. 2/3 of patients have elevated serum free lambda light chain and most of them have either MGUS or smouldering myeloma on bone marrow biopsy. Diagnoses are mostly made on renal biopsy but rectal biopsy seems to be sensitive for diagnosis of amyloidosis infiltration as well. Bortezomib based therapy appeared to be effective treatment as first line therapy with 79% achieving good haematological response with sustainable remission status. Ongoing follow up and larger cohort will be required for more conclusive results.

PS1488 ATYPICAL HAEMOLYTIC URAEMIC SYNDROME IN THE ECULIZUMAB ERA: PRESENTATION, RESPONSE TO TREATMENT AND EVALUATION OF AN ECULIZUMAB WITHDRAWAL STRATEGY

Background:Atypical haemolytic uraemic syndrome (aHUS) is a rare thrombotic microangiopathy with a predilection for the kidneys, and results from dysregulation of the alternative pathway of complement. The prognosis has historically been poor but the humanised monoclonal anti‐C5 antibody eculizumab has revolutionised management in the last decade. Whilst haematological and renal efficacy has been demonstrated, the optimum treatment duration is unknown, and is of key clinical relevance given the high drug costs and potential adverse effects including bacterial meningitis.Aims:‐ To review presenting features and responses to eculizumab therapy in cases of acute aHUS‐ To assess outcomes of eculizumab withdrawal in cases of complete responseMethods:All cases of acute aHUS presenting to a single UK centre between 2012–2018 and managed with eculizumab were retrospectively reviewed, from diagnosis to last follow up in our institution. AHUS was diagnosed according to international consensus criteria. Withdrawal of eculizumab, with subsequent close monitoring, was offered to all patients achieving complete haematological response (platelets &gt;150 x109/L and normal LDH) and complete renal recovery (eGFR back to baseline without significant proteinuria), with discussion of risks/benefits.Results:22 patients (68% female, median age 32 years (range 16–67), all with native kidneys and no known chronic kidney disease (CKD), were identified. 21/22 were de novo presentations. Median nadir platelet count was 23 x109/L (range 7–85), and median nadir eGFR was 11.5 ml/min/1.73m2 (range 3–57), with a high incidence of nephrotic range proteinuria (47%). 14/22 (64%) of patients required renal replacement therapy (RRT). GI (64%) and neurological (41%) symptoms were common. 77% had elevated cardiac troponin T (median 64.5 ng/L, range 17–397, NR 0–14), suggesting subclinical cardiac involvement. 41% had an associated complement genetic abnormality but mutation status did not affect severity of clinical presentation.Eculizumab followed a median of 6 days (range 2–38) of plasma exchange (PEX). After a median duration of therapy of 11 weeks (range 1–227), haematological recovery was seen in 100%, while 81% achieved at least partial renal recovery (median increase in eGFR 49 ml/min/1.73m2 (range 22–80)). At median duration of follow up of 85 weeks (range 4–255), 54.5% had eGFR &gt;60 ml/min/1.73m2, 27% had CKD, 14% were on RRT, and 4.5% had died.Eculizumab was withdrawn in 13/22 (59%) following complete haematological and renal recovery, after a median 10 weeks (range 1–26). 10/13 remained in remission at median 66 weeks (range 14–238) since withdrawal. 3/13 (23%) subsequently relapsed, all within 1 year of withdrawal, with defined triggers in 2/3. All made a full recovery with rapid resumption of eculizumab without need for PEX or RRT. Those who relapsed were more likely to have a complement genetic abnormality, with a trend for a shorter duration of initial therapy (Table 1).Summary/Conclusion:The cohort demonstrates the multisystem nature of aHUS, and reiterates that severe thrombocytopenia and mild renal impairment, although classically associated with TTP, can also be seen in aHUS. Haematological and renal outcomes in the cohort compare favourably with the existing prospective and retrospective literature, demonstrating a positive outlook for aHUS in the eculizumab era. Our withdrawal strategy led to no long term adverse effects, with undeniable benefits (including drug cost savings of over £11 million), and as such adds to the growing body of evidence in favour of such an approach.image

Microfilaria in Kidney Biopsy Presenting with Nephrotic Range Proteinuria

Background: A 59 year old male from the North was referred with Nephrotic Syndrome and heavy proteinuria (8gm) and weakness. Urine examination showed 2-3 pus cells, 4+ protein. Two cores of renal tissue were submitted in buffered formalin and Michel’s transport medium. Objective: The case is presented for its rarity. The discussion will include immunological review and glomerular patterns of injury associated with Microfilaria. Result: The immunofluorescence pattern was negative for IgG, IgM, IgA, C3, C4, C1q, kappa and lambda. The light microscopy revealed 3 glomeruli showing mild increase in mesangial cellularity. Tubules show cloudy change. Interstitium shows focal lymphoid infiltrate. An unusual finding is the presence of segmented microfilaria in glomerular capillaries. Conclusion: Diagnosis of filariasis on kidney biopsy by identifying microfilaria is rare. High index of suspicion is required to diagnose filariasis due to its wide range of clinical presentation and laboratory findings. In the archives of 11O8 renal biopsies over a period of 4 years, this is the first case we came across.