scholarly journals Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage

2021 ◽  
Vol 118 (13) ◽  
pp. e2022722118
Author(s):  
Talat H. Malik ◽  
Daniel P. Gitterman ◽  
Deborah P. Lavin ◽  
Hannah J. Lomax-Browne ◽  
E. Christina Hiemeyer ◽  
...  
Keyword(s):  
Significant Proportion ◽  
Kidney Injury ◽  
Factor H ◽  
Complement C3 ◽  
Definitive Treatment ◽  
Gain Of Function ◽  
Adeno Associated Virus ◽  
Superior Surface ◽  
Stage Renal Disease ◽  
End Stage

Genetic variation within the factor H–related (FHR) genes is associated with the complement-mediated kidney disease, C3 glomerulopathy (C3G). There is no definitive treatment for C3G, and a significant proportion of patients develop end-stage renal disease. The prototypical example is CFHR5 nephropathy, through which an internal duplication within a single CFHR5 gene generates a mutant FHR5 protein (FHR5mut) that leads to accumulation of complement C3 within glomeruli. To elucidate how abnormal FHR proteins cause C3G, we modeled CFHR5 nephropathy in mice. Animals lacking the murine factor H (FH) and FHR proteins, but coexpressing human FH and FHR5mut (hFH-FHR5mut), developed glomerular C3 deposition, whereas mice coexpressing human FH with the normal FHR5 protein (hFH-FHR5) did not. Like in patients, the FHR5mut had a dominant gain-of-function effect, and when administered in hFH-FHR5 mice, it triggered C3 deposition. Importantly, adeno-associated virus vector-delivered homodimeric mini-FH, a molecule with superior surface C3 binding compared to FH, reduced glomerular C3 deposition in the presence of the FHR5mut. Our data demonstrate that FHR5mut causes C3G by disrupting the homeostatic regulation of complement within the kidney and is directly pathogenic in C3G. These results support the use of FH-derived molecules with enhanced C3 binding for treating C3G associated with abnormal FHR proteins. They also suggest that targeting FHR5 represents a way to treat complement-mediated kidney injury.

scholarly journals A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4182-4191 ◽  
Author(s):  
Lubka T. Roumenina ◽  
Marie Frimat ◽  
Elizabeth C. Miller ◽  
Francois Provot ◽  
Marie-Agnes Dragon-Durey ◽  
...  
Keyword(s):  
At Risk ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement C3 ◽  
Rapid Progression ◽  
Incomplete Penetrance ◽  
Inflammatory Stimuli ◽  
Uremic Syndrome ◽  
Stage Renal Disease ◽  
End Stage

Abstract Atypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonly associated with rare genetic variants in complement system genes, unique to each patient/family. Here, we report 14 sporadic aHUS patients carrying the same mutation, R139W, in the complement C3 gene. The clinical presentation was with a rapid progression to end-stage renal disease (6 of 14) and an unusually high frequency of cardiac (8 of 14) and/or neurologic (5 of 14) events. Although resting glomerular endothelial cells (GEnCs) remained unaffected by R139W-C3 sera, the incubation of those sera with GEnC preactivated with pro-inflammatory stimuli led to increased C3 deposition, C5a release, and procoagulant tissue-factor expression. This functional consequence of R139W-C3 resulted from the formation of a hyperactive C3 convertase. Mutant C3 showed an increased affinity for factor B and a reduced binding to membrane cofactor protein (MCP; CD46), but a normal regulation by factor H (FH). In addition, the frequency of at-risk FH and MCP haplotypes was significantly higher in the R139W-aHUS patients, compared with normal donors or to healthy carriers. These genetic background differences could explain the R139W-aHUS incomplete penetrance. These results demonstrate that this C3 mutation, especially when associated with an at-risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event.

scholarly journals Quantification and Dosing of Renal Replacement Therapy in Acute Kidney Injury: A Reappraisal

2017 ◽  
Vol 44 (2) ◽  
pp. 140-155 ◽  
Author(s):  
William R. Clark ◽  
Martine Leblanc ◽  
Zaccaria Ricci ◽  
Claudio Ronco
Keyword(s):  
Acute Kidney Injury ◽  
Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Journal Club ◽  
Kidney Injury ◽  
Accurate Estimation ◽  
Stage Renal Disease ◽  
End Stage ◽  
Dose Assessments ◽  
Solute Clearance

Background/Aims: Delivered dialysis therapy is routinely measured in the management of patients with end-stage renal disease; yet, the quantification of renal replacement prescription and delivery in acute kidney injury (AKI) is less established. While continuous renal replacement therapy (CRRT) is widely understood to have greater solute clearance capabilities relative to intermittent therapies, neither urea nor any other solute is specifically employed for CRRT dose assessments in clinical practice at present. Instead, the normalized effluent rate is the gold standard for CRRT dosing, although this parameter does not provide an accurate estimation of actual solute clearance for different modalities. Methods: Because this situation has created confusion among clinicians, we reappraise dose prescription and delivery for CRRT. Results: A critical review of RRT quantification in AKI is provided. Conclusion: We propose an adaptation of a maintenance dialysis parameter (standard Kt/V) as a benchmark to supplement effluent-based dosing of CRRT. Video Journal Club “Cappuccino with Claudio Ronco” at http://www.karger.com/?doi=475457

scholarly journals Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 457
Author(s):  
Kyeong-Seok Kim ◽  
Jin-Sol Lee ◽  
Jae-Hyeon Park ◽  
Eun-Young Lee ◽  
Jong-Seok Moon ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Early Stage ◽  
Kidney Injury ◽  
Diabetic Patients ◽  
High Morbidity ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Zucker Diabetic Fatty Rats ◽  
Kidney Injury Molecule 1 ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. After development of DN, patients will progress to end-stage renal disease, which is associated with high morbidity and mortality. Here, we developed early-stage diagnostic biomarkers to detect DN as a strategy for DN intervention. For the DN model, Zucker diabetic fatty rats were used for DN phenotyping. The results revealed that DN rats showed significantly increased blood glucose, blood urea nitrogen (BUN), and serum creatinine levels, accompanied by severe kidney injury, fibrosis and microstructural changes. In addition, DN rats showed significantly increased urinary excretion of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Transcriptome analysis revealed that new DN biomarkers, such as complementary component 4b (C4b), complementary factor D (CFD), C-X-C motif chemokine receptor 6 (CXCR6), and leukemia inhibitory factor (LIF) were identified. Furthermore, they were found in the urine of patients with DN. Since these biomarkers were detected in the urine and kidney of DN rats and urine of diabetic patients, the selected markers could be used as early diagnosis biomarkers for chronic diabetic nephropathy.

Peritoneal Dialysis

2019 ◽  
Author(s):  
Karlien François ◽  
Joanne M. Bargman
Keyword(s):  
Renal Failure ◽  
Peritoneal Dialysis ◽  
Peritoneal Cavity ◽  
Fluid Overload ◽  
Kidney Injury ◽  
Dialysis Fluid ◽  
Keywords Peritoneal Dialysis ◽  
Stage Renal Disease ◽  
End Stage ◽  
Developed World

In peritoneal dialysis (PD), the peritoneum serves as a biological dialyzing membrane. The endothelium of the vast capillary network perfusing the peritoneum functions as a semipermeable membrane and allows bidirectional solute and water transfer between the intravascular space and dialysate fluid dwelling in the peritoneal cavity. PD is a renal replacement strategy for patients presenting with end-stage renal disease. It can also be offered for ultrafiltration in patients with diuretic-resistant fluid overload even in those without advanced renal failure. PD can also be used for patients with acute kidney injury, although in the developed world this occurs rarely compared to the use of extracorporeal therapies. This review contains 9 videos,  8 figures, 4 tables, and 73 references.  Keywords: peritoneal dialysis, peritoneal cavity, catheter, dialysis fluid, ultrafiltration, tunnel infection, osmotic pressure, renal failure

MO302ACUTE POST-INFECTIOUS GLOMERULONEPHRITIS IN ADULTS: A TUNISIAN SINGLE CENTER EXPERIENCE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Imen El Meknassi ◽  
Mrabet Sanda ◽  
Guedri Yosra ◽  
Zellema Dorsaf ◽  
Azzabi Awatef ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Acute Glomerulonephritis ◽  
Industrialized Countries ◽  
Single Center Experience ◽  
Nephritic Syndrome ◽  
Stage Renal Disease ◽  
End Stage ◽  
Post Infectious

Abstract Background and Aims Acute post-infectious glomerulonephritis (APIGN) is a reactive immunological disease. Its prevalence in industrialized countries is declining contrasting with developed ones. It is uncommon in adults but the prognosis may be reserved. The aim of our study was to evaluate the epidemiological, clinical and histological features of APIGN as well as its prognosis. Method A retrospective and descriptive study was conducted in our department. Were included all cases of histologically proven APIGN between December 2006 and December 2017. Results We had collected 38 cases. The mean age was 37.7 ± 17.8 years. The sex ratio was 1.92. Twelve (31.6%) patients were diabetic and four of them had already a chronic kidney disease (CKD). APIGN was preceded by an infection in 27 cases with an average interval of 10 ± 5 days. The most common site of infection was the respiratory tract (15 cases). At presentation, 27 patients had nephritic syndrome and 13 had nephrotic-range proteinuria. Hematuria was observed in 97.4%, peripheral edema in 84.2% and hypertension in 73.7% of cases. Most patients (78.9%) had acute kidney injury and 10 (26.3%) patients required dialysis. Renal biopsy had shown benign acute glomerulonephritis in 31 cases and malignant form in 7 cases. An underlying nephropathy was found in 12 cases with mostly a diabetic nephropathy. Corticosteroids were used in 3 cases of benign APIGN and 5 cases of malignant form. During the follow-up, CKD was noted in 14(36.8%) patients including 7(18.4%) patients who progressed to end-stage renal disease. Poor prognostic factors were diabetes, the presence of an underlying nephropathy in the biopsy, acute kidney injury and the need for dialysis. Conclusion The APIGN is uncommon in adults, yet its prognosis may be reserved with progression to CKD.

Microscopic Polyangiitis: New Insights into Pathogenesis, Clinical Features and Therapy

2018 ◽  
Vol 39 (04) ◽  
pp. 459-464 ◽  
Author(s):  
Alexandre Karras
Keyword(s):  
Microscopic Polyangiitis ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Cause Of Deaths ◽  
Optimal Maintenance ◽  
General Signs ◽  
Rapidly Progressive Renal Failure ◽  
Stage Renal Disease ◽  
End Stage

AbstractMicroscopic polyangiitis (MPA) is one of the main clinical presentations of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Although the disease is defined by clinical and pathological criteria, the anti-myeloperoxidase (MPO) specificity of ANCAs is observed in almost 80% of MPA patients. The direct pathogenic role of anti-MPO antibodies has been proven in animal models, in which the disease was transmitted by transfer of anti-MPO antibodies or anti-MPO–specific splenocytes. The most frequently affected organs in this disease are the kidneys and the lungs. Necrotizing and crescentic glomerulonephritis can be revealed by rapidly progressive renal failure, but kidney injury can be more slowly progressive and lead to end-stage renal disease without major extrarenal manifestations. The most frequent pulmonary manifestation is diffuse alveolar hemorrhage, but some patients may present with chronic interstitial fibrosis leading to respiratory failure. General signs such as fever and weight loss, muscular and articular symptoms, peripheral neuropathy, and cutaneous involvement may also reveal the disease. Although the relapse rate is quite low after induction of remission, 5-year mortality is 25%, with even higher mortality rates in older patients (> 65 years old), or those with significant kidney dysfunction. Iatrogenic causes (particularly infections) are an important cause of deaths in these vulnerable patients. Future studies are warranted to determine the optimal maintenance immunosuppressive regimen to minimize side effects of immunosuppression.

scholarly journals De Novo Atypical Haemolytic Uremic Syndrome after Kidney Transplantation

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Arnaud Devresse ◽  
Martine de Meyer ◽  
Selda Aydin ◽  
Karin Dahan ◽  
Nada Kanaan
Keyword(s):  
Kidney Transplantation ◽  
De Novo ◽  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor ◽  
Haemolytic Uremic Syndrome ◽  
Hinman Syndrome ◽  
Uremic Syndrome ◽  
Stage Renal Disease ◽  
End Stage

De novo thrombotic microangiopathy (TMA) can occur after kidney transplantation. An abnormality of the alternative pathway of complement must be suspected and searched for, even in presence of a secondary cause. We report the case of a 23-year-old female patient who was transplanted with a kidney from her mother for end-stage renal disease secondary to Hinman syndrome. Early after transplantation, she presented with 2 episodes of severe pyelonephritis, associated with acute kidney dysfunction and biological and histological features of TMA. Investigations of the alternative pathway of the complement system revealed atypical haemolytic uremic syndrome secondary to complement factor I mutation, associated with mutations in CD46 and complement factor H related protein genes. Plasma exchanges followed by eculizumab injections allowed improvement of kidney function without, however, normalization of creatinine.

scholarly journals Outcomes of Chronic Hemodialysis Patients in the Intensive Care Unit

2013 ◽  
Vol 2013 ◽  
pp. 1-7
Author(s):  
Melanie Chan ◽  
Marlies Ostermann
Keyword(s):  
Intensive Care Unit ◽  
Renal Function ◽  
Intensive Care ◽  
Kidney Injury ◽  
Chronic Hemodialysis ◽  
Current Evidence ◽  
Icu Outcome ◽  
Stage Renal Disease ◽  
End Stage

Patients with end-stage renal disease (ESRD) experience higher rates of hospitalisation, cardiovascular events, and all-cause mortality and are more likely to require admission to the intensive care unit (ICU) than patients with normal renal function. Sepsis and cardiovascular diseases are the most common reasons for ICU admission. ICU mortality rates in patients requiring chronic hemodialysis are significantly higher than for patients without ESRD; however, dialysis patients have a better ICU outcome than those with acute kidney injury (AKI) requiring renal replacement therapy suggesting that factors other than loss of renal function contribute to their prognosis. Current evidence suggests, the longer-term outcomes after discharge from ICU may be favourable and that long-term dependence on dialysis should not prejudice against prompt referral or admission to ICU.

scholarly journals Distal Radial Artery Ligation for Dialysis Access Steal Syndrome

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
David Fung ◽  
Yaasin Abdulrehman
Keyword(s):  
Radial Artery ◽  
Surgical Techniques ◽  
Limb Ischemia ◽  
Definitive Treatment ◽  
Dialysis Access ◽  
Artery Ligation ◽  
Stage Renal Disease ◽  
End Stage ◽  
Steal Syndrome ◽  
Distal Radial Artery

Renal replacement therapy is the definitive treatment for end stage renal disease apart from transplant. Steal syndrome, which can lead to distal limb ischemia, is a rare but serious complication in patients who undergo hemodialysis with an arteriovenous fistula. We present a case of a 48-year-old female with limited options for dialysis access who presented with symptoms of steal syndrome. Given the need to keep her current fistula, we opted to treat her with distal radial artery ligation. This case report summarizes the various surgical techniques available for treating dialysis access-associated steal syndrome and why distal radial artery ligation should be considered a viable management strategy, especially in the context of our patient.

scholarly journals Complete Renal Recovery in Pediatric Patient with C3 Glomerulonephritis: A Case Report

2021 ◽  
pp. 261-269
Author(s):  
Rabheh Abdul-Aziz ◽  
Rong Deng ◽  
Lin Liu ◽  
Shauna Tarsi ◽  
Wayne R. Waz ◽  
...  
Keyword(s):  
Oral Intake ◽  
Oral Prednisolone ◽  
Factor H ◽  
Microscopic Hematuria ◽  
Response To Treatment ◽  
C3 Glomerulonephritis ◽  
Significant Past Medical History ◽  
C3 Nephritic Factor ◽  
Stage Renal Disease ◽  
End Stage

C3 glomerulonephritis (C3GN) is a rare kidney disease resulting from dysregulation of the alternative complement cascade. Without treatment, approximately 70% of affected children and 30–50% of affected adults will develop worsening of proteinuria and progress to end-stage renal disease within 10 years of diagnosis. Here, we describe a 9-year-old Sudanese girl with no significant past medical history who presented to the Emergency Department with a 2-month history of fatigue, poor oral intake, and worsening facial and lower extremity edema, and subsequently found to have anemia, hypoalbuminemia, microscopic hematuria, and proteinuria. Additional laboratory testing revealed that the patient had low C3, high C3 nephritic factor (C3NeF), and high factor H. Renal function was normal. The diagnosis of C3GN was confirmed by renal biopsy. The patient was treated with ACE inhibitor, mycophenolate mofetil (600 mg per m<sup>2</sup> per dose, every 12 h), in combination with “pulse” methylprednisolone at 30 mg/kg/day IV bolus (maximum 1 g) for 3 consecutive days, followed by 2 months of daily oral prednisolone (2 mg/kg/day) and alternate-day prednisolone weaning from 1 mg/kg to 0.1 mg/kg for additional 12 months. Mycophenolate was continued throughout her treatment course and for maintenance therapy. In response to treatment, anemia, microscopic hematuria, hypoalbuminemia, and proteinuria resolved. Complete complement profile before and at 6 months therapy showed normalization of C3NeF, complement regulatory factor H and C3. This present case provides evidence of the full responsiveness of a rare form of complement dysregulation C3GN to a combination of mycophenolate and corticosteroids. The disease has NOT recurred in &#x3e;2 years after initial presentation.

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