KDIGO 2016 Controversies Conference ATYPICAL HEMOLYTIC UREMIC SYNDROME

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KDIGO 2016 Controversies Conference ATYPICAL HEMOLYTIC UREMIC SYNDROME AND C 3 GLOMERULOPATHY This presentation

KDIGO 2016 Controversies Conference ATYPICAL HEMOLYTIC UREMIC SYNDROME AND C 3 GLOMERULOPATHY This presentation is based on: Goodship T. et al. , Kidney Intl (2017) 91: 539 -551.

SUPPORTED BY The content of this presentation reflects the position of the authors of

SUPPORTED BY The content of this presentation reflects the position of the authors of the original paper. It does not reflect the official opinion of Alexion or Achillion and should not be viewed as a position endorsed by them. Responsibility for the information and views expressed in this presentation lies entirely with the authors. Disclaimer: Eculizumab is not currently approved for the treatment of C 3 G. Kidney Disease: Improving Global Outcomes

PART 1: INTRODUCTION Kidney Disease: Improving Global Outcomes

PART 1: INTRODUCTION Kidney Disease: Improving Global Outcomes

THE ROLES OF COMPLEMENT Ricklin D, et al. Nat Rev Nephrol 12: 383 -401,

THE ROLES OF COMPLEMENT Ricklin D, et al. Nat Rev Nephrol 12: 383 -401, 2016. Kidney Disease: Improving Global Outcomes

ATYPICAL HEMOLYTIC UREMIC SYNDROME (a. HUS) • Ultra-rare disease characterized by acute kidney injury

ATYPICAL HEMOLYTIC UREMIC SYNDROME (a. HUS) • Ultra-rare disease characterized by acute kidney injury (AKI), thrombocytopenia, and microangiopathic hemolytic anemia. • At least 50% of a. HUS patients have an underlying inherited and/or acquired complement abnormality. • Eculizumab, a humanized m. Ab against C 5, makes it possible to control a. HUS and prevent development of ESRD in the majority of patients. Kidney Disease: Improving Global Outcomes

C 3 GLOMERULOPATHY (C 3 G) • C 3 G comprises a group of

C 3 GLOMERULOPATHY (C 3 G) • C 3 G comprises a group of kidney diseases driven by uncontrolled activation of the complement cascade that leads to C 3 deposition within the glomerulus. • The dysregulation of C 3 convertase is driven by genetic and/or acquired defects. • A biopsy is required to make the diagnosis. • Two major subtypes are recognized: dense deposit disease (DDD) and C 3 glomerulonephritis (C 3 GN). Kidney Disease: Improving Global Outcomes

COMPLEMENT DYSREGULATION IN C 3 G & a. HUS Mastellos DC, et al. Trends

COMPLEMENT DYSREGULATION IN C 3 G & a. HUS Mastellos DC, et al. Trends in Immunology 38: 383 -394, 2017 Kidney Disease: Improving Global Outcomes

SECTION A Atypical Hemolytic Uremic Syndrome (a. HUS) Kidney Disease: Improving Global Outcomes

SECTION A Atypical Hemolytic Uremic Syndrome (a. HUS) Kidney Disease: Improving Global Outcomes

PART 2: RENAL PATHOLOGY: a. HUS Kidney Disease: Improving Global Outcomes

PART 2: RENAL PATHOLOGY: a. HUS Kidney Disease: Improving Global Outcomes

a. HUS PATHOLOGY • a. HUS is a thrombotic microangiopathy (TMA). • Pathology resembles

a. HUS PATHOLOGY • a. HUS is a thrombotic microangiopathy (TMA). • Pathology resembles tissue responses to endothelial injury. • The presence of C 5 b-9 staining is not a reliable indicator of a. HUS. • In general, it is not possible to determine etiology from morphology. Kidney Disease: Improving Global Outcomes

MORPHOLOGICAL FEATURES IN MICROANGIOPATHY Active Lesions Chronic Lesions Glomeruli Thrombi Endothelial swelling or denudation

MORPHOLOGICAL FEATURES IN MICROANGIOPATHY Active Lesions Chronic Lesions Glomeruli Thrombi Endothelial swelling or denudation Fragmented red blood cells Subendothelial flocculent material by EM Mesangiolysis Microaneurysms Arterioles Thrombi Endothelial swelling or denudation Intramural fibrin Fragmented red blood cells Intimal swelling Myocyte necrosis Arteries Thrombi Myxoid intimal swelling Intramural fibrin Fragmented red blood cells Glomeruli Double contours of peripheral capillary walls by LM, with variable mesangial interposition New subendothelial basement membrane by EM Widening of the subendothelial zone by EM Kidney Disease: Improving Global Outcomes Arterioles Hyaline deposits Arteries Fibrous intimal thickening with concentric lamination (onion skin)

a. HUS CASE STUDY • 30 -y. o. male, 2 -week history of general

a. HUS CASE STUDY • 30 -y. o. male, 2 -week history of general malaise, presented with AKI (plasma creatinine (Cr) 250 µmol/L) and microangiopathic hemolytic anemia (hemoglobin (Hb) 9. 5 g/d. L and fragmented cells on a peripheral blood film). • Platelet count 130 x 109/L. • Renal biopsy showed endothelial swelling and denudation, mesangiolysis, double contours of the glomerular basement membrane and subendothelial accumulation of electron-lucent, flocculent material. • No evidence of intraluminal thrombus. • Patient’s maternal grandmother had developed kidney failure after the delivery of her second child. Kidney Disease: Improving Global Outcomes

a. HUS CASE STUDY Which of the following are correct? A. The renal biopsy

a. HUS CASE STUDY Which of the following are correct? A. The renal biopsy appearances are not compatible with a diagnosis of a. HUS. B. Screening for secondary causes of a renal thrombotic microangiopathy should be undertaken. C. Genetic screening for inherited complement abnormalities should be undertaken. D. The family history is not relevant. E. Treatment with high-dose steroids should be commenced. F. Both B and C. G. Both D and E. Kidney Disease: Improving Global Outcomes

PART 3: CLINICAL PHENOTYPE AND ASSESSMENT: a. HUS Kidney Disease: Improving Global Outcomes

PART 3: CLINICAL PHENOTYPE AND ASSESSMENT: a. HUS Kidney Disease: Improving Global Outcomes

a. HUS: PRESENTATION • Current classifications of a. HUS reflect a better understanding of

a. HUS: PRESENTATION • Current classifications of a. HUS reflect a better understanding of disease mechanisms, including the impact of genetic background and etiologic triggers. • Precipitating factors include autoimmune conditions, transplants, pregnancy, infections, drugs, and metabolic conditions. • The time course and persistence of an a. HUS episode are not well understood. • Many patients appear to be at life-long risk for the recurrent acute presentation of a. HUS. • Disease penetrance for an acute episode of a. HUS in carriers of known pathogenic mutations increases with age. Kidney Disease: Improving Global Outcomes

a. HUS: EXTRARENAL MANIFESTATIONS • Extrarenal manifestations are reported in up to 20% of

a. HUS: EXTRARENAL MANIFESTATIONS • Extrarenal manifestations are reported in up to 20% of patients. • It is unclear whether these manifestations are a direct consequence of complement activation, TMA, or other factors such as severe hypertension and uremia. (Suppl Table 1) Kidney Disease: Improving Global Outcomes

a. HUS: EXTRARENAL MANIFESTATIONS • Digital gangrene, skin • Cerebral artery thrombosis/stenosis • Extracerebral

a. HUS: EXTRARENAL MANIFESTATIONS • Digital gangrene, skin • Cerebral artery thrombosis/stenosis • Extracerebral artery stenosis • Cardiac involvement/myocardial infarction • Ocular involvement • Neurologic involvement • Pancreatic, gastrointestinal involvement • Pulmonary involvement • Intestinal involvement Kidney Disease: Improving Global Outcomes

a. HUS: LABORATORY ANALYSIS • Investigations should focus on determining the underlying etiology and

a. HUS: LABORATORY ANALYSIS • Investigations should focus on determining the underlying etiology and excluding other diagnoses. • Measure ADAMTS 13 activity to diagnose or exclude thrombotic thrombocytopenic purpura (TTP). o Because the incidence of TTP is much lower in children than in adults, expert opinion recommends that in children, treatment with eculizumab should not be delayed while ADAMTS 13 activity is being determined; however, signs of nonresponse should be carefully monitored. • Investigation for STEC-HUS should be routine in all patients with presumed a. HUS. Kidney Disease: Improving Global Outcomes

a. HUS: LABORATORY ANALYSIS • Serum/plasma levels of complement proteins should be measured in

a. HUS: LABORATORY ANALYSIS • Serum/plasma levels of complement proteins should be measured in all patients with primary a. HUS prior to plasma therapy. o C 3 levels will be low in 30 -50% of a. HUS cases. o Low C 3 levels are also noted in acute STEC-a. HUS and pneumococcal a. HUS. • Complement split products and assays of complement function can also be obtained, although the significance of some of these assays requires further study. Kidney Disease: Improving Global Outcomes

a. HUS CASE STUDY 24 -y. o. female presented with: • AKI (Cr 500

a. HUS CASE STUDY 24 -y. o. female presented with: • AKI (Cr 500 µmol/L) • thrombocytopenia (platelet count 50 x 109/L); and • a microangiopathic haemolytic anaemia, following a 2 -week history of intermittent diarrhea. Kidney Disease: Improving Global Outcomes

a. HUS CASE STUDY Which of the following investigations should be undertaken to elucidate

a. HUS CASE STUDY Which of the following investigations should be undertaken to elucidate the cause of illness? A. Measure serum levels of C 3 and C 4. B. Measure ADAMTS 13 activity. C. Screen for STEC infection. D. Screen for factor H autoantibodies. E. Screen for anticardiolipin antibodies. F. All of the above. G. None of the above. Kidney Disease: Improving Global Outcomes

PART 4: GENETIC AND ACQUIRED DRIVERS OF DISEASE: a. HUS Kidney Disease: Improving Global

PART 4: GENETIC AND ACQUIRED DRIVERS OF DISEASE: a. HUS Kidney Disease: Improving Global Outcomes

a. HUS: GENETIC DRIVERS OF DISEASE • Studies of hundreds of a. HUS patients

a. HUS: GENETIC DRIVERS OF DISEASE • Studies of hundreds of a. HUS patients have provided an excellent understanding of genetic drivers of disease, leading to the development of individualized care. • Genetic screening and molecular diagnostics, with expert interpretation of the results, should inform therapeutic decisions. Kidney Disease: Improving Global Outcomes

a. HUS: GENETIC TESTING • The minimum set of genes that should be screened

a. HUS: GENETIC TESTING • The minimum set of genes that should be screened includes CFH, CD 46, CFI, C 3, CFB, THBD, CFHR 1, CFHR 5, and DGKE. • Genetic testing should also include the risk haplotypes CFHCFHR 3 and MCPggaac as they modify disease penetrance and severity. o Delays in obtaining results from genetic or molecular diagnostic studies should not prevent a clinical diagnosis or postpone treatment, as early anticomplement treatment is crucial to preserve renal function and avoid irreversible sequelae. • Technologies to detect copy number variation, hybrid genes and other complex genomic rearrangements in the CFH/CFHRs genomic region must be included in the genetic testing. Kidney Disease: Improving Global Outcomes

a. HUS: GENETIC TESTING • Genetic analysis is essential in living-related kidney donor transplantation.

a. HUS: GENETIC TESTING • Genetic analysis is essential in living-related kidney donor transplantation. o Transplantation from living-related kidney donors should only be considered if causative genetic or acquired factors are clearly identified in the recipient and the related donor is free of these factors. • Genetic testing is recommended for patients in whom discontinuation of eculizumab is being considered. Kidney Disease: Improving Global Outcomes

UNDERSTANDING GENETIC VARIANTS • Genetic variants should be classified as “benign, ” “likely benign,

UNDERSTANDING GENETIC VARIANTS • Genetic variants should be classified as “benign, ” “likely benign, ” “variant of uncertain significance (VUS), ” “likely pathogenic, ” or “pathogenic, ” following international guidelines. • Pathogenic variants compromise protection of host endothelial cells and platelets from complement damage/activation. Kidney Disease: Improving Global Outcomes

a. HUS: ACQUIRED DRIVERS OF DISEASE • Acquired drivers of disease are autoantibodies to

a. HUS: ACQUIRED DRIVERS OF DISEASE • Acquired drivers of disease are autoantibodies to complement proteins or protein complexes that impair normal function. • The best-studied acquired drivers are FH autoantibodies, which are usually seen in association with deletion of the CFHR 3 and CFHR 1 genes. o The deletion of CFHR 3 and CFHR 1 is a common copy number variation that can be identified on genetic testing. o The finding of FH autoantibodies should be confirmed in a second sample at least 4 weeks after the initial sample. Kidney Disease: Improving Global Outcomes

a. HUS: ACQUIRED DRIVERS OF DISEASE • Testing should also be performed in the

a. HUS: ACQUIRED DRIVERS OF DISEASE • Testing should also be performed in the pre-renal transplant period. • In pediatric patients, FH autoantibody assays should be performed following consensus guidelines: at diagnosis and if positive, at day 7, 14, 28, monthly and one year. • Relapses of anti-FH associated HUS occur in about 20 -25% patients. Kidney Disease: Improving Global Outcomes

a. HUS CASE STUDY • 35 -y. o. female presented with AKI, thrombocytopenia, and

a. HUS CASE STUDY • 35 -y. o. female presented with AKI, thrombocytopenia, and a microangiopathic hemolytic anemia. • Treated with eculizumab and made a full recovery. • On genetic screening, she was found to carry a heterozygous CFH/CFHR 1 hybrid gene. • Family history: § Both parents alive. § Two brothers and 3 sisters. § Two children aged 6 and 2. Kidney Disease: Improving Global Outcomes

a. HUS CASE STUDY Which of the following are correct? A. Other members of

a. HUS CASE STUDY Which of the following are correct? A. Other members of the family are not at risk of developing a. HUS. B. There is no need to offer screening to other family members for the CFH/CFHR 1 hybrid gene. C. The finding of the CFH/CFHR 1 hybrid gene in an unaffected family member has no implications for that individual. D. Family members should be offered genetic counselling. E. a. HUS can present at any age in unaffected carriers of the CFH/CFHR 1 hybrid gene. F. Both A and C. G. Both D and E. Kidney Disease: Improving Global Outcomes

PART 5: TREATMENT STRATEGIES: a. HUS Kidney Disease: Improving Global Outcomes

PART 5: TREATMENT STRATEGIES: a. HUS Kidney Disease: Improving Global Outcomes

a. HUS: TREATMENT • All patients with a clinical diagnosis of primary a. HUS

a. HUS: TREATMENT • All patients with a clinical diagnosis of primary a. HUS are eligible for treatment with eculizumab. o The dosing schedule reported in the trials that led to the approval of eculizumab should be followed. • Treatment duration is controversial as there is no evidence to support life-long therapy in all a. HUS patients. Kidney Disease: Improving Global Outcomes

a. HUS: TREATMENT • Two options for long-term dosing have been considered: o The

a. HUS: TREATMENT • Two options for long-term dosing have been considered: o The minimal dose required to achieve complement blockade. o A discontinuation dosing schedule. • No data exist to support either option, and both require monitoring of complement activity. • There are no data to inform the frequency of testing • Dose reduction or discontinuation require ongoing monitoring of complement activity. • In patients who have undergone transplant, especially patients who have lost previous allografts, discontinuation is not recommended. Kidney Disease: Improving Global Outcomes

a. HUS: TREATMENT • If access to eculizumab is unavailable, plasma therapy can be

a. HUS: TREATMENT • If access to eculizumab is unavailable, plasma therapy can be used. • The use of plasma exchange when eculizumab is available may be associated with some improvement, but delaying use of eculizumab may lead to a suboptimal therapeutic outcome. • Eculizumab increases the risk of meningococcal infection. o Patients should receive vaccination against meningococcus (including Type B); however, vaccination should not delay the start of eculizumab therapy. o Antibiotic prophylaxis is mandated during the first 2 weeks. Kidney Disease: Improving Global Outcomes

a. HUS TREATMENT: TRANSPLANT • Kidney transplantation should be delayed for at least 6

a. HUS TREATMENT: TRANSPLANT • Kidney transplantation should be delayed for at least 6 months after the start of dialysis as limited renal recovery is possible several months after starting eculizumab. • Living-related kidney donation carries a risk for recurrence in the recipient and a risk of de novo disease in the donor should the donor carry an at-risk genetic variant. • Liver transplant remains an option in patients with liverderived complement protein abnormalities, in particular for renal transplant recipients with uncontrolled disease activity despite eculizumab therapy. Kidney Disease: Improving Global Outcomes

Clinical diagnosis of a. HUS High titer FH autoantibody 1 Plasma therapy 2 Simultaneous

Clinical diagnosis of a. HUS High titer FH autoantibody 1 Plasma therapy 2 Simultaneous start of anticellular therapy 3 Continue plasma therapy indefinitely 4 Periodic monitoring of FH autoantibody level 5 Discontinue therapy when antibody titer falls below a pathogenic titer for at least 6 months 6 Kidney Disease: Improving Global Outcomes Eculizumab Simultaneous start of anticellular therapy 3 Continue eculizumab therapy indefinitely 4 Periodic monitoring of FH autoantibody level 5 Discontinue therapy when antibody titer falls below a pathogenic titer for at least 6 months 6

a. HUS CASE STUDY • 44 -y. o. male on hemodialysis for 15 years.

a. HUS CASE STUDY • 44 -y. o. male on hemodialysis for 15 years. • Primary renal disease is a. HUS. • Received two cadaver renal transplants, both of which were lost within 3 months of transplantation to recurrent disease despite treatment with plasma exchange. • Genetic screening showed a heterozygous mutation in factor H, which has been reported previously in six other patients with a. HUS. • Being considered for a third transplant. Kidney Disease: Improving Global Outcomes

a. HUS CASE STUDY Which of the following are correct? A. Prophylactic use of

a. HUS CASE STUDY Which of the following are correct? A. Prophylactic use of eculizumab immediately before and then long-term after the transplant is unlikely to prevent disease recurrence in the transplanted kidney. B. Prophylactic plasma exchange immediately before and then long-term after the transplant is highly likely to prevent disease recurrence after the transplant. C. A living-related transplant should not be considered under any circumstances. D. If he receives prophylactic eculizumab, he should be vaccinated against meningococcus. Kidney Disease: Improving Global Outcomes

a. HUS RESEARCH RECOMMENDATIONS: SUMMARY o A comparative study of biopsies from patients with

a. HUS RESEARCH RECOMMENDATIONS: SUMMARY o A comparative study of biopsies from patients with well-documented malignant hypertension and patients with well-documented alternative complement pathway disease. o A longitudinal study of patients with features of chronic microangiopathy on biopsy but without a history of acute presentation. • Clinical studies o Define how complement biomarkers correlate with current or impending a. HUS relapse and/or renal involvement. o Identify risk factors for relapse upon cessation of anti-complement therapy. o Identify alternative anti-complement therapeutics. Kidney Disease: Improving Global Outcomes

SECTION B C 3 Glomerulopathy (C 3 G) Kidney Disease: Improving Global Outcomes

SECTION B C 3 Glomerulopathy (C 3 G) Kidney Disease: Improving Global Outcomes

PART 2: RENAL PATHOLOGY: C 3 G Kidney Disease: Improving Global Outcomes

PART 2: RENAL PATHOLOGY: C 3 G Kidney Disease: Improving Global Outcomes

C 3 G PATHOLOGY • The C 3 G disease spectrum is caused by

C 3 G PATHOLOGY • The C 3 G disease spectrum is caused by abnormal control of complement activation, deposition or degradation that results in predominant glomerular C 3 fragment deposition. • A renal biopsy using immunofluorescence (IF) is required to diagnose C 3 G. • Electron microscopy (EM) is used to sub-classify C 3 G as DDD or C 3 GN. Kidney Disease: Improving Global Outcomes

MORPHOLOGICAL FEATURES Light Microscopy Active lesions • Mesangial expansion with or without hypercellularity •

MORPHOLOGICAL FEATURES Light Microscopy Active lesions • Mesangial expansion with or without hypercellularity • Endocapillary hypercellularity including monocytes and/or neutrophils • Capillary wall thickening with double contours (the combination of capillary wall thickening and mesangial increase is referred to as a membranoproliferative pattern) • Necrosis • Cellular/fibrocellular crescents Chronic lesions • Segmental or global glomerulosclerosis • Fibrous crescents Immunofluorescence Microscopy • Typically dominant C 3 staining Electron Microscopy • DDD: Dense osmiophilic mesangial and intramembranous electron dense deposits • C 3 GN: Amorphous mesangial with or without capillary wall deposits including subendothelial, intramembranous and subepithelial electron dense deposits • Sub-epithelial ‘humps’ may be seen in both DDD and C 3 GN Kidney Disease: Improving Global Outcomes

C 3 G PATHOLOGY: CONTROVERSIES • Correlations between renal biopsy appearances, etiology, and clinical

C 3 G PATHOLOGY: CONTROVERSIES • Correlations between renal biopsy appearances, etiology, and clinical outcome are ill-defined. • IF staining is subjective and semiquantitative. o Well-defined for dense deposit disease (DDD). o Not clear if characteristic for C 3 glomerulonephritis (C 3 GN). • Distinguishing DDD and C 3 GN by EM can be difficult. Kidney Disease: Improving Global Outcomes

C 3 G CASE STUDY • 7 -y. o. male with 3 -day h/o

C 3 G CASE STUDY • 7 -y. o. male with 3 -day h/o macroscopic hematuria 4 -wk after being culture-positive for Group A β-hemolytic Strep pharyngitis. • Normal blood pressure and urine output, no edema. • Urinalysis: numerous RBCs; RBC casts; 4+ protein; negative leukocytes and nitrites. • Serum Cr 1. 0 mg/d. L (normal 0. 2 -0. 6 mg/d. L); normal electrolytes and albumin. • ASO elevated (1240 IM/m. L [normal <150 IU/m. L]); ANA negative; C 3 39 mg/d. L (normal 87 -181 mg/d. L). • FH: negative for renal disease. Kidney Disease: Improving Global Outcomes

C 3 G CASE STUDY • Diagnosed with APSGN and monitored as an outpatient.

C 3 G CASE STUDY • Diagnosed with APSGN and monitored as an outpatient. One month later, creatinine has improved to 0. 7 mg/d. L, UPC ratio is 0. 7 (normal <0. 2), and C 3 is 22 mg/d. L. What would you do now? A. Get a renal biopsy. B. Continue to monitor and get a renal biopsy 3 months after onset if C 3 has not improved. C. Start an oral course of prednisone at 2 mg/kg/day. D. Get genetic testing. E. Get comprehensive complement studies. Kidney Disease: Improving Global Outcomes

PART 3: CLINICAL PHENOTYPE AND ASSESSMENT: C 3 G Kidney Disease: Improving Global Outcomes

PART 3: CLINICAL PHENOTYPE AND ASSESSMENT: C 3 G Kidney Disease: Improving Global Outcomes

C 3 G: PRESENTATION • C 3 G generally follows a chronic, indolent course

C 3 G: PRESENTATION • C 3 G generally follows a chronic, indolent course with persistent AP activation resulting in a 10 -year renal survival of approximately 50%. • There are, however, cases of C 3 G that present as a rapidly progressive GN. Kidney Disease: Improving Global Outcomes

C 3 G: EXTRARENAL MANIFESTATIONS • Acquired partial lipodystrophy (APL) and retinal drusen are

C 3 G: EXTRARENAL MANIFESTATIONS • Acquired partial lipodystrophy (APL) and retinal drusen are reported and appear to be direct consequences of complement activation. Kidney Disease: Improving Global Outcomes

C 3 G: LABORATORY ANALYSIS • Serum/plasma levels of complement proteins should be measured

C 3 G: LABORATORY ANALYSIS • Serum/plasma levels of complement proteins should be measured in all patients with C 3 G prior to plasma therapy. o C 3 levels will be low in 30 -50% of a. HUS cases and up to 75% of C 3 G cases. • Complement split products and assays of complement function can also be obtained, although the significance of some of these assays requires further study. Kidney Disease: Improving Global Outcomes

C 3 G CASE STUDY • 33 -y. o. female with a diagnosis of

C 3 G CASE STUDY • 33 -y. o. female with a diagnosis of DDD. • Ophthalmologic examination showed drusen. • Complement labs showed: § C 3, <0. 15 g/L (normal 0. 9 -1. 8 g/L); C 3 c, 3. 3 mg/L (normal <2. 0 mg/L) § B, 23. 9 mg/L (normal 22 -50 mg/d. L); Bb, 2. 3 mg/L (normal <2. 2 mg/L) § C 5, 12 mg/d. L (normal 10 -21 mg/d. L); soluble C 5 b-9, 0. 25 mg/L (normal <0. 3 mg/L) § CH 50, <5 U/ml (normal 30 -90 U/ml); alternative pathway functional assay (APFA) 0% (normal 50 -130%) Kidney Disease: Improving Global Outcomes

C 3 G CASE STUDY What do these results mean? A. There is no

C 3 G CASE STUDY What do these results mean? A. There is no ongoing complement activity. B. The ongoing complement activity is primarily at the level of the alternative pathway. C. The ongoing complement activity is primarily at the level of the classical pathway. D. The ongoing complement activity is primarily at the level of the terminal pathway. Kidney Disease: Improving Global Outcomes

PART 4: GENETIC AND ACQUIRED DRIVERS OF DISEASE: C 3 G Kidney Disease: Improving

PART 4: GENETIC AND ACQUIRED DRIVERS OF DISEASE: C 3 G Kidney Disease: Improving Global Outcomes

C 3 G: GENETIC DRIVERS OF DISEASE • Understanding of the genetics of C

C 3 G: GENETIC DRIVERS OF DISEASE • Understanding of the genetics of C 3 G is not yet comparable to that of a. HUS. • There is no clear benefit to performing genetic analysis in all cases of C 3 G. Kidney Disease: Improving Global Outcomes

C 3 G: GENETIC TESTING • The minimum set of genes that should be

C 3 G: GENETIC TESTING • The minimum set of genes that should be screened includes CFH, CD 46, CFI, C 3, CFB, THBD, CFHR 1, CFHR 5, and DGKE. • Technologies to detect copy-number variation, hybrid genes, and other complex genomic rearrangements in the CFH/CFHRs genomic region must be included in the genetic testing. Kidney Disease: Improving Global Outcomes

C 3 G: GENETIC TESTING • Genetic analysis is essential in living-related kidney donor

C 3 G: GENETIC TESTING • Genetic analysis is essential in living-related kidney donor transplantation. o All planned recipients of a living-related kidney should be screened. If a genetic abnormality is found, the donor should be tested to exclude that genetic abnormality. Kidney Disease: Improving Global Outcomes

UNDERSTANDING GENETIC VARIANTS • Genetic variants should be classified as “benign, ” “likely benign,

UNDERSTANDING GENETIC VARIANTS • Genetic variants should be classified as “benign, ” “likely benign, ” “variant of uncertain significance (VUS), ” “likely pathogenic, ” or “pathogenic, ” following international guidelines. • C 3 G appears mechanistically more complex than a. HUS. o There is limited information about genotype/phenotype correlations to distinguish different C 3 G subtypes, inform prognosis and/or recommend treatment. Kidney Disease: Improving Global Outcomes

C 3 G: ACQUIRED DRIVERS OF DISEASE • Acquired drivers of disease are autoantibodies

C 3 G: ACQUIRED DRIVERS OF DISEASE • Acquired drivers of disease are autoantibodies to complement proteins or protein complexes that impair normal function. • In C 3 G, the most common autoantibodies are to C 3 convertase, a serine protease formed from C 3 b and Bb. o These autoantibodies are called C 3 Nefs. o They stabilize C 3 convertase and prolong its half-life. • Other antibodies in C 3 G include FH autoantibodies, C 4 Nefs and C 5 Nefs. • In older adults, serum free light chains (FLC) should be assayed. Kidney Disease: Improving Global Outcomes

C 3 G CASE STUDY • 24 -y. o. male with a diagnosis of

C 3 G CASE STUDY • 24 -y. o. male with a diagnosis of DDD on hemodialysis. • Planning living-related donor transplant from sibling. • Family history: Cousin also on dialysis. • Genetic testing identified: § An ultra-rare variant in the complement factor H gene, CFH c. 3229 T>C, which substitutes Cys at position 1077 for Arg (p. Cys 1077 Arg); this is classified as a VUS (variant of uncertain significance). § A common copy-number variant (CNV) in which one copy of the complement factor H–related 3 and –related 1 genes are deleted (del. CFHR 3 -CFHR 1). Kidney Disease: Improving Global Outcomes

C 3 G CASE STUDY What do these results mean and what would you

C 3 G CASE STUDY What do these results mean and what would you do? A. These results can be dismissed. B. He should not receive a kidney transplant because factor H is synthesized by the liver, and his disease will recur. C. The donor sibling should be screened for the complement factor H gene variant and, if found, he should be excluded from donating. D. The donor sibling should be screened for the complement factor H gene variant and, if found, he should be cleared to donate. Kidney Disease: Improving Global Outcomes

PART 5: TREATMENT STRATEGIES: C 3 G Kidney Disease: Improving Global Outcomes

PART 5: TREATMENT STRATEGIES: C 3 G Kidney Disease: Improving Global Outcomes

C 3 G TREATMENT: ALL PATIENTS All Patients Moderate Disease Severe Disease • Optimal

C 3 G TREATMENT: ALL PATIENTS All Patients Moderate Disease Severe Disease • Optimal blood pressure control (suggested blood pressure below the 90% in children and ≤ 120/80 in adults) o Priority agents include angiotensin converting enzyme inhibitors and angiotensin receptor blockers Optimal nutrition for both normal growth in children, healthy weight in adults Lipid control Description Urine protein over 500 mg/24 hours despite supportive therapy OR Moderate inflammation on renal biopsy OR Recent increase in serum creatinine suggesting risk for progressive disease Recommendation Prednisone Mycophenolate mofetil Description Urine protein over 2000 mg/24 hours despite immunosuppression and supportive therapy OR Severe inflammation represented by marked endo- or extracapillary proliferation with or without crescent formation despite immunosuppression and supportive therapy OR Increased serum creatinine suggesting risk for progressive disease at onset despite immunosuppression and supportive therapy Recommendation Methylprednisolone pulse dosing as well as other anti-cellular immune suppressants have had limited success in rapidly progressive disease Data are insufficient to recommend eculizumab as a first-line agent for the treatment of rapidly progressive disease Kidney Disease: Improving Global Outcomes

C 3 G: TREATMENT • A retrospective study supports the effectiveness of mycophenolate mofetil

C 3 G: TREATMENT • A retrospective study supports the effectiveness of mycophenolate mofetil in C 3 GN patients. • No specific recommendation can be made for plasma therapy or rituximab (an anti-CD 20 antibody). • Since the pathogenesis of C 3 G is due to dysregulation and hyperactivity of the alternative pathway of complement, eculizumab has been tried in a limited number of patients with varied results. Kidney Disease: Improving Global Outcomes

C 3 G TREATMENT: TRANSPLANT • No specific data are available to inform decisions

C 3 G TREATMENT: TRANSPLANT • No specific data are available to inform decisions surrounding transplantation in C 3 G. • Recommendations reflect expert opinion and limited case reports. • C 3 G recurs in allografts at a high rate, leading to graft loss in ~50% of patients. Kidney Disease: Improving Global Outcomes

C 3 G CASE STUDY • 32 -y. o. male with C 3 GN

C 3 G CASE STUDY • 32 -y. o. male with C 3 GN diagnosed 2 years ago. • On ACEs and ARBs with good control of HTN but increasing proteinuria and decreasing renal function. § CKD G 3 with e. GFR 45 m. L/min/1. 73 m 2 • Complement studies: § No rare genetic variants identified in CFH, CD 46, CFI, C 3, CFB, THBD, CFHR 1, CFHR 5, and DGKE § C 3, <0. 55 g/L (normal 0. 9 -1. 8 g/L; C 3 c, 2. 2 mg/L (normal <2. 0 mg/L); C 5, 8. 5 mg/d. L (normal 10 -21 mg/d. L); soluble C 5 b-9, 5. 45 mg/L (normal <0. 3 mg/L); CH 50, <26 U/m. L (normal 30 -90 U/m. L); APFA (alternative pathway functional assay 3% (normal 50 -130%) § C 3 Nef +2; C 5 Nef +4 Kidney Disease: Improving Global Outcomes

C 3 G CASE STUDY What would you do next? A. Add rituximab. B.

C 3 G CASE STUDY What would you do next? A. Add rituximab. B. Begin plasma exchange. C. Add mycophenolate mofetil. D. Add eculizumab. Kidney Disease: Improving Global Outcomes

C 3 G RESEARCH RECOMMENDATIONS: SUMMARY • A multicenter study analyzing biopsies to define

C 3 G RESEARCH RECOMMENDATIONS: SUMMARY • A multicenter study analyzing biopsies to define the relationship of morphology to etiology, clinical course, and response to therapy. • Comprehensive genetic testing to fill the knowledge gap in establishing robust phenotype-genotype correlations. • Clinical studies o Assess the value of proximal (at the level of the AP) anti-complement therapy. Ø Development and trial of novel complement inhibitors. o Determine value of complement biomarkers to inform clinical outcome in C 3 G patients and stratify them into targeted treatment groups. Kidney Disease: Improving Global Outcomes

CONCLUSIONS • While there are knowledge gaps in both a. HUS and C 3

CONCLUSIONS • While there are knowledge gaps in both a. HUS and C 3 G, the evidence base for the management of patients with C 3 G lags behind that of a. HUS; addressing this disparity should be a priority. • Although these two diseases are presented as distinct entities, there is substantial overlap in their pathogenesis and clinical presentation. Kidney Disease: Improving Global Outcomes

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