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Presentation
A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2. Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.
Differential Diagnosis
A glomerular disease can be assumed to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.
Glomerulonephritis occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients may also experience hypertension and kidney function impairment. Diagnoses to consider include:
- Postinfectious glomerulonephritis
- Crescentic glomerulonephritis
- Diffuse proliferative glomerulonephritis
- Glomerulonephritis associated with nonstreptococcal infection
- Membranoproliferative glomerulonephritis
- Membranous glomerulonephritis
- Poststreptococcal glomerulonephritis
- Rapidly Progressive glomerulonephritis
All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.
Diagnosis
This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).
The diagnosis of C3G is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, additional testing should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.
For all patients diagnosed with C3G, especially those who are older than 50 years, it is important to rule out monoclonal gammopathy which can be done through various tests such as serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and may be responsible for the condition.
Expert opinion recommends a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.
Complement evaluation may include:
- Serum C3 and C4
- Soluble C5b-9 (soluble membrane attack complex)
- Serum factor H
- Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)
All patients with C3G should also undergo screening for autoantibodies:
- C3 nephritic factor (C3NeF)
- C5 nephritic factor (C5NeF)
- C4 nephritic factor (C4NeF)
- Other autoantibodies against factor H, factor B, and/or C3b
It is recommended that genetic testing be considered for patients with C3 glomerulopathy to screen for complement genes including C3, CFB, CFH, CFHR5, and CFI and copy number variations and rearrangements of the CFH-CFHR gene cluster. The value of genetic testing in the clinical setting is still being defined; however, it has been observed that patients with mutations in complement genes generally respond less favorably to mycophenolate mofetil (MMF) compared with those who are positive for nephritic factors.
Management
The patient was managed with an angiotensin-converting enzyme (ACE) inhibitor to treat proteinuria and hypertension and MMF for immunosuppression. Enrollment in a clinical trial of an investigational complement inhibitor was discussed with the patient.
Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G, and an optimal treatment for C3 glomerulopathy has not been established.
Various nonspecific therapies have been used to treat C3G, including plasmapheresis, steroids, rituximab, cyclophosphamide, and MMF and have shown positive results. For patients with C3G who have a known genetic variant (eg, CFH mutation) or who have acute kidney injury, plasmapheresis and plasma exchange may be helpful. Using these agents judiciously and in conjunction with optimal blood pressure control is important for maximum benefit in treating C3G. When someone with end-stage renal disease (ESRD) caused by C3G chooses to have a kidney transplant, it is important to know that C3G is likely to return in almost all cases and is the leading cause of transplant failure in 50%-90% of recipients.
Prognosis
The prognosis of C3G varies and is affected by various clinical and histological factors. While some patients may have consistently low levels of protein in their urine and maintain stable kidney function over time, others may experience severe nephrotic syndrome or rapidly progressive glomerulonephritis, which often leads to a poor prognosis.
Progression to ESRD is a major complication of C3G, with approximately 70% of affected children and 30%-50% of adults reaching this stage. In addition, disease recurrence is common after kidney transplantation, with about 50% of patients experiencing allograft loss within 10 years. Predictive factors for disease progression, although not robustly established, include initial eGFR at diagnosis, percentage of tubular atrophy, and extent of interstitial fibrosis in the cortical area as observed on kidney biopsies.
Clinical Takeaways
For patients exhibiting symptoms like proteinuria and hematuria indicative of glomerulonephritis, a comprehensive evaluation including laboratory tests and a kidney biopsy is essential to confirm a C3G diagnosis through characteristic findings on immunofluorescence microscopy or electron microscopy.
Additional tests to rule out associated conditions like monoclonal gammopathy and comprehensive complement evaluation are also recommended to understand the underlying etiology and guide therapy.
Though there are no treatments specifically targeting the underlying complement dysregulation unique to C3G, nonspecific therapies like ACE inhibitors, immunosuppressants (eg, MMF), and plasmapheresis are commonly used.
Some anticomplement therapies are available or under investigation, which might offer more targeted intervention options.
The prognosis for patients with C3G can vary widely and factors such as initial eGFR, the extent of tubular atrophy, and interstitial fibrosis are important predictors of disease progression.
Dr. Alper is an associate professor, Nephrology, Tulane University School of Medicine, New Orleans, Louisiana. He has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Presentation
A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2. Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.
Differential Diagnosis
A glomerular disease can be assumed to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.
Glomerulonephritis occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients may also experience hypertension and kidney function impairment. Diagnoses to consider include:
- Postinfectious glomerulonephritis
- Crescentic glomerulonephritis
- Diffuse proliferative glomerulonephritis
- Glomerulonephritis associated with nonstreptococcal infection
- Membranoproliferative glomerulonephritis
- Membranous glomerulonephritis
- Poststreptococcal glomerulonephritis
- Rapidly Progressive glomerulonephritis
All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.
Diagnosis
This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).
The diagnosis of C3G is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, additional testing should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.
For all patients diagnosed with C3G, especially those who are older than 50 years, it is important to rule out monoclonal gammopathy which can be done through various tests such as serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and may be responsible for the condition.
Expert opinion recommends a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.
Complement evaluation may include:
- Serum C3 and C4
- Soluble C5b-9 (soluble membrane attack complex)
- Serum factor H
- Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)
All patients with C3G should also undergo screening for autoantibodies:
- C3 nephritic factor (C3NeF)
- C5 nephritic factor (C5NeF)
- C4 nephritic factor (C4NeF)
- Other autoantibodies against factor H, factor B, and/or C3b
It is recommended that genetic testing be considered for patients with C3 glomerulopathy to screen for complement genes including C3, CFB, CFH, CFHR5, and CFI and copy number variations and rearrangements of the CFH-CFHR gene cluster. The value of genetic testing in the clinical setting is still being defined; however, it has been observed that patients with mutations in complement genes generally respond less favorably to mycophenolate mofetil (MMF) compared with those who are positive for nephritic factors.
Management
The patient was managed with an angiotensin-converting enzyme (ACE) inhibitor to treat proteinuria and hypertension and MMF for immunosuppression. Enrollment in a clinical trial of an investigational complement inhibitor was discussed with the patient.
Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G, and an optimal treatment for C3 glomerulopathy has not been established.
Various nonspecific therapies have been used to treat C3G, including plasmapheresis, steroids, rituximab, cyclophosphamide, and MMF and have shown positive results. For patients with C3G who have a known genetic variant (eg, CFH mutation) or who have acute kidney injury, plasmapheresis and plasma exchange may be helpful. Using these agents judiciously and in conjunction with optimal blood pressure control is important for maximum benefit in treating C3G. When someone with end-stage renal disease (ESRD) caused by C3G chooses to have a kidney transplant, it is important to know that C3G is likely to return in almost all cases and is the leading cause of transplant failure in 50%-90% of recipients.
Prognosis
The prognosis of C3G varies and is affected by various clinical and histological factors. While some patients may have consistently low levels of protein in their urine and maintain stable kidney function over time, others may experience severe nephrotic syndrome or rapidly progressive glomerulonephritis, which often leads to a poor prognosis.
Progression to ESRD is a major complication of C3G, with approximately 70% of affected children and 30%-50% of adults reaching this stage. In addition, disease recurrence is common after kidney transplantation, with about 50% of patients experiencing allograft loss within 10 years. Predictive factors for disease progression, although not robustly established, include initial eGFR at diagnosis, percentage of tubular atrophy, and extent of interstitial fibrosis in the cortical area as observed on kidney biopsies.
Clinical Takeaways
For patients exhibiting symptoms like proteinuria and hematuria indicative of glomerulonephritis, a comprehensive evaluation including laboratory tests and a kidney biopsy is essential to confirm a C3G diagnosis through characteristic findings on immunofluorescence microscopy or electron microscopy.
Additional tests to rule out associated conditions like monoclonal gammopathy and comprehensive complement evaluation are also recommended to understand the underlying etiology and guide therapy.
Though there are no treatments specifically targeting the underlying complement dysregulation unique to C3G, nonspecific therapies like ACE inhibitors, immunosuppressants (eg, MMF), and plasmapheresis are commonly used.
Some anticomplement therapies are available or under investigation, which might offer more targeted intervention options.
The prognosis for patients with C3G can vary widely and factors such as initial eGFR, the extent of tubular atrophy, and interstitial fibrosis are important predictors of disease progression.
Dr. Alper is an associate professor, Nephrology, Tulane University School of Medicine, New Orleans, Louisiana. He has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Presentation
A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2. Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.
Differential Diagnosis
A glomerular disease can be assumed to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.
Glomerulonephritis occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients may also experience hypertension and kidney function impairment. Diagnoses to consider include:
- Postinfectious glomerulonephritis
- Crescentic glomerulonephritis
- Diffuse proliferative glomerulonephritis
- Glomerulonephritis associated with nonstreptococcal infection
- Membranoproliferative glomerulonephritis
- Membranous glomerulonephritis
- Poststreptococcal glomerulonephritis
- Rapidly Progressive glomerulonephritis
All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.
Diagnosis
This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).
The diagnosis of C3G is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, additional testing should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.
For all patients diagnosed with C3G, especially those who are older than 50 years, it is important to rule out monoclonal gammopathy which can be done through various tests such as serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and may be responsible for the condition.
Expert opinion recommends a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.
Complement evaluation may include:
- Serum C3 and C4
- Soluble C5b-9 (soluble membrane attack complex)
- Serum factor H
- Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)
All patients with C3G should also undergo screening for autoantibodies:
- C3 nephritic factor (C3NeF)
- C5 nephritic factor (C5NeF)
- C4 nephritic factor (C4NeF)
- Other autoantibodies against factor H, factor B, and/or C3b
It is recommended that genetic testing be considered for patients with C3 glomerulopathy to screen for complement genes including C3, CFB, CFH, CFHR5, and CFI and copy number variations and rearrangements of the CFH-CFHR gene cluster. The value of genetic testing in the clinical setting is still being defined; however, it has been observed that patients with mutations in complement genes generally respond less favorably to mycophenolate mofetil (MMF) compared with those who are positive for nephritic factors.
Management
The patient was managed with an angiotensin-converting enzyme (ACE) inhibitor to treat proteinuria and hypertension and MMF for immunosuppression. Enrollment in a clinical trial of an investigational complement inhibitor was discussed with the patient.
Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G, and an optimal treatment for C3 glomerulopathy has not been established.
Various nonspecific therapies have been used to treat C3G, including plasmapheresis, steroids, rituximab, cyclophosphamide, and MMF and have shown positive results. For patients with C3G who have a known genetic variant (eg, CFH mutation) or who have acute kidney injury, plasmapheresis and plasma exchange may be helpful. Using these agents judiciously and in conjunction with optimal blood pressure control is important for maximum benefit in treating C3G. When someone with end-stage renal disease (ESRD) caused by C3G chooses to have a kidney transplant, it is important to know that C3G is likely to return in almost all cases and is the leading cause of transplant failure in 50%-90% of recipients.
Prognosis
The prognosis of C3G varies and is affected by various clinical and histological factors. While some patients may have consistently low levels of protein in their urine and maintain stable kidney function over time, others may experience severe nephrotic syndrome or rapidly progressive glomerulonephritis, which often leads to a poor prognosis.
Progression to ESRD is a major complication of C3G, with approximately 70% of affected children and 30%-50% of adults reaching this stage. In addition, disease recurrence is common after kidney transplantation, with about 50% of patients experiencing allograft loss within 10 years. Predictive factors for disease progression, although not robustly established, include initial eGFR at diagnosis, percentage of tubular atrophy, and extent of interstitial fibrosis in the cortical area as observed on kidney biopsies.
Clinical Takeaways
For patients exhibiting symptoms like proteinuria and hematuria indicative of glomerulonephritis, a comprehensive evaluation including laboratory tests and a kidney biopsy is essential to confirm a C3G diagnosis through characteristic findings on immunofluorescence microscopy or electron microscopy.
Additional tests to rule out associated conditions like monoclonal gammopathy and comprehensive complement evaluation are also recommended to understand the underlying etiology and guide therapy.
Though there are no treatments specifically targeting the underlying complement dysregulation unique to C3G, nonspecific therapies like ACE inhibitors, immunosuppressants (eg, MMF), and plasmapheresis are commonly used.
Some anticomplement therapies are available or under investigation, which might offer more targeted intervention options.
The prognosis for patients with C3G can vary widely and factors such as initial eGFR, the extent of tubular atrophy, and interstitial fibrosis are important predictors of disease progression.
Dr. Alper is an associate professor, Nephrology, Tulane University School of Medicine, New Orleans, Louisiana. He has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>168139</fileName> <TBEID>0C050365.SIG</TBEID> <TBUniqueIdentifier>MD_0C050365</TBUniqueIdentifier> <newsOrJournal>News</newsOrJournal> <publisherName>Frontline Medical Communications</publisherName> <storyname/> <articleType>353</articleType> <TBLocation>QC Done-All Pubs</TBLocation> <QCDate>20240521T145712</QCDate> <firstPublished>20240522T091109</firstPublished> <LastPublished>20240522T091109</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20240522T091109</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline/> <bylineText>A. BRENT ALPER, MD</bylineText> <bylineFull>A. BRENT ALPER, MD</bylineFull> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType/> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:imng"> <name>IMNG Medical Media</name> <rightsInfo> <copyrightHolder> <name>Frontline Medical News</name> </copyrightHolder> <copyrightNotice>Copyright (c) 2015 Frontline Medical News, a Frontline Medical Communications Inc. company. All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually</metaDescription> <articlePDF/> <teaserImage/> <teaser>The patient was diagnosed with complement 3 glomerulonephritis, which may have a genetic component.</teaser> <title>Don’t Miss the Dx: A 24-Year-Old Man With Sudden-Onset Hematuria, Proteinuria, Edema, and Hypertension</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>card</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>fp</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term>5</term> <term>15</term> <term canonical="true">21</term> </publications> <sections> <term canonical="true">52</term> </sections> <topics> <term canonical="true">255</term> <term>285</term> <term>229</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Don’t Miss the Dx: A 24-Year-Old Man With Sudden-Onset Hematuria, Proteinuria, Edema, and Hypertension</title> <deck/> </itemMeta> <itemContent> <h2>Presentation</h2> <p>A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m<sup>2</sup>. Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.</p> <h2>Differential Diagnosis</h2> <p>A <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842189/">glomerular disease can be assumed</a></span> to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.</p> <p><span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9613507/">Glomerulonephritis</a></span> occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737660/">may also experience hypertension</a></span> and kidney function impairment. <span class="Hyperlink"><a href="https://emedicine.medscape.com/article/239392-differential">Diagnoses to consider</a></span> include:</p> <ul class="body"> <li>Postinfectious glomerulonephritis</li> <li>Crescentic glomerulonephritis</li> <li>Diffuse proliferative glomerulonephritis</li> <li>Glomerulonephritis associated with nonstreptococcal infection</li> <li>Membranoproliferative glomerulonephritis</li> <li>Membranous glomerulonephritis</li> <li>Poststreptococcal glomerulonephritis</li> <li>Rapidly Progressive glomerulonephritis</li> </ul> <p>All patients presenting with proteinuria and hematuria <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842189/">should undergo a thorough evaluation</a></span> for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.<br/><br/></p> <h2>Diagnosis</h2> <p>This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).</p> <p>The diagnosis of C3G is established by kidney biopsy <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1425/">demonstrating the characteristic findings</a></span> on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876298/">additional testing</a></span> should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.<br/><br/>For all patients diagnosed with C3G, especially those who are older than 50 years, it is <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162413/">important to rule out monoclonal gammopathy</a></span> which can be done through various tests such as <span class="Hyperlink"><a href="https://emedicine.medscape.com/article/2087113-overview">serum protein electrophoresis</a></span> and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and <span class="Hyperlink"><a href="https://pubmed.ncbi.nlm.nih.gov/26154922/">may be responsible</a></span> for the condition.<br/><br/><span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9613507/">Expert opinion recommends</a></span> a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.<br/><br/>Complement evaluation may include:</p> <ul class="body"> <li>Serum C3 and C4</li> <li>Soluble C5b-9 (soluble membrane attack complex)</li> <li>Serum factor H</li> <li>Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)</li> </ul> <p>All patients with C3G should also undergo <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876298/">screening for autoantibodies</a></span>:</p> <ul class="body"> <li>C3 nephritic factor (C3NeF)</li> <li>C5 nephritic factor (C5NeF)</li> <li>C4 nephritic factor (C4NeF)</li> <li>Other autoantibodies against factor H, factor B, and/or C3b</li> </ul> <p>It is recommended that <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9613507/">genetic testing be considered</a></span> for patients with C3 glomerulopathy to screen for complement genes including <span class="Emphasis">C3</span>, <span class="Emphasis">CFB</span>, <span class="Emphasis">CFH</span>, <span class="Emphasis">CFHR5</span>, and <span class="Emphasis">CFI</span> and copy number variations and rearrangements of the <span class="Emphasis">CFH</span>-<span class="Emphasis">CFHR</span> gene cluster. The value of genetic testing in the clinical setting is <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9186056/">still being defined</a></span>; however, it has been observed that patients with mutations in complement genes generally respond less favorably to <span class="Hyperlink"><a href="https://reference.medscape.com/drug/cellcept-myfortic-mycophenolate-343209">mycophenolate</a></span> mofetil (MMF) compared with those who are positive for nephritic factors.<br/><br/></p> <h2>Management</h2> <p>The patient was managed with an angiotensin-converting enzyme (ACE) inhibitor to treat proteinuria and hypertension and MMF for <span class="Hyperlink"><a href="https://emedicine.medscape.com/article/432316-overview">immunosuppression</a></span>. Enrollment in a clinical trial of an investigational complement inhibitor was discussed with the patient.</p> <p>Currently, there are <span class="Hyperlink">no therapeutic agents</span> specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G, and an optimal treatment for C3 glomerulopathy has not been established.<br/><br/>Various <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876298/">nonspecific therapies</a></span> have been used to treat C3G, including plasmapheresis, steroids, <span class="Hyperlink"><a href="https://reference.medscape.com/drug/rituxan-truxima-rituximab-342243">rituximab</a></span>, <span class="Hyperlink"><a href="https://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214">cyclophosphamide</a></span>, and MMF and have shown positive results. For patients with C3G who have a <span class="Hyperlink"><a href="https://pubmed.ncbi.nlm.nih.gov/32553242/">known genetic variant</a></span> (eg, <span class="Emphasis">CFH</span> mutation) or who have <span class="Hyperlink"><a href="https://emedicine.medscape.com/article/243492-overview">acute kidney injury</a></span>, plasmapheresis and plasma exchange may be helpful. Using these agents judiciously and in conjunction with optimal blood pressure control is <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1425/">important for maximum benefit</a></span> in treating C3G. When someone with end-stage renal disease (ESRD) caused by C3G chooses to have a kidney transplant, it is important to know that C3G is likely to return in almost all cases and is the leading cause of transplant failure in <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1425/">50%-90% of recipients</a></span>.<br/><br/></p> <h2>Prognosis</h2> <p>The <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876298/">prognosis of C3G varies</a></span> and is affected by various clinical and histological factors. While some patients may have consistently low levels of protein in their urine and maintain stable kidney function over time, <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876298/">others may experience severe nephrotic syndrome</a></span> or rapidly progressive glomerulonephritis, which often leads to a poor prognosis.</p> <p>Progression to ESRD is a <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876298/">major complication of C3G</a></span>, with approximately 70% of affected children and 30%-50% of adults reaching this stage. In addition, disease recurrence is common after <span class="Hyperlink"><a href="https://emedicine.medscape.com/article/430128-overview">kidney transplantation</a></span>, with <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504691/">about 50% of patients</a></span> experiencing allograft loss within 10 years. <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876298/">Predictive factors</a></span> for disease progression, although not robustly established, include initial eGFR at diagnosis, percentage of tubular atrophy, and extent of interstitial fibrosis in the cortical area as observed on kidney biopsies.<br/><br/></p> <h2>Clinical Takeaways</h2> <p>For patients exhibiting symptoms like proteinuria and hematuria indicative of glomerulonephritis, a comprehensive evaluation including laboratory tests and a kidney biopsy is essential to confirm a C3G diagnosis through characteristic findings on immunofluorescence microscopy or electron microscopy.</p> <p>Additional tests to rule out associated conditions like monoclonal gammopathy and comprehensive complement evaluation are also recommended to understand the underlying etiology and guide therapy.<br/><br/>Though there are no treatments specifically targeting the underlying complement dysregulation unique to C3G, nonspecific therapies like ACE inhibitors, immunosuppressants (eg, MMF), and plasmapheresis are commonly used.<br/><br/>Some anticomplement therapies are available or under investigation, which might offer more targeted intervention options.<br/><br/>The prognosis for patients with C3G can vary widely and factors such as initial eGFR, the extent of tubular atrophy, and interstitial fibrosis are important predictors of disease progression.<span class="end"/></p> <p> <em>Dr. Alper is an associate professor, Nephrology, Tulane University School of Medicine, New Orleans, Louisiana. He has disclosed no relevant financial relationships.</em> </p> <p> <em>A version of this article first appeared on <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/1000656#vp_2">Medscape.com</a></span>.</em> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>