#250 Nephrotic Syndrome vs. Glomerulonephritis with Kidney Boy, Dr. Joel Topf

January 11, 2021 | By Elena Gibson

Kashlak’s esteemed Chief of Nephrology, Dr Joel Topf @kidney_boy walks us through the evaluation and differentiation of nephrotic syndrome and glomerulonephritis. Embrace the kidney again as we sort the different diagnostics, managements, and prognosis for these two pathologies.

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Credits

• Producer, writer, infographic, cover art: Elena Gibson MD
• Hosts: Elena Gibson MD, Stuart Brigham MD; Matthew Watto MD, FACP; Paul Williams MD, FACP  
• Editor: Emi Okamoto MD (written); Clair Morgan of nodderly.com (audio)
• Guest: Joel Topf MD

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Time Stamps*

*Note: Time Stamps refer to ad free version

• Intro, disclaimer, guest bio – 00:00
• Picks of the Week – 3:10
• Case from Kashlak – 6:30
• Nephrotic syndrome definition- 12:30
• Proteinuria evaluation – 15:04
• Additional lab testing – 27:08; 40:09
• Types of Nephrotic syndrome – 30:15
• Mechanism of nephrotic syndrome edema – 33:08
• Management of nephrotic syndrome – 44:07
• Second Kashlak Case- Glomerulonephritis – 55:05
• Treatment of glomerulonephritis – 65:05
• Outro and post-credits scene – 73:20

Nephrotic syndrome and Glomerulonephritis Pearls

1. Nephrotic syndrome (NS) is defined by the presence of the following: 1) proteinuria >3.5g in 24 hours or >2 g/g  spot protein/creatinine 2) hypoalbuminemia  < 2.5 g/dl and 3) peripheral edema 
2. Hyperlipidemia and hypercoagulability are characteristics  of nephrotic syndrome though they are not part of the definition
3. A spot urine protein/creatinine can be used to measure proteinuria and diagnose NS, but a 24 hour urine remains the gold standard 
4. Spot urine albumin/creatinine ratio should be used in the setting of DM and CV disease 
5. The initial lab evaluation for NS should include: ANA, SPEP/UPEP, hepatitis C & B serologies, HIV testing, anti-PLA2R 
6. Anti-PLA2R is an antibody to the antigen that causes most cases of primary membranous nephropathy and it is helpful in the diagnosis, treatment and monitoring of disease 
7. Glomerulonephritis (GN) is associated with acute kidney injury (AKI), hypertension and proteinuria/hematuria/pyuria
8. Three categories of rapidly progressive GN include pauci-immune, immune complex and anti-GBM 
9. Treatment of several types of glomerulonephritis, as for lupus nephritis, is diagnosis specific. Some diseases like IgA have no proven therapies while others like SLE use mycophenolate mofetil or cyclophosphamide. Plasma exchange is part of the therapy for Goodpasture disease.

Nephrotic Syndrome & Glomerulonephritis Notes 

Nephrotic syndrome

1. Nephrotic syndrome (NS) is defined by 
2. proteinuria 3.5g in 24 hours or >2 g/g  spot protein/creatinine 
3. peripheral edema (only clinical sign)
4. hypoalbuminemia < 2.5 g/dl
   *Also frequently associated with hyperlipidemia and hypercoagulability (KDIGO 2012;Kodner 2016)

Initial Evaluation 

Rule out other causes of edematous states: Consider the heart, and liver, and kidneys to make sure you aren’t missing heart failure or cirrhosis. Watch for rapid progression, hypertension, and prominent hematuria (including casts and dysmorphic rbc) to consider a nephritic syndrome.

Quantify proteinuria: The gold standard for measurement of proteinuria is a 24 hour urine collection, but spot protein/creatinine and albumin/creatinine ratios provide fast alternatives to detect proteinuria from glomerular disease (Price et al 2005). Dr Topf recommends using a spot protein/creatinine of > 2g/g as a cutoff for further evaluation with a nephrology consultation and possible biopsy. Gram to gram comparisons of spot ratios to 24-hour collections assume there is approximately 1 gram of creatinine excretion in a 24-hour period.  However, many people will excrete more than 1.5g in a 24-hour period. If creatinine excretion is much >1 gram, the spot ratio will underestimate proteinuria and if it is much <1 gram, it will overestimate proteinuria (Carter et al 2012). 

A urine dipstick only measures albumin, and urine concentration can significantly influence results. In glomerular disease (NS/glomerulonephritis) the dominant protein in the urine is albumin, but a protein/creatinine ratio or a 24 hour urine will provide increased precision. For DM, microvascular disease, CV risk measurement of albumin is most helpful as it provides a  more standardized measurement across institutions (AACC 2018) . 

Additional labs : After a diagnosis of NS is made, Dr Topf recommends the following additional lab workup aimed at identifying the etiology of NS: SPEP/UPEP (multiple myeloma), ANA (lupus), hepatitis C serology (Membranoproliferative glomerulonephritis, cryoglobulinemia), hepatitis B serology (membranous nephropathy), HIV screening  (collapsing FSGS), and anti-PLA2R (idiopathic membranous nephropathy). An anti-phospholipase A2 receptor (PLA2R) titer measures autoantibodies responsible for 70-80% of idiopathic membranous nephropathy. The test was identified in 2009 and can be used for diagnosis, prognosis and monitoring in patients with idiopathic membranous nephropathy(Beck et al 2009). In addition to labs aimed at evaluating the etiology of NS, Dr. Topf recommends a CBC and PT/PTT before a renal biopsy is completed.

Edema, is it underfill or overfill?

The underfill hypothesis was classically used to describe the pathophysiology of edema in NS, but there is now more support and evidence for the overfill hypothesis (Siddall & Radhakrishnan 2012; Chen et al 2019). 

Underfill hypothesis: loss of albumin in the serum leads to decreased plasma oncotic pressure and increased fluid movement into the interstitium. The blood vessels are then “underfilled” leading to secondary sodium retention via activation of the renin-angiotensin-aldosterone system (RAAS).

Overfill hypothesis: primary renal sodium retention, independent of blood volume levels or albumin. Serum plasminogen gets activated to plasmin and this activates the epithelial sodium channel in the distal nephron to reabsorb sodium (Chen et al 2019). One line of evidence for the validity of the overfill hypothesis is the natural history of minimal change disease. Steroids result in rapid resolution of proteinuria and edema in minimal change disease. There is improvement in edema prior to increased albumin levels (Siddall & Radhakrishnan 2012). 

Causes of Nephrotic syndrome 

Dr. Topf initially categorizes the causes as DM vs. “other” given the prevalence of diabetic nephropathy (Boer et al 2011; Hass et al 1997). Other causes of NS include membranous, focal segmental glomerulosclerosis (FSGS), minimal change disease, light chain deposition, amyloidosis, and preeclampsia in pregnancy. Membranous, FSGS, and  minimal change disease are primary glomerular pathology conditions. Dr Topf recommends categorizing NS as primary or secondary after getting a pathologic diagnosis with a biopsy. For example,  once a biopsy leads to the diagnosis of membranous nephropathy, an evaluation of primary vs. secondary causes of membranous nephropathy should be completed.

General Management 

Edema: Managed with loop diuretics and sodium restriction (see diet). Dr. Topf recommends watching for diuretic resistance and the need for higher doses than expected. In theory, adding amiloride could help by targeting the epithelial sodium channels , but the evidence to support this is limited to case reports (Henrichs 2018). 

Diet: Sodium restriction (1.5 to 2 g per 24 hours) is recommended, and most studies on RAAS inhibition have been completed in the setting of concomitant sodium restriction to help control edema (KDIGO 2012). KDIGO guidelines also recommend a low protein diet (0.8-1.0g/kg daily), but Dr. Topf recommends focusing on sodium restriction first. 

Hyperlipidemia: Statins are recommended for patients based on usual CV risk guidelines (KDIGO 2012). Dr. Topf discontinues statin therapy with resolution or remission of NS, unless indicated for another reason. 

Proteinuria: Initiation of an ACE or ARB is recommended to reduce proteinuria and/or treat hypertension in NS (RENALL trial; KDIGO 2012). 

Hypercoagulability: NS patients are at increased risk of venous thromboembolism (VTE), particularly those with membranous nephropathy. Hypercoagulability risk increases with decreased albumin levels (<2.5g/dl). Dr. Topf recommends using the GN Tools calculator from the University of North Carolina to help with weighing the risks and benefits of anticoagulation. The  KDIGO guidelines recommend considering therapeutic anticoagulation in patients with additional increased risk factor for thrombosis including heavy proteinuria >10g/d,  BMI >35, family history of genetic VTE, congestive heart failure NYHA stage III or IV, prolonged immobilization, or recent surgery. If indicated, warfarin is recommended for anticoagulation (KDIGO 2012). 

Prognosis 

1. Diabetic nephropathy has a poor prognosis with loss of approximately 4-6ml/min of renal function per year, so in 10 years patients often progress to ESRD. The rate of decline can be improved with RAAS inhibition (Umanath & Lewis 2018) and SGLT2i.
2. Minimal change disease: excellent prognosis with rapid response to steroids. There is a high rate of relapse but patients usually respond equally well to steroids during a relapse (KDIGO 2012).
3. FSGS: variable prognosis with a 10-year risk of ESRD ranging from 40-70% and improved if remission is achieved (KDIGO 2012; Wehrmann et al 1990). Steroids, cyclosporine, and tacrolimus are used for treatment with variable response. Dr. Topf describes new experimental therapies that warrant referral to a center with available trial enrollment for interested patients. 
4. Membranous nephropathy: Dr. Topf describes how ~1/3 will have spontaneous remission, ~1/3 have lasting smoldering proteinuria with relatively stable renal function, and ~1/3  have aggressive progressive disease that requires treatment with cyclophosphamide and steroids.

Glomerulonephritis 

The three elements of glomerulonephritis (GN) include: (Atkins et al 2005)

1. AKI
2. Hypertension 
3. Hematuria/Proteinuria/Pyuria 

Evaluation

First, Dr Topf recommends looking for hematuria, proteinuria or pyuria with a urinalysis and evaluating the AKI timeline. In addition to labs sent for the workup of NS,  Dr Topf recommends: C3/C4, ANCA, cryoglobulins, and anti-glomerular basement membrane (GBM) testing. Dr. Topf describes 3 categories of rapidly progressive GN 

1. Pauci immune GN: ANCA associated small vessel vasculitis
2. Anti-glomerular basement membrane (GBM): autoantibodies against the glomerular basement membranes 
3. Immune complex GN: lupus nephritis (has wide range of presentations), IgA nephropathy, membranoproliferative, post infectious 

GN Treatment 

• Lupus nephritis: Standard regimens for treatment of class III-IV often include mycophenolate mofetil or cyclophosphamide and steroids. Responses to initial treatment with mycophenolate or cyclophosphamide are similar and either are recommended first line (Parikh 2020). 
• IgA nephropathy: not clearly defined. Usually steroids, but a couple of studies have found that they are not very effective.
• Infectious GN (post strep, staph, endocarditis): treat the primary infection and this should resolve.
• ANCA associated GNs:  classically treated with steroids, cyclophosphamide and plasma exchange (PLEX). However PEXIVAS, a 2×2 trial comparing PLEX vs. no PLEX and high dose steroids vs. lower doses found no mortality or ESRD benefit with PLEX or high dose steroids (Walsh et al 2020).
• Anti-GBM (Goodpasture’s):  PLEX  to remove the basement membrane antibodies.

Links*

1. Counterpart Show– seasons 1&2 (correction: on Amazon Prime!) 
2. 007 Aston Martin Lego Set 
3. Blacklist – on Amazon Prime (paid) and Netflix
4. Tiny Desk Concerts 
5. Relevant Prior Curbsiders Episodes 
   1. #67 Chronic Kidney Disease Pearls with @kidney_boy 
   2. #226 AKI
6. GN Tools UNC

Goal

Listeners will develop an approach to the basic evaluation and initial management of nephrotic syndrome and glomerulonephritis. 

Learning objectives

After listening to this episode listeners will…  

1. Define nephrotic syndrome 
2. Recognize when and how to use a protein to creatinine ratio 
3. Identify the various etiologies of nephrotic syndrome
4. Review the management of nephrotic syndrome and its complications 
5. Develop an approach to evaluating glomerulonephritis 
6. Identify relationships between etiologies of nephritic syndrome and lab testing
7. Define rapidly progressive glomerulonephritis and its clinical implications 
8. Recognize basic treatment options for nephrotic syndrome and glomerulonephritis 

Disclosures

Dr Topf reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Gibson E, Topf J, Williams PN, Brigham SK, Okamoto E, Watto MF. “#250 Nephrotic Syndrome vs. Glomerulonephritis with Kidney Boy, Dr Joel Topf”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list Final publishing date January 11, 2021.