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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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.
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).
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.
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.
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).
The three elements of glomerulonephritis (GN) include: (Atkins et al 2005)
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
Listeners will develop an approach to the basic evaluation and initial management of nephrotic syndrome and glomerulonephritis.
After listening to this episode listeners will…
Dr Topf reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
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.
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