Nephrotic Syndrome GRANT GALLIMORE, MD, MAJ, USAF, MC NEPHROLOGY CHIEF, KEESLER MEDICAL CENTER Overview o History and terminology o Major causes of nephrotic syndrome and prevalence o Patient presentation, history and exam o Laboratory and imaging based on potential etiology o Selected pathology and microscopy o Complications and management History and Terminology o Nephrotic was coined in 1905 by Friedrich von Müller, a distinguished German Pathologist o The term nephrotic syndrome is attributed to Louis Leiter of the University of Chicago, using the term in a widely read review in 1930 o Percutaneous renal biopsy was introduced in 1951, resulting in description of many distinct disease entities Glassock RJ, Fervenza FC, Hebert L, Cameron JS. Nephrotic syndrome redux. Nephrology Dialysis Transplantation. 2014;30(1):12–7. History and Terminology o Berman and Schreiner 1958 biopsy series threshold of 3.5g/24h was determined o All patients had hypoalbuminemia and oval fat bodies in urine o Edema was absent in 27% and hyperlipidemia absent in 25% Glassock RJ, Fervenza FC, Hebert L, Cameron JS. Nephrotic syndrome redux. Nephrology Dialysis Transplantation. 2014;30(1):12–7. History and Terminology o Definition should be based on 24h urine excretion of protein rather than albumin, although 60-90% of proteinuria should be albumin o Many conditions can give rise to nephrotic range proteinuria but not to nephrotic syndrome o With preserved albumin, responsible lesions are likely to result from secondary processes like hyperfiltration, obesity, nephron loss o For example, the majority of African Americans with FSGS have nephrotic-range proteinuria but not nephrotic syndrome Glassock RJ, Fervenza FC, Hebert L, Cameron JS. Nephrotic syndrome redux. Nephrology Dialysis Transplantation. 2014;30(1):12–7. Glassock RJ, Fervenza FC, Hebert L, Cameron JS. Nephrotic syndrome redux. Nephrology Dialysis Transplantation. 2014;30(1):12–7. Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Sara Conti, Norberto Perico, et al. Early and late scanning electron microscopy findings in diabetic kidney disease. Scientific Reports 8, Article number: 4909 (2018) https://doi.org/10.1038/s41598-018-23244-2 Sara Conti, Norberto Perico, et al. Early and late scanning electron microscopy findings in diabetic kidney disease. Scientific Reports 8, Article number: 4909 (2018) https://doi.org/10.1038/s41598-018-23244-2 Figure 3 American Journal of Kidney Diseases 2015 66, 376-377DOI: (10.1053/j.ajkd.2015.04.006) Copyright © 2015 National Kidney Foundation, Inc. Terms and Conditions Patient History o Wide spectrum varying from asymptomatic to life-threatening disease o The following historical elements may be relevant: oSystemic disease o SLE, RA, Crohn’s, DM, HTN, obesity, nephron loss, frequent UTI o Family history o FSGS, complement disorders o Medications o NSAIDs, interferon, bisphosphonates o History of malignancy o Breast, lung, gastrointestinal, lymphoma o History of infection o HIV, Hepatitis B or C, syphilis, malaria Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Exam o Edema is often periorbital in the morning (no orthopnea) o This is in contrast to heart failure (pulmonary congestion producing orthopnea) and cirrhosis (diaphragmatic pressure from ascites) o Massive weight gain is common, with fluid overload including ascites, pleural effusions, abdominal and genital edema o Muehrcke lines and xanthelasma may be seen o Palpable purpura in vasculitis, SLE, cyroglobulinemia Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Parvovirus Metabolic, Autoimmune, Infectious, Neoplastic, Drugs Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Laboratory o Consider serology for Hepatitis B (MN) and C (MPGN), HIV (FSGS) o Low C3/C4 may be seen in SLE, MPGN, infection-associated, dense deposit disease, HUS o ANA to screen SLE as a cause of membranous o RF may be positive due to RA (MN, amyloid) or cryoglobulinemia o SPEP and serum free light chains may reveal paraprotein-associated disease whether myeloma, amyloidosis, or others Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Imaging o Ultrasound scanning to ensure 2 kidneys, rule out obstruction or anatomic abnormalities o Large kidneys (>14cm) may suggest diabetic nephropathy, amyloid disease, HIV, acute severe GN, or AIN o Small kidneys (<9cm) and/or cortical thinning should limit enthusiasm for biopsy or aggressive immunosuppression Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Figure 2 American Journal of Kidney Diseases 2015 66, 376-377DOI: (10.1053/j.ajkd.2015.04.006) Copyright © 2015 National Kidney Foundation, Inc. Terms and Conditions Couser WG. Primary Membranous Nephropathy. CJASN June 2017, 12 (6) 983-997; DOI: https://doi.org/10.2215/CJN.1176111 Membranous Nephropathy Beck LH et al. N Engl J Med 2009; 361: 11-21. FSGS light microscopy patterns Focal Segmental Glomerulsclerosis [Internet]. [cited 2019 Jul 5]. Available from https://unckidneycenter.org/kidneyhealthlibrary/glomerular-disease/focal-segmental-glomerulosclerosis-fsgs/ Complications and Management Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Edema formation o Overfill is actually much more common than underfill o This seems to be related to activation of the epithelial sodium channel (ENaC) by proteolytic enzymes in tubular lumen o Leads to increased blood volume, RAAS suppression, tendency to hypertension o Increased blood volume with low oncotic pressure leads to transudation of fluid into interstitium Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Edema formation o The argument for overfill theory o Individuals lacking serum albumin often do not have sodium retention o During recovery, natriuresis occurs prior to improvement in hypoalbuminemia o IV albumin does not consistently improve natriuresis o Studies with radioactive albumin have demonstrated low plasma and blood volumes in as few as 2% of cases o Adrenalectomized rats with nephrotic syndrome have sodium retention o Proteases such as plasminogen have been shown to activate ENAC Ray, E. C., Rondon-Berrios, H., Boyd, C. R., & Kleyman, T. R. (2015). Sodium Retention and Volume Expansion in Nephrotic Syndrome: Implications for Hypertension. Advances in Chronic Kidney Disease, 22(3), 179-184. doi:10.1053/j.ackd.2014.11.006 Treatment of edema o Diuretic efficacy is likely to be impaired o Transport from peritubular capillaries requires protein binding o Increased protein binding in tubular lumen limits access to transporters o Gastrointestinal absorption may be limited o Ways to overcome diuretic resistance o Use of IV therapy o Use of thiazide in addition to loop diuretic with close monitoring o Addition of amiloride (ENaC highly relevant to pathophysiology) o Consideration of IV albumin Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Addition of thiazide Addition of amiloride Use of IV therapy Use of albumin Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Response to hypoalbuminemia o Increased protein synthesis is not discriminating, as the synthesis of many proteins other than albumin is upregulated o This includes large molecular weight proteins that are not filtered and may actually increase in concentration o This has implications for both hyperlipidemia and hypercoagulability Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen, Tonelli M, Johnson RJ. Comprehensive clinical nephrology. Edinburgh: Elsevier; 2019. p. 184-98 Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jürgen,