Nephrotic Syndrome

Home , Nephrology, Nephrotic syndrome, Uremia

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

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

Use of IV therapy

Use of albumin

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

o Hyperlipidemia o Xanthelasmas may have rapid onset o Raises concern for cardiovascular risk o Many nephrotic patients will also develop hypertension, uremia, making it difficult to isolate the cardiovascular effects of hyperlipidemia o Approximately fivefold cardiovascular risk is now accepted (except MCD) o While beneficial effect of statins in nephrotic syndrome is not proven prospectively, they are generally indicated based on cardiovascular risk

o Hypercoagulability o Thromboembolism occurs in up to 10% of nephrotic adults o Abnormal levels of multiple coagulation proteins o Enhanced platelet aggregation o Immobility, hemoconcentration, incident infections o Highest risk in membranous nephropathy o Higher risk in patients with albumin <2g/dL o Renal vein thrombosis in 10-50% (if sought systematically)

o Large fluid collections, fragile skin, and dilution of local humoral immune factors all play a role o Loss of IgG, complement factor B, zinc and transferrin in urine o Neutrophil phagocytic function is impaired o Primary peritonitis due to pneumococci is characteristic in children. β-hemolytic streptococci and gram-negatives may also be causative o Cellulitis by β-hemolytic streptococci is also common

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 Treatment

o Treatment of hypercoagulability o Risk for thrombotic events increases with degree of hypoalbuminemia o Full-dose anticoagulation (low-molecular-weight heparin or warfarin) should be strongly considered for albumin <2g/dL o Treatment of infection o ESR is not helpful, but CRP may raise suspicion o Regimen should include coverage for pneumococcus o If repeated infections occur, measure immunoglobulins

o Progression to CKD is strongly associated with degree of proteinuria o Uncommon progression if proteinuria <2g/day o Marked risk for progression if proteinuria >5g/day o Severe proteinuria identifies glomerular injury, but experimental and clinical evidence suggests proteinuria is harmful to tubulointerstitium

o Preventing CKD progression o Minimize proteinuria and control blood pressure o Consider ACE/ARB as well as nondihydropyridine calcium channel blockers o Low dose aldosterone antagonist may overcome aldosterone breakthrough o Lifestyle modification including sodium restriction, weight normalization o Avoid monotherapy with dihydropyridine calcium channel blocker due to risk for afferent arteriolar dilatation, worsened proteinuria and progression o Avoid nephrotoxic agents

o Primary drugs used depending on indication include o Corticosteroids o Cyclophosphamide o Mycophenolate mofetil and azathioprine o Calcineurin inhibitors (cyclosporine, tacrolimus) o Rituximab

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 Questions?