Nephrotic Syndrome - Amazon Web Services...History and Terminology oNephrotic was coined in 1905 by...

Nephrotic SyndromeGRANT GALLIMORE, MD, MAJ, USAF, MC

NEPHROLOGY CHIEF, KEESLER MEDICAL CENTER

Overviewo 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%


History and Terminologyo 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



Floege J, Feehaly J. Introduction to Glomerular Disease. In: Feehally J, Floege Jurgen, 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

http://www.elsevier.com/termsandconditions

Patient Historyo 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 infectiono HIV, Hepatitis B or C, syphilis, malaria



Examo 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






Parvovirus

Metabolic, Autoimmune, Infectious, Neoplastic, Drugs

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


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


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

http://www.elsevier.com/termsandconditions

Couser WG. Primary Membranous Nephropathy. CJASN June 2017, 12 (6) 983-997; DOI: https://doi.org/10.2215/CJN.1176111

Beck LH et al. N Engl J Med 2009; 361: 11-21.

Membranous Nephropathy

Focal Segmental Glomerulsclerosis [Internet]. [cited 2019 Jul 5]. Available from https://unckidneycenter.org/kidneyhealthlibrary/glomerular-disease/focal-segmental-glomerulosclerosis-fsgs/

FSGS light microscopy patterns

Complications and Management


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


Edema formation

o The argument for overfill theoryo 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 impairedo 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 resistanceo 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

Addition of thiazide

Addition of amiloride

Use of albumin

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



Metabolic complications

o Hyperlipidemiao 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



Metabolic complications

o Hypercoagulabilityo 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)


Infectious risk

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


Treatment

o Treatment of hypercoagulabilityo 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



Chronic kidney disease

o Progression to CKD is strongly associated with degree of proteinuriao 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



Treatment

o Preventing CKD progressiono Minimize proteinuria and control blood pressureo 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


Immunosuppression

o Primary drugs used depending on indication includeo Corticosteroids

o Cyclophosphamide

o Mycophenolate mofetil and azathioprine

o Calcineurin inhibitors (cyclosporine, tacrolimus)

o Rituximab


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