Nephrotic Syndrome

The answer first

Nephrotic syndrome is the clinical consequence of a disrupted glomerular filtration barrier producing nephrotic-range proteinuria — greater than 3.5 g per 24 hours (or a protein-to-creatinine ratio above approximately 350 mg/mmol) — accompanied by hypoalbuminaemia (albumin less than 30 g/L), peripheral oedema, and hyperlipidaemia ^[1].

Nephrotic syndrome is not a diagnosis. It is a glomerular phenotype, the way a pneumonia is a lung phenotype. Your job is to find the cause, because the cause determines the immunosuppression, cancer screen, prognosis, and the surveillance plan. ^[1]

The two clinical questions that dominate management: ^[1]

1. What is causing the protein leak, and is it a primary glomerular disease or secondary to a systemic process? Primary causes (minimal change disease, FSGS, membranous nephropathy, membranoproliferative GN) have distinct immunosuppressive pathways. Secondary causes (diabetic nephropathy, amyloidosis, lupus, viral, malignancy) require treatment of the underlying disease.
2. What complications of the nephrotic state are present or imminent, and how do I prevent them? Thromboembolism (especially renal vein thrombosis in membranous nephropathy), infection (encapsulated organisms from urinary immunoglobulin loss), hyperlipidaemia, AKI, and progressive CKD. ^[1]

The management mandate, in priority order: ^[1]

1. Confirm the nephrotic state with quantified proteinuria (24-hour protein or PCR), serum albumin, renal function, and urine microscopy. Decide whether biopsy is indicated.
2. Treat the cause — cause-specific immunosuppression for primary glomerular disease (steroids for minimal change disease, rituximab for membranous nephropathy per MENTOR ^[2]); treat the underlying systemic disease for secondary causes.
3. Reduce proteinuria with an ACE inhibitor or ARB in every patient, titrated to maximum tolerated dose. This is a renal-protective intervention independent of blood pressure.
4. Prevent and manage complications — anticoagulate when albumin is below 25 g/L (especially in membranous nephropathy), give pneumococcal and influenza vaccination, manage oedema with salt restriction and loop diuretics, treat hyperlipidaemia with a statin.
5. Protect the long-term kidney — manage volume and blood pressure, avoid nephrotoxins (NSAIDs), and surveil for progression to CKD.

The single most important exam principle: the biopsy answer, the PLA2R antibody, and the cause-by-age distribution are the three highest-yield discriminators. A child with nephrotic syndrome is treated empirically with steroids; an adult with new nephrotic syndrome is biopsied and screened for secondary causes before any immunosuppression. ^[1]

---

References9ShowHide

1. [1]Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases Kidney Int, 2021.PMID 34556256
2. [2]Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy N Engl J Med, 2019.PMID 31269364
3. [3]Dahan K, Debiec H, Plaisier E, et al. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up J Am Soc Nephrol, 2017.PMID 27352623
4. [4]Beck LH Jr, Bonegio RGB, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy N Engl J Med, 2009.PMID 19571279
5. [5]Fernández-Juárez G, Rojas-Rivera J, Logt AV, et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy Kidney Int, 2021.PMID 33166580
6. [6]Iijima K, Sako M, Nozu K, et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial Lancet, 2014.PMID 24965823
7. [7]Llach F Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome Kidney Int, 1985.PMID 3906225
8. [8]Abdelghani E, Waller AP, Wolfgang KJ, et al. Exploring the Role of Antithrombin in Nephrotic Syndrome-Associated Hypercoagulopathy: A Multi-Cohort Study and Meta-Analysis Clin J Am Soc Nephrol, 2023.PMID 36754010
9. [9]Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease Kidney Int, 2024.PMID 38490803