Nephrotic syndrome

Diagnosis of the syndrome

• Peripheral fluid overload (typically with periorbital puffiness/facial oedema, unlike orthopneic patients with cardiac failure and hypostatic fluid leak, which, associated with dislike for lying flat, tend not to have facial swelling)
• A 24 hour protein excretion greater than 3g.

Spot protein measurement (protein/creatinine ratio > 0.2 g of protein per mmol creatinine) is a convenient screening measure and is useful for follow-up. (This ratio works as a screen (with a sensitivity of only about 85%) because in patients in steady state in terms of daily creatinine output, this output is about 0.2 mmol/kg/day, or about 14 mmol creatinine per day for a 70 kg man. So a 70 kg individual with a protein/creat ratio of 0.3 would have 4.2 (14 x0 .3) g of protein in a 24 hour specimen. (The ‘magic formula’ of multiplying the protein creatinine ratio number by 10 to get the 24 hour protein excretion makes the sometimes correct assumption that the individual under consideration is excreting 10 mmol per day of creatinine… ). A more appropriate process is to adjust for age, BMI, and gender when estimating steady state creatinine excretion. The figure below is derived from a Swiss cohort:¹

The practical implication of this is that when estimating protein excretion from a spot specimen in a young male, multiplying by 20 may make more sense.

Aetiology

Minimal change, membranous and focal glomerulosclerosis are some of the commonest causes, with exact proportions varying according to the series and prevalence of HIV.

Perspective – oedema formation and its management in nephrotic syndrome

(Karl Popper argued for falsifiability as a mechanism for testing scientific theories. Mechanisms for oedema formation are fascinating examples of how medical science has stuck (for decades) with falsifiable theories in this field; the issue is how much weight one gives to the value of the traditional osmotic gradient versus “newer” alternatives. What cannot be in doubt is how rigorously a falsifiable theory is till taught in medical schools:)

Pathophysiology

The argument rests on whether one regards the underfill or overfill hypothesis as more likely or assumes that both can be at play in different clinical scenarios…. ².

The underfill hypothesis works on hypoalbuminaemia causing reduced capillary oncotic pressure and this osmotic “pull” into the interstitium results in hypovolaemia with resultant renin-aldosterone system activation and sodium and water retention. However measurements of plasma volume found it only decreased in 2% of a cohort³ and RAAS blockade with ACE inhibitors does not reverse fluid retention in this condition.

The overfill hypothesis has gained traction recently, and basically sets as the key pathophysiological step the activation of an energy dependent epithelial Na pump (eNaC) in the renal tubular cells, perhaps associated with increased aquaporin expression in the peritoneum and increased vascular permeability. The pathogenesis of eNaC activation is linked to a glomerular leak of plasminogen which, when converted into active plasmin, enzymatically activates the NaC pump, which is blocked by amiloride but not furosemide. ⁴

Role of renal biopsy

This is indicated for most patients unless the aetiology is clear from other grounds – e.g. proven myeloma, severe long-standing diabetes (no haematuria!), or suppurative lung disease with amyloid identified on subcutaneous fat or rectal biopsy. Most patients with HIV and nephrotic syndrome have focal glomerulosclerosis or HIVICK, which in general are not treatable other than by managing the HIV with anti-retroviral therapy, and with managing secondary manifestations.

Primary management

Response to corticosteroids is determined by the degree of renal scarring and fibrosis already present. Minimal change disease, and to a lesser extent, membranous GN, are steroid sensitive and focal segmental glomerulsclerosis less so, but dependent on aetiology and disease stage. Standard doses of 1 mg/kg/day of prednisone are reasonable while awaiting biopsy.⁵

Management of the secondary manifestations in nephrotic syndrome.

• Restrict salt to less than 2g per day
• Low dose furosemide (it is quite easy to over-do the diuresis. In some patients large doses may eventually be required, and sometimes, in ‘underfilled’ patients, diuresis may be initiated by furosemide infused in albumin.)
• An ACE inhibitor may reduce proteinuria and is indicated for most patients, but watch for the (rare) fall off in creatinine clearance.
• A statin to reduce the hypercholesterolaemia.
• Warfarin to keep INR between 2 and 3 (patients with nephrotic syndrome are hypercoagulable.) Initial heparin may be appropriate. (The risk of thrombotic events is increased in nephrotic syndrome, with rates of 1% to 15% per year being reported. Membranous nephropathy patients appear to be at higher risk than patients with other conditions (e.g IgA nephropathy), and an albumin below 25-30 also identifies increased risk. Pharmacokinetics of warfarin are unpredictable (increased free levels and sometimes also increased excretion) so monitor levels carefully.)⁶

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1. Forni Ogna, V., Ogna, A., Vuistiner, P. et al. New anthropometry-based age- and sex-specific reference values for urinary 24-hour creatinine excretion based on the adult Swiss population. BMC Med 13, 40 (2015). https://doi.org/10.1186/s12916-015-0275-x ↩

2. Gupta S, Pepper RJ, Ashman N, Walsh SB. Nephrotic Syndrome: Oedema Formation and Its Treatment With Diuretics. Front Physiol. 2019 Jan 15;9:1868. doi: 10.3389/fphys.2018.01868. PMID: 30697163; PMCID: PMC6341062. ↩

3. Geers, A. B., Koomans, H. A., Boer, P., and Dorhout Mees, E. J. (1984). Plasma and blood volumes in patients with the nephrotic syndrome. Nephron 38, 170–173. doi: 10.1159/000183302 ↩

4. Siddall EC, Radhakrishnan J. The pathophysiology of edema formation in the nephrotic syndrome. Kidney Int. 2012 Sep;82(6):635-42. doi: 10.1038/ki.2012.180. Epub 2012 Jun 20. PMID: 22718186. ↩

5. Canetta PA, Radhakrishnan J. The Evidence-Based Approach to Adult-Onset Idiopathic Nephrotic Syndrome. Front Pediatr. 2015 Sep 25;3:78. doi: 10.3389/fped.2015.00078. PMID: 26442238; PMCID: PMC4585181. ↩

6. Lin R, McDonald G, Jolly T, et al. A Systematic Review of Prophylactic Anticoagulation in Nephrotic Syndrome. Kidney Int Rep. 2019 Dec 12;5(4):435-447. doi: 10.1016/j.ekir.2019.12.001. PMID: 32274450; PMCID: PMC7136344. ↩

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