Nephrology Hypertension

Glomerular and Vascular Diseases: Minimal Change Disease & Focal segmental Glomerulosclerosis

Does this patient have minimal change disease and focal segmental glomerulosclerosis?

Presentation

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) present with symptoms and signs of the nephrotic syndrome, characterized by edema, heavy proteinuria (greater than 3 g/day), hypoalbuminemia, and hyperlipidemia. Patients may complain of foamy or frothy urine. Hypertension and microscopic hematuria may be present. The onset of the nephrotic syndrome is typically abrupt in MCD, whereas the progression of proteinuria in FSGS categorized as secondary may occur over years. Nephrotic-range proteinuria increases the risk for acute kidney injury, thrombosis, and infections, which may be present or develop after diagnosis.

Epidemiology

MCD is the most common cause of pediatric nephrotic syndrome but accounts for less than 15% of adult nephrotic syndrome. MCD may be idiopathic or develop in association with other pre-existing diseases or drugs. Common disease associations are hematologic malignancies and atopy, whereas rare disease associations are solid tumors, syphilis, tuberculosis, HIV, HCV, mycoplasma, erlichiosis, echinococcus, systemic lupus erythematosus, diabetes, polycystic kidney disease, graft-versus-host-disease, sclerosing cholangitis, sarcoidosis, Graves' disease, thyroiditis, vasculitis, myasthenia gravis, Guillain-Barre syndrome, dermatitis herpetiformis, primary biliary cirrhosis, and antiphospholipid syndrome. Drug associations include non-steroidal anti-inflammatory drugs (NSAIDS. most common), lithium, ampicillin, cephalosporins, rifampicin, penicillamine, bisphosphonates, mesalazine, salazopyrine, trimethadone, and interferons.

FSGS accounts for up to 35% of nephrotic syndrome in adults but is much rarer in children. FSGS may be idiopathic, familial/genetic, or develop in association with other pre-existing diseases or drugs. FSGS that is associated with reflux nephropathy, hypertension, partial nephrectomy, severe preeclampsia, obesity, or other glomerular diseases is often termed secondary FSGS. Secondary FSGS and familial FSGS do not typically respond to steroids or other immunosuppressives. Drug associations include anabolic steroids, interferons, and heroin.

What tests to perform?

Renal biopsy

A renal biopsy is required to diagnose MCD (Figure 1) and FSGS, as almost any glomerular disease can develop proteinuria greater than 1 g/day. Since MCD is the most common cause of pediatric nephrotic syndrome, children are often biopsied only after failing empiric treatment for MCD. Renal pathologists may describe FSGS as one of following five morphologic variants: classic (Figure 2), hilar (Figure 3), tip (Figure 4), cellular (Figure 5), or collapsing (Figure 6). Typically, the collapsing and tip variants have more proteinuria at the time of biopsy than the other variants of FSGS.

Figure 1.

Electron micrograph showing extensive foot process effacement (arrowheads) in MCD. Spiral arrows point to microvillous transformation of podocytes.

Figure 2.

FSGS, classic variant showing obliterated capillary loops (*), hyaline deposition, and adhesion of tuft to Bowman’s capsule.

Figure 3.

FSGS, hilar variant showing segmental sclerosis at the vascular pole (*).

Figure 4.

FSGS, tip variant showing segmental sclerosis (arrow) at the glomerulotubular junction (*)

Figure 5.

FSGS, cellular variant showing foam cells (arrowhead) infiltrating capillary loops of sclerotic segment and prominent overlying podocytes (spiral arrow).

Figure 6.

FSGS, collapsing variant showing collapse of capillary loops and proliferation of glomerular epithelial cells (*).

Laboratory testing before diagnosis

Urinalysis; total protein in a 24 hour urine collection or total protein-to-creatinine ratio in a random spot urine sample; serum creatinine; serum albumin; and serum lipids. In conjunction with renal biopsy, additional screening laboratory testing helps to exclude other glomerular diseases causing proteinuria and include the following: serum and urine protein electrophoresis and immunofixation, serum free light chains, anti-nuclear antibodies, C3, C4, cryoglobulins, and viral serologies for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV).

Laboratory testing after diagnosis

Once the diagnosis of MCD or FSGS is made by renal biopsy, the degree of proteinuria and the serum creatinine are followed at 2- to 4-week intervals to assess the response to treatment. Full remission is often defined as a reduction in proteinuria to less than 300 mg/day. Partial remission is often defined as a reduction in proteinuria by 50% and to less than 3.5 g/day. Relapse is often defined as a return in proteinuria to greater than 3.5 g/day. An increase in serum creatinine indicates worsening renal insufficiency and is more probable if complete or partial remission is not achieved with treatment.

Interpretation of tests

Urinalysis shows no active sediment, with the 24-hour urine protein greater than 3 g or spot urine total protein-to-creatinine ratio greater than 3 g/g indicating nephrotic-range proteinuria. Serum albumin may be less than 3 g/dL, and hyperlipidemia may be present. Additional laboratory tests may suggest the presence of other glomerular diseases; however, the renal pathologist determines on biopsy whether MCD, FSGS, or another glomerular disease is responsible for the patient’s proteinuria.

Controversies in diagnostic testing

Debate exists as to whether the morphologic variants of FSGS represent the same general glomerular disease. The differing response to treatment suggests that the variants of FSGS are not the same disease.

How should patients with minimal change disease and focal segmental glomerulosclerosis be managed?

Treatment

MCD is highly responsive to steroids, which is first-line treatment. Almost all children respond within 2 months after initiating steroid treatment, whereas up to 95% of adults respond within 4 months. Failure to remit, relapse after remission, or intolerance to steroids may require second-line treatment with cyclophosphamide or cyclosporine.

First-line treatment for FSGS not categorized as secondary is steroids, with responses differing amongst the variants of FSGS. Adults failing to show evidence of remission within 4-6 months, relapse after remission, or are intolerant of steroids may require second-line treatment with cyclosporine or mycophenolate mofetil (MMF). The collapsing and cellular variants of FSGS are more refractory to treatment than the other variants of FSGS, whereas the tip variant of FSGS is highly responsive to steroids. Secondary FSGS typically does not respond to immunosuppressives and therefore these drugs are not used.

Elimination of associated diseases or drugs may lead to remission of MCD and FSGS and should always be a goal of treatment.

Management of the complications of nephrotic syndrome includes diuretics for the edema, ACE inhibitors for hypertension, statins for hyperlipidemia, and therapy for thromboembolic events.

What happens to patients with minimal change disease and focal segmental glomerulosclerosis?

Prognosis

The prognosis of MCD and FSGS is linked to the response to treatment. Patients that fail to remit or relapse after remission are at risk for the complications of nephrotic syndrome and progression to end-stage renal disease. The collapsing and cellular variants of FSGS carry a worse prognosis than other variants of FSGS.

How to utilize team care?

Nephrologist

The diagnosis and treatment of MCD or FSGS is done under the consultation and care of a nephrologist.

Renal pathologist

The tissue diagnosis of MCD or FSGS following renal biopsy is done by a renal pathologist.

Other providers

Primary care providers, physician assistants, and nurses assist nephrologists through laboratory screening and assessing patients for disease and treatment complications of MCD and FSGS.

Are there clinical practice guidelines to inform decision making?

The 2012 KDIGO Clinical Practice Guideline for Glomerulonephritis provides recommendations for the treatment of MCD and FSGS.

Other considerations

  • ICD-10 code for MCD: N04.0

  • ICD-10 code for FSGS: N04.0

What is the evidence?

Cameron, JS. "The nephrotic syndrome and its complications". Am J Kidney Dis. vol. 10. 1987. pp. 157.

(This is a classic review article describing key features of the nephrotic syndrome.)

Meyrier, A, Niaudet, P, Davison, AM, Cameron, JS, Grünfeld, E. "Minimal change disease and focal-segmental glomerulosclerosis". Oxford Textbook of Clinical Nephrology. vol. vol. 1. Oxford University Press. 2005.

(A book chapter that comprehensively describes clinical features of minimal change disease and focal segmental glomerulosclerosis.)

Schnaper, HW, Robson, AA, Kopp, JB, Schrier, RW. "Nephrotic syndrome: minimal change nephropathy, focal segmental glomerulosclerosis, and collapsing glomerulopathy". Diseases of the Kidney and Urinary Tract. Lippincott Williams & Wilkins. 2007.

(Another book chapter that covers clinical features of minimal change disease and focal segmental glomerulosclerosis. A section on the the collapsing variant of focal segmental glomerulosclerosis is included.)

Glassock, RJ. "Secondary minimal change disease". Nephrol Dial Transplant. vol. 18. 2003. pp. vi52.

(An important review article that indicates features and considerations for secondary causes of minimal change disease.)

Waldman, M, Crew, RJ, Valeri, A, Busch, J, Stokes, B, Markowitz, G, D'Agati, V, Appel, G. "Adult minimal-change disease: clinical characteristics, treatment, and outcomes". Clin J Am Soc Nephrol. vol. 2. 2007. pp. 445.

(A retrospective review of 95 adults with MCD seen at a single referral center. Features examined were: response to daily versus alternate-day steroids, response to second-line agents, relapse patterns, complications of the disease and therapy, presence of acute renal failure, and clinical outcome data.)

Meyrier, A, Molony, DA, Craig, JC. "Management of idiopathic nephrotic syndrome in adults: Minimal change disease and focal segmental glomerulosclerosis". Evidence-Based Nephrology. Wiley-Blackwell. 2009.

(A book chapter focused on clinical treatment of patients with nephrotic syndrome attributable to minimal change disease and focal segmental glomerulosclerosis.)

D'Agati, V. "Pathologic classification of focal segmental glomerulosclerosis". Semin Nephrol. vol. 23. 2003. pp. 117.

(This paper reviews the current pathological system for classifying focal segmental glomerulosclerosis.)

Thomas, DB, Franceschini, N, Hogan, SL, Ten Holder, S, Jennette, CE, Falk, RJ, Jenette, JC. "Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants". Kidney Int. vol. 69. 2006. pp. 920.

(Histologic variants of idiopathic focal segmental glomerulosclerosis (FSGS) may have prognostic value. A recent working classification system has distinguished five FSGS variants. This retrospective study evaluated a cohort of adult patients with biopsy-proven FSGS diagnosed between March 1982 and July 2001 to determine how subtypes associate with clinical outcomes.)

Chun, MJ, Korbet, SM, Schwartz, MM, Lewis, EJ. "Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants". J Am Soc Nephrol. vol. 15. 2004. pp. 2169.

(The diagnosis of primary focal segmental glomerulosclerosis (FSGS) includes a number of histologic variants, but the prognostic significance of these different lesions is controversial. A retrospective analysis was conducted in 87 nephrotic adult patients with biopsy-proven primary FSGS categorized on the basis of histologic criteria into those with a classic scar, the cellular or collapsing lesion, or the tip lesion to evaluate differences in presentation, response to therapy, and clinical outcomes.)

Pollak, MR. "The genetic basis of FSGS and steroid-resistant nephrosis". Semin Nephrol. vol. 23. 2003. pp. 141.

(Studies of Mendelian forms of focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome have provided insights into disease mechanisms. Congenital nephrotic syndrome has been linked to mutations in genes for nephrin, while familial forms of FSGS are associated with mutations in podocin and actin. FSGS may also be part of several rare multi-system inherited syndromes. This paper reviews the genetic basis of FSGS in humans.)
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