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Nephrology - Glomerular Diseases - Fast Facts | NEJM Resident 360

A full review of glomerular diseases is beyond the scope of this rotation guide. We provide a brief overview of the classification of glomerular disease and details about the common associated conditions you will see and treat on the wards.

Glomerular diseases are often divided into nephrotic and nephritic syndromes, based on the urine sediment and degree of proteinuria. However, overlap is extensive. Glomerular disease can also be defined as primary disease or as a secondary feature of another glomerulonephritis or systemic disease. Some entities (e.g., lupus, nephritis, and nephritis associated with hepatitis C) can present with nephrotic and/or nephritic features.

Nephrotic Syndrome

Signs and Symptoms

Nephrotic syndrome is defined by a combination of classic signs and symptoms:

• edema

• nephrotic-range proteinuria (>3.5 gm/day on 24-hour collection or spot protein/creatinine ratio)

• hypoalbuminemia (<3 g/dL)

• hyperlipidemia

Some forms of nephrotic syndrome are primary and others may be noted during the course of a systemic disease (e.g., lupus). The pathologic diagnosis from a biopsy should prompt the clinician to search for an underlying cause (e.g., a biopsy showing membranous nephropathy should prompt the clinician to rule out malignancy), because appropriate treatment depends on the underlying causes.

Classification of Nephrotic Syndrome

The major forms of nephrotic syndrome, based on biopsy:

• minimal-change disease (more common in children) — primary and secondary (e.g., as a paraneoplastic condition)

• focal segmental glomerulosclerosis (FSGS) — primary and secondary (e.g., HIV, toxins, vasculitis, lupus)

• membranous nephropathy — primary (now associated with certain antiibodies, most commonly to the M-type phospholipase A2 receptor [PLA2R] and thrombospondin type 1- domain-containing 7A [THSD7A]) and secondary (e.g., associated with hepatitis B and C, nonsteroidal anti-inflammatory drugs [NSAIDS], lupus, malignancy)

• diabetes mellitus (diabetic nephropathy)

• amyloidosis

• lupus

Management

Treatment of the specific form of nephrotic syndrome with resolution of signs and symptoms may be feasible. Treatment of nephrotic syndrome per se focuses on specific physiological and biochemical abnormalities of nephrotic syndrome such as hypercoagulability, proteinuria and hyperlipidemia.

• Treatment with ACE inhibitors or angiotensin receptor blockers (ARBs) can lower intraglomerular pressure and reduce proteinuria. However, patients may experience adverse events such as hypotension or hyperkalemia. Loop diuretics may be started to reduce symptoms of edema.

• Hyperlipidemia can be treated with a statin; A change in diet is unlikely to bring the hyperlipidemia under control. There may be resolution of hyperlipidemia once the nephrotic syndrome responds to therapy.

• Among patients with membranous nephropathy and other types of nephrotic syndrome, the risk of arterial and venous thromboembolism is higher than normal, but anticoagulation may not prevent half or more of the possible episodes. Therefore, prophylactic anticoagulants may be considered on a case-by-case basis.

The risks of infection also need to be considered, and the KDIGO guidelines recommend that vaccinations such as the influenza and pneumococcal vaccination be current. Live vaccines are contraindicated if patients receive immunosuppressive agents and should not be administered until the prednisone dose is <20mg/day or the immunosuppressive therapy has been stopped for 3 months.

Nephritic Syndrome

Signs and Symptoms

• hypertension

• hematuria

• proteinuria

• rapidly progressive azotemia (elevated blood urea nitrogen [BUN] and creatinine levels)

Classification

In 2016, renal pathologists and nephrologists established an etiology/pathogenesis-based system to classify types of glomerulonephritis. The five main pathogenic types and examples of conditions for each type are listed in the table below.

Classification of Glomerulonephritis

Pathogenic Type	Examples of Conditions
Immune-complex

• IgA nephropathy

• IgA vasculitis (Henoch–Schönlein purpura)

• Postinfectious nephritis

• Lupus nephritis

• Hepatitis C

• Fibrillary glomerulonephritis

| | Pauci-immune |

• Microscopic polyangiitis

• Granulomatosis with polyangiitis (formerly Wegener granulomatosis)

• Eosinophilic granulomatosis with polyangiitis (formerly Churg–Strauss syndrome)

• Polyarteritis nodosa

| | Anti–glomerular
basement
membrane | Goodpasture syndrome | | Monoclonal
immunoglobulin | Cryoglobulin-associated nephritis (e.g., Waldenström macroglobulinemia)

Other rare glomerulonephritides (e.g., fibrillary and immunotactoid glomerulonephritis) | | C3 | C3 glomerulonephritis

Dense deposit disease |

(Reference: Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN. JASN 2016.)

Management

The main issues related to management of nephrotic syndrome (i.e., treatment of proteinuria, hypertension and hypercoagulability) are also important for various glomerulonephritides. Treatment with glucocorticoids, other immunosuppressive therapies and cytotoxic agents such as cyclophosphamide, rituximab and mycophenolate mofetil can be employed, depending on the biopsy findings and pathogenesis. Management is also influenced by any underlying disorders such as the presence of an autoimmune condition.

Workup for Glomerular Diseases

Workup for glomerular diseases includes:

• basic laboratory testing (including plasma or serum creatinine, albumin, electrolytes, calcium, phosphorus, and complete blood count)

• urinalysis of sediment (critical in establishing the presence of most of the nephritic syndromes; red blood cell [RBC] casts or dysmorphic RBCs are hallmarks)

• estimation of protein excretion (spot protein/creatinine ratio or 24-hour urine collection)

• serologic testing for disorders that cause glomerular disease (e.g., lupus and hepatitis serologies, antistreptolysin O [ASO], cryogobulins, antinuclear antibody, ANCA, anti-GBM, and protein electrophoresis)

• measurement of serum complement levels

• kidney biopsy (generally required to document the underlying pathology and to identify the type of glomerular disease)

  • Positive ANCA or anti-GBM tests in the context of nephritic syndrome may be sufficient to make the diagnosis without the need for a biopsy, depending on the clinical status and kidney function.

  • If membranous nephropathy is seen on biopsy, then molecular and antibody studies should be considered.

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