Clinical Presentation & Management of Glomerular Diseases: Hematuria, Nephritic & Nephrotic Syndrome

Abstract

Because the differential diagnosis for glomerulonephritis (GN) is broad, using a classification schema is helpful to narrow the causes of GN in a systematic manner. The etiology of glomerulonephritis can be classified by their clinical presentation (nephrotic, nephritic, rapidly progressive GN, chronic GN) or by histopathology. GN may be restricted to the kidney (primary glomerulonephritis) or be a secondary to a systemic disease (secondary glomerulonephritis). The nephrotic syndrome is defined by the presence of heavy proteinuria (protein excretion greater than 3.0 g/24 hours), hypoalbuminemia (less than 3.0 g/dL), and peripheral edema. Hyperlipidemia and thrombotic disease may be present. The nephritic syndrome is associated with hematuria and proteinuria and abnormal kidney function and carries poorer prognosis and is typically associated with hypertension. The predominant cause of the nephrotic syndrome in children is minimal change disease. The most common causes of nephritic syndrome are post infectious GN, IgA nephropathy and lupus nephritis. Chronic GN is slowly progressive and is associated with hypertension and gradual loss of kidney function. Treatment includes non-specific measure aimed at controlling hypertension, edema, proteinuria and disease modifying immunosuppression.

Introduction

It is fairly common for glomerular disease patients to be asymptomatic and during a doctor’s visit incidentally find abnormal urinary findings. A good history, physical examination and common urine investigations can narrow down the differential diagnosis to few conditions. On the other extreme, a severely ill patient of acute glomerulonephritis (GN) could present with acute renal failure, edema, hypertension and possibly seizure, but such presentations are relatively less common. This review will focus on summarizing common, glomerular diseases management in an out-patient set up.

Clinical Presentations

The clinical presentation can vary from being asymptomatic to acutely severe illness. See Figure 1. Specific history should include questioning for early morning periorbital puffiness and evening time lower extremities edema, foamy urine, and change in urine color, volume and/or odor. Systemic diseases that are commonly associated with glomerular disease are diabetes, hypertension, lupus, vasculitis, and viral infections like hepatitis B, C and HIV ^1,2,3. A positive family history of Alport’s syndrome in association with hearing loss, uncommon forms of familial focal segmental glomerulosclerosis (FSGS), or IgA disease is invaluable in arriving at a specific diagnosis. Certain common drugs are associated with glomerular disease (See Table 1). Several glomerulonephritis are preceded by acute streptococcal infection, infective endocarditis or viral infections. Frequently IgA nephropathy is brought to attention by hematuria caused by an acute systemic infection. Several malignancies are frequently associated with glomerular disease (See Table 2). It is not uncommon for some malignancies to first manifest with renal problems. Physical examination findings that point toward glomerular disease include dependent edema, periorbital edema, generalized anasarca, white nails, and xanthelasmas pointing nephrotic syndrome, or pulmonary signs particularly hemorrhage suggestive of nephritic syndrome.

Figure 1.

Glomerular Diseases

Table 1.

Common Drugs Known to Cause Glomerular Diseases

Minimal change disease: NSAIDs Interferon

Membranous GN: NSAIDs Penicillamine Mercury in skin lightening creams

Focal Segmental Glomerulosclerosis: Pamodronate Heroin

Hemolytic Uemic Syndrome: Cyclosporine Tacrolimus mitomycin C Oral contraceptives

Table 2.

Glomerular Diseases Associated with Common Malignancies

Membranous GN: Lung, breast, and GI carcinomas

Minimal change disease: Hodgkin’s disease

Membrano-proliferative GN: Non-Hodgkin’s lymphoma Amyloid: Renal carcinoma

Urine examination findings are very critical in determining the direction of further work up. Often urine findings of hematuria, proteinuria or both may be the first sign of glomerular disease. Glomerular origin of RBCs is substantiated by findings of dysmorphic RBCs, acanthocytes, abnormal casts and proteinuria. Presence of isolated monomorphic RBCs necessitates work-up for lower urinary tract bleeding or lower urinary tract infection.

Asymptomatic Mild Proteinuria

Normal proteinuria is less than 150 mg/day, which may contain up to 20–30 mg of albumin. Non-nephrotic proteinuria is defined as a urine protein excretion of less than 3.5 gm/day or a random urine protein to creatinine ratio of less than 3. Increased protein excretion is a hallmark of glomerular disease. When the urine dipstick for albumin is negative while the quantitative proteinuria is excessive suggests urinary excretion of light chain proteins. Functional proteinuria is usually transient and is typically associated with exercise and transient systemic illness. Orthostatic proteinuria occurs in children and young adults only in upright position and absent while recumbent in absence of any identifiable secondary cause. Prognosis is uniformly good.

Stable asymptomatic non-nephrotic proteinuric patient with normal kidney function is managed by close observation and a kidney biopsy is usually not indicated. However, presence of microscopic hematuria in association with a proteinuria though asymptomatic does change the prognosis and requires a kidney biopsy.

Nephrotic Syndrome

Nephrotic syndrome (see Figure 1) is usually a chronic condition and with the exception of MCD, most causes eventually lead to chronic progressive renal failure. Common causes of nephrotic syndrome are listed in Table 3. Most minimal change diseases do respond to corticosteroids and a small fraction of patients are steroid dependent. Edema in nephrotic syndrome is a combination of hypoalbuminemia and salt and water retention⁴. In some could lead to hypertension especially in association with abnormal kidney function. Proteinuria causes low albumin state and marked negative nitrogen balance and hyperlipidemia⁵. Loss of coagulation proteins lead to hypercoagulable state and increased platelet aggregation. These patients have increased risk of venous and arterial thromboembolism⁶. Low protein state increases risk for bacterial infection⁷. It is not uncommon to have acute renal failure due to volume depletion, renal vein thrombosis, or adverse drug reactions.

Table 3.

Common Causes of Nephrotic Syndrome

Minimal change disease Focal segmental glomerulosclerosis Membranous GN Membranoproliferative GN (Type 1 and 2 and associated with cryoglobinemia) Daibetic nephropathy Amyloid

Nephritic Syndrome

Usually a result of glomerular inflammation (See Figure 1) and is associated with reduced kidney function, non-nephrotic proteinuria, hematuria with red cell casts, hypertension and edema. A common mode of presentation, represented by the acute post-streptococcal GN, is oliguria, cola colored urine, weight gain, edema, and hypertension over a few days. Distinction between nephrotic and nephritic syndrome is usually straight forward. However, some glomerular diseases especially the MPGN can present as nephrotic or nephritic. Common causes of nephritic syndrome are listed in Table 4. Rapidly progressive renal failure is a hall mark of rapidly progressive glomerulonephritis syndrome and presents with nephritic urine picture⁸.

Table 4.

Common Causes of Nephritic Syndrome

Post-streptococcal GN Infective endocarditis Shunt nephritis IgA nephropathy Lupus Nephritis Goodpasture’s Vasculitis

Chronic Glomerulonephritis

Patients with chronic GN progresses slowly and are typically associated with hypertension, edema, chronic anemia, mild to moderate proteinuria, abnormal urine sediment, chronic renal bone disease and mild metabolic acidosis. Both kidneys gradually shrink in size. Kidney biopsy may help in diagnosis and prognosis prediction, but is therapeutically low in value. Nevertheless, biopsy is indicated especially for those who are potential kidney transplant candidates.

Treatment of Glomerular Disease

Focus of treatment for secondary glomerular disease is to aggressively manage the underlying systemic disease such as underlying infection. In most instances this approach results in resolution of GN. For primary GN the therapy consists of supportive management and disease modifying specific therapy. Supportive therapy is aimed at controlling blood pressure, relieving edema, reduction of proteinuria and hyperlipidemia, and management of any other metabolic derangement that may be present. In a small minority of patients, such non-specific therapies allow spontaneous resolution of GN. If successful, patients could be spared of toxic immunosuppression medications, which have serious inevitable side effects. There are only a handful of GNs where immunosuppression and/or supportive therapy predictably results in complete remission such as minimal change disease, post-infectious GN.

The general principles of disease modifying immunosuppression therapy are aimed at blocking, reduction or rarely elimination of antigen effects. More severe and acute illnesses, such as rapidly progressive glomerulonephritis⁸ are the ones that have the most benefit from aggressive immunosppressive management. On the contrary, chronic GNs are rather resistant to immunosuppression. Conditions where kidney biopsy demonstrates extensive scarring, renal function is rapidly declining and is associated with anuria (urine output >200 ml/day) should be managed conservatively because the risk benefit ratio is unfavorable. Dialysis may be given as needed.

As most immunosuppressive protocols are non-specific in nature, patients are heavily immunosuppressed and are at risk for atypical infections. The major drugs that are included in most protocols are corticosteroids azathioprine and cyclophosphamide. Recently favorable results have been reported with drugs used in kidney transplant patients such as calcineurin inhibitors, mycophenalic acid and rapamycin.

The nephrology community is slowly experimenting drugs developed and used in oncology field, including rituximab. The literature reports of immunosuppressive therapies are difficult to interpret and not easy to translate in practice due to studies that consist of small number of patients, lack of prospective randomized trials, variable nature of GNs.

Summary

Because the differential diagnosis for GN is broad, using a classification schema is helpful to narrow the causes of GN in a systematic manner. The etiology of glomerulonephritis can be classified by their clinical presentation (nephrotic, nephritic, rapidly progressive GN, chronic GN) or by histopathology. GN may be isolated to the kidney (primary glomerulonephritis) or be a component of a systemic disorder (secondary glomerulonephritis).

The nephrotic syndrome is defined by the presence of heavy proteinuria (protein excretion greater than 3 g/24 hours), hypoalbuminemia (less than 3.0 g/dL), and peripheral edema. Hyperlipidemia and thrombotic disease may be present.

The nephritic syndrome is associated with hematuria and proteinuria and abnormal kidney function and carries poorer prognosis and is typically associated with hypertension. The predominant cause of the nephrotic syndrome in children is minimal change disease. The most common causes of nephritic syndrome are post infectious GN, IgA nephropathy and lupus nephritis.

Chronic GN is slowly progressive and is associated with hypertension and gradual loss of kidney function. Treatment includes non-specific measure aimed at controlling hypertension, edema, proteinuria and disease modifying immunosuppression.

Biography

Ramesh Khanna, MD, MSMA member since 2010, is the Karl D. Nolph, MD, Chair in Nephrology, Professor of Medicine, Director, Division of Nephrology, at the University of Missouri School of Medicine.

Contact: khannar@health.missouri.edu.