SCIENCE OF MEDICINE
Clinical Presentation & Management
of Glomerular Diseases:
Hematuria, Nephritic & Nephrotic Syndrome
by Ramesh Khanna, MD
•‹‰ƒ…Žƒ••‹Ƥ…ƒ–‹‘
schema is helpful to
narrow the causes of
glomerulonephritis in a
systematic manner.
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.
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.
108:1 Missouri Medicine | January/February 2011 | 33
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
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Figure 1
relatively less common. This review will focus on summarizing common,
Glomerular Diseases glomerular diseases management in an out-patient set up.
Asymptomatic
Ȉ Proteinuria < 2gm/day Clinical Presentations
Ȉ Microscopic Hematuria > 2-3 The clinical presentation can vary from being asymptomatic to acutely
Ȉ Dysmorphic RBC/HPF
severe illness. See Figure 1. Specific history should include questioning
Gross Hematuria for early morning periorbital puffiness and evening time lower extremities
Ȉ No pain edema, foamy urine, and change in urine color, volume and/or odor. Systemic
Ȉ No blood clots
Ȉ Associated systemic infection diseases that are commonly associated with glomerular disease are diabetes,
hypertension, lupus, vasculitis, and viral infections like hepatitis B, C and
Rapidly Progressive
Ȉ Glomerulonephritis HIV 1,2,3. A positive family history of Alport’s syndrome in association with
Ȉ Renal failure hearing loss, uncommon forms of familial focal segmental glomerulosclerosis
Ȉ Sub-neprotic proteinuria
Ȉ Hematuria with RBC casts
(FSGS), or IgA disease is invaluable in arriving at a specific diagnosis. Certain
Ȉ Normal BP common drugs are associated with glomerular disease (See Table 1). Several
glomerulonephritis are preceded by acute streptococcal infection, infective
Nephrotic Syndrome
Ȉ Proteinuria > 3 gms/day endocarditis or viral infections. Frequently IgA nephropathy is brought
Ȉ Low serum Albumin < 3.5 gms/day to attention by hematuria caused by an acute systemic infection. Several
Ȉ Edema
Ȉ High lipids
malignancies are frequently associated with glomerular disease (See Table 2). It
is not uncommon for some malignancies to first manifest with renal problems.
Nephritic Syndrome Physical examination findings that point toward glomerular disease include
Ȉ Low urine output
Ȉ Hematuria with RBC casts dependent edema, periorbital edema, generalized anasarca, white nails, and
Ȉ Sub-nephrotic Proteinuria xanthelasmas pointing nephrotic syndrome, or pulmonary signs particularly
Ȉ High BP
hemorrhage suggestive of nephritic syndrome.
Chronic GN Urine examination findings are very critical in determining the direction
Ȉ Slowly progressive renal failure
Ȉ Hypertension
of further work up. Often urine findings of hematuria, proteinuria or both
Ȉ Normocytic Normochromic anemia may be the first sign of glomerular disease. Glomerular origin of RBCs is
Ȉ Secondary Hyperparathyroidism 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.
Table 1
Common Drugs Known to Cause
Glomerular Diseases Asymptomatic Mild Proteinuria
Normal proteinuria is less than 150 mg/day, which may contain up to
Minimal change disease: 20-30 mg of albumin. Non-nephrotic proteinuria is defined as a urine protein
Ȉ NSAIDs
Ȉ Interferon 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
Membranous GN:
Ȉ NSAIDs disease. When the urine dipstick for albumin is negative while the quantitative
Ȉ Penicillamine proteinuria is excessive suggests urinary excretion of light chain proteins.
Ȉ Mercury in skin lightening creams
Functional proteinuria is usually transient and is typically associated with
Focal Segmental Glomerulosclerosis: exercise and transient systemic illness. Orthostatic proteinuria occurs in
Ȉ Pamodronate children and young adults only in upright position and absent while recumbent
Ȉ Heroin
in absence of any identifiable secondary cause. Prognosis is uniformly good.
Hemolytic Uemic Syndrome: Stable asymptomatic non-nephrotic proteinuric patient with normal
Ȉ Cyclosporine
Ȉ Tacrolimus
kidney function is managed by close observation and a kidney biopsy is usually
Ȉ mitomycin C not indicated. However, presence of microscopic hematuria in association with
Ȉ Oral contraceptives a proteinuria though asymptomatic does change the prognosis and requires a
kidney biopsy.

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Nephrotic non-nephrotic proteinuria, hematuria with red cell

Table 2
Glomerular Diseases Associated
with Common Malignancies
Membranous GN:
Ȉ Lung, breast, and GI carcinomas
Minimal change disease:
Ȉ Hodgkin’s disease
Membrano-proliferative GN:
Ȉ Non-Hodgkin’s lymphoma
Amyloid:
Ȉ Renal carcinoma
Syndrome casts, hypertension and edema. A common mode of
Nephrotic presentation, represented by the acute post-streptococcal
syndrome (see GN, is oliguria, cola colored urine, weight gain, edema,
Figure 1) is and hypertension over a few days. Distinction between
usually a chronic nephrotic and nephritic syndrome is usually straight
condition and forward. However, some glomerular diseases especially
with the exception the MPGN can present as nephrotic or nephritic.
of MCD, most Common causes of nephritic syndrome are listed in
causes eventually Table 4. Rapidly progressive renal failure is a hall mark
lead to chronic of rapidly progressive glomerulonephritis syndrome and
progressive presents with nephritic urine picture8.

Table 3 Chronic Glomerulonephritis

Common Causes of Nephrotic Syndrome Patients with chronic GN progresses
Ȉ Minimal change disease
Ȉ Focal segmental glomerulosclerosis
slowly and are typically associated with
Ȉ Membranous GN hypertension, edema, chronic anemia,
Ȉ Membranoproliferative GN (Type 1 and 2 and associated with cryoglobinemia) mild to moderate proteinuria, abnormal
Ȉ Daibetic nephropathy
Ȉ Amyloid urine sediment, chronic renal bone
disease and mild metabolic acidosis. Both
kidneys gradually shrink in size. Kidney
Table 4
renal failure. biopsy may help in diagnosis and prognosis prediction,
Common Causes of
Nephritic Syndrome Common causes but is therapeutically low in value. Nevertheless, biopsy
Ȉ Post-streptococcal GN of nephrotic is indicated especially for those who are potential kidney
Ȉ Infective endocarditis
Ȉ Shunt nephritis
syndrome are transplant candidates.
Ȉ IgA nephropathy listed in Table 3.
Ȉ Lupus Nephritis Most minimal
Ȉ Goodpasture’s Treatment of Glomerular Disease
Ȉ Vasculitis change diseases Focus of treatment for secondary glomerular
do respond to disease is to aggressively manage the underlying systemic
corticosteroids disease such as underlying infection. In most instances
and a small fraction of patients are steroid dependent. this approach results in resolution of GN. For primary
Edema in nephrotic syndrome is a combination of GN the therapy consists of supportive management and
hypoalbuminemia and salt and water retention4. In some disease modifying specific therapy. Supportive therapy
could lead to hypertension especially in association is aimed at controlling blood pressure, relieving edema,
with abnormal kidney function. Proteinuria causes low reduction of proteinuria and hyperlipidemia, and
albumin state and marked negative nitrogen balance and management of any other metabolic derangement that
hyperlipidemia5. Loss of coagulation proteins lead to may be present. In a small minority of patients, such
hypercoagulable state and increased platelet aggregation. non-specific therapies allow spontaneous resolution
These patients have increased risk of venous and arterial of GN. If successful, patients could be spared of toxic
thromboembolism6. Low protein state increases risk immunosuppression medications, which have serious
for bacterial infection7. It is not uncommon to have inevitable side effects. There are only a handful of GNs
acute renal failure due to volume depletion, renal vein where immunosuppression and/or supportive therapy
thrombosis, or adverse drug reactions. predictably results in complete remission such as minimal
change disease, post-infectious GN.
Nephritic Syndrome The general principles of disease modifying
Usually a result of glomerular inflammation (See immunosuppression therapy are aimed at blocking,
Figure 1) and is associated with reduced kidney function, reduction or rarely elimination of antigen effects. More

108:1 Missouri Medicine | January/February 2011 | 35

SCIENCE OF MEDICINE
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).
36 | January/February 2011 | 108:1 Missouri Medicine
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.
References
1. Braden, GL, Mulhern, JG, O’Shea, MH, et al. Changing incidence of
glomerular diseases in adults. Am J Kidney Dis 2000; 35:878.
2. Malafronte, P, Mastroianni-Kirsztajn, G, Betônico, GN, et al. Paulista
Registry of glomerulonephritis: 5-year data report. Nephrol Dial Transplant
2006; 21:3098.
3. Heaf, J. The Danish Renal Biopsy Register. Kidney Int 2004; 66:895.
4. Wasserstein, AG. Membranous glomerulonephritis. J Am Soc Nephrol
1997; 8:664.
5. Crew, RJ, Radhakrishnan, J, Appel, G. Complications of the nephrotic
syndrome and their treatment. Clin Nephrol 2004; 62:245.
6. Llach, F. Hypercoagulability, renal vein thrombosis, and other thrombotic
complications of nephrotic syndrome. Kidney Int 1985; 28:429.
7. Orth, SR, Ritz, E. The nephrotic syndrome. N Engl J Med 1998;
338:1202.
8. Jennette, JC. Rapidly progressive crescentic glomerulonephritis. Kidney
Int 2003; 63:1164.
Disclosure
None reported. MM