1. What is nephrotic syndrome?

Nephrotic syndrome is one of the most rigidly defined entities in clinical medicine. The term is not a specific diagnosis, but instead represents a cluster of abnormal findings. Specifically, it is comprised of four distinct elements: one physical sign, edema; and three laboratory test abnormalities, massive proteinuria, hypoalbuminemia, and hypercholesterolemia. A hypercoagulable state is an optional fifth feature, especially in adults, who have a 10-fold higher risk of thromboembolic complications compared to pediatric patients. The hypercoagulable state in the nephrotic syndrome is due to many factors including urinary loss of antithrombin III, increased platelet aggregation, and endothelial dysfunction. It is important to note that reduced glomerular filtration rate or azotemia is not a defining feature of the nephrotic syndrome in any age group.

Edema is a key feature in patients with nephrotic syndrome. Studies suggest that it can develop by two distinct mechanisms. According to the underfill hypothesis, the hypoalbuminemia leads to decreased plasma oncotic pressure, reduction in the effective intravascular compartment size, activation of the renin–angiotensin axis, and stimulation of renal sodium reabsorption. In contrast, the overfill hypothesis posits that sodium retention in nephrotic syndrome is a primary abnormality in the kidney due to corin-mediated activation of the epithelial sodium channel. It is likely most patients have a component of each mechanism operating in the formation of edema. In most cases, the edema is controlled with modest dietary salt restriction and the administration of diuretics. In cases with severe underfilling, infusions of albumin and furosemide may be required to control edema.

2. How does one make the diagnosis of nephrotic syndrome?

The diagnosis is made in a patient with edema and massive proteinuria; that is, a urine protein:creatinine ratio greater than 2 (mg:mg) in a first morning sample in children or >3.5 g/24 hours in adults. Quantitation of urine protein excretion is mandatory to confirm the diagnosis of new-onset nephrotic syndrome. However, subsequent monitoring can be accomplished using qualitative dipstick urine testing. It is important to exclude cirrhosis, congestive heart failure, or gastrointestinal disease (protein-losing enteropathy or malabsorption) before conclusively attributing edema to kidney disease.

3. What are the causes of nephrotic syndrome?

Nephrotic syndrome is classified into primary (or idiopathic) and secondary causes. There are four principal primary etiologies of nephrotic syndrome:

• 1.
  

  Minimal change nephrotic syndrome (MCNS)

  
  
• 2.
  

  Focal segmental glomerulosclerosis (FSGS)

  
  
• 3.
  

  Membranous nephropathy (MN)

  
  
• 4.
  

  Membranoproliferative glomerulonephritis (MPGN)

There are variants of MCNS characterized by subtle changes in mesangial cell hypercellularity or the deposition of specific immunoglobulins such as IgM. However, the clinical significance of these entities is unclear. In adults, IgA nephropathy, fibrillary, and immunotactoid glomerulonephritis can present with nephrotic syndrome.

The secondary causes of nephrotic syndrome include:

• •
  

  Post-infectious glomerulonephritis

  
  
• •
  

  Systemic lupus erythematosus

  
  
• •
  

  Henoch-Schoenlein purpura

  
  
• •
  

  Medications

  
  
• •
  

  Infections (e.g., hepatitis B, hepatitis C, HIV)

  
  
• •
  

  Malignancies (Hodgkin’s diseases)

  
  
• •
  

  Amyloidosis

  
  
• •
  

  Diabetes

This chapter will focus on primary nephrotic syndrome as a group, because the secondary causes are detailed in specific chapters for each entity.

4. What is the incidence and prevalence of nephrotic syndrome and has it changed in recent years?

The incidence of nephrotic syndrome is approximately 2 to 4 new cases per 100,000 population per year. There are data suggesting that the incidence of nephrotic syndrome is rising in certain populations around the world, such as Indians and Southeast Asians. However, the overall figure has been fairly steady and is applicable around the world and in most racial and ethnic groups.

There may be a difference in the incidence of specific types of primary nephrotic disease in children and adults. The prevalence of nephrotic syndrome as a cause of chronic kidney disease varies from country to country depending on the practice patterns for disease detection and treatment. Nonetheless, primary nephrotic syndrome is an uncommon illness and qualifies for designation as a rare disease.

5. What is the clinical presentation of patients with nephrotic syndrome?

The most common presenting complaint for patients with nephrotic syndrome is edema. It usually involves the lower extremities in adults because they are more sedentary. While children also have pedal edema, it tends to be less severe because of increased physical activity. Periorbital edema and ascites occur in all age groups. The edema is symmetric and painless.

6. Are there extra-renal manifestations of nephrotic syndrome?

Less common presentations include peritonitis. This can even occur before the implementation of immunosuppressive therapy. In addition, thromboembolic events can complicate the course of nephrotic syndrome. The latter complaint is much more common, at least ten fold higher, in adults. Patients with nephrotic syndrome can present with acute kidney injury, attributable either to intra-renal edema and tubular obstruction or severe contraction of the effective intravascular compartment. In addition, patients with unremitting nephrotic syndrome and persistent hypercholesterolemia are at risk of premature atherosclerosis and cardiovascular disease.

7. What is the natural history of nephrotic syndrome?

The natural history of the primary nephrotic syndrome depends on the underlying cause.

• •
  

  MCNS: Patients have an excellent long-term prognosis. Most patients are responsive to therapy, and while the majority will follow a relapsing course, eventually most patients outgrow the disease without permanent kidney injury. However, there are some children with MCNS who continue to have relapsing disease well into adulthood.

  
  
• •
  

  FSGS: Nearly half of patients with primary FSGS progress to end-stage kidney disease (ESKD) over 5 to 10 years. Additionally, there is recurrent disease in 25% to 30% following a kidney transplant.

  
  
• •
  

  MPGN: Nearly 50% of patients with MPGN will progress to ESKD over 10 to 15 years and 20% to 25% of these patients develop recurrent disease in a transplanted kidney.

  
  
• •
  

  Membranous nephropathy: The long-term course of MN is more variable. Approximately one-third will go into remission, another third have persistent proteinuria with stable kidney function, and the remaining patients will experience a steady decline in kidney function. Recent findings suggest that monitoring the level of antibody to M-type phospholipase A(2) receptor (PLA(2)R) can be useful to predict prognosis and response to therapy.

8. Are there any patient groups at special risk of developing nephrotic syndrome or adverse long-term outcomes?

Primary nephrotic syndrome occurs in all racial ethnic groups. It affects boys more commonly than girls; however, the outcomes are similar irrespective of the patient’s gender.

9. What is the appropriate work-up for patients with nephrotic syndrome?

• •
  

  Patients with primary nephrotic syndrome require quantitation of urine protein excretion to demonstrate nephrotic-range proteinuria. This can be accomplished by measuring the protein:creatinine ratio in the first morning urine specimen where a value >2 (mg:mg) in children is indicative of nephrotic syndrome. Alternatively, in adults, a 24-hour urine collection can be performed, and a level of protein in excess of 3.5 g is diagnostic of nephrotic-range proteinuria. While assessment of the first morning urine specimen is the standard of care in pediatric patients, there is greater diversity of practice in adult patient, with use of first morning urine samples, spot urine specimens, and 24-hour urine collections to monitor disease activity.

  
  
• •
  

  A complete metabolic profile is obtained to demonstrate hypoalbuminemia and hypercholesterolemia. The blood urea nitrogen and creatinine are generally normal. Total serum calcium level is low secondary to the low hypoalbuminemia. Serum sodium concentration may be low if there is water reabsorption in excess of sodium. Pseudohyponatremia secondary to hyperlipidemia is no longer a concern with the widespread use of ion selective electrodes in clinical chemistry analyzers.

  
  
• •
  

  The C3 level is measured in all patients to exclude MPGN.

  
  
• •
  

  A complete blood count is part of the routine evaluation even though it usually has little information value about the cause of nephrotic syndrome. In select cases in which the nephrotic syndrome is secondary to a systemic illness or malignancy, the complete blood count may provide useful data.