NEPHROTIC SYNDROME

Nephrotic Syndrome

The nephrotic syndrome is characterized by

proteinuria,

hypoproteinemia,

edema,

hyperlipidemia.

ETIOLOGY.

90%       Idiopathic nephrotic syndrome;

minimal-change disease 85%,

mesangial proliferation in 5%,

focal sclerosis in 10%.

10%       mediated by some form of glomerulonephritis,

PATHOPHYSIOLOGY.

increase in glomerular capillary wall permeability.                      proteinuria                            nephrosis

may be related, to loss of negatively charged glycoproteins within the capillary wall.

In the nephrotic state,

the protein loss generally exceeds 2 g/24 hr

composed primarily of albumin;[ hypoproteinemia is fundamentally a "hypoalbuminemia."]

In general, edema appears when the serum albumin level falls below 2.5 g/dL (25 g/L).

The mechanism of edema formation in nephrosis is incompletely understood.

In the nephrotic state,

almost all serum lipid (cholesterol, triglycerides) and lipoprotein levels are elevated.

Two factors offer at least partial explanation:

(1) the hypoproteinemia stimulates generalized protein synthesis in the liver, including the

lipoproteins

(2) lipid catabolism is diminished, owing to reduced plasma levels of lipoprotein lipase, the

major enzyme system that removes lipids from the plasma.

Whether lipoprotein lipase is lost in the urine is unclear.

Idiopathic Nephrotic Syndrome

ETIOLOGY.

The cause of the syndrome remains unknown.

PATHOLOGY.

minimal-change disease       (85%),

Findings on immunofluorescent microscopic studies are typically negative.

More than 95% of children respond to corticosteroid therapy.

mesangial proliferative group (5%)

Approximately 50–60% of patients respond to corticosteroid therapy.

focal sclerosis lesion            (10%),

frequently progressive,

ultimately involving all glomeruli,

leads to end-stage renal failure in most patients.

Approximately 20% of patients respond to prednisone or cytotoxic therapy or both.

The disease may recur in a transplanted kidney.

CLINICAL MANIFESTATIONS.

more common in boys than in girls (2:1)

appears between the ages of 2 and 6 yr.

initial episode and subsequent relapses may follow an apparent viral upper respiratory tract infection.

The disease usually presents as

edema,

initially noted around the eyes and in the lower extremities, where it is "pitting" in nature.

edema becomes generalized and may be associated with weight gain, the development of ascites

and/or pleural effusions, and declining urine output.

edema accumulates in dependent sites and appears to shift from the face and back to the abdomen, perineum, and legs as the day progresses.

Anorexia,

abdominal pain,

diarrhea are common;

hypertension is uncommon.

DIAGNOSIS.

Urinalysis reveals +3 or +4 proteinuria; [Protein excretion exceeds 2 g/24 hr. ]

microscopic hematuria may be present, but gross hematuria is rare.

Renal function may be normal or reduced.

serum cholesterol and triglyceride levels are elevated,

serum albumin level is generally less than 2 g/dL (20 g/L)

serum calcium level is diminished, owing to a reduction in the albumin-bound fraction.

C3 level is normal.

Children with onset

1 and 8 yr are likely to have steroid-responsive minimal-change disease, and corticosteroid

therapy should be initiated without renal biopsy.

Above 8y Minimal-change disease common in children above the age of 8 yr who present with

nephrosis, but membranous and membranoproliferative glomerulonephritis become increasingly common; renal biopsy is recommended in this group to establish a firm diagnosis prior to considering therapy.

COMPLICATIONS.

1.  Infection is the major complication of nephrosis;

results from increased susceptibility to bacterial infections during relapse.

decreased immunoglobulin levels,

the edema fluid acting as a culture medium,

protein deficiency,

decreased bactericidal activity of the leukocytes,

"immunosuppressive" therapy,

decreased perfusion of the spleen due to hypovolemia

loss in the urine of a complement factor (properdin factor B) that opsonizes certain bacteria.

spontaneous peritonitis [most frequent type of infection]

sepsis,

pneumonia,

cellulitis,

urinary tract infections

Streptococcus pneumoniae is the most common organism causing peritonitis; gram-negative bacteria are also encountered.

Fever and physical findings may be minimal in the presence of corticosteroid therapy.

Accordingly, a high index of suspicion, prompt evaluation (including cultures of blood and peritoneal fluid), and the early initiation of therapy that covers both gram-positive and gram-negative organisms are critical to prevention of life-threatening illness.

When in remission, all patients having nephrosis should receive polyvalent pneumococcal vaccine.

2. increased tendency to arterial and venous thrombosis (owing at least in part to elevated plasma levels of certain

coagulation factors and inhibitors of fibrinolysis, decreased plasma level of anti-thrombin III, and increased platelet aggregation);

3. deficiencies of coagulation factors IX, XI, and XII;

4. reduced serum levels of vitamin D.

TREATMENT.

  • The child may be hospitalized with the first episode of nephrosis for diagnostic, educational, and therapeutic purposes.
  • When edema develops, sodium intake is reduced by the initiation of a "no added salt diet."
  • Salt restriction is terminated when the edema resolves.
  • Unless the edema is severe, fluid intake is not restricted but need not be encouraged.
  • Physical activities as tolerated.

If the edema becomes severe, resulting in respiratory distress from massive pleural effusions and ascites or in severe scrotal edema, the child should be hospitalized.

  1. Sodium restriction should be continued, but further reduction in intake is rarely effective in controlling edema.
  2. The swollen scrotum is elevated with pillows to enhance the removal of fluid by gravity.
  3. oral administration of furosemide (1–2 mg/kg every 4 hr) in conjunction with metolazone (0.2–0.4 mg/kg/24 hr in two divided doses); metolazone may act in both the proximal and distal tubules
  4. intravenous administration of 25% human albumin (1 g/kg/24 hr) may be necessary, but the effect is usually transient and volume overload with hypertension and heart failure must be avoided.

After the diagnosis is confirmed by the appropriate laboratory studies, the pathophysiology and treatment of nephrosis is reviewed with the family to enhance their understanding of the child's disease.

Remission is then induced by administration of prednisone,

dosage of 60 mg/m2/24 hr (maximum daily dose 60 mg), divided into 3 or 4 doses over the day.

The time needed for response to prednisone averages about 2 wk, the response being defined as the point at

which urine becomes free of protein.

If the child continues to have proteinuria (2+ or greater) after 1 mo of continuous, daily, divided-dose prednisone, the nephrosis is termed steroid resistant and renal biopsy is indicated to determine the precise etiology of the disease.

Five days after the urine becomes free (negative, trace, or 1+ on the dipstick) of protein,

the dose of prednisone is changed to 60 mg/m2 (maximum dose of 60 mg) taken EOD as a single dose with breakfast.

This alternate-day regimen is continued for 3–6 mo.

The purpose of alternate-day therapy is to maintain the remission using a relatively nontoxic dose of prednisone, thus avoiding frequent relapses of the disease and the cumulative toxicity of frequent courses of daily administration of corticosteroids.

After such a period of alternate-day therapy, the prednisone may be discontinued abruptly.

  • there has been sufficient recovery of pituitary-adrenal axis function that the patient is not at risk for adrenal insufficiency after abrupt withdrawal of the alternate-day prednisone.
  • for up to 1 yr after completing corticosteroid therapy, the child will require corticosteroid supplementation for severe illness or surgery.

Each relapse of the nephrosis is treated in a similar manner.

A relapse is defined as the recurrence of edema and not simply of proteinuria, as many children with this condition will have intermittent proteinuria that resolves spontaneously.

A small number of patients who respond to daily, divided-dose therapy will have relapses shortly after switching to or after terminating EOD therapy. Such patients are termed steroid dependent.

If there are repeated relapses and especially if the child suffers severe corticosteroid toxicity (cushingoid appearance, hypertension, growth failure), then cyclophosphamide therapy should be considered. Cyclophosphamide has been shown to

·         prolong the duration of remission

·         prevent relapses in children with frequently relapsing nephrotic syndrome. T

potential side effects of the drug

1.       leukopenia,

2.       disseminated varicella infection,

3.       hemorrhagic cystitis,

4.       alopecia,

5.       sterility

The dose of cyclophosphamide is 3 mg/kg/24 hr as a single dose, for a total duration of 12 wk. Alternate-day prednisone therapy is often continued during the course of cyclophosphamide administration.

During cyclophosphamide therapy, the white count must be monitored weekly and the drug withheld if the count falls below 5,000/mm3.

Steroid-resistant patients may respond to an extended course (3–6 mo) of cyclophosphamide, pulse methylprednisolone, or cyclosporine.

Renal transplantation is indicated for end-stage renal failure due to steroid-resistant focal and segmental glomerulosclerosis

Recurrent nephrotic syndromes develop in 15–55% of patients.

PROGNOSIS.

Most children with steroid-responsive nephrosis will have repeated relapses until the disease resolves itself spontaneously toward the end of the 2nd decade of life.

It is important to indicate to the family that the

  • child will have no residual renal dysfunction
  • disease is generally not hereditary
  • child (in the absence of cyclophosphamide or chlorambucil therapy) will remain fertile.

To minimize the psychologic effects of the nephrosis, we emphasize that when in remission the child is normal and may have unrestricted diet and activity.

While the child is in remission it is generally unnecessary to test the urine for protein.

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