Nephrotic syndrome refers to a number of diseases that express themselves in a common pathway of oedema, massive proteinuria, hypoproteinaemia, and/or hyperlipidemia. The oedema here is massive and generalized(anarsaca) with nephrotic range proteinuria. It is a feature of a number of kidney diseases, not a disease entity on its own.
Epidemiology of nephrotic syndrome
It is relatively rare, occurs in <10/100,000 children. Nephrotic syndrome can be found in any age group but it is very rare in infancy. The peak age in Caucasians is 2 years while in Nigeria and other developing countries, it is between 7-9 years. Both sexes are affected, but there is male preponderance. It is found world-wide, but presents differently across races. Genetic and environmental factors may therefore play some roles in the determination of the diseases pattern and features.
etiology of nephrotic syndrome
Nephrotic syndrome is classified based on its causes:
- Primary- no known cause is identified
- Secondary causes
- Protozoal e.g. P.malariae (common), P.falciparum, toxoplasmosis etc
- Parasitic e.g. S. mansoni, S. hematobium, filariasis
- Viral e.g cytomegalovirus, HIV, varicella, hepatitis B and C.
- Bacterial e.g. post streptococci AGN, syphilis, infective endocarditis, shunt nephritis.
B). Multisystemic & Connective Tissue Diseases e.g. systemic lupus erythromatosis, Henoch-Schonlein -Purpura, Sarcoidosis, amyloidosis.
- C) Allergic Disorders g. bee sting, serum sickness, pollens, poison oak, poison ivy
- D) Drugs & Heavy metals e.g. mercury bleaching cream, lead, gold, penicillamine, gold, trimethadione. Improves with drug withdrawal.
- E) Neoplastic e.g. lymphomas, leukemias, wilms tumor
- F) Heredofamilial disorder e.g. sickle cell disease, Alport’s Syndrome, nail-Patella syndrome.
- G) Metabolic diseases e.g. diabetes milletus and hypothyroidism
- Congenital cause- Patient is born with it. It is nephrotic syndrome that manifests at birth or the first 3 months of life. Usually have poorer prognosis. The finnish is a classic example
- Acquired: Examples are minimal change disease, focal sclerosing glomerulosclerosis, membraneous nephritis, membranoproliferative glomerulosclerosis, immune complex glomerulonephritis. Developed in later life. The minimal change disease has a good prognosis and responds to steroid therapy.
Pathogenesis of nephrotic syndrome
The glomerular basement membrane serves as a sieve preventing passage of proteins into the t proximal convoluted tubule. The glomerular basement membrane is made up of fenestrations which may allow low molecular weight proteins. There is also an electrical barrier i.e. the GBM carries a negative charge, and proteins by their nature are negatively charged, thus they are repelled at the GBM. Any alterations in these barriers e.g. due to infections, causing the pores to be larger, or altering the electric charge, allows proteins to pass through leading to proteinuria. Loss of large amounts of protein in urine causes hypoproteinemia. Because of the hypoproteinemia, there is fluid shift from the intracellular fluid due to decreased oncotic pressure (it is proteins in blood that builds up the oncotic pressure but I nephrotic syndrome, proteins are massively lost hence the reduced pressure) and edema.
A compensatory mechanism by the body for hypoproteinemia is the production of lipoproteins by the liver (this is dependent on good nutrition; thus, hyperlipidemia is not always seen in patients with nephrotic syndrome in developing nations). Disintegration of lipoproteins to lipids and proteins lead to the hyperlipidemia seen.
Symptoms and signs of nephrotic syndrome
- Oedema: Usually starts from the face, around the periorbital tissues. Oedema is gravity dependent. Fluid may also collect in potential spaces leading to pleural effusion, ascites, massive scrotal oedema.
Due to the gravity dependent nature of the oedema, the patient wakes up with puffy face, and this clear, as the day goes by, the fluid gravitates to the extremities (lower limbs).
- Repeated skin lesions
- Fluffy, brownish and friable hair
- For children, the child will be small be age
- Abdominal swelling due to ascitis
- There may be decreased urinary output
Diagnosis of nephrotic syndrome
The diagnosis is both clinical and from the lab. The diagnosis is made with the 3 basic features below:
- Proteinuria of 2gm/24hours or 1gm/m2/day or greater than or equal to +++ on dipstick.
- Hypoproteinemia of <250mg/dl
- Massive oedema and/or
- Hyperlipidemia of > 250mg/dl
Differential diagnosis of nephrotic syndrome
There are other disease conditions that has similar signs and symptoms as nephrotic syndrome. They are:
- Acute glomerulonephritis: oedema is not usually massive, mild proteinuria, blood pressure is usually elevated. Blood electrolytes, urea and creatinine are usually deranged.
- Congestive cardiac failure: generalized oedema is seen in congestive cardiac failure, but here face is almost-always clear. Cardiac reserve here is decreased, there will be effort intolerance, orthopnea, paroxysmal nocturnal dyspnea, but no proteinuria
- Liver disease (cirrhosis): oedema is mainly central ie around the abdomen, sparing the other parts of the body.
- Protein Energy Malnutrition: especially in poor countries, kwashiorkor, marasmic-kwashiorkor, acute kwashiorkor manifest as nephrotic syndrome. Not coomon in children > 3 years. There is no proteinuria.
- Chronic kidney disease: chronic anemia, lassitude, swelling, elevated creatinine.
- Severe chronic anemia: may produce generalized oedema, mild swelling, no proteinuria.
- Endomyocardial fibrosis(EMF): impaired cardiac function, oedema spares the face.
Investigations of nephrotic syndrome
Reasons for investigations include
- To clinch the diagnosis
- To establish baseline parameters
- To rule out differentials
- For follow-up
- Urinalysis; urine appears frothy and foamy
- Urine microscopy culture and sensitivity; RBCs, WBCs may be covered in protein and appear waxy on microscopy. Urine culture is important because these patients are prone to urinary tract infection.
- 24hour urine protein; urine sample at 0 hour is discarded. Samples are collected till the 24th hour, and sulphosalicylic acid is used to test for proteins.
- Spot urine assay for protein/creatinine. Values in >200mg/mmol is indicative for nephrotic syndrome.
- Liver function test; to assess for blood protein and urea
- Blood culture; patients are predisposed to infection/sepsis
- Electrolyte/urea;urea is almost normal in nephrotic syndrome. K+ and HCO3– is normal in most cases, but will be deranged if patient is tilting to chronic renal failure.
- Serum creatinine is almost always normal. If deranged, patient may be tilting to chronic renal failure.
- Lipid profile
- Serum total protein and albumin
- Ultrasound scan(USS); kidneys are usually normal. If enlarged, it is most likely acute glomerulonephritis. USS is also used to identify the level of ascites.
- Chest X-ray; to identify complications like pleural effusion.
- Renal biopsy + histology
- Not always done, but done if patient is not responding to treatment, or is deteriorating, or in presence of symptoms such as hematuria.
Histologic types of nephrotic syndrome
- Minimal change disease
- Focal segmental glomerulosclerosis (FSGS)
- Membranous type
- Membranoproliferative type
Minimal change disease is associated with the best prognosis
Complications of nephrotic syndrome
- Increased predisposition to infection due to loss of immunoglobulin(proteins), complement factors and opsonins in urine.
- Infections could be viral, thus these patients cannot take live vaccines
- Spontaneous bacteria peritonitis
- Thromboembolic events e.g. stroke
- Hyperlipidemia may predispose to thrombosis
- Hypertension especially in patients with unfavorable histologic types
- Pleural effusion
- Renal vein thrombosis
- Renal failure
Management of nephrotic syndrome
- Diet: it was previously recommended that that increase protein diet be given, but thiswas discarded because the more protein given, the more it is lost in urine and protein lost in urine may further increase glomerular damage. Thus, a balanced diet is required.
- Low salt diet
- Keep input-output chart
- Educate patient on the tendency for recurrence
- Activity: patient is not restricted in activity. Children are usually active.
- Drugs: steroids are the mainstay of treatment. Methylprednisolone is preferred. Prednisolone is however used because it is more readily available. Dose is 2mg/kg/day up to a ceiling of 60mg/day given in divided doses (preferred because it reduces the side effect) or in a single dose.
- Diuretics (frusemide and spironolactone)
- Salt-free (salt poor) albumin if oedema is resistant to diuretics.
- Treat underlying cause
- Steroid regimen is center specific and it is given irrespective of the weight of the child
Treatment is for 30 days. Dose is scaled down because onset time and duration of action of the drug is long. Treatment aims to decrease oedema and proteinuria. 90-95% of patients will respond to the initial 30days treatment. 5% of patients will not respond and will require another 30-day course. However, 5% of these non-responders (resistant nephrotic syndrome) may also not respond to the second course, thus are treated symptomatically. 10% of the non-responders may relapse after initial response to therapy, thus will require another course of treatment.
In summary; patients may be responders (early or late), non-responders or relapsers (frequent relapsers or steroid dependent relapsers). For frequent relapsers, they develop oedema and proteinuria once in a year or twice in 6 months. Of the steroid dependent, the require steroids to stay symptom free, no matter how low the dose. Some may be steroid resistant and given low dose prednisolone + cyclophosphamide or chlorambucil, 2mg/kg. The complications of cyclophosphamide are hemorrhagic cystitis and pancytopenia.
Complications of treatment (steroid use)
- Growth failure
- Skin and hair changes
- Insulin deficiency
- Diabetes milletus
- Steroid induced psychosis
Prognosis of nephrotic syndrome
In terms of morbidity and mortality.
- Prognosis of nephrotic syndrome generally is usually good though variable. Mortality is usually from complications e.g. chronic renal failure or drug resistance.
- Quartan Malarial Nephropathy
-Develop Hypertension with End – stage Renal Disease within 5 to 7 years.
- Minimal Change Disease
– Better outcome
-May have relapses till the 2nd decade
Loss of school time, discrimination and isolation will psychological trauma. Burden to family members as treatment is expensive.
- A patient with nephrotic syndrome who develops measles or any other infections will go into remission. Also, patients should be immunized against many illnesses of the vaccines that are available (killed vaccines only).
Vaccination in nephrotic syndrome
- Polyvalent Pneumococcal vaccine should be administered.
- Zoster immunoglobulin would be needed if there is exposure to Herpes zoster.
- Acyclovir could be administered if there is serious threat of chicken pox.
- Another threat is measles infection, which could be treated with gamma globulin.
- Live vaccines should be avoided.
- Killed vaccines however could be administered.
Do you know that tetanus can cause kidney failure?