2. Incidence
In US, Diabetic nephropathy with nephrotic syndrome is most common, at an estimated rate of at least 50 cases per million
population.
Nephrotic syndrome affects 1–3 per 100,000 children below 16 years of age. Nephrotic syndrome is often
It is 15 times more common in children than in adults
Because diabetes is major cause of nephrotic syndrome, American Indians, Hispanics, and African Americans have a higher
incidence of nephrotic syndrome than do white persons.
HIV nephropathy is a complication of HIV infection that is unusual in whites; it is seen with greater frequency in African American.
Focal glomerulosclerosis appears to be overrepresented as a cause of nephrotic syndrome in African-American as compared with
white children.
There is a male predominance in the occurrence of nephrotic syndrome, as for chronic kidney disease in general.
This male overrepresentation is also seen in paraneoplastic membranous nephropathy. But lupus nephritis affects mostly women.
The image below shows typical ages at which a given cause of nephrotic syndrome may occur. (Timeline not to scale.)
5. Primary glomerulonephrosis
•Minimal change disease (MCD): is the most common cause of nephrotic syndrome in children (77-
85%). It owes its name to the fact that the nephrons appear normal when viewed with an optical
microscope as the lesions are only visible using an electron microscope.
•Focal segmental glomerulosclerosis (FSGS): is the most common cause of nephrotic syndrome in
adults.It is characterized by the appearance of tissue scarring in the glomeruli. The term focal is used as
some of the glomeruli have scars, while others appear intact; the term segmental refers to the fact that
only part of the glomerulus suffers the damage.
•Membranous glomerulonephritis (MGN): The inflammation of the glomerular membrane causes
increased leaking in the kidney. It is not clear why this condition develops in most people, although an
auto-immune mechanism is suspected.
•Membranoproliferative glomerulonephritis (MPGN): is the inflammation of the glomeruli along with the
deposit of antibodies in their membranes, which makes filtration difficult.
•Rapidly progressive glomerulonephritis (RPGN): (Usually presents as a nephritic syndrome) A patient’s
glomeruli are present in a crescent moon shape. It is characterized clinically by a rapid decrease in the
glomerular filtration rate (GFR) by at least 50% over a short period, usually from a few days to 3
months.
They are considered to be "diagnoses of exclusion", i.e. they are diagnosed only after secondary
causes have been excluded.
CAUSES
6. Secondary glomerulonephrosis
•Diabetic nephropathy
•Systemic lupus erythematosus; deposit of immunocomplexes causing lupus nephritis.
•Sarcoidosis , accumulation of inflammatory granulomas in the glomeruli.
•Syphilis
•Hepatitis B
•Sjögren's syndrome
•HIV.
•Amyloidosis: deposit of amyloid substances in the glomeruli.
•Multiple myeloma: accumulation and precipitation of light chains, resulting in renal obstruction. Toxic on
proximal renal tubules.
•Vasculitis
•Cancer
•Genetic disorders: congenital nephrotic syndrome is a rare which the protein nephrin, a component of the
glomerular filtration barrier, is altered.
•Drugs ( e.g. gold salts, penicillin, captopril)
CAUSES
7.
8.
9.
10. Investigations
FBC : anemia,total white count, platelet
Renal profile: Urea,Creatinine,Na,K
Total Albumin < 2.5gm%
Increased serum cholesterol
24-hour protein excretion remains the reference (‘‘gold standard’’) method
Spot urine Protein creatinine ratio(PCR), C3,ANA,Hep B
proteinuria >3.5g per 24 hours (in children, >40mg/m2/hr or PCR >2000mg/g
[>200mg/ mmol] or >300mg/dl or 3+ on urine dipstick) plus hypoalbuminemia and
edema.
Asymptomatic proteinuria, in the range of 0.3–1.5g per 24 hours (or equivalent).
11. Except for SSNS, clinical definition that is sufficiently robust to direct initial treatment,
with the kidney biopsy reserved for identifying pathology only when the clinical response is atypical.
12.
13.
14. General management consideration
Control hypertension
Reducing proteinuria
Control hyperlipidemia
Reducing nephrotic edema
Considering hypercoagulopathy
Considering risk of infection
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012
15. Hypertension
Aim to protect against the cardiovascular risks and delay progressive loss of
GFR.
Lifestyle modification (salt restriction, weight normalization, regular
exercise, and smoking cessation)
Current recommendations suggest that 130/80mmHg should be the treatment
goal.
First-choice therapy; (ACE-I) and (ARB)
Children with GN should have blood pressure controlled to below the 50th
percentile for systolic and diastolic pressure for age and sex.
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012
16. Proteinuria
Reduction in proteinuria reflects control of the primary disease, reduction of glomerular
hypertension, and also reduction of podocyte damage.
Most studies suggest that the loss of kidney function in the progressive histologic patterns discussed
in this guideline can largely be prevented if proteinuria can be reduced to levels below 0.5g/d.
The exceptions are MCD and SSNS where complete remission defines the disease.
In nephrotic syndrome, a reduction of proteinuria to a non-nephrotic range often results in an
elevation to normal of serum proteins (particularly albumin).
Later, it will alleviates many of the patient’s symptoms as well as the metabolic complications of
the nephrotic syndrome, thus improving quality of life.
The antiproteinuric agents of choice are ACE-I or ARB (reduce proteinuria by up to 40–50% in a
dosedependent manner, particularly if the patient complies with dietary salt restriction.)
Since ACE-I and ARBs lower GFR, a 10–20% increase in SCr is often observed. Unless SCr continues to
rise, this moderate increase reflects their effect on kidney hemodynamics and not worsening
disease, and should not prompt withdrawal of the medication.
Adequate dietary protein should be ensured in the proteinuric patient (0.8–1.0g/kg daily) with a
high carbohydrate intake to maximize utilization of that protein.
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012
17. Hyperlipidemia
Dietary restriction of fats and cholesterol
Statins (HMG CoA reductase inhibitors) are well tolerated and effective in
correcting the lipid profile.
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012
18. Nephrotic edema
The mainstay of treatment is diuretics accompanied by moderate dietary sodium restriction
(1.5–2g [60–80mmol] sodium per 24 hours).
Nephrotic patients are often diuretic-resistant even if GFR is normal: oral loop diuretics with
once- or twice-daily administration are usually preferred, given the ease of administration
and longer therapeutic effect compared to i.v. therapy.
In severe nephrotic syndrome, gastrointestinal absorption of the diuretic may be uncertain
because of intestinal-wall edema, and i.v. diuretic, by bolus injection or infusion, may be
necessary to provoke an effective diuresis.
Alternatively, combining a loop diuretic with a thiazide diuretic or with metolazone is often
an effective oral regimen that may overcome ‘‘diuretic resistance’’.
Occasionally, mechanical ultrafiltration is required for resistant edema.
Significant hypovolemia is not often a clinical problem, provided that fluid removal is
controlled and gradual, but the pediatric and the elderly populations are at more risk
Daily weight measurement.
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012
19. Hypercoagulability
The risk of thrombotic events becomes progressively more likely as serum albumin values fall below
2.5g/dl (25g/l).
Immobility as a consequence of edema, obesity, malignancy, intercurrent illness, or admission to
hospital for surgery can further aggravate the risk.
Prophylactic low-dose anticoagulation (e.g., S/C Heparin 5000 units BD) is common practice at times
of high risk.
Full-dose anticoagulation with lowmolecular-weight heparin or warfarin is mandatory if an arterial
or venous thrombosis, or pulmonary embolism, is documented.
Contraindications to prophylactic anticoagulation are: an uncooperative patient; a bleeding
disorder; prior gastrointestinal bleeding; a central nervous lesion prone to hemorrhage (brain tumor,
aneurysms); or a genetic abnormality influencing warfarin metabolism or efficacy.
During treatment with heparin, a significantly higher than average dose may be required because
part of the action of heparin depends on antithrombin III, which may be lost in the urine in the
nephrotic patient.
Warfarin is the long-term treatment of choice but should be monitored with special care because of
potential alterations in the protein binding of the drug with fluctuations in serum albumin in the
nephrotic patient. A target (INR) of 2–3 is usually recommended.
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012
20. Risk of infection
Particularly important in nephrotic children with ascites, in whom the fluid should be examined
microscopically and cultured for spontaneous bacterial peritonitis (SBP).
ESR is unhelpful, but an elevated CRP may be informative.
Parenteral antibiotics should be started once cultures are taken and the regimen should include
benzylpenicillin (to treat pneumococcal infection).
If repeated infections occur, serum immunoglobulins should be measured. If serum IgG is less than 600mg/dl
(6g/l), there is limited evidence that infection risk is reduced by monthly administration of i.v.
immunoglobulin 10–15g to keep serum IgG >600mg/dl (>6g/l).
Those with GN and nephrotic syndrome are at increased risk of invasive pneumococcal infection and should
receive pneumococcal vaccination with the heptavalent conjugate vaccine (7vPCV) and the 23-valent
polysaccharide vaccine (23vPPV) as well as the annual influenza vaccination.
Vaccination with live vaccines (measles, mumps, rubella, varicella, rotavirus, yellow fever) is
contraindicated while on immunosuppressive or cytotoxic agents, and should be deferred until prednisone
dose is <20mg/d and/or immunosuppressive agents have been stopped for at least 1–3 months.
Exposure to varicella can be life-threatening, especially in children. Treatment should be given with zoster
immune globulin if exposure does occur and antiviral therapy with acyclovir or valaciclovir begun at the first
sign of chicken pox lesions.
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012
21. Specfic approach
Nephrotic syndrome affects 1–3 per 100,000 children below 16 years of age.
80% of children respond to corticosteroid therapy.
A kidney biopsy diagnosis is not required routinely at presentation because the International Study of Kidney
Disease in Children (ISKDC) demonstrated,
93% of children with MCD responded to corticosteroids,
25–50% of children with mesangial proliferative glomerulonephritis (MPGN) or FSGS also responded to corticosteroids.
The majority of children who relapse continue to respond completely to corticosteroids throughout their
subsequent course, and the long-term prognosis, including maintenance of normal kidney function, is good.
Without treatment, nephrotic syndrome in children is associated with high risk of death, particularly from
bacterial infection.
Before the use of corticosteroids and antibiotics, 40% of children died, with half of these deaths being from
infection.
A recent study reports only one death (0.7%) associated with nephrotic syndrome among 138 children with
SSNS presenting between 1970 and 2003.
The likelihood of initial corticosteroid unresponsiveness is increased with increasing age at presentation,in
African and African-American children,and in children with kidney pathologies other than MCD.
22.
23.
24. Steroid-sensitive nephrotic syndrome (SSNS) in children
Treatment of the initial episode of SSNS
We recommend that corticosteroid therapy (prednisone or prednisolone)* be
given for at least 12 weeks. (1B)
We recommend that oral prednisone be administered as a single daily dose
(1B) starting at 60mg/m2/d or 2mg/kg/d to a maximum 60mg/d. (1D)
We recommend that daily oral prednisone be given for 4–6 weeks (1C)
followed by alternate-day medication as a single daily dose starting at
40mg/m2 or 1.5mg/kg (maximum 40mg on alternate days) (1D) and
continued for 2–5 months with tapering of the dose. (1B)
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012
25. Treatment of relapsing SSNS with corticosteroids
We suggest that infrequent relapses of SSNS in children be treated with a
single-daily dose of prednisone 60mg/m2 or 2mg/kg (maximum of 60mg/d)
until the child has been in complete remission for at least 3 days. (2D)
We suggest that, after achieving complete remission, children be given
prednisone as a single dose on alternate days (40mg/m2 per dose or
1.5mg/kg per dose: maximum 40mg on alternate days) for at least 4 weeks.
(2C)
We suggest that frequently relapsing (FR) and steroid-dependent (SD) SSNS
be treated with daily prednisone until the child has been in remission for at
least 3 days, followed by alternate-day prednisone for at least 3 months. (2C)
*Prednisone and prednisolone are equivalent, used in the same dosage, and
have both been used in RCTs depending on the country of origin.
Steroid-sensitive nephrotic syndrome (SSNS) in children
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012
26. If having Corticosteroid side effects, suggest for corticosteroid-sparing agents :
A) Cyclophosphamide or Chlorambucil, FR SSNS(1B) and SD SSNS. (2C)
cyclophosphamide (2mg/kg/d) be given for 8–12 weeks (maximum cumulative dose 168mg/kg). (2C)
chlorambucil (0.1–0.2mg/kg/d) may be given for 8 weeks (maximum cumulative dose 11.2mg/kg) as an
alternative to cyclophosphamide. (2C)
B) Levamisole (1B)
levamisole 2.5mg/kg on alternate days (2B) for at least 12 months (2C) as most children will relapse when
levamisole is stopped.
C) Calcineurin inhibitors (CIN) : Cyclosporine or Tacrolimus (1C)
Cyclosporine 4–5mg/kg/d (starting dose) in two divided doses. (2C)
Tacrolimus 0.1mg/kg/d (starting dose) given in two divided doses be used instead of cyclosporine when the
cosmetic side-effects of cyclosporine are unacceptable. (2D)
At least 12 months, as most children will relapse when CNIs are stopped. (2C)
D) MMF (Mycophenolic Acid mofetil) (2C)
MMF (starting dose 1200mg/m2/d) be given in two divided doses for at least 12 months, as most children will
relapse when MMF is stopped. (2C) 3.3.6:
Not used mizoribine in FR and SD SSNS. (2C), & Azathioprine in FR and SD SSNS. (1B)
Indication for kidney biopsy in children with SSNS are (Not Graded):
Late failure to respond following initial response to corticosteroids
High index of suspicion for a different underlying pathology
Decreasing kidney function in children receiving CNIs.
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012
27.
28. Steroid-resistant nephrotic syndrome (SRNS)
in children
Define as minimum of 8 weeks treatment with corticosteroids. (2D)
Requirements to evaluate the child with SRNS (Not Graded):
Diagnostic kidney biopsy;
Evaluation of kidney function by GFR or eGFR;
Quantitation of urine protein excretion.
Calcineurin inhibitor (CNI) as initial therapy for children with SRNS. (1B)
A minimum of 6 months and then stopped if a partial or complete remission of proteinuria is not achieved. (2C)
Continued for a minimum of 12 months when at least a partial remission is achieved by 6 months. (2C)
Low-dose corticosteroid therapy be combined with CNI therapy. (2D)
ACE-I or ARBs for children with SRNS.(1B)
In children who fail to achieve remission with CNI therapy:
Mycophenolate mofetil (2D), high-dose corticosteroids (2D), or a combination of these agents (2D) be considered in
children who fail to achieve complete or partial remission with CNIs and corticosteroids.
Cyclophosphamide not be given. (2B)
In patients with a relapse of nephrotic syndrome after complete remission, we suggest that therapy be
restarted using any one of the following options: (2C)
Oral corticosteroids (2D)
Return to previous successful immunosuppressive agent (2D)
An alternative immunosuppressive agent to minimize potential cumulative toxicity (2D).
29. Minimal-change disease (MCD) in adults
Recommend that corticosteroids be given for initial treatment of nephrotic syndrome. (1C)
Prednisone or prednisolone* be given at a daily single dose of 1mg/kg (maximum 80mg) or alternate-day
single dose of 2mg/kg (maximum 120mg). (2C)
Suggest the initial high dose of corticosteroids, if tolerated, be maintained for a minimum period of 4 weeks
if complete remission is achieved, and for a maximum period of 16 weeks if complete remission is not
achieved. (2C)
In patients who remit, corticosteroids be tapered slowly over a total period of up to 6 months after
achieving remission. (2D)
For patients with relative contraindications or intolerance to high-dose corticosteroids (e.g., uncontrolled
diabetes, psychiatric conditions, severe osteoporosis), we suggest oral cyclophosphamide or CNIs as
discussed in frequently relapsing MCD. (2D)
FR/SD MCD
Oral cyclophosphamide 2–2.5mg/kg/d for 8 weeks. (2C)
CNI (cyclosporine 3–5mg/kg/d or tacrolimus 0.05–0.1mg/kg/d in divided doses) for 1–2 years for FR/SD MCD
patients who have relapsed despite cyclophosphamide, or for people who wish to preserve their fertility. (2C)
MMF 500–1000mg twice daily for 1–2 years for patients who are intolerant of corticosteroids,
cyclophosphamide, and CNIs. (2D)
Corticosteroid-resistant: Re-evaluate patients who are corticosteroid-resistant for other causes of
nephrotic syndrome. (Not Graded)
30. Idiopathic focal segmental glomerulosclerosis
(FSGS) in adults
Undertake thorough evaluation to exclude secondary forms of FSGS. (Not Graded).Do not routinely perform
genetic testing. (Not Graded)
Recommend that corticosteroid and immunosuppressive therapy be considered only in idiopathic FSGS
associated with clinical features of the nephrotic syndrome. (1C)
Prednisone* be given at a daily single dose of 1mg/kg (maximum 80mg) or alternate-day dose of 2mg/kg
(maximum 120mg). (2C)
Initial high dose of corticosteroids be given for a minimum of 4 weeks; continue high-dose corticosteroids up to a
maximum of 16 weeks, as tolerated, or until complete remission has been achieved, whichever is earlier. (2D)
Tapered slowly over a period of 6 months after achieving complete remission. (2D)
CNIs be considered as first-line therapy for patients with relative contraindications or intolerance to high-
dose corticosteroids (e.g., uncontrolled diabetes, psychiatric conditions, severe osteoporosis). (2D)
Relapse of nephrotic syndrome is treated as per the recommendations for relapsing MCD in adults. (2D)
For steroid-resistant FSGS, we suggest that cyclosporine at 3–5mg/kg/d in divided doses be given for at
least 4–6 months. (2B)
If there is a partial or complete remission, we suggest continuing cyclosporine treatment for at least 12 months,
followed by a slow taper. (2D)
If not tolerate cyclosporine, treated with a combination of mycophenolate mofetil and high-dose
dexamethasone. (2C)
31.
32. Idiopathic membranous nephropathy (MN)
Perform appropriate investigations to exclude secondary causes in all cases of biopsy-proven MN. (Not Graded)
Initial therapy be started only in patients with nephrotic syndrome AND when at least one of the following
conditions is met:
Urinary protein excretion persistently exceeds 4g/d AND remains at over 50% of the baseline value, AND does not show
progressive decline, during antihypertensive and antiproteinuric therapy in observation period of at least 6 months;
(1B)
Presence of severe, disabling, or life-threatening symptoms related to the nephrotic syndrome; (1C)
SCr has risen by 30% or more within 6 to 12 months from the time of diagnosis but the eGFR is not less than 25–
30ml/min/1.73m2 AND this change is not explained by superimposed complications. (2C)
Do not use immunosuppressive therapy in patients with a SCr persistently >3.5mg/dl (>309lmol/l) (or an eGFR
<30ml/min per 1.73m2) AND reduction of kidney size on ultrasound (e.g., <8cm in length) OR those with
concomitant severe or potentially life-threatening infections. (Not Graded)
Initial therapy consist of a 6-month course of alternating monthly cycles of oral and i.v. corticosteroids, and oral
alkylating agents (1B)
Using cyclophosphamide rather than chlorambucil for initial therapy. (2B)
Managed conservatively for at least 6 months following the completion of this regimen before being considered a
treatment failure if there is no remission, unless kidney function is deteriorating or severe, disabling, or
potentially life-threatening symptoms related to the nephrotic syndrome are present (1C)
Alternative regimens cyclosporine or tacrolimus be used for a period of at least 6 months.
Corticosteroid monotherapy not be used for initial therapy(1B) and MMF also not for initial therapy of IMN. (2C)
33. Idiopathic membranoproliferative
glomerulonephritis (MPGN)
Evaluate patients with the histological (light-microscopic) pattern of MPGN
for underlying diseases before considering a specific treatment regimen. (Not
Graded)
Suggest that adults or children with presumed idiopathic MPGN accompanied
by nephrotic syndrome AND progressive decline of kidney function receive
oral cyclophosphamide or MMF plus low-dose alternate day or daily
corticosteroids with initial therapy limited to less than 6 months. (2D)
34.
35.
36. Case Presentation
A 21-year-old Japanese woman, NKMI previously. Non smoker, non obese, never
took OCP
Complaint of palpitation and chest pain started the day before.
Associated with lower extremities swelling for 2 weeks.
Physical characteristics: Weight 53kg; Height 166cm; body mass index 19.2kg/m2;
Vitals: BP 110/62mmHg; pulse rate 120 beats/minute; RR 20 breaths/minute and
SPO2 97% (room air).
Her physical examination was normal except for the edema of the lower
extremities.
37. Lab investigation
Leucocyte 9660 cells/μL; HB 14.8g/dL; Platelets 329,000/μL; HCT 42.2%;
Urea 19mg/dL; Creat 1.26mg/dL; serum albumin 1.7g/dL; TP 4.3g/dL; TC 497mg/dL; TG 187mg/dL;
Serum C3 116mg/dL and C4 34mg/dL.
ANA was negative.
The coagulation profile revealed the following: PT 15.2 sec; (APTT) 84.5 sec;
D-dimer 6.9μg/mL (normal: 0 to 0.4μg/mL);
Fibrinogen 832mg/mL (normal: 150 to 410mg/mL);
Fibrin-fibrinogen degradation product 10.5μg/dL (normal: 0 to 5μg/dL);
Antithrombin III 70% (normal: 80% to 120%);
protein C 29% (normal: 70% to 140%); and protein S 66% (normal: 65% to 135%).
Urinary protein excretion was 4g/d , and microhematuria was absent.
ABG: pH 7.46, carbon dioxide 35.5mmHg, partial pressure of oxygen 88.6mmHg, and bicarbonate
26.0mEq/L (room air).
38. Radio
Her chest radiograph and ECG were normal.
A CT angiogram revealed thrombi of her bilateral pulmonary arteries and left
common iliac vein.
Presumably, the pulmonary thrombosis originated from the thrombi of the left iliac
vein.
Computed tomography angiogram showing thrombi (arrows) in the pulmonary
trunk, bilateral pulmonary artery (A) and left common iliac vein (B).
39. Treatment
Treatment of thrombosis was initiated with intravenous administration of heparin and urokinase.
First, 18IU/kg of heparin per hour was initiated while adjusting the dose to maintain APTT between 60 and
85 seconds,
urokinase was infused at 10,000U/hour for 24 hours. Oral warfarin administration was also started,
aiming at a prothrombin time-international normalized ratio of between 1.5 and 2.5, and heparin infusion
was gradually decreased.
An inferior vena cava (IVC) filter was placed percutaneously to avoid further development of pulmonary
thrombosis by the left common iliac vein thrombi.
Furthermore, corticosteroid therapy was initiated with prednisolone at a dose of 0.8mg/kg per day.
Contrast-enhanced CT performed on day 14 revealed a reduction of the pulmonary thrombi and capture of
the thrombi in the inferior vena cava (IVC) filter
The patient’s proteinuria resolved after 3 weeks of treatment.
The prompt and complete response to the corticosteroid therapy suggested that minimal change disease
was the etiology of NS and pulmonary artery thrombosis.
40. References
KDIGO Clinical Practice Guideline for Glomerulonephritis June 2012,
Kidney International Supplements (2012)
http://www.cochrane.org/CD001533/RENAL_corticosteroid-therapy-children-
nephrotic-syndrome
https://emedicine.medscape.com/article/244631-overview
An adult case of nephrotic syndrome presenting with pulmonary artery
thrombosis: Journal of Medical Case Reports
