management of nephrotic syndrome in adults in the primary care setting

1. OVERVIEW OF MANAGEMENT OF NEPHROTIC
SYNDROME
DR OGECHUKWU MBANU
FAMILY MEDICINE DEPARTMENT
AKTH KANO
11/7/2019

2. OUTLINE
•What is nephrotic snydrome
•Diagnostic criteria
•Epidemiology
•Case definitions related to
nephrotic syndrome
•Etiology
•Pathophysiology
•Evaluation
•Management
•Differential diagnosis
•Complications
•Indications for referral
•Indications for renal biopsy
•Conclusion

3. WHAT IS NEPHROTIC SYDROME
•A clinical syndrome defined as proteinuria
>3.5g/1.73m 2 /day that is associated with
hypoalbuminaemia, oedema, hyperlipidemia,
lipiduria (and thrombotic tendency)

4. Diagnostic criteria
• Nephrotic syndrome, is a manifestation of glomerular disease (due to
various etiologies) characterized by,
• Heavy proteinuria
• Spot urine showing protein to creatinine ratio > 3 to 3.5 mg
protein/mg creatinine (300 to 350 mg/mmol), or
• 24 hr. urine collection showing >3 to 3.5 g protein
• Hypoalbuminemia
• Serum albumin < 2.5 g/dL(25g per L)
• Hyperlipidemia(not required for diagnosis)
• Serum cholesterol >350 mg/dL( 9.06 mmol per L)
• Edema
• Clinical evidence of peripheral edema

5. EPIDEMIOLOGY
• The annual incidence of NS in adults is three per 100,000 persons
• Approximately 80% to 90% of NS cases in adults are idiopathic
• Membranous nephropathy is the most common cause in whites, and
focal segmental glomerulosclerosis is most common in blacks; each of
these disorders accounts for approximately 30% to 35% of NS cases in
adults
• Minimal change disease account for approximately 15% of cases.
• The remaining 10% of cases are secondary to an underlying medical
condition

6. CASE DEFINITIONS RELATED TO NEPHROTIC SYNDROME
• REMISSION : Urine albumin nil or trace for 3 consecutive early
morning specimens.
• RELAPSE : Urine albumin 3+ or 4+ (or proteinuria >3.5g/1.73 m2 ) for
3 consecutive early morning specimens, having been in remission
previously.
• FREQUENT RELAPSES : Two or more relapses in six months (or) four or
more relapses in any twelve months.
• STEROID DEPENDENCE : Two consecutive relapses when on alternate
day steroids or within 14 days of its discontinuation.
• STEROID RESISTANCE : Absence of remission despite therapy with
daily prednisolone at a dose of 1mg/kg per day for 4 weeks
• INFREQUENT PELAPSE :1 relapse in 6 months , 1 to 3 relapse in 12
months

7. ETIOLOGY OF NEPHROTIC SYNDROM
 Primary glomerulonephritis
 Minimal change disease (80% paeds cases)
 Focal segmental glomerulosclerosis (most common cause in adults)
 Membranous glomerulonephritis
 Systemic causes – Secondary glomerulonephritis
 Diabetic nephropathy
 Sarcoidosis
 Autoimmune: SLE, Sjogrens
 Infection: Syphilis, hepatitis B, HIV
 Amyloidosis
 Multiple myeloma
 Vasculitis
 Cancer
 Drugs: gold, penicillamine, captopril, NSAIDs
• Hereditary nephropaties

8. PATHOPHYSIOLOGY
• Nephrotic syndrome involves disruption
in the structure and function of
glomerular basement membrane ,
podocytes ,slit diaphragm and therefore
glomerular filtration .
• This leads to massive proteinuria which
can be selective (MCD) or non – selective
(FSGS AND MENBRANOUS
NEPHROPATHY)
• Reduction plasma colloid osmotic
pressure secondary to
hypoalbuminemia Edema and
hypovolemia
• Loss of lipoproteins ,reflex liver
lipoprotein production, diminished
catabolism of lipoproteins

11. EVALUATION
• History & examinations
• Pay attention to - secondary
etiologies
• prior therapies
• Edema
• blood pressure
• anthropometry (height, weight)
• infections
• Regular weight record helps
monitor the decrease or increase
of edema
• Infections should be treated
before starting therapy with
corticosteroids
LABORATORY INVESTIGATIONS
• Urine
• Complete Blood Count
• Renal parameters :
• Spot Urine Protein : Creatinine ratio
• Creatinine, urea, albumin, cholesterol
• Liver Function Test
• Urine culture & sensitivity
• PPD test & X- Ray chest
ADDITIONAL TESTS
• C3 and ASO
• ANA
• Hepatitis B surface antigen
• HIV screening
• Abdominal uss

12. EVALUATION – PRESENTATION
 New-onset oedema
 Initially periorbital or peripheral
 Later genitals, ascites, anasarca
 Frothy urine
 Generalised symptoms – lethargy, fatigue, reduced appetite
 Oedema
 BP normal/raised
 Leukonychia
 Breathlessness:
 Pleural effusion, fluid overload, AKI
 DVT/PE/MI
 Eruptive xanthomata/ xanthalosmata

13. MANAGEMENT
 Conservative
 Monitor U&E, BP, fluid balance, weight
 Salt and fluid restriction
 Treat underlying cause
 Medical
 Diuretics
 ACE-inhibitors/ARBs
 Corticosteroids/immunomodulators
 Anticoagulation
 Dialysis
 Surgical
 Renal transplant

14. GENERAL MANAGEMENT PRINCIPLES –1
SALT AND FLUID RESTRICTION
• Monitor volume status carefully.
• Include regular measurement of weight, aiming for 0.5 – 1kg loss/day.
• Chart fluid intake and output wherever possible
• Salt-restrict to ≤ 2g/day
• Diuretics: a loop diuretic, such as furosemide, e.g. 40mg/day PO, increasing, as
necessary, to 250mg daily.
• In massive oedema, IV diuretics may be required to overcome impaired oral drug
absorption ( due to gut oedema).
• Add-on thiazide-type diuretics (e.g. metolazone 2.5 – 5mg PO od)
• May help to promote diuresis through a synergistic effect
• Requires regular (often daily) measurement of Na + and K + to prevent profound
electrolyte imbalances —(caution, in outpatient setting)

15. SALT AND FLUID RESTRICTION –
• IV furosemide in combination with salt-poor albumin (e.g. 50 – 100mg
furosemide in 100mL 20% human albumin solution over 1h) may be
used in the setting of
• Severe edema
• Ascites
• Pleural effusion
• Genital edema
• Low serum albumin
• Severe edema: Intake of fluid is restricted to insensible water loss
• Moderate edema: Fluid intake = Insensible water loss (400 mL/m2/day)
+ Previous day's urine output
• Mild edema: Fluid is minimally restricted

16. GENERAL MANAGEMENT PRINCIPLES – 2
•REDUCTION OF PROTEINURIA
• ACE-I or ARB are used for their anti- proteinuric effect.
• Titrate carefully toward full dose (consider night-time administration
if hypotension).
• May reduce proteinuria by up to 50% at 8 weeks and therefore
prevent progression.
• Treat  BP, aiming for ≤125/75mmHg.

17. GENERAL MANAGEMENT PRINCIPLES – 3
HYPERCOAGULABILITY
• Risk factors for thrombosis in nephrotic syndrome:
• Duration of syndrome.
• Degree of proteinuria
• Serum albumin <20g/L
• Underlying membranous nephropathy (Up to 20% of patients with
nephrotic syndrome due to membranous nephropathy will develop a
DVT)
• Breathlessness, Flank pain and heamaturia may indicate pulmonary
thromboembolism or renal vein thrombosis respectively
• Prevention: Avoid prolonged bed rest, maintenance of hydration, avoid
injudicious use of diuretics

18. Hypercoagulability – 2
• Prophylactic anticoagulation with SC heparin (and sometimes
warfarin) initially followed by oral-anti coagulants on the long term in
high-risk patients is advised. These include :
• Previous history of thromboembolism
• An underlying hypercoagulation disorder other than nephrotic
syndrome
• Presence of a central venous catheter
• Formally anticoagulate those with proven DVT or thromboembolic
episode.
• Treat for the duration of the nephrotic syndrome;
• Aim for INR 2 – 3

19. GENERAL MANAGEMENT PRINCIPLES – 4
INFECTION – this may be due to :
•Low IgG levels predispose to infection.
•Impaired T-lymphocyte function
•Edema fluid acting as potential culture medium
•Impaired tissue perfusion due to edema
•Low factor B (C3 pro-activator) & Factor D levels -decreased
bacterial opsonization
•Immunosuppressive therapy
•Skin breaks due to stretching of edematous skin, are easy
portal of entry for organisms
•An URTI or some other infection usually precipitates a relapse

20. INFECTION –2
•Appropriate therapy of an infection before starting
therapy might result in spontaneous remission
•Infection may complicate immune suppressive
treatment of the nephrotic syndrome
•Infections should be treated promptly, with appropriate
cover for polysaccharide encapsulated organisms: Strep
pneumoniae, Neisseria meningitidis, Klebsiella
pneumoniae, Haemophilus influenzae, Salmonella typhi,
Cryptococcus neoformans, Pseudomonas aeruginosa

21. INFECTION –3
•ESR, leukocyte count are poor markers of infection in nephrotic
syndrome.
•CRP, pro-calcitonin can be helpful instead
•Mantoux test is to be done before starting steroid therapy.
•Those with Mantoux positive but show no evidence of TB,
should receive INH prophylaxis (10 mg/kg/day) for 6 months.
•Those showing evidence of active tuberculosis should receive
standard anti-tubercular therapy
•persistently nephrotic patients should be vaccinated against
pneumococcal disease

23. GENERAL MANAGEMENT PRINCIPLES –5
•DYSLIPIDEMIA
• Mechanism: Hypoalbuminemia upregulates HMG-CoA reductase and
downregulates lipoprotein lipase, VLDL receptor and hepatic triglyceride
lipase.
• Successful treatment of elevated LDL cholesterol may prevent CV morbidity
and slow decline in renal function.
• Dietary restriction is usually insufficient
• statins are often used
• Treatment of underlying nephrotic syndrome will usually lead to resolution
of dyslipidaemia unless
• Dyslipidaemia can be a pointer to relapse

24. GENERAL MANAGEMENT PRINCIPLES –6
DIETARY MANAGEMENT
•A balanced diet, adequate in protein (1.5-2 g/kg) and
calories is recommended.
•Patients with persistent proteinuria should receive 2-2.5
g/kg of protein daily.
•Dietary fat should be restricted to <30% of calories.
Saturated fat should be <10% of total calorie intake.
Dietary cholesterol intake should be <300 mg/day.

25. DIETARY MANAGEMENT – 2
• Treatment with corticosteroids stimulates appetite, so adequate physical activity is
to be ensured to prevent excessive weight gain.
• Patients on prolonged (>3 months) treatment with steroids should receive daily
supplements of oral calcium (250-500 mg/day) and vitamin D (125-250 IU/day).

26. GENERAL MANAGEMENT PRINCIPLES – 7
HYPERTENSION
•Hypertension may be present at the onset or may appear
late due to steroid toxicity.
•Low salt diet, exercise, weight reduction.
•ACE inhibitors and Angiotensin Receptor Blockers are the
first line agents as they also reduce proteinuria.
•Calcium channel blockers and β2agonists can also be
used.

27. GENERAL MANAGEMENT PRINCIPLES
CORTICOSTEROID THERAPY
•Appropriate therapy at the first episode is an important
determinant of the long term course of the disease.
•Prednisolone is the drug of choice
•Prednisolone 1mg/kg daily (to maximum of 80mg/day) until
remission achieved.
•Taper prednisolone fortnightly, then weekly, until discontinued.
•Treatment should be continued is for at least 12 weeks at first
presentation to minimize risk of relapse.
•Tapered slowly, e.g. over 6 months

28. CORTICOSTEROID THERAPY – 2
•MCD remits rapidly with corticosteroids therapy; 80 –
90% of adults will be in remission after 12 weeks of
therapy
•Relapse can be expected in 30 – 70% of cases.
•First relapse and infrequent relapses should be treated as
described earlier.
• If relapses are more frequent and respond quickly to
steroids, then taper immediately on remission, aiming for
a shorter course

29. GENERAL MANAGEMENT PRINCIPLES
OTHER IMMUNOMODULATOR DRUGS
Those that are ‘ FREQUENT RELAPSE ’ , ‘ STEROID - DEPENDENT ’ ,
‘ STEROID - RESISTANT ’ can be managed with any of the following immunomodulating
drugs :-
• Levamisole
• Calcineurin inhibitors
• Ciclosporin and tacrolimus
• Cyclophosphamide
• Rituximab
• Anti proliferative agents
• mycophenolate mofetil
• Proliferation signal inhibitors
• Rapamycin – a product of soil actinomycete Streptomyces hygroscopicus ( preferable for women of
child bearing age)
• Everolimus

30. GENERAL MANAGEMENT PRINCIPLES – 8
•EDUCATION OF PARENT
• Patients should be provided information about the course, complications &
outcome of the disease.
• Urine examination with dipstick Daily during relapse or during periods of infection.
Once or twice a week during remission.
• Maintain a dairy containing information about proteinuria, medications &
infections.
• Ensure that the patient remains active during periods of remission. No restrictions
are imposed.
• As infections constitute significant proportion of morbidity, need for appropriate
immunization should be stressed.

31. DIFFERENTIAL DIAGNOSIS OF NEPHROTIC SYNDROME
• Protein –losing enteropathy
• Hepatic Failure.
• HF
• Protein energy malnutrition
• Acute and chronic GN
• urticaria? Angioedema

32. COMPLICATIONS
 Increased susceptibility to infection
 20% adult cases
 Due to reduced serum IgG, reduced complement activity, reduced T cell
function
 Spontaneous peritonotis
 Thromboembolism
 40% adult cases
 Partly due to increased clotting factors and platelet abnormalities
 Hyperlipidaemia
 due to hepatic lipoprotein synthesis to restore osmotic pressure
 ARF :pre – renal and renal
 Hypovolemic shock

33. INDICATIONS FOR REFERRAL
•Features suggesting diagnosis other than minimal change dx
•Severe, difficult to control oedema
•Elevated creatinine despite correction of any hypovolemia
•Not in remission after 4 weeks of steroid therapy
•Relapses (while taking steroids or within two weeks of
cessation, >2 in first 6 months or >4 in 12 months)
•Steroid toxicity prompting consideration of alternative agent
•Patients requiring care beyond the comfort of the local health
care facility

34. INDICATIONS FOR RENAL BIOPSY
• Features suggesting a diagnosis other than minimal change nephropathy.
• NS presenting in first year of life.
• NS presenting after six years.
• Failure to respond to adequate dose of steroid therapy in 28 days.
• Frequently relapsing NS.
• Steroid dependent NS.
• Development of Steroid resistance
• Change in clinical course.
• Before starting immunosuppressive therapy.
• Patient with renal insufficiency and NS.
• Sustained hypertension

35. CONTRAINDICATIONS TO RENAL BIOPSY
•Solitary kidneys
•Renal mass
•Advanced chronic renal failure
•Active urinary infection
•Uncontrolled hypertension
•Coagulation disorders
•Renal artery aneurysm
•Perinephric abscess
•Horseshoe kidneys.

36. CONCLUSION
•Treat the initial episode adequately
•Prednisolone only for initial episode.
•Monitor for steroid toxicity features
•Prompt treatment of infections and complications
•Steroid responsiveness - Prognostic indicator.
•Patient education – essential
•Consultation with nephrologists should guide decisions about
use of anticoagulation and immunosuppressants,need for
renal biopsy, and for other areas of uncertainty

38. REFERRENCE
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