1. CHILD WITH PROTIENUREA
Dr.Farah Sameer Yahya
Lecturer / dep. pediatics/mosul college of medicine

2. Proteinuria is a hallmark of glomerular and/or tubular injury
Proteinuria is a hallmark of glomerular and/or tubular injury. Both can be associated with hematuria.
The aim of evaluating a patient with proteinuria is to differentiate clinically significant, generally persistent (or recurrent) proteinuria from transient or physiological proteinuria.

3. LAB. EVALUATION OF PROTIENURIA
Qualitative :-
The urinary dipstick test offers a qualitative assessment of urinary protein excretion.
Dipsticks primarily detect albuminuria and are less sensitive for other forms of proteinuria
The dipstick is reported as :-
negative , trace (10-20 mg/dL) 1+ (30 mg/dL), 2+ (100 mg/dL), 3+ (300 mg/dL), and 4+ ( mg/dL).

6. 2-QUNTITIVE :-
A- children with persistent proteinuria should have proteinuria quantitated with the more precise spot urine protein:creatinine ratio (UPr:UCr),
IT IS is best performed on a first morning voided urine specimen to eliminate the possibility of orthostatic (postural) proteinuria .
Ratios <0.5 in children <2 yr of age and <0.2 in children ≥2 yr of age suggest normal protein excretion. A ratio >2 suggests nephrotic-range proteinuria.

7. B- Timed (24-hr) urine collections offer more precise information regarding UPr excretion.
normal protein excretion in healthy children is 150 mg/24 hr or ≤4 mg/m2/hr;
abnormal is defined as 4-40 mg/m2/hr; and nephrotic range is defined as >40 mg/m2/hr.
Timed urine collections are cumbersome to obtain, and have largely been replaced by the spot protein:creatinine ratio.

8. TRANSIENT PROTIENURIA :-
Approximately 10%
adolescents > in younger children which resolved after serial testing .
cause remains elusive.
Defined contributing factors include :-
a temperature >38.3C , exercise , dehydration, cold exposure, heart failure, seizures, or stress.
The proteinuria usually does not exceed 1-2+ on the dipstick. No evaluation or therapy is needed for children with this benign condition.

9. Orthostatic (Postural) Proteinuria
Orthostatic proteinuria is the most common cause of persistent proteinuria in school-aged children and adolescents
Patients with orthostatic proteinuria excrete normal or minimally increased amounts of protein in the supine position. In the upright position, urinary protein excretion may be increased 10-fold, up to 1 g/24 hr.
Hematuria, hypertension, hypoalbuminemia, edema, and renal dysfunction are absent.

10. The absence of proteinuria (dipstick negative or trace for protein and urine Pr : Cr ratio <0.2) in the first morning urine sample for 3 consecutive days confirms the diagnosis of orthostatic proteinuria.
No further evaluation is necessary, and the patient and family should be reassured of the benign nature of this condition.

11. Fixed (glumerular) Proteinuria
Persons found to have significant proteinuria on a first morning urine sample on 3 consecutive days (>1+ on dipstick or protein : creatinine ratio >0.2) have fixed proteinuria.
Fixed proteinuria indicates renal disease and may be caused by either glomerular or tubular disorders.

12. Nephrotic syndrome
NS a manifestation of glomerular disease, is characterized by nephrotic range proteinuria , hypoalbuminemia, edema, and hyperlipidemia.
Nephrotic range proteinuria is defined as
protein excretion of > 40 mg/m2/hr or a first morning protein : creatinine ratio of >2-3 : 1
Hypoalbuminemia<2,5gm /dl
generalized edema
Hyperlipidemia >250 mg /dl

14. Etiology
Most children with nephrotic syndrome have a form of primary or idiopathic nephrotic syndrome
Glomerular lesions associated with idiopathic nephrotic syndrome include :-
minimal change disease (the most common)
focal segmental glomerulosclerosis,
membranoproliferative glomerulonephritis,
membranous nephropathy
and diffuse mesangial proliferation

15. Secondary Causes:-
Vasculitis (lupus nephritis, henoch-schonlein purpura ,wegner’ granulomatosis )
Post infection (poststreptococcal , hepatitis B,C syphilis,HIV, others)
Drugs (NSAIDs, gold)
DM (rare in children )

16. Pathogenesis The glomerular filtration barrier is made up of:
Glomerular basement membrane: a very thick membrane rich in negatively charged glycosaminoglycans which repels negatively charged proteins.
Podocyte slit diaphragm: podocytes line the other side of the basement membrane and form an interdigitating network of foot processes. Neighbouring foot processes are connected by a continuous membrane-like structure called the slit diaphragm. The permeability-selectivity (permselectivity) allows small ions to pass freely but bars large proteins such as haemoglobin and albumin.

17. The underlying abnormality in nephrotic syndrome is an increased permeability of the glomerular capillary wall
On biopsy, the extensive effacement of podocyte foot processes
disturbances in the immune system, especially T cell–mediated immunity.

18. What happen in nephrotic syndrome
Hypoalbuminemia
Reduced intravascular oncotic pressure
Shifting of fluid to interstitial space
Increased albumin
production &lipoprotein
synthesis
Reduced plasma volume
Increased aldosterone secretion
Reduced renal tension
Increased TG & LDL
Salt and water retention
Edema

19. Increase glomerular permeability
Loss of
Immunoglobulin loss of
coagulation factors
Increase platelets
aggregation
albuminuria malnutrition Hyperlipidemia
hypoalbuminemia increase lipogenesis
synthesis
thrombosis
Increase
Infection
edema

20. Idiopathic Nephrotic Syndrome
Approximately 90% of children with nephrotic syndrome have idiopathic nephrotic syndrome.

21. Idiopathic NS include :-
1-minimal change nephrotic syndrome (MCNS) (about 85% of total cases of nephrotic syndrome in children the glomeruli appear normal or show a minimal increase in mesangial cells and matrix.
Findings on immunofluorescence microscopy are typically negative
and electron microscopy simply reveals effacement of the epithelial cell foot processes.
More than 95% of children with minimal change disease respond to corticosteroid therapy.

22. 2-Mesangial proliferation is characterized by a diffuse increase in mesangial cells
3- focal segmental glomerulosclerosis (FSGS), glomeruli show lesions that are both focal and segmental .The lesions consist of mesangial cell proliferation segmental scarring on light microscopy

23. Clinical Manifestations
The idiopathic nephrotic syndrome is more common in boys than in girls (2 : 1) and most commonly appears between the ages of 2 and 6 yr .
MCNS is present in 85-90% of patients <6 yr of age. In contrast, only 20-30% of adolescents who present for the first time with nephrotic syndrome have MCNS. The more common cause of idiopathic nephrotic syndrome in this older age group is FSGS.

25. The initial episode of idiopathic nephrotic syndrome usually follows minor infections and, uncommonly, reactions to insect bites.
Children usually present with mild edema, which is initially noted around the eyes (periorbital) and in the lower extremities.
Nephrotic syndrome can initially be misdiagnosed as an allergy.

27. With time, the edema becomes generalized, with the development of ascites, pleural effusions, and genital edema. Anorexia, irritability, abdominal pain, and diarrhea are common.
Important features of minimal change idiopathic nephrotic syndrome are the absence of hypertension and gross hematuria.

28. ‘foamy’ urine is present in NS ,, microscopic hematuria seen in 20% of case but macroscopic hematuria is unusual.

29. Examination
Examination is focused on diagnostic features, presence or absence of ‘atypical’ features and complications.
Oedema: periorbital, lower limb, abdominal wall, sacral,
scrotal. Pleural effusions, ascites
CVS: look for intravascular volume status: heart rate, blood pressure, capillary refill time
Fever: look for sepsis, peritonitis
Abdominal examination: abdominal pain and tenderness may be a sign of hypovolaemia, ascites or peritonitis. Look for renal mass(renal v. thrombosis)

31. Features of atypical nephrotic syndrome
Age: <12 months or >12 years
Macroscopic haematuria
Persistent hypertension
Persistent high creatinine
Low C3 concentration
Systemic features: rash, arthropathy (HSP or SLE)
Family history of FSGS
No response to corticosteroids by 28 days

32. Laboratory diagnosis :-
1-urinalysis :-
The urinalysis reveals 3+ or 4+ proteinuria, and microscopic hematuria is present in 20% of children.
A spot urine protein:creatinine ratio exceeds 2.0, and urinary protein excretion exceeds 40 mg/m2/hr.

33. Plasma albumin: <25 g/L in nephrotic syndrome
2- Blood tests
Plasma albumin: <25 g/L in nephrotic syndrome
renal function is normal in most patients .
Hyponatraemia is usually artefactual due to hyperlipidaemia.
CBC : high Hb and PCV with hypovolaemia.
Complement C3 and C4 levels (normal)
Serum cholesterol and triglycerides (elevated)

34. 3- Imaging :- CXR and renal ultrasound
3- Imaging :- CXR and renal ultrasound. (pleural effusin ,ascitis, renal mass)
4- A renal biopsy is not routinely performed if the patient fits the standard clinical picture of MCNS , it done for atypical cases of NS.

35. Indications for Renal Biopsy in Patients with Nephrotic Syndrome
Age <12 months or >10 years at presentation
Glucocorticoid resistance
Persistently low plasma C3 and/or C4
Sustained hypertension not related to glucocorticoid
Serum creatinine elevation
Secondary nephrotic syndrome with features of systemic disease (e.g. SLE,)

36. Treatment 1-general measures
Children with their first episode of nephrotic syndrome and mild to moderate edema may be managed as outpatients.
Indications of admission Children with severe symptomatic edema, including large pleural effusions, ascites, or severe genital edema, should be hospitalized.

37. In hospital Monitoring of temperature, heart rate, BP, capillary refill time, respiratory rate and oxygen saturation, fluid balance and urine output, daily weight.
A salt-restricted diet is recommended (no added salt). In the absence of hypovolaemia fluid intake may be modestly restricted.
Children with nephrotic syndrome should attend school and participate in physical activities as tolerated.

38. 2- Treatment of oedema
Moderate oedema will resolve spontaneously when steroid induced remission and diuresis occurs.
Diuretics may be cautiously used to control oedema provided there is no hypovolaemia, renal impairment, or hypotension.
Severe, diuretic resistant oedema may be treated using IV administration of 25% albumin ( g albumin/kg), as a slow infusion followed by furosemide (1-2 mg/kg/dose IV) is sometimes necessary , There is a risk of circulatory volume expansion and acute cardiac failure.
A swollen scrotum may be elevated with pillows to enhance fluid removal by gravity

39. 3- Steroid
Children with onset of uncomplicated nephrotic syndrome between 1 and 8 yr of age are likely to have steroid-responsive MCNS, and steroid therapy may be initiated without a diagnostic renal biopsy. Renal biopsy indicated for atypical cases.

40. In children with presumed MCNS, prednisone should be administered (after confirming a negative PPD test and administering the polyvalent pneumococcal vaccine) at a dose of 60 mg/m2/day (maximum daily dose, 80 mg) in a single daily dose for 4-6 consecutive wk.
About 80-90% of children respond to steroid therapy (clinical remission, diuresis, and urine trace or negative for protein for 3 consecutive days) within 3 wk.

41. After the initial 6-wk course, the prednisone dose should be tapered to 40 mg/m2/day given every other day as a single daily dose for at least 4 wk.
The alternate-day dose is then slowly tapered and discontinued over the next 1-2 mo.

42. Children who continue to have proteinuria (2+ or greater) after 8 wk of steroid therapy are considered steroid resistant, and a diagnostic renal biopsy should be performed
A subset of patients relapse while on alternate-day steroid therapy or within 28 days of completing a successful course of prednisone therapy. Such patients are termed steroid dependent.
Patients who respond well to prednisone therapy but relapse ≥4 times in a 12-mo period are termed frequent relapsers.

43. 4- immunosuppressive therapy
Steroid-resistant nephrotic syndrome is usually caused by FSGS (80%)
4- immunosuppressive therapy
Indicated for Steroid-dependent patients, frequent relapsers, and steroid-resistant patients or those suffer from steroid toxicity
Immunosuppressive drugs that used are cyclophosphamide, Cyclosporine or tacrolimus or Mycophenolate

44. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II blockers may be helpful as adjunct therapy to reduce proteinuria in steroid-resistant patients

45. Complications
1- Infection:- is a major complication of nephrotic syndrome because of urinary losses of immunoglobulins and properdin factor B, defective cell-mediated immunity, their immunosuppressive therapy, malnutrition, and edema or ascites acting as a potential culture medium.
Spontaneous bacterial peritonitis is a common infection, although sepsis, pneumonia, cellulitis, and urinary tract infections may also be seen.
Although Streptococcus pneumoniae is the most common organism causing peritonitis, gram-negative bacteria such as Escherichia coli may also be encountered.

46. Children with nephrotic syndrome should receive the pneumococcal vaccine given according to the routine childhood immunization schedule, ideally administered when the child is in remission and off daily prednisone therapy.
Live virus vaccines should not be administered to children who are receiving daily or alternate-day high-dose steroids (≥2 mg/kg/day of prednisone. Vaccines can be administered after corticosteroid therapy has been discontinued for at least 1 mo

47. Nonimmune nephrotic children in relapse, if exposed to varicella, should receive varicella-zoster immunoglobulin (1 dose ≤96 hours after significant exposure).
Influenza vaccine should be given on a yearly basis.

48. 2-thromboembolic events
The risk of thrombosis is related to increased prothrombotic factors (fibrinogen, thrombocytosis, hemoconcentration, relative immobilization) and decreased fibrinolytic factors (urinary losses of antithrombin III, proteins C and S).
The incidence of this complication in children is 2-5%,
Both arterial and venous thromboses may be seen, including renal vein thrombosis, pulmonary embolus, sagittal sinus thrombosis, and thrombosis of indwelling arterial and venous catheters

49. 3-Hyperlipidemia
may be a risk factor for cardiovascular disease; myocardial infarction is a rare complication in children.
It has been suggested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-inhibiting drugs should be used to treat the hyperlipidemia seen in persistent nephrotic syndrome.

50. 4- Other complications :-
Hypothyroidism: deficiency of the thyroglobulin transport protein thyroxin (subclinical )
Iron deficiency anemia caused by the loss of ferritin
Iatrogenic due to :-
-Steroid related toxicity
-Immunosuppressant –related toxicity

51. Prognosis
Most children have a decrease in relapse rate and enter long term remission, but up to 20% continue to relapse through adolescence and into adulthood.
It is important to indicate to the family that the child with steroid-responsive nephrotic syndrome is unlikely to develop chronic kidney disease
A minority develop ‘secondary’ steroid resistance and a small subset of these (mainly with FSGS histology) develop chronic kidney disease.

53. Haemolytic uraemic syndrome (HUS)
Haemolytic uraemic syndrome (HUS) is a disease of infancy and early childhood characterized by the triad of:
1 Microangiopathic haemolytic anaemia
2 Thrombocytopaenia
3 Acute renal failure.

54. Aetiology and pathogenesis
HUS D+HUS (typical) and D–HUS (atypical).
HUS: infectious agents
Bacteria: Shiga toxin producing E. coli 0157:H7 Shigella, Salmonella, Citrobacter, and Campylobacter account for Clostridium difficile, Strep. Pneumonia
Viruses: varicella, echovirus, coxsackie A and B, HIV.
HUS: non-infectious caused by Inherited: (complement factor H deficiency), Drugs, Malignancy or SLE.

55. Clinical features
Children usually present following an acute diarrhoeal illness with grossly bloody stools,, pallor, petechiae, or bleeding, and reduced or absent urine output within 2–14 (mean 6) days of onset of intestinal symptoms.
Fever (low grade)
Pallor ± jaundice: haemolytic anaemia
Petechiae and bleeding: thrombocytopaenia
Oligo/anuria, hypertension: acute renal failure
CNS signs: encephalopathy due to uraemia.

56. Investigations :-
1) Blood tests
a) FBC and film: anaemia (Hb <8 g/dL) with fragmented red cells on fi lm . Thrombocytopaenia , raised reticulocytes & Leucocytosis
b) Coagulation screen: usually normal
c) Low haptoglobin, elevated LDH and bilirubin: haemolysis
Raised creatinine, urea concentrations. Hyponatraemia and hyperkalaemia.
Hyperglycaemia
f) Serum amylase, lipase (pancreatic involvement)
g) LFTs: abnormal with low albumin.

57. 2) Urine tests Dipstick for proteinuria, haematuria, microscopy: red cells, white cells ± casts 3) Stool and blood culture FOR E. coli : 4) Imaging CXR, renal ultrasound

58. Treatment
1 Supportive • Fluid balance :- • Acute renal failure : 50% of typical HUS patients need dialysis. • Blood transfusion to maintain Hb >7.0 g/dL. Platelets avoided except in active bleeding. • Nutrition with high calorie intake. • Antibiotics are not indicated

59. 2- Specific No specifi c treatment is available for typical HUS
2- Specific No specifi c treatment is available for typical HUS. Atypical HUS may benefit from administration of fresh frozen plasma (FFP) or plasmapheresis . Prognosis Most patients with diarrhea-associated acquired forms of HUS recover completely with little risk of long-term sequelae . Patients with atypical HUS have a worse prognosis.