GOOD MORNING. Welcome Applicants! Friday, October 31, (Happy Halloween!)

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1 GOOD MORNING Welcome Applicants! Friday, October 31, 2014 (Happy Halloween!)

2 PREP QUESTION A 14-year-old girl has had 3 days of new, unremitting headache associated with vomiting and awakening from sleep and 1 day of double vision. Physical examination reveals normal visual acuity in each eye, normal pupillary responses in each eye, subjective diplopia when looking to the left, and incomplete abduction of the left eye. Fundoscopic examination reveals bilateral papilledema. Noncontrast head CT scan yields normal results. Of the following, the MOST likely diagonsis is: A. Brain tumor in the posterior fossa B. Communicating hydrocephalus C. Complicated migraine D. Optic neuritis E. Pseudotumor cerebri

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6 DIFFERENTIAL DIAGNOSIS Allergies Protein deficiency Dietary (ie Kwashikor) Protein-losing enteropathy Liver failure Nephrotic Syndrome Angioedema Congestive heart failure Venous obstruction Sickle cell related swelling Renal failure Medications (CCB s) Lymphatic disturbance Capillary leak syndromes Sepsis Burns Glomerulonephritis Henoch-Schonlein Purpura Know the differential diagnosis of nephrotic syndrome with and without hematuria.

7 NEPHROTIC SYNDROME What s the Triad? 1. Hypoalbuminemia 2. Edema 3. Hyperlipidemia

8 EPIDEMIOLOGY Incidence: 2.7/100,000 children per year Prevalence: 16/100,000 children per year 2:1 males to females (in childhood) Peak age of onset: 2-3 years of age (75% of patients are <10 years old) Familial component African American and Hispanic children at increased risk of developing nephrotic syndrome and having a more severe form with a poorer prognosis

9 SIGNS AND SYMPTOMS The most common presenting sign:. edema 1/3 with microscopic hematuria Other common complaints: headache, dysphnea, anorexia, irritability, fatigue, abdominal discomfort, diarrhea. Know the presenting signs and symptoms of minimal-change nephrotic syndrome.

10 NEPHROTIC SYNDROME Primary Causes Minimal change Nephrotic Syndrome Focal Segmental Glomerulosclerosis Membranous Nephropathy Secondary Causes Infections: Hepatitis B and C, HIV, Malaria, Toxoplasmosis, Syphillis, PIGN Drugs: Gold, NSAID s, Pamidronate, Interferon, Heroin, Lithium Malignancies: Leukemia, Lymphoma Miscellaneous: SLE, MPGN, Ig A nephropathy, DM, Sickle cell disease

11 GLOMERULUS

12 ANATOMY Integrity of glomerular filtration barrier is compromised Fenestrated endothelium Glomerular basement membrane Visceral glomerular epithelium (podocytes and slit diaphragms)

13 PRIMARY (IDIOPATHIC) NEPHROTIC SYNDROME Minimal change nephrotic syndrome (MCNS) Focal segmental glomeruloscerlosis (FSGS) Membranous nephropathy (MN)

14 MINIMAL CHANGE DISEASE

15 FOCAL SEGEMENTAL GLOMERULOSCERLOSIS

16 MEMBRANOUS NEPHROPATHY

17 OTHER ETIOLOGIES (10%) Mesangioproliferative glomerulonephritis Lupus nephritis Immunoglobulin A nephropathy Membranoproliferative glomerulonephritis due to Hepatitis C HIV nephropathy

18 DIFFERENTIAL DIAGNOSIS Allergies Protein deficiency Dietary (ie Kwashikor) Protein-losing enteropathy Liver failure Nephrotic Syndrome Angioedema Congestive heart failure Glomerulonephritis Venous obstruction Sickle cell related swelling Renal failure Medications (CCB s) Lymphatic disturbance Capillary leak syndromes Sepsis Burns Henoch-Schonlein Purpura Know that nephrotic syndrome in association with Henoch-Schonlein purpura is a poor prognostic sign

19 PREP QUESTION 1 A 14-year-old boy presents to the emergency department with a 2-week history of bilateral leg edema and a 3-day history of abdominal swelling. His vital signs are: temperature 98.4 F, BP 125/67, HR 84 beats/min, RR 20 breaths/min. Physical examination shows moderate ascites and 2+ leg edema. His urinalysis reveals negative blood and 4+ protein. Serum complement concentrations are ordered and found to be normal. Of the following, the MOST likely cause of his edema and proteinuria is A. Immunoglobulin A nephropathy B. Lupus nephritis C. Membranous nephropathy D. Membranoproliferative glomerulonephritis E. Post-infectious acute glomerulonephritis

20 NEPHROTIC SYNDROME- LABORATORY STUDIES Proteinuria Low plasma protein concentration (often albumin less than 2.5 g/dl) High levels of cholesterol, triglycerides, and lipoproteins Hyponatremia Low plasma calcium (normal ionized calcium) +/- Microscopic hematuria Understand the etiology of hyponatremia in nephrotic syndrome. C3 Normal MCNS Low post-infectious glomerulonephritis; HSP Recognize the laboratory findings in children with minimal change nephrotic syndrome Recognize that the prognostic significance of a decreased serum C3 concentration in a patient with nephrotic syndrome is an indication of a diagnosis other than minimal change disease.

21 PREP QUESTION 2 A 4-year-old boy is seen in the emergency department because of recurrent facial swelling. The mother reports that the boy has been evaluated by her pediatrician on several occasions with a similar complaint. Each time, the boy was treated with 3 to 5- day courses of an antihistamine or oral steroid. The mother maintains full adherence with these treatment recommendations. Physical examination shows a healthy-appearing boy who has normal growth parameters. He is afebrile with a RR 18 breaths/min, HR of 84 beats/min, and a BP 90/60 mm Hg. The only finding of significance is facial puffiness and periorbital edema. Of the following, the MOST appropriate next step is to A. Obtain C1 esterase concentration B. Obtain a specimen for urinalysis C. Prescribe a 5-day course of diphenhydramine and prednisone D. Reassure the mother and discharge the patient home E. Refer the patient for an allergy evaluation

22 EVALUATION 1 st confirm diagnosis! 2 nd rule out secondary causes Thorough history and physical examination! Is there Severe proteinuria? Hypoalbuminemia? Edema? Does the patient have Normal blood pressure? Normal renal function? Hematuria? Microscopic or Gross? Labs Complement C3 and C4 values Anti-nuclear antibody Anti-double-stranded DNA Hepatitis B surface antigen Hepatitis C antibody HIV antibody CBC with differential PPD

23 URINE DIPSTICK Protein: 1+ = 30 mg/dl 2+ = 100 mg/dl 3+ = 300 mg/dl 4+ = 1,000 mg/dl Then quantitative measurement: U protein/creatinine : 6 months-2 years of age:. <0.5 >2 years of age:. <0.2 >3 = nephrotic syndrome 12 or 24-hour urine collection: Nephrotic range: 50 mg/kg/day or 40 mg/m2/hr False positives (alkaline urine, concentration dependent, or contamination)

24 PREP QUESTION 3 A mother brings in her 4-year-old son because his eyelids are swollen. On physical examination, the boy has normal growth parameters, normal blood pressure, bilateral periorbital edema, and pitting pretibial edema. Laboratory findings include normal electrolyte concentrations, BUN 14 mg/dl, creatinine of 0.3 mg/dl, albumin 1.9 g/dl, and normal C3 and C4 complement values. Urinalysis reveals a specific gravity of 1.030, ph of 6.5, 4+ protein, and 1+ blood, and microscopy demonstrates 5-10 RBC/hpf. ANA test results are negative, and serologic tests are negative for hepatitis B surface antigen, negative for hepatitis C, and nonreactive for HIV. A ppd is nonreactive after 48 hours. Of the following, the MOST appropriate treatment for this patient is: A. Diphendyramine B. Furosemide C. Low-sodium diet D. Prednisone E. Protein-rich diet

25 TREATMENT Plan the initial treatment for a child with an initial episode of nephrotic syndrome. Understand the appropriate initial management of a nephrotic patient. Recognize the indications for alkalating agents in corticosteroid-responsive nephrotic syndrome

26 MANAGEMENT The Steroid-dependent Kidney Children's disease: Disease: Nephrotic Prednisone Improving Syndrome remains Global the Consensus Outcomes preferred : Conference: therapy Initial +/- therapy: levamisole, therapy: Prednisone cyclophosphamide, Prednisone 2 2 mg/kg/day mycophenolate mg/kg/day or x 60 6 mg/mmofetil, weeks, 2 x then 4-6 and weeks, calcineurin alternate-day then alternate-day inhibitors prednisone (ie, cyclosporine 1.5 mg/kg or tacrolimus) or 40 mg/m prednisone 1.5 mg/kg x 6 weeks 2 x 2-5 months Steroid-resistant First relapse/infrequent disease: Therapy relapse: is based Prednisone upon the 2 mg/kg/day histologic or findings 60 mg/m found 2 on renal First until biopsy. the relapse/infrequent urine Treatment protein tests may relapse: are include: negative Prednisone ACE-I or trace or y ARB s for 2 mg/kg/day 3 consecutive and supportive until days, the care focused urine then on alternate-day protein managing tests the prednisone are complications negative 1.5 or mg/kg trace of nephrotic for 403 mg/m consecutive syndrome. 2 x 4 weeks. days, then alternate-day Frequent relapses: prednisone Prednisone 1.5 therapy mg/kg x 2 4 mg/kg weeks. per day or 60 mg/m 2 Frequent until the urine relapses: protein Prednisone tests are negative therapy or 2 trace mg/kg for per 3 consecutive day until the days, urine then lowest necessary alternate-day prednisone x at least 3 months protein tests are negative or trace for 3 consecutive days, then +/- oral cyclophosphamide, cyclosporine, tacrolimus, chlorambucil, levamisole, alternate-day and mycophenolate prednisone mofetil 1.5 mg/kg x 4 weeks, which is then tapered over 2 +/- months Rituximab by 0.5 mg/kg every other day. +/- oral cyclophosphamide, cyclosporine, and mycophenolate mofetil

27 MANAGEMENT Ancillary support: Diuretics Blood pressure control Salt-poor albumin infusions Anti-angiotensin ACE inhibitors Angiotensin receptor blockers +/- Statins Low-sodium, low-fat diet Vaccinations

28 MANAGEMENT Indications for renal biopsy at time of diagnosis include: Macroscopic or persistent hematuria Severe hypertension Persistent renal insufficiency Low serum C3 complement values Age >10 years old Indications for renal biopsy subsequent to treatment: Persistent proteinuria despite 4 weeks of daily prednisone

29 PREP QUESTION 4 A 4-year-old boy presents with peri-orbital edema. He is receiving no medications, and his family history is negative for renal disease. On physical examination, he is afebrile; his HR is 88 beats/min, RR 18 breaths/min, BP 106/62 mm Hg. He has periorbital edema and pitting pretibial edema. Laboratory evaluation shows normal electrolyte values, BUN of 14 mg/dl, creatinine of 0.3 mg/dl, and albumin of 1.6 g/dl. Urinalysis demonstrates a specific gravity of 1.020; ph of 6.5, 3+ protein, and negative blood, leukocyte esterase, and nitrite. Microscopy results are normal. Additionally, complement component (C3 and C4) values are normal, and results of serologic testing for ANA, hepatitis B and C, and HIV are negative. Of the following, you are MOST likely to advise the parents that A. A renal biopsy is warranted to determine the optimal treatment B. Disease relapse can be expected in fewer than 25% of those achieving remission C. Patients who relapse have a similar prognosis as those who do not respond to steroids D. Remission is expected in more than 75% of patients who receive corticosteroid treatment E. Tacrolimus is the preferred treatment for patients who do not respond to corticosteroids

30 PREP QUESTION 5 A 14-year-old girl presents with peri-orbital swelling for the past week this is worsening. She had upper respiratory tract symptoms approximately 10 days ago. She denies itching at her eyes. Otherwise, she has been well. On physical examination, she is afebrile with a pulse rate of 76 beats/min, a respiratory rate of 16 breaths/,min, and blood pressure of 136/86 mm Hg. Her examination is remarkable for bilateral periorbital edema with normal conjunctivae. She also has pitting edema from her pretibial region to the level of her knees. You suspect that the patient may have nephrotic syndrome. The following are results of her urinalysis: Specific gravity 1.025, ph 7, 3+ protein, 1+ blood. Of the following, the laboratory finding that is MOST likely to indicate a poor renal prognosis for this girl is A. Serum albumin of 1.4 g/dl B. Serum complement component 3 (C3) of 40 C. Serum creatinine of 0.7 mg/dl D. Urine microscopy of RBC/hpf E. Urine protein to creatinine ratio of 14 C3 Normal Range

31 COMPLICATIONS Acute Renal Failure Pulmonary edema Infection Spontaneous bacterial peritonitis Hypercoaguability Thrombotic events Steroid effects Recognize the complications of nephrotic syndrome (eg, peritonitis, thromboses) Recognize peritonitis as a major complication of minimal-change nephrotic syndrome

32 COURSE/PROGNOSIS Know The the best factors prognostic (i.e. indicator in hypertension) children who have that nephrotic predict syndrome the prognosis is:. steroid of responsiveness nephrotic syndrome. Recognize that response to therapy is one 95% of of the children best indicators who eventually of the prognosis respond to in steroids nephrotic do so syndrome within the Understand first 4 (four) that minimal-change weeks of treatment. nephrotic syndrome is a relapsing disease 60% respond to steroids initially but relapse.

33 STEROID-RESISTANT NEPHROTIC SYNDROME ~10% of children with nephrotic syndrome Poor prognosis Alkylating agents often necessary Renal biopsy indicated Most often dx: Focal segmental glomerulosclerosis

34 OUR KIDDO.

35 CONGENITAL NEPHROTIC SYNDROME Proteinuria present at birth (or up to 3 months of age) Often massive proteinuria during fetal life metabolic disturbances (lipid abnormalities, thyroid abnormalities, atherosclerotic changes) Edema and abdominal distention develop soon after birth Diagnosis: increased alpha fetoprotein in amniotic fluid + normal fetal ultrasound Histology: slight-to-moderate mesangial proliferation, effacement of foot processes, thin GBM Course: Eventually become sclerotic with disappearance of slit diaphragms Finnish type Autosomal recessive disease NPHS1/2 code for nephrin mutated Recognize the presentation and intrauterine diagnosis of congenital nephrotic syndrome

36 CONGENITAL NEPHROTIC SYNDROME Treatment: Good nutritional support Control edema (often requires unilateral or bilateral nephrectomy) Often require peritoneal dialysis Prevent complications (ie infections, thrombosis) Eventually require renal transplantation Recognize the improved outcome of children with congenital nephrotic syndrome through early intervention and renal transplantation

37 SUMMARY Most with nephrotic syndrome have MCNS and respond to steroid therapy. Steroid-responsiveness is the best prognostic indicator. Renal biopsy can be deferred and prednisone started empirically if high suspicion for MCNS. 60% of children with MCNS will relapse. Most children with nephrotic syndrome and fail steroid therapy will have FSGS with a poor prognosis

38 HAVE A GREAT DAY!! Noon conference: Personal Perspective on Evaluation of UTI Visiting professor, Dr. Douglas Canning