Medical Affairs Department of Pediatrics Clinical Practice Guideline

MANAGEMENT OF HENOCH-SCHONLEIN NEPHRITIS IN CHILDREN

Document # Date CPG Formulated Next Review Date

PEDS-NEPRHO# 012 JULY 17, 2011 JULY 2013

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 2 of 14

INTRODUCTION Henoch-Schnlein purpura (HSP) is a systemic vasculitis with a prominent cutaneous component. The classic tetrad of HSP is rash, arthralgias, abdominal pain and renal disease, which can develop in any order and at any time over a period of several days to several weeks. HSP is characterized by the tissue deposition of IgA-containing immune complexes. The pathogenesis of this disorder may be similar to that of IgA nephropathy, which is associated with identical histologic findings in the kidney. IgA deposition is prominent in both HSP and IgA nephropathy, but the renal injury may be mediated at least in part by IgG autoantibodies directed against mesangial cell antigens. HSP occurs more often in children than in adults, but renal involvement is more likely to occur, and to be severe, in older children and in adults, prompting more aggressive therapy.

DIAGNOSIS The diagnosis is typically based on the clinical presentation. Confirmation of the diagnosis of HSP requires evidence of tissue deposition in the skin or kidney of IgA by immunofluorescence microscopy. Biopsy of the skin lesions reveals inflammation of the small blood vessels, called a leukocytoclastic vasculitis that is most prominent in the postcapillary venules. RENAL MANIFESTATIONS Renal involvement is typically noted within a few days to one month, rarely later than 2 months, after the onset of systemic symptoms. Renal involvement is not predictably related to the severity of extrarenal involvement. However, there appears to be an increased risk of renal disease in children with bloody stool. From 16 to 50%of children may have some degree of renal involvement at initial presentation. Age greater than 8 years conferred a 2.7-fold increase in the risk of nephritis. Most children have relatively mild renal involvement, with asymptomatic hematuria and sometimes proteinuria, with a normal or only slightly elevated plasma creatinine concentration. However, more marked findings may occur including the nephrotic syndrome, hypertension, and acute renal failure. The urinalysis in affected patients reveals an active sediment characterized by microscopic (or macroscopic) hematuria with red cell and other cellular casts, with or without proteinuria. There is a general correlation between the severity of the renal manifestations and the findings on renal biopsy.

Renal biopsy Indications for renal biopsy in HSP are: 1. Acute nephritic syndrome (urgent) 2. Nephrotic syndrome (urgent)

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 3 of 14

3. Persistent proteinuria >1 g/day/m2 BSA for 1 month or 0.51 g/day/m2 for more than 3 months. Histology: Patients with only asymptomatic hematuria, for example, usually have only focal mesangial proliferation, whereas patients with proteinuria have more marked cellular proliferation and, if nephrotic, crescent formation. Histological diagnoses: Glomerular changes were graded according to the International Study of Kidney Disease in Children classification, as follows : 1. Grade I, minor glomerular abnormalities. 2. Grade II, pure mesangial proliferation. 3. Grade III, minor glomerular abnormalities or mesangial proliferation, with crescents/segmental lesions (sclerosis, adhesion, thrombosis, necrosis) in <50% of glomeruli. 4. Grade IV, same as grade III but with crescents/segmental lesions in 5075% of glomeruli. 5. Grade V, same as grade III but with crescents/segmental lesions in >75% of glomeruli. 6. Grade VI, membranoproliferative-like lesions. **Patients with repeated attacks of purpura or macroscopic hematuria often have exacerbation of renal symptoms and biopsy-confirmed worsening of glomerular lesions. The renal biopsy findings in HSP are essentially indistinguishable from IgA nephropathy. The diagnostic finding is dominant or co-dominant IgA deposition in the mesangium on immunofluorescence. In general, the extent of renal injury parallels the clinical severity of renal disease. The percentage of glomeruli showing crescents seems to be the most important prognostic finding. PROGNOSIS The short-term outcome of renal disease in HSP is favorable in most patients, with complete recovery reported in 94 and 89 percent of children and adults, respectively, at a mean followup of approximately 18 months. Among children, the manifestations of active HSP usually resolve spontaneously; the renal prognosis is excellent when transient hematuria and proteinuria resolves within several months, a course that is generally associated with only focal glomerular involvement. Recurrence (relapse) of HSP is common, occurring in up to one-third of patients, and may be more likely among patients with renal involvement. Recurrent symptoms and signs, which tend to mimic the original episode (but tend to be less severe), are normally observed within four months of resolution of the initial symptoms. Recurrent disease may not predict worse long term outcomes.

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 4 of 14

Persistent and progressive disease A minority of affected patients have persistent renal manifestations. Late deterioration can occur even among patients with initial complete resolution of renal manifestations. One third of pregnancies among previously affected individuals were complicated by hypertension and/or proteinuria. Some children progress to requiring dialysis (3-10%). As with other disorders, a poor renal prognosis is more common among those with the following disease or biopsy manifestations: Nephrotic syndrome, Renal insufficiency, Hypertension, Crescentic glomerulonephritis (>50 percent) and Tubulointerstitial fibrosis.

Treatment of renal disease: Specific treatment should be considered only in patients with marked proteinuria and/or impaired renal function during the acute episode. It is recommended obtaining a renal biopsy in this setting, since the severity of the histologic lesions (particularly the degree of crescent formation) appears to be the best indicator of prognosis. There is no evidence that therapy with conventional doses of corticosteroids or cyclophosphamide has a beneficial effect in patients with renal involvement. However, more aggressive therapy may be beneficial in patients with advanced disease, which is usually defined as crescentic nephritis. General rules for the treatment for HSP nephritis: Medical treatment should be based on both clinical and histopathological findings, i.e. kidney biopsy should be done before starting the treatment. Patients with moderately severe HSPN (histological grades IIII and serum albumin [Alb] >25 g/L) receive angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARB). Patients with severe HSPN (histological grade IVV or Alb25 g/L), including patients with rapidly progressive HSPN, receive combination therapy . Monitoring the effect of therapies is based on changes in U-Pr/Cr and eGFR.

ACEi/ARB regimen: The ACEi, i.e. lisinopril, is started at 0.1 mg/kg and increased to 0.4 mg/kg (maximum dose, 20 mg). The ARB, i.e. candesartan, is started at 0.05 mg/kg and increased to 0.2 mg/kg (maximum dose, 20 mg).

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 5 of 14

An ACEi is prescribed first and increased to the maximum dose. If the ACEi offers little benefit after several months, an ARB is added and increased to the maximum dose. If the ARB added to ACEi offers little benefit after several months and massive proteinuria with hypoalbuminemia is detected, the patient will be given combination therapy, as described below.

Combination therapy: Patients were initially treated with 2 mg/kg/day prednisolone, given in three divided doses (maximum dose, 80 mg/day) for the first 4 weeks, followed by prednisolone at 2 mg/kg given as a single dose every other morning for 8 weeks . The dose then can be decreased by 0.5 mg/kg every 2 weeks . The immunosuppressants: azathioprine (2 mg/kg/day as a single dose; maximum dose, 100 mg) or MMF (30 mg/kg/day) for 6 months . Dipyridamole is started at 3 mg/kg/day given in three divided doses, and is increased to 6 mg/kg/day (maximum dose, 300 mg/day), and maintained for 8 weeks if the patient experienced no adverse effects, such as headache. Warfarin is started at 1 mg/day given as a single dose each morning. The warfarin dose is then adjusted to give a thrombo-test result of 2050%. All drugs are started at the same time. Patients treated with combination therapy are not treated with ACEI or ARB, as they are treated based on severe IgA nephropathy. All therapies were finished after 6 months. Another regimen for steroids consists of pulse intravenous methylprednisolone (250 to 1000 mg per day for three days) followed by oral prednisone (1 mg/kg per day for three months). Some experts recommend a six-month course of daily or alternate day tapering corticosteroids for all patients with nephrotic range proteinuria and for those with a decreased GFR and significant histologic damage on their biopsy. Other regimens for crescentic nephritis include: Corticosteroids and azathioprine (or MMF). Or multidrug regimens such as o Corticosteroids, cyclophosphamide, and dipyridamole, o Or corticosteroids, cyclophosphamide, heparin/warfarin, and dipyridamole. However, since spontaneous recovery is often observed in patients with crescent formation, it remains unknown whether these regimens are superior to no or less aggressive therapy.

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 6 of 14

Plasmapheresis PF has also been used in a number of patients with severe disease. Its efficacy is uncertain and there are potential side effects. However, limited data suggests that plasmapheresis alone may be curative in some patients. Renal transplantation Can be performed in those patients who progress to end-stage renal disease. Mild recurrent disease occurs in approximately 35 percent of patients at five years after transplantation. Approximately 10 percent of patients experience graft loss due to recurrent disease. Diagram for approach to children with HSP for possible renal involvement

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 7 of 14

REFERENCES: 1. www.uptodate.com website, as of July 2011. 2. Treatment strategies for Henoch-Schnlein purpura nephritis by histological and clinical severity. Pediatr Nephrol (2011) 26:563569. 3. Oxford Handbook of Pediatric Nephrology by Lesley Rees, Nicholas J.A. Webb, Paul A. Brogan, 1st edition, 2007. 4. Clinical Pediatric Nephrology, Informa; by Kanwal Kehr, H Schnapper, Sudesh Makker, 2nd edition, 2007. 5. Early prednisone therapy in Henoch-Schnlein purpura: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2006 Aug;149(2):241-7. 6. A randomized, placebo-controlled trial of prednisone in early Henoch Schnlein Purpura. BMC Med. 2004 Apr 2;2:7. 7. Effect of early corticosteroid therapy on development of Henoch-Schnlein nephritis. J Nephrol. 2007 Jul-Aug;20(4):406-9. 8. Treatment of severe Henoch-Schnlein nephritis: justifying more immunosuppression. Turk J Pediatr. 2009 Nov-Dec;51(6):551-5.

Prepared by Dr. Ibrahim Al Attrach Definition of CKD: Disorder that lasts 3 months with either kidney damage defined by structural or functional renal abnormalities. Classification: Is based on GFR for children older than 2 years as follows: - CKD1 Normal GFR ( 90 mL/min per 1.73 m2) with kidney damage** CKD2 GFR between 60 and 89 mL/min per 1.73 m2 CKD3 GFR between 30 and 59 mL/min per 1.73 m2 CKD4 GFR between 15 and 29 mL/min per 1.73 m2 CKD5 GFR of less than 15 mL/min per 1.73 m2 or end-stage renal disease (ESRD)

** Kidney damage: (chronic) pathologic abnormalities in blood or urine tests or imaging studies related to the kidney. GFR can be calculated as per the Schwartz formula: GFR = k X Height (cm) / sCreat - K is 0.33 in premature infants and 0.45 for term infants <1 year. K is 0.55 in children and adolescent girls, and 0.7 in adolescent boys.

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 8 of 14

Normal GFR in Children Mean GFR SD Age (Gender) mL/min/1.73m2 1 week 40.6 14.8 2-8 weeks 65.8 24.8 >8 weeks 95.7 21.7 2-12 years 133.0 27.0 13-21 years (males) 140.0 30.0 13-21 years (females) 126.6 22.0 GENERAL PRINCIPLES: Treat reversible kidney dysfunction, Prevent or slow the progression of kidney disease, Treat the complications of CKD, Identify and adequately prepare the child/family in whom renal replacement therapy will be required. CKD Complications: Sodium and intravascular volume: - In CKD 4/5 water and sodium retention may result in volume overload which needs sodium restriction. - Salt wasters (i.e. obstructive uropathy or dysplastic kidneys) require ongoing fluid and sodium replacement. Hyperkalemia: Hyperkalemia does not usually occur until the GFR is < 10%. Special attention should be paid to serum potassium in patients receiving ACEi/ARBs when approaching CKD5. Management consists of: a) Low potassium diet, b) administration of a loop diuretic, c) correction of metabolic acidosis and sodium polystyrene sulfonate (Kayexalate). Metabolic acidosis: Overt acidosis is characteristically present in CKD 4/5. It is associated with growth impairment. The aim is to maintain the serum bicarbonate level 22 mEq/L. Sodium bicarbonate can be given to correct acidosis. Bone metabolism and bone disease: Subtle signs of renal osteodystrophy begin to be observed when the GFR decreases to 50% of normal (CKD3). Physical findings may include muscle pain, weakness, and bony changes such as varus and valgus deformities of the long bones. Laboratory abnormalities of bone metabolism (e.g., elevated PTH) are common in CKD3 and require therapeutic interventions.

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 9 of 14

Types: - Osteitis fibrosa cystica (high bone turnover) results from secondary hyperparathyroidism. Adynamic bone disease (low bone turnover) and is related to excessive suppression of the parathyroid gland. Mixed osteodystrophy

Diagnosis: - Bone biopsy is the gold standard; consider if persistent hypercalcemia with a serum intact PTH between 42 and 63 pmol/L. Radiology is only helpful for monitoring severe cases, as it may be normal even with moderate hyperparathyroidism. PTH level >21 pmol/L and ca <2.5 mmol/L identified patients with high turnover bone disease. PTH <21 pmol/L and ca >2.5 mmol/L identified patients with adynamic bone lesions. Children on hemodialysis: all patients with a serum PTH concentration >13 pmol/L and a serum calcium value <2.5 mmol/L have either osteitis fibrosa or mixed osteodystrophy. Tertiary HPT will be caused by a cycle of PTH stimulation as increased hydroxylation of Vit D induced by PTH stimulation will increase not only Ca but also PO4 absorption from the gut.

Management: Level of PTH aimed for in CRF to maintain normal bone turnover are the following: - CKD 2/3: 3.7 to 7.4 pmol/L (normal range 0.5 to 6 pmol/L) CKD4: 7.4 to 11.6 pmol/L (~up to 2x the upper NL) CKD 5: 21 to 32 pmol/L (or 3-5 times normal value) to allow normal growth.

Monitoring: For calcium and phosphorus the recommendations for measurements are at least: - CKD 2 yearly CKD3 q 6 months CKD 4 q 3 months CKD5 monthly

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 10 of 14

For PTH and alkaline phosphatase measurements: - CKD2 yearly. CKD3 q 6 months CKD4/5 q 3 months

Phosphate: - In CKD4 hyperphosphatemia will usually occur unless appropriate therapy is given. The targeted goals: to avoid serum phosphorus below the target range because of the potential adverse effects of hypophosphatemia on linear growth. CKD 5: The serum phosphorus should be maintained between 1.3 to 1.9 mmol/L in children 1 to 12 years of age and between 1.1 to 1.8 mmol/L in adolescents. CaCO3 can decrease absorption to 30-40 % if given before or during the meals. Non-calcium phosphate binder (Sevelamer) should be added if hypercalcemia (s Ca >2.55 mmol/L).

Calcium: - The total serum calcium should be maintained within a normal range. If the total serum calcium value exceeds 2.55 mmol/L, the dose of calcium-based phosphate binders should be reduced and/or therapy changed to Sevelamer. Vitamin D therapy should also be discontinued until the serum calcium returns to the targeted range.

Vitamin D: - Deficiency of 25-hydroxyvitamin D is common in children with CKD. The patients with CKD 2 to 4 and serum PTH values above the target range, serum 25-hydroxyvitamin D concentrations should be measured yearly. If the PTH remains elevated after having the phosphate within the normal range, the serum calcium level is <2.37 mmol/L and the serum 25-hydroxyvitamin D is >75 nmol/L, the recommended starting dose for Calcitriol is based on the body weight of the child: o Weight <10 kg: 0.05 mcg q 48 hrs. o Weight 10 - 20 kg: 0.1 - 0.15 mcg/d. o Weight > 20 kg: 0.25 mcg/d.

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 11 of 14

o Alfacalcidol (1mo-12 yr): 15-30 ng/kg/d (max 500 ng or 0.5 mcg/d) Once Calcitriol/Alfacalcidol is started, serum PTH should be measured at least every three months.

Hypertension: - The prevalence of hypertension in children with CKD is high, even when the GFR is only mildly reduced. Aggressive blood pressure control slows the progression of CKD. Based on that the target BP goals are: The NHBPEP recommended a reduction in PB to below the 90th percentile based upon the age, gender, and height of the patient. Target ABPM is a mean BP <50th percentile (ESCAPE trial). Ambulatory blood pressure monitoring (ABPM) should be considered with the following indications: Suspected white coat hypertension, Resistant hypertension, Hypotensive symptoms while taking antihypertensive medications, Episodic hypertension and Autonomic dysfunction.

Left ventricular hypertrophy: - LVH is commonly seen in children with CKD especially patients on dialysis as a response to mechanical or hemodynamic overload. Echocardiograms should be performed in all patients: a) at the initiation of dialysis, b) once patients have achieved dry weight (ideally within 13 months of dialysis initiation), and c) at 3-yearly intervals thereafter.

Anemia: - Anemia due to reduced kidney erythropoietin production develops when the GFR is below 30 mL/min/ 1.73 m2. The anemia of CKD is principally normocytic and normochromic.

Treatment: - The target hemoglobin is 11 - 12 g/dL. Serum ferritin should be kept between 100 to 800 ug/l and TSAT 20, All patients receiving therapy with erythropoiesis stimulating agent (ESA) require iron supplementation to prevent the development of iron deficiency.

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 12 of 14

The initial rHuEPO is 80 to 120 u/kg per week in 2-3 divided doses (up to 300 u/kg per week for <5 years of age or children on dialysis). Darbepoetin alfa is a long-acting erythropoietic agent can be used at a dose of 0.5 (range 0.25 to 0.75) mcg/kg/week. In PD patient it can be given q 2 weeks and in CKD 4 it can be given once a month.

Monitoring: - The expected increase in Hgb (Hct) after the initiation of rHuEPO therapy or after a dose change is between 2 - 8% over a 2 - 4 week period. Monitor the Hgb (Hct) every 1-2 weeks until a stable target Hgb (Hct) and then every 4 weeks. Growth: - Growth retardation occurs in up to 50% of children with GFR<50ml/min/1.73m2. The most important cause of poor growth is inadequate intake of calories and protein leading to malnutrition. Water, electrolyte, and acid-base imbalance, renal osteodystrophy, and growth hormone resistance are also important. The criteria for initiating recombinant human growth hormone (rHuGH) in children with CKD include all of the following: 1. Height SDS that is <-1.88 and/or a height velocity SDS <-2 persists beyond 3 months despite treatment of nutritional deficiencies and metabolic abnormalities. 2. Growth potential that is documented by open epiphyses. 3. There are no contraindications for rHuGH. 4. The use of rHuGH is continued until the child a) reaches the 50th percentile for mid-parental height, b) achieves a final adult height with closed epiphyses, or c) receives a kidney transplant. Dyslipidemia: - Abnormal lipid metabolism is common in patients with CKD and adds to the risk for cardiovascular disease (CVD) in children with CKD. Evaluation should be performed at presentation, and annually thereafter or 2-3 months following a change in treatment or subsequent to the presentation of another condition known to cause dyslipidemia.

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 13 of 14

Nutrition: Refer to separate CPG on TOL (in process). Immunization: Refer to separate CPG on TOL (in process). References: - www.uptodate.com, as of July 2011 Oxford Handbook of Pediatric Nephrology by Lesley Rees, Nicholas J.A. Webb, Paul A. Brogan, 1st edition 2007. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) Clinical Practice Guidelines (http://www.kidney.org/professionals/kdoqi, as of July 2011). Bajo MA et. al. Nefrologia. 2009; 29 (2):136-42 (Changing the frequency of administration of darbepoetin alfa (from weekly to fortnightly) maintains the hemoglobin levels in patients undergoing peritoneal dialysis).

Prepared by: Dr Issam Abou Najab, Pediatric Nephro Specialist Dr Ibrahim Al Attrach. Consultant Pediatric Nephrologist

MEDICAL AFFAIRS CLINICAL PRACTICE GUIDELINE TITLE Document #: Page 14 of 14

Approval: Name Head of the Department: Dr. Aiman Al Rahmani Other Involved Department Head/Manager: Division Chief Dr. Ibrahim Al Attrach Dr. Amar Shibli Tawam/JHopkins CMO Dr. Walid Kaplan Reviewed By Johns Hopkins Member: Yes Johns Hopkins Member Signature Date

No