Nephrology Grand Rounds Mansi Mehta November 24, 2015
Case 51yo F with PMH significant for Hypertension referred to renal clinic for evaluation of elevated Cr. no known history of CKD; baseline creatinine of 0.9 in 2010 recent swelling in her feet x 3-4 weeks and intermittent joint pains ROS: negative for fevers/chills, shortness of breath, hematuria, urinary frequency, dysuria, frothy urine, or rash
PMH: Hypothyroidism, Hypertension PSx: none FHx: unknown history of renal disease SH: moved from Ecuador 7 years prior; denied any tobacco, EtOH or illicit drug use Meds: Synthroid 100mcg daily, Norvasc 5mg daily Allergies: KNDA
Physical Exam VS: Afebrile, BP: 169/98 P: 63 RR: 18 O2: 98 Gen: NAD, middle-aged Hispanic F, well-appearing CVS: +s1s2, RRR, no murmurs Resp: CTA B/l Abd: soft, NT/ND, +BS Ext: trace pitting edema of B/l LE up to mid-tibia Skin: no rashes
Labs BMP 142 4.5 106 27 40 2.6 88 CBC 7.0 12.2 36.6 271 UA: 2+ blood, 3+ protein, 0 WBCs, 10-15 RBCs UPr/Cr: 277/99.5 = 2.78g/g
Additional Work-Up Hepatitis Panel: HbSAg: negative HbSAb: negative HCV Ab: negative ANA : negative ANCA: negative C3: 132 C4: 39 ESR: 14 CRP: 0 Renal US: R kidney: 11.4cm L kidney: 10.3cm Increased cortical echogenicity, no hydronephrosis
Differential Diagnosis IgA nephropathy Minimal Change Disease Post-infectious GN MPGN
Renal Biopsy Sclerosing IgA Nephopathy LM: 12 glomeruli; 8 globally sclerotic. 50% interstitial fibrosis w/ tubular atrophy; No crescents IF: Diffuse and global mesangial staining for IgA 3+ EM: 40% visceral epithelial cell foot process effacement
Follow-up Started on Lisinopril 10mg daily 7/24/14 10/30/14 5/22/15 10/29/15 BP 168/98 132/92 122/78 140/97 Creatinine 2.6 2.9 2.7 2.6 GFR 19ml/min 19ml/min 19ml/min 19ml/min UA 2+ blood; 10-15 RBCs, >300 Protein Trace blood, 0-2 RBCs, 100 protein 2+ blood, 0-2 RBCs, 100 protein 1+ blood, 0-2 RBCs, 100 protein Urine Protein 277 107 66 Urine Creatinine 99.5 98.7 89.8 Urine P/Cr 2.78g 1.08g.73g
IgA Nephropathy Most common cause of primary GN disease worldwide Peak incidence in 2 nd and 3 rd decades of life Highest incidence in SE Asia; 2:1 male to female predominance in North American and Western European populations Immune-complex mediated GN characterized by the presence of IgA mesangial deposits with mesangial proliferation and expansion
Pathogenesis IgA molecule exists as 2 isoforms IgA1 and IgA2 IgA1 includes a hinge region that carries a complement of O-linked carbohydrates changes in the galactosylation of these sugars is believed to play a central role in the pathogenesis of IgAN Poorly galactosylated IgA1 O-glycoforms form high molecular weight circulating immune complexes either through selfaggregation or through generation of specific autoantibodies to the hinge region
Multihit Pathogenesis Model Hit1 increased production of galactose-deficient IgA1 Hit 2 formation of auntoantibodies that recognize the galactosedeficient IgA1 Hit 3 formation of pathogenic immune complexes in the mesangium Hit 4 - activation of mesangial cells and induction of glomerular injury
Oxford Classification international scoring system for evaluating pathological features on renal biopsy that have been validated to be predictive of renal outcome independent of other clinical risk factors 4 histological components combine to form the MEST score Mesangial hypercellularity (M: M0<.5, M1>.5) Endocapillary hypercellularity (E: E0=absent, E1 =present) Segmental glomerulosclerosis (S: S0=absent, S1 =present) Tubular atrophy / interstitial fibrosis (T: T0<25%, T1=26-50%, T2>50)
Clinical Features Episodic Gross Hematuria Presenting complaint in 40-50% of patients Often follows an upper respiratory tract or a GI infection; characteristic time course is 24hrs after onset of symptoms of infection Persistent asymptomatic microscopic hematuria; alone or with proteinuria Nephrotic Syndrome Uncommon, occurs in only 5% of all patients w/ IgAN Acute Kidney Injury Rare, occurs in less than 5% of patients Secondary to an acute, severe immune and inflammatory mechanism resulting in crescentic formation
Clinical Predictors of Progression Elevated serum creatinine concentration or reduced GFR at time of diagnosis associated with a worse prognosis The presence of hypertension at the time diagnosis is predictive of a worse outcome Protein Excretion above 1g/day Rate of progression is very low among patients excreting <1g/day and greatest among those excreting >3.5g/day
Approach to Therapy Supportive ACEi or ARB Statin therapy Fish Oil Immunosuppressive Therapy Glucocorticoids Combined therapy Tonsillectomy
Non-established and Controversial Treatment Approaches Fish oil may be potentially useful in patients with persistent proteinuria >1g/d, despite 3-6 months of optimized supportive care (KDIGO 2012) Recent meta-analysis of fish-oil therapy in patients w/ IgAN showed no statistical benefit Tonsillectomy in patients at risk for progressive IgAN Small study in Japan in transplanted patients w/ recurrent IgAN reported that tonsillectomy reduces proteinuria while little change was noted in the non-operated group JASN 22: 1785-1794, 2011
Corticosteroid therapy 3 RCT have shown that a 6 month course of corticosteroids in IgAN patients with GFR >50ml/min can reduce proteinuria and slow the progression of renal failure (LV, Manno and Pozzi et al) Hogg et al showed that after using a 12 month steroid regimen there was no benefit in the steroid versus placebo group after 2 years
2012 KDIGO Treatment Recommendations for IgAN Long-term use of ACEi or ARBs for patients w/ proteinuria >1g/d with up titration of the drug as tolerated by BP to achieve proteinuria <1g/d 6 month trial of corticosteroids for patients w/ persistent proteinuria of >1g/d despite 3-6months of optimal supportive care and GFR>50ml/min Crescentic IgAN involving >50% of glomeruli and rapidly progressive course should be treated with steroids and cyclophosphamide KDIGO: Kidnay Int Suppl. 2012;2(2):209.
Corticosteroids in IgA Nephropathy: A Retrospective Analysis from the VALIGA Study Current guidelines have not addressed whether benefit of corticosteroids extends to patients w/ GFR <50ml/min at time of diagnosis Retrospective study of 184 patients from the VALIGA cohort to determine whether the benefits of this treatment extend to patients w/ a GFR <50ml/min and to other levels of proteinuria
In patients w/ GFR <50, CS-treated group had a slower rate of renal function decline and a higher percentage of patients reached a proteinuria level <1g (74% vs 37%)
Response to CS and RASB compared w/ RASB alone stratified by proteinuria A: <1g/d no statistical difference between the 2 groups (p=.97) B: 1-3g/d - absolute difference in rate of renal functional decline = 2.1ml/min per year C: >3g/d 64% of those receiving CS reached a level of <1g/d compared with only 4% in RASB group. Achieving proteinuria of <1g closely paralleled a greater survival and slower rate of functional decline
Current on-going trials STOP IgAN Study Multicenter RCT of 150 IgAN patients w/ persistent proteinuria of >.75g daily despite RAS inhibition and supportive therapy Patients w/ GFR >60ml/min are randomized to alternate- day steroid treatment + solumedrol versus placebo Patients with GFR of 30-60ml/min are randomized to a regimen of cyclophosphamide for 3months followed by azathioprine versus placebo TESTING Study RCT of 1000 patients w/ proteinuria >1g/d and GFR>20ml/min; randomized to corticosteroids or placebo