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 CBC

UA: 2+ blood, 3+ protein, 0 WBCs, 10-15 RBCs

UPr/Cr: 277/99.5 = 2.78g/g

27 106

4.5 142 2.6

40 88 36.6

12.2

271 7.0

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 2nd and 3rd 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 self-aggregation 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 galactose-deficient 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