A boy with fever, hypertension and impaired renal function

DEPARTMENT OF PAEDIATRICS

QUEEN ELIZABETH HOSPITAL

One fine afternoon......

Consulted for…… M/12 years admitted to Adolescent ward

- Hypertension

- Proteinuria

Background information 12 years old boy

Good past health

Immunisation up to date

Strong family history of hypertension on paternal side

Height 160cm

Weight 75kg

BMI 29kg/m2

Background information Admitted to adolescent ward due to

◦ Abdominal pain with pyrexia of unknown origin

◦ P/E showed hepatosplenomegaly

◦ Extensive workup was performed with no cause found

Noted hypertension and proteinuria during hospitalization • SBP 160-180 mmHg

• DBP 110-120 mmHg

• Urine protein ++ and RBC trace/ +

Workup Creatinine 60-75 umol/L (eGFR 78-97ml/min/1.73m2)

Cortisol 513 nmol/ L (N 101 – 536)

TSH 1.05 mIU/ L (N 0.35 – 4.94)

Renin supine 2.75 ng/ml /hour (N 0.50 – 3.30)

Aldosterone supine 78 pmol/ L (N erect <= 583; supine values are on average 50% lower)

Echocardiogram: no coarctation of aorta; normal contractility; No LVH

Renal Doppler USG: no renal artery stenosis; kidneys normal in size

24 hour urine catecholamine: normal

Urine microscopy: nothing abnormal seen; culture negative

Workup Fasting glucose 5.6/5.3

OGTT: normal

HbA1C 5.1 normal

Lipid profile normal

Workup 24-hour urine:

◦ Protein 0.91 gram/ day (22.3mg/m2/hour)

◦ Albumin 477.5 mg/ day

◦ Creatinine 10.3 mmol/ day

Impression Hypertension

Proteinuria

Obesity

Strong family history of hypertension

PUO?

Elevated Creatinine?

Progress Started Norvasc 10mg daily with good BP control

24 hour BP (while on Norvasc 10mg daily) signified good control of hypertension

◦ Daytime average BP 114/77, MAP 89mmHg

◦ Nocturnal average BP 100/61, MAP 74mmHg

A course of antibiotics was started empirically

PUO spontaneously resolved

Patient discharged by parent team with follow-up in clinic

Upon follow-up…… BP partially controlled with Norvasc 10mg daily

Ramipril was added

Creatinine level was static 70-90umol/L

Further investigations ◦ Repeat 24 hour urine for creatinine, protein

◦ Repeat 24 hour blood pressure 6 months later

◦ MRI renal angiogram and captopril MAG3 scan were arranged

Four months later……

Fever again!

2015 2017 Dec Jan Feb Mar - May Jun Jul Aug Sep Oct

PUO

Initial presentation Intermittent low-grade fever for 6 days

◦ Epigastric pain + Vomiting

◦ Family members had flu like symptoms

◦ Ate a lot of Xmas food, soft drink, ice cream……

Physical examination upon admission: ◦ Pink, no jaundice/ lymph nodes

◦ Tender epigastrium

◦ No guarding/ rebound

◦ No abdominal mass

◦ Other systemic exam unremarkable

Initial presentation Initial blood tests:

◦ WCC 15.2, ANC 12.8

◦ Plt 106

◦ Hb 11.1, MCV 78.6

◦ Na 132, K 3.9, Urea 5.1, Creatinine 76

◦ Amylase 74

◦ Random glucose 8.1

Initial presentation Increasing epigastric pain on Day 2 admission

Repeated blood tests: ◦ WCC 15.0, ANC 11.3 ◦ Plt 106 84 ◦ Hb 11.1 10.4 ◦ ESR 115 ◦ CRP 131 ◦ PT 18.1, INR 1.51, APTT 62.4 ◦ D-dimer >5000, Fibrinogen >6 ◦ Na 135, K 4.2, Urea 5.0, Creatinine 70 ◦ CK 28, LDH 249 ◦ Total bilirubin 33 ◦ ALP 138, ALT 29, AST 26; GGT 106

Initial presentation Urgent USG abdomen on Day 2 admission:

◦ Splenomegaly, measuring ~14.8cm in length

◦ Normal liver, biliary tree, gallbladder, pancreas and kidneys

Started IV cefuroxime + metronidazole

Later switched to IV meropenem

Initial presentation Persistent symptoms

◦ Intermittent fever without obvious pattern ◦ Epigastric + RUQ pain ◦ Vomiting

Gradually enlarging hepatosplenomegaly ◦ smooth tender hepatomegaly 5-6cm below costal margin ◦ palpable spleen 5-6cm below costal margin

Blood tests showed persistent finding of: ◦ Low platelet and haemoglobin ◦ Elevated PT, APTT, D-dimer, fibrinogen ◦ Elevated inflammatory markers

Workup – infection Blood culture

Nasopharyngeal swab

Urine culture

Stool culture (bacterial, ova/cyst, clonorchis sinensis)

Mantoux, interferone gamma tuberculin stimulation

Widal’s test

VDRL

Monospot, EBV serology

Hepatitis serology

Anti-HIV

Urine CMV

Beta-1-D-glucan

Echocardiography

Workup – autoimmune ANA, anti-ENA, ANCA – negative

Direct coomb’s test – negative

C3 1.33 g/ L (N 0.80 – 1.70)

C4 0.14 g/ L (N 0.14 – 0.44)

Ig pattern: ◦ IgA 1.72 g/L (N 0.63 – 4.84)

◦ IgG 18.7 g/L (N 5.4 – 18.22)

◦ IgM 4.41 g/L (N 0.22 – 2.40)

Workup - malignancy Blood smear

◦ no blast cells, only occasional atypical lymphocytes

◦ RBC Rouleaux

◦ Occasional schistocytes

Bone marrow examination: ◦ active marrow with mild plasmacytosis

◦ Chromosome 46 XY, not diagnostic for haemic malignancy

◦ no cytogenetics abnormalities detected

AFP, HCG – normal

24 hour urine catecholamine – normal

Workup - imaging Contrast CT abdomen (week 3 fever):

◦ Hepatosplenomegaly (liver 20cm along right MCL, spleen 16.8cm)

◦ Minimal ascites

◦ Portal veins are patent

◦ Multiple prominent to enlarged mesenteric, hepatoduodenal, para-aortic, portal and aortocaval lymph nodes

Workup - malignancy Contrast CT neck + thorax:

◦ No significant lymphadenopathy

◦ Prominent right level II lymph node of indeterminate significance

Cervical lymph node biopsy – high risk (lymph node closely abut the right common carotid artery)

Workup - miscellaneous Triglyceride, ferritin, NK cell count – normal

◦ Diagnostic criteria for HLH not met

Initial presentation Antibiotics given for 3 weeks

No steroid/ immunosuppressant were given

Day 24: fever down by lysis

Day 27: afebrile

Day 28: decreasing size of hepatosplenomegaly, CRP normalized

Day 32: platelet 179

Day 39: haemoglobin 11.0

2015 2017 Dec Jan Feb Mar - May Jun Jul Aug Sep Oct

PUO Fever down

Outpatient 4 weeks

Antibiotics

During out-patient follow-ups Late Feb – March,

◦ Intermittent fever for 2 weeks

Late March, ◦ Re-appearance of splenomegaly

◦ Platelet count 80-110

Booked follow-up USG abdomen

USG Abdomen Hepatosplenomegaly

Short segment of stenosis at diaphgramatic IVC

Non-visualization of left hepatic vein and middle hepatic vein

Portovenous shunt in liver. Collateral formation draining into right heaptic vein.

Budd-chiari syndrome!

2015 2017 Dec Jan Feb Mar - May Jun Jul Aug Sep Oct

PUO Fever down

Outpatient 4 weeks

Budd-Chiari syndrome

Antibiotics

Positive findings Fever

Hepatosplenomegaly

Hypertension, proteinuria

Thrombocytopenia with DIC-like picture

Rouleaux, schistocyte on blood smear

Borderline elevated creatinine

Mildly deranged LFT and mildly elevated bilirubin

Elevated ESR and CRP

Budd-chiari syndrome

Differential diagnosis?

Further workup Anti-cardiolipin IgM 9.2 MPL (N < 12.5)

Anti-cardiolipin IgG 98.3 GPL U/ ml (N ≤ 13.3)

Lupus anti-coagulant present

Further workup Protein C 52% (N 70 – 140)

Protein S 115% (N 70 – 140)

Anti-thrombin III 74% (N 75 – 125)

Factor VII 47% (N 50 – 200)

Further workup Proteinuria

Hypertension

Impaired renal function

Suspected underlying autoimmune disease

Decided to proceed to renal biopsy

Around 25 glomeruli are present, 3 of them are globally sclerosed (red). 10% renal cortex is affected by tubular atrophy and interstitial fibrosis (blue).

Ischaemic wrinkling of glomerular basement membrane

A pinkish thrombus extending from an arteriole into the glomerular hilum

This small artery shows luminal pinkish thrombus, endothelial cell swelling, increase in blood vessel tortuosity

Some renal tubules show luminal pinkish granular casts (blue). Some renal tubules show irregular spacing of nuclei and apical sloughing (red). These are compatible with ischaemic acute tubular injury

Segmental double layer of glomerular basement membrane (two dark lines, blue arrows)

Podocyte (within urinary space)

Endothelial cell nucleus (within capillary loop)

Comment Crescents/ subepithelial spikes not seen.

IF: No significant deposit

Diagnosis: Thrombotic microangiopathy with acute* and subacute changes^

Comment: Can be related to antiphospholipid syndrome. Pathological features overlap with malignant HT and haemolytic uraemic syndrome

* e.g. endothelial cell swelling, thrombus, GBM wrinkling, acute tubular injury, etc. ^e.g. double contour of GBM, parenchymal scarring, etc.

Further workup Urine pneumococcal antigen negative

Stool culture no growth

ANA, ANCA, Anti-ENA negative

ADAMTS13 activity 105% (normal)

MRI brain pending

(Neurological exam normal, no seizure)

Diagnosis ANTI-PHOSPHOLIPID SYNDROME (APS)

APS NEPHROPATHY

Lupus anticoagulant +ve Anti-cardiolipin IgG +ve

Clinical thrombosis (Budd-chiari syndrome) Renal biopsy: Thrombotic microangiopathy

Before going to management… DR. ALVIN HUI

Progress

2015 2017 Dec Jan Feb Mar - May Jun Jul Aug Sep Oct

PUO Fever down

Outpatient

Antiphospholipid Syndrome

4 weeks

Budd-Chiari syndrome

Antibiotics Renal Biopsy

28th July 2016 Day 7 fever

P/E:

- pallor, jaundice

- no rash

- no joint swelling/ tenderness

- abdomen distended, large hepatosplenomegaly, both ~6cm below costal margin

- systolic BP 140-150mmHg and diastolic BP 85-105mmHg

Investigations Hb 9.4, WCC 12.0, Platelet 87

Rouleaux, schistocytes present

ESR 134, CRP 338

PT 19.4, APTT >120.0

Na 129, K 5.0, Urea 6.4, Creatinine 89

Albumin 30, Globulin 40

Total bilirubin 42

ALT 48, AST 71, GGT 165, ALP 121

LDH 318

24 hour urine protein 1.31 gram/ day

Management Anti-thrombosis

◦ LMWH

◦ Warfarin

Hypertension, proteinuria ◦ ACEI

◦ Labetalol

◦ Diuretics

Immunosuppression ◦ Steroid, hydroxychloroquine

◦ Azathioprine

◦ IVIG

◦ Plasmapheresis

Management – thrombosis Enoxaparin since 28/7

◦ Anti-Xa level adequate

Switched to warfarin since 31/8

Management – BP Labetalol

Enalapril

Lasix

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Platelet

LMWH Steroid Plasmapheresis IVIG Plasmapheresis Azathioprine Warfarin

Immunosuppression Methylprednisolone 1 gram daily for 3 days,

then prednisolone 60mg/ day ◦ Since 28/7/2016

◦ Total 6 weeks P60, then gradually wean down

Fever down soon after starting steroid

Decreased in size of hepatosplenomegaly

Platelet transiently rose to ~190

Immunosuppression Since early August (1 week after admission):

◦ Gradually dropping platelet, deranged LFT, re-appearance of splenomegaly

1st course plasmapheresis (5 sessions) was started three weeks after admission

After initial course of plasmapheresis ◦ Platelet transiently normalized

◦ Anti-cardiolipin IgG <13.3 normalized

Immunosuppression 2 weeks later, platelet downtrend again

◦ Started hydroxychloroquine 200mg daily

◦ Given a course of IVIG@0.4 gram/ kg/ day

◦ Diluted to 3%, slow infusion

◦ (Concentration >5% is associated with risk of thrombosis)

No significant improvement

Immunosuppression 2nd course of plasmapheresis (5 sessions) was started (One month after 1st course) ◦ Decreased in size of hepatosplenomegaly

◦ Platelet normalized

Started tailing down steroid gradually

Azathioprine was started

Monitoring

Clinical Fever

Liver and spleen size

Blood pressure

Proteinuria

Laboratory Platelet

LDH

Others? ◦ ALT, bilirubin

◦ APTT

◦ ESR, CRP

◦ Lupus anticoagulant

◦ Blood smear – Schistocytes, rouleaux

0

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100

150

200

250

Platelet

LMWH Steroid Plasmapheresis IVIG Plasmapheresis Azathioprine Warfarin

Imaging USG Abd 9th September 2016

◦ Focal stenosis site at diaphragmatic region of IVC, above the level of hepatic vein confluence, is still seen.

CT Abd 20th September 2016 ◦ Interval decrease in extent of hepatosplenomegaly and intra-abdominal

lymph nodes

◦ Liver: 20cm-->15.3cm along right MCL, Spleen 16.8cm-->14.5cm

MRI abdomen + pelvis booked on December 2016

2015 2017 Dec Jan Feb Mar - May Jun Jul Aug Sep Oct

PUO Fever down

Outpatient

Antiphospholipid Syndrome

4 weeks

Budd-Chiari syndrome

Plasmapharesis Plasmapharesis Antibiotics Renal Biopsy

Patient Discharged

P60 Azathioprine IVIG

Follow-up 11th October 2016 No fever after discharge

BP measured at home: SBP 125-135; DBP 88-90

Good compliance to medications

Liver 2cm and spleen 1cm

Blood tests ◦ Hb 11.2; WCC 5.5; Plt 193; smear no schistocytes/ rouleaux ◦ RFT 143 / 3.8 / 9.3 / 83 (eGFR 73ml/min/1.73m2) ◦ HCO3 20; Cl 108 ◦ LFT: ALT 48; GGT 185; Others normal ◦ Albumin 39 ◦ INR 2.26

Current medications Prednisolone 30mg daily

Azathioprine 75mg daily

Hydroxychloroquine 400mg daily

Enalapril 2.5mg daily

Labetalol 300mg Q6H

Warfarin 4.5mg daily

Calcichew 1 tablet daily

Plan Gradually tail down steroid

Maintenance with Azathioprine

Close monitoring in outpatient

Keep warfarin with INR target 2.5-3.0

Repeat imaging for IVC stenosis later

May need further course plasmapheresis/ rituximab if disease not under control

Discussion How to monitor disease activity?

Immunosuppression ◦ Duration of steroid

◦ Choice of maintenance therapy

◦ Role of Rituximab / further courses of plasmapheresis

Anti-thrombosis ◦ Choice of agent (warfarin vs newer agents)

◦ Duration of treatment