ClinicopathologicConferenceOS 214 - Renal ModuleGroup IV

Tan-Tanchuling-Te-Teo-Tindoc-Tugano-Urquiza-Uy-Velasco-Ventigan-Ventura-Verdolaga-Villanueva-Villanueva-Visperas-Yabut-Yambot-Yap-Yap

General Data

R.V.

45 y/o, F

Separated

Filipino, Roman Catholic

From Port Area Manila

CC: Bipedal Edema

History of Present IllnessOverview

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LBMGeneralized Body WeaknessPalpitationsEasy FaltigabilityEdema

History of Present IllnessOne Month Prior to Consult

Enzyme/Hormone Panel↑ ALT↑ TSH↔ FT4↓ FT3

UrinalysisColor: Yellow

pH: 6.8Slightly Turbid

Albumin +3↑ WBC↑ RBC

Trichomonas

CBC↔ Hemoglobin↔ Hematocrit

↑ WBC↑ Neutrophils

↓ Lymphocytes↔ Platelets

LBM (2 episode, 1 cup/ episode)Generalized Body Weakness/Palpitations/Easy Fatigability

Prescribed with silymarin 140 mg BID for 1 monthNorfloxacin 400 mg BID for 7 days

History of Present IllnessTwo Weeks Prior to Consult

Generalized Body Weakness/Palpitations

UrinalysisProteinuria

↑ WBC Prescribed with Metronidazole 500 mg TIDCiprofloxacin 500 mg BID

Developed Edema on the 3rd day of intake of antibiotics

Consulted another physician and was prescribed with:Potassium Citrate / Diltiazem / Spironolactone / Methylprednisone / Furosemide

Laboratory Work-up was requested

Laboratory Work-up was requested

CBC↔ Hemoglobin↔ Hematocrit↔ Platelets

↑ WBC↑ Neutrophils

↓ Lymphocytes

UrinalysisColor: L. Yellow

pH: 6.0Slightly Turbid

(-) Glucose(-) CrystalsProtein +4

↑ WBC↑ RBC

+ Cast (Coarse/Fine)Bacteria – Moderate

Blood Chemistry↔ ALT↔ AST↔ BUN

↔ Creatinine ↔ Total Protein

↔ Globulin↔ Sodium

↔ Potassium↓ Albumin

↑ ALP

Tumor Markers↔ CEA↔ AFP

SerologyHBsAg – non-reactive

AntiHCV – non-reactive

Thyroid Hormone↔ FT3↔ FT4↑ TSH

Radiological Findings

UTZLiver normal size with solid mass

(3.5x3.3x3.9cm) in left lobenormal portal vein, tributaries,

intrahepatic and CBDGallbladder normal findings

Pancreas and Spleen normal

KUB X-RayNormal Kidneys

Urinary Bladder Normal

Patient was lost to follow up

Seek Consult with a GI consultant

Advised a CT Scan with Triple IV Referred to a Nephrologist

24 hr Urine↑ Protein

↑ Total Volume↑ Protein Excretion

Lipid Profile↑ Cholesterol↑ Triglyceride

↑ LDL↑ VLDL↓ HDL

Prothrombin Time9.5/11.90/>100%/INR 0.78

Normal

Patient was lost to follow up

Day of Consult

History

Review of Systems(+) Hair Loss (thinning)

No joint painsMalar rash

Family History(+) DM - Mother

No intake of NSAIDS and other nephrotoxic drugs or previous Blood Transfusion

Personal/Social HistoryWorked as a photographerClaims Ex-husband was

promiscuous hence separatedNo vices

OB/Gyne HistoryG1P1 (1001)

Physical Exam

BP: 110/80HR: 76 bmp

Bipedal Edema Grade 2Periorbital Edema

LaboratoryANA Negative

Anti dsDNA Negative↔ BUN

↔ Creatinine↔ Sodium

↔ Potassium↓ C3

↓ Albumin↓ Calcium

CBC↔ WBC↔ MCV↔ MCH

↔ Neutrophils↔ Lymphocytes

↔ PlateletsPT: NoramalPTT: Normal

↓ Hgb↓ Hct

Laboratory Results

UrinalysisColor: Yellow

SG: 1.020Slightly Turbid

↔ WBC↔ RBC

(-) Glucose(+) Cast (Waxy/Fine

Granular)Bacteria – Moderate

Protein +4

Non-obstructing Nephrolithiasis in left

kidneyPelvocaliectasis in

right kidney,normal urinary

bladder

Radiologic Findings X-Ray/UTZ

.

Differential Diagnosis

Nephrotic Syndrome

Proteinuria Hyperlipidemia Edema

Minimal change disease

Membranous Glomerulonephritis

Focal Segmental Glomerulonephritis

Membranoproliferative Glomerulonephritis

IgA Nephropathy

Post-streptococcal Glomerulonephritis

Nephrotic Syndrome

Membranous GlomerulonephritisIgA Nephropathy

Rule in: Nephrotic syndrome(10%) Onset following GI infection/UTI Lethargy(if renal function is

impaired)Rule out:x Frank hematuria following

infection(most common presentation)

x Normal to increased C3 complement

Rule in: Nephrotic syndrome(80%) Microscopic hematuria(~50%) Peak incidence 30-50 y/o Non-spcific complaints – fatigue,

malaiseRule out:x Hypertension – not characteristic

but absence makes it unlikelyx Normal C3 Complementx Edema usually generalized

Nephrotic Syndrome

Minimal change disease

Membranous Glomerulonephritis

Focal Segmental Glomerulonephritis

Membranoproliferative Glomerulonephritis

IgA Nephropathy

Post-streptococcal Glomerulonephritis

Nephrotic Syndrome

Minimal change disease

Focal Segmental Glomerulonephritis

Rule in: Proteinuria Hypoalbuminemia hyperlipidemia Benign urinary sediments – casts Dependent edema Facial edema (Periorbital) Microscopic Hematuria (<15%)

Rule out:x More common in childrenx Normal C3 Complement

Rule in: Nephrotic syndrome(~60%) RBC’s and leukocytes in urine

Rule out:x Gross hematuria is more

commonly seenx Hypertension is found as a

presenting feature in one third of patients

x Normal C3 Complement

Nephrotic Syndrome

Minimal change disease

Focal Segmental Glomerulonephritis

Membranoproliferative Glomerulonephritis

Post-streptococcal Glomerulonephritis

Nephrotic Syndrome

Rule in: Nephrotic syndrome Hematuria(may be microscopic) Low C3 Complement Periorbital or dependent edema Fatigue

Rule out:x Can’t be ruled out

Rule in: Hematuria Malaise Weakness Low C3 Complement

Rule out:x Gross hematuria is more

commonly seenx Hypertensionx No history of infection weeks

prior to edema (no latent period)

Membranoproliferative Glomerulonephritis

Post-streptococcal Glomerulonephritis

Nephrotic Syndrome

Membranoproliferative Glomerulonephritis

Post-streptococcal Glomerulonephritis

Nephrotic Syndrome

Membranoproliferative Glomerulonephritis

Type I Type II

Rule in: Nephrotic syndrome Hematuria(may be microscopic) Low C3 Complement Periorbital or dependent edema Fatigue

Rule out:x Can’t be ruled out

Rule in: Hematuria Low C3 Complement

Rule out:x More Nephriticx Red cellsx Red call castsx Hypertensionx No history of infection weeks

prior to edema (no latent period)

Primary Impression

Nephrotic Syndrome2○ Membranoproliferative Glomerulonephritis Type I

Nephrotic Syndrome

Membranoproliferative Glomerulonephritis Type I

Idiopathic

Hepatitis C and B

Cryoglobulinemia

Infective endocarditis

Visceral abscesses

SarcoidosisSjögren syndrome

Scleroderma

Systemic lupus erythematosus

Leukemia

Lymphoma

Carcinoma

HIV Nephropathy

Nephrotic Syndrome

Membranoproliferative Glomerulonephritis Type I

Hepatitis C and BInfective endocarditis Scleroderma

No Evidential Findings in the History and PE

Negative for Serologic Tests

No Evidential Findings in the History and PE

Nephrotic Syndrome

Membranoproliferative Glomerulonephritis Type I

No Evidential Findings in the History and PE

No Lymphadenopathy

No other Evidential

Findings in the History and PE

No Evidential Findings in the History and PE

SarcoidosisSjögren syndrome Lymphoma Leukemia

AnemiaNo other

evidential findings in the History and

PE

Nephrotic Syndrome

Membranoproliferative Glomerulonephritis Type I

No Evidential Findings in the History and PE

Liver MassNo weight lossNegative CEANegative AFP

No Malar RashNegative ANA

Negative Anti-dsDNA

Visceral abscesses Systemic lupus erythematosusCarcinoma

Nephrotic Syndrome

Membranoproliferative Glomerulonephritis Type I

More Common in Type I EBV Infection

Promiscuous HusbandAnemia

Predisposition of repeated Infection

Cryoglobulinemia Idiopathic HIV Nephropathy

Primary Impression

Nephrotic Syndrome2○ Membranoproliferative Glomerulonephritis Type I

2○ to EBV Infectious Mononucleosis vs. HIV Infection

Pathophysiology

HIV Nephropathy

Epstein-Barr Virus

Liver massMPGN Type 1

Nephrotic Syndrome

Cryoglobulin

Low C3 Complement

MPGN Type 1

Nephrotic SyndromeHypothyroid state

HypocalcemiaHyperlipidemia

Proteinuria

Decrease in TBG

Easy fatigability; weakness

Nephrolithiasis due to increased

excretion of calcium

Hypoalbuminemia leading to Edema

Increase in Cholesterol,

Triglycerides, LDL, VLDL

Decrease in HDL

Most have low CD4 counts <200 and advanced HIV

Mechanism is not well understood but in vitro study suggested HIV can infect glomerular endothelial cells, mesangial cells and tubular cells.

Presents with renal insufficiency with heavy proteinuria (>10g), few red or white cells in urine sediment and hypoalbuminemia, nl to large hyperechogenic kidneys on US. HTN and peripheral edema is not common.

Rapid decline in renal function due to severe glomerular injury and marked damage to the tubular cells

In histology, tendency to collapse and sclerosis of the entire glomerular tuft rather than segmental injury.

HIV Infection

EBV Infectious Mononucleosis

Epstein-Barr virus (EBV) is ubiquitous. It is estimated that more than 90% of adult humans demonstrate serologic evidence of a prior infection with EBV.

Most cases of IM are due to EBV, but the vast majority of EBV infections do not result in infectious mononucleosis.

The most common mode of transmission of EBV is through exposure to infected saliva from asymptomatic individuals, often as a result of kissing.

Most patients with Epstein-Barr virus (EBV) infectious mononucleosis are asymptomatic

Prodromal symptoms consisting of 1-2 weeks of fatigue, malaise, and myalgia are common.

ManagementConfirmatory Diagnostics

HIV InfectionRapid HIV tests

Test for HIV antibodies with an enzyme-linked immunosorbent assay (ELISA).

Next steps if rapid test positive Confirm reactive tests with Western blot or immunofluorescent

assay (IFA).

Nonreactive tests with high suspicion for acute HIV infection should be followed up with a virologic test such as HIV RNA assay (viral load).

Viral load is very high (>100,000 copies/mL) in acute HIV infection.

If virologic test is positive, then repeat antibody testing in 3 months after seroconversion.

Patient should undergo the heterophile test to diagnose EBV with IM.

Human serum is absorbed wth guinea pig kidney.

Heterophile titer is defined as greatest serum dilution that agglutinates sheep, horse or cow erythrocytes.

A titer of greater than or equal to 40-fold is diagnostic of acute EBV infection in a person with symptoms of IM with atypical lymphocytes.

The patient can also undergo the monospot test which is slightly more accurate and more commercially available.

The patient can also choose to undergo EBV-specific serologic studies which is considered the “gold standard”.

EBV Infection

Renal Biopsy

Liver Biopsy

Biopsy

ManagementTherapeutics

Treatment of nephrotic syndrome involves:

1. Specific treatment of the underlying morphologic entity

2. General measures to control proteinuria if remission is not achieved through immunosuppresssive therapy and other specific measures

3. General measures to control nephrotic complications

Nephrotic Syndrome

Corticosteroids

Immunoregulators

Diuretics

Anticoagulation to prevent thromboembolic complications

Hypolipidemic agents may be used, but if the nephrotic syndrome cannot be controlled, there will be persistent hyperlipidemia.

In secondary nephrotic syndrome, angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers are used. These may reduce proteinuria by reducing the systemic blood pressure and by reducing intraglomerular pressure.

Nephrotic Syndrome

Diet

For patients with nephrotic syndrome, their diet should provide adequate energy (caloric) intake and adequate protein (1-2 g/kg/d). Supplemental dietary protein is of no proven value.

A diet with no added salt will help to limit fluid overload.

Management of hyperlipidemia could be of some importance if the nephrotic state is prolonged.

Nephrotic Syndrome

1/3 of patients with Type 1 MPGN will have spontaneous remission, 1/3 will have progressive disease, and 1/3 will have a disease process that will wax and wane but never completely disappear.

The goals of treatment:

reduce symptoms

prevent complications, and

slow the progression of the disorder.

Type 1 MPGN

There is no clearly defined treatment for Type 1 MPGN.

After ruling out secondary causes, it consists of corticosteroid therapy (there is no standard dosage for adults) and antiplatelet drugs (aspirin, 500–975 mg/d orally, plus dipyridamole 225 mg/d orally). The rationale for antiplatelet therapy is that platelet consumption is increased in MPGN and may play a role in glomerular injury.

Prednisone – low dose, alternate-day may have salutary effect on improving renal function.

However studies for this have been limited to children.

Type 1 MPGN

a host of other forms of immunosuppressive and anti-coagulant treatment has been used in the management of type I MPGN.

Ex. dipyridamole, aspirin, and warfarin with and without cyclophosphamide

A study using acetylsalicylic acid with dipyridamole demonstrated a slight decrease in urine protein excretion by 3 years without differences in renal function.

Important to treat the associated diseases, if any.

Treatment with inhibitors of the renin-angiotensin system is prudent if there is proteinuria.

Type 1 MPGN

Clinical course is generally self-limited

Does not usually require specific therapeutic intervention beyond the use of aspirin or acetaminophen for antipyresis and mild pain relief

Short courses of corticosteroids have been used to hasten symptomatic recovery in cases in which the symptoms are severe or refractory.

Excessive physical activity during the first month should be avoided.

Antiviral agents (like acyclovir) have not been demonstrated to significantly accelerate resolution of symptoms or prevent complications of the disease.

EBV-associated IM

Six classes of antiretroviral agents currently exist, as follows:

Nucleoside reverse transcriptase inhibitors (NRTIs)

Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Protease inhibitors (PIs)

Integrase inhibitors (IIs)

Fusion inhibitors (FIs)

Chemokine receptor antagonists (CRAs)

HIV – Antiretrovirals