Morning Report Jieli Li 03/28/05

Chief Complaint Generalized edema x 1 week

HPI 46 y/o AAM with hx of htn, Hep C, syphillis presented to Urgent Care with generalized edema x 1 week Pt noticed progressive lower extremity edema, then scrotal edema, as well as tightness in abdomen. + facial edema as well Pt was seen by PMD and started on HCTZ last week without any relief

HPI cont. + 2 pillow orthopnea + 1 episode of PND and wheezing recently + occasional wheezes x 1 yr + SOB with exertion + occasional cough with yellow phlegm Baseline exercise capacy excellent No CP, f/c/s, no diarrhea/constipation No dysuria, no hemauria

PMH Htn – dx’d 1 yr ago Hep C – never treated Syphillis – treated in 1989 Depression Hyperlipidemia Bilateral leg fractures in the past

Meds & Allergies Meds: Allergy: Atenolol 50 qd HCTZ 12.5 qd Simvastatin 10 qhs Ascorbic acid 500 qd Alleve prn (OTC) Allergy: NKDA

Social and Family History SH: Single, lives at Midnight Mission Hx of incarceration x 37 months until Nov 2004, HIV neg in 2000 Hx of cocaine, MJ, no IVDU Hx of heavy etoh use, quit 40 months ago Hx of tobacco (1/2 pk per day x 20 yrs), quit 2 yrs ago FH: Mother: DM & htn Father: CAD with triple bypass

Physical Exam VS: 96.8, 73, 20, 178/99, 0/10 Gen: obese AAM with anasarca, NAD, AAO x 4 HEENT: PERRLA, EOMI, op moist and intact, no lesions Heart: distant heart sounds, no murmurs appreciated Lungs: cta bilaterally, no crackles/wheezes Abd: obese, mildly distended, NT, na bs, no hsm

PE cont. GU: + large scrotal edema, non-tender, testes palpable and intact, no masses Ext: 2-3+ pitting edema bilateral legs, generalized anasarca, + patchy flesh-colored papular lesions bilateral shins, faint pulses bilaterally

Lab Studies UA Spot protein/Cr: 2967/396 = 7.5 Spec grav 1.04 PH 6.5 Protein > 600 Glucose neg Ketones neg Bilirubin neg Small occult blood Urobilinogen 0.2 Spot protein/Cr: 2967/396 = 7.5 24 hr urine protein: 12.1g Nitrite neg LE neg RBC 4 WBC 8 Hyaline casts 40

Lab Studies cont. 15.2 8.6 356 44.8 141 106 27 93 4.57 31.6 1.4 Alk Phos 66 ALT 14 Total bili 0.7 Alb 1.1 Total cholesterol 411 Trig 157 HDL 121 LDL 259

Glomerulonephritis Panel RPR 1:1 MHA-TP: 4+ ESR: 89 HIV neg C3 and C4: nl RF: neg ASO: nl SPEP: hypogammaglobulinemia Cryoglobulin neg Hep A ab R, IgM NR Hep B surface Ag NR Hep B core Ab NR HCV RNA 1,010,000 HIV neg

Renal u/s Right kidney 14.6 cm, left kidney 13 cm No definitive abnormalities although there is very mild increased cortical echogenicity Mildly enlarged prostate without bladder outlet obstruction

Hospital Course Pt was admitted to GMED for workup of his nephrotic syndrome Hep C induced MPGN vs FSGS vs membranous GN was high on the differential Pt was started on lasix, titrated up to 40 po bid eventually for his anasarca He was placed on low salt diet ACEI was held during diuresis, Cr improved to baseline (1.1)

Hospital Course cont. GI was consulted for possible Hep C treatment after HCV RNA came back > 1 million Pt’s proteinuria was followed by serial protein/Cr ratio and 24 hr urine protein Renal biopsy showed minimal change disease confirmed by EM This was believed to be 2/2 hx of NSAIDS By the time of discharge, pt has only trace protein on UA, he did not receive any further tx

1 week follow up At the renal clinic f/u one week after discharge, pt’s proteinuria has dropped from 12 g/day to 0.3 g/day. He has lost nearly 100 lbs on diuresis (back to baseline wt). He is no longer taking NSAIDs.

Nephrotic Syndrome Defined by presence of: heavy proteinuria (> 3g/24hrs) Hypoalbuminemia (< 3.0 g/dL) Peripheral edema Isolated heavy proteinuria is more likely to be due to secondary focal glomerulosclerosis Urinary sediment: few cells or casts Lipiduria (oval fat bodies)

Oval Fat Bodies

Etiology In children In adults In elderly Minimal change disease is predominant In adults Systemic disease related: 30% Primary renal disorders: 70% Membranous nephropathy Focal glomerulosclerosis Minimal change disease Amyloidosis In elderly Increased incidence of amyloidosis and decreased incidence of SLE

Etiology cont. Although nephrotic syndrome can develop in patients with postinfectious GN, membranoproliferative GN, and IgA nephropathy, most commonly these disorders present with a “nephritic” picture, i.e., RBC and cellular casts in UA

Minimal Change Disease 90% of nephroitic syndrome in children under the age of 10 50% of cases in older children In adults, can occur as an ideopathic condition or be associated with: NSAIDs Cancers as a paraneoplastic phenomenon, most often Hodgekin’s Disease

Minimal Change Disease Light Microscopy Either normal or reveals only mild mesangial cell proliferation EM Diffuse fusion of the epithealial cell foot processes

Minimal Change Disease

Focal Glomerulosclerosis (FGS) 35% of all cases of nephrotic syndrome in the U.S. > 50% of cases among African Americans Can occur as an ideopathic condition or be associated with: HIV disease reflux nephropathy Healed previous glomerular injury NSAIDs Massive obesity

Diagnostic Considerations for FGS Sampling error in renal biopsy may lead to misclassification of FGS as minimal change disease Steroid-resistance in minimal change disease pts should raise suspicion for FGS Primary FGS usually presents with acute onset nephrotic syndrome, tx is corticosteroids. Secondary FGS usually presents with slowly increasing proteinuria, nephrotic syndrome is rare. Tx is ACEI.

Focal Glomerulosclerosis

Collapsing FGS A histologic variant usually associated with HIV infection Tendency to collapse and sclerosis of the entire glomerular tuft, rather than segmental injury Often severe tubular injury with proliferative microcyst formation and tubular degeneration Often with rapidly progressive renal failure Optimal therapy is uncertain

Collapsing FGS

Membranous Nephropathy Basement membrane thickening with little or no cellular proliferation or infiltration Presence of electron dense deposits across the glomerular basement membrane Can occur as ideopathic condition or be associated with: Hep B Autoimmune diseases Thyroiditis Carcinoma Certain drugs (e.g., gold, penicillamine, captopril and NSAIDs)

Membranous Nephropathy

Amyloidosis 4-17% of nephrotic syndrome Increased frequency among elderly Two major types: Primary amyloid (AL) A light chain dyscracia Fragments of monoclonal light chains form the amyloid fibrils Secondary amyloid (AA) Acute phase reactant serum amyloid A forms the amyloid fibrils Assoc with chronic inflmmatory diseases such as RA or osteomyelitis

Amyloidosis

Pathophysiology Proteinuria Increased filtration of macromolecules across the glomerular capillary wall Commonly due to abnormalities in podocytes Increased loss of: Albumin Clotting inhibitors Transferrin Hormone binding proteins (e.g., Vit D binding protein)

Pathophysiology Hypoalbuminemia Edema Presumably 2/2 proteinuria Unclear why hepatic synthesis can not compensate sufficiently Edema Marked hypoalbuminemia leading to movement of fluid into the interstitial space by decreasing plasma oncotic pressure Primary renal sodium retention in collecting tubules

Pathophysiology Hyperlipidemia and lipiduria Decreased plasma oncotic pressure stimulates hepatic lipoprotein synthesis Diminished clearance may also play a role Impaired metabolism is primarily responsible for nephrotic hypertriglyceridemia Oval fat bodies are thought to be degenerated renal tubular epithelial cells containing cholesterol esters

Complications of Nephrotic Syndrome Protein malnutrition Hypovolemia Acute renal failure Urinary loss of hormones Hyperlipidemia and the potential for accelerated atherosclerosis Thrombosis Increased susceptibility to infection

Protein malnutrition Loss in lean body mass due to proteinuria May be masked by concurrent edema May be compounded by GI symptoms of anorexia and vomiting 2/2 bowel edema

Hypovolemia Often as a result of overdiuresis in those with a serum albumin < 1.5 g/dL Occurs more often in children

Acute Renal Failure Can be seen in: Mechanism not well understood Minimal Change Disease Collapsing FGS Crescentic glomerulonephritis superimposed upon membranous nephropathy Mechanism not well understood Hypovolemia Interstitial edema Ischemic tubular injury NSAIDs

Thromboembolism Increased incidence of arterial and venous thromboemboli, particularly DVT and renal vein thrombosis Mechanism not well understood Renal vein thrombosis is most often found with membranous nephropathy Can present acutely with flank pain, gross hematuria and ARF or Indolent disease without symptoms, suspected only when PE occurs

Infection Before abx became available, this used to be the leading cause of death in children with nephrotic syndrome Pneumococcal infections, esp peritonitis were most common Mechanism is not well understood Low levels of IgG may play a role

Proximal tubular dysfunction Often associated with advanced disease Can result in: Glucosuria Aminoaciduria Phosphaturia renal tubular acidosis Vitamin D deficiency Thyroid dysfunction – due to loss of thyroxine-binding globulins

Diagnosis 24 hour urine collection > 3 g/day Total protein to creatinine ratio on spot urine specimen Correlates with daily protein excretion in g/1.73 m2 of body surface area In history, should look for hx of DM, SLE, HIV, drugs such as NSAIDs, gold, penicillamine

Serologic Studies Certain serologic tests may preclude the need for renal biopsy: SPEP/UPEP Presence of a paraprotein should be followed by fat pad or rectal biopsy to look for amyloidosis ASO poststreptococcal glomerulonephritis Cryoglobulins Mixed cryoglobulinemia, commonly 2/2 Hep C

Renal Biopsy In adults, renal biopsy is usually required to determine diagnosis Contraindications: Uncorrectable bleeding diathesis Uncontrolled hypertension Small kidneys generally indicative of chronic irreversible disease Multiple bilateral cysts or renal tumor Hydronephrosis Active renal or perirenal infection Uncooperative patient

Management Proteinuria ACEI / ARB To lower intraglomerular pressure, which may reduce protein excretion and slow the rate of disease progression Potential adverse effects include ARF and hyperkalemia Evidence is unclear on protein restriction

Management Edema Dietary sodium restriction Diuretics Edema is due to primary renal sodium retention in most cases Diuretics Proceed slowly to prevent acute hypovolemia Generally there is lesser natriuresis than in normal patients because of hypoalbuminemia and albuminuria Serial body weight is important in guiding the titration of diuretics

Management Hyperlipidemia Hypercoagulability Usually reverse with resolution of the renal disease In case of persistent nephrosis, dietary modification is usually of little value and a statin is usually required Hypercoagulability Some have suggested prophylactic anticoagulation in membranous nephropathy due tot high incidence of thromboemboli In others, if unexplained thrombosis occurs, they should be put on heparin followed by warfarin for as long as the nephrotic syndrome persists