Nephrotic Syndrome Secondary to Minimal Change Disease (12/3/2018)

Narges presented a case today with a middle age woman with uncontrolled insulin dependent diabetes Type 2, multiple malignancies s/p resection, presenting with acute anasarca and shortness of breath developed over a few days. She was anasarcic up to the mid back on presentation, with an albumin of 0.9 (baseline of 3.8 a month ago). Her UA had 3+ protein and a urine protein/Cr ratio of 23. If you’re thinking nephrotic syndrome, that’s right! Biopsy revealed the diagnosis of minimal change disease (MCD) with concurrent ATN!

Nephrotic Syndrome

Some definitions

  • Nephrotic range proteinuria: > 3.5g proteinuria per day or spot urine protein/cr ratio of > 3.5
  • Nephrotic syndrome: Above + symptoms (edema, HLD, hypoalbuminemia, lipiduria, etc)


  • Most common primary cause of nephrotic syndrome in adults in the US is FSGS
  • Most common secondary cause of nephrotic syndrome in adults in the US is Diabetic Nephropathy


  • AKI (underlying glomerulonephritis vs hypovolemia vs sepsis vs ATN)
  • Hypercoagulability (loss of anticoagulant proteins namely antithrombin III, C, S)
  • Hyperlipidemia (reactive hepatic synthesis of proteins due to hypoproteinuria)
  • Malnutrition (gut edema, dec body weight, edema) leading to anemia, osteomalacia, vitamin D deficiency
  • Immunocompromise (inc risk for infection due to hypoimmunogammopathy)
  • Edema (low oncotic pressure due to hypoalbuminemia)


  • 24 urine protein > 3.5g is diagnostic
  • Spot urine protein/cr ratio > 3.5 is also diagnostic
  • Exactly cause will require additional work up, to be discussed below in differential

General Management Strategies

  • Proteinuria control (ACEi, ARB)
  • BP Control
  • Volume Control (Diuretics, low salt)
  • HLD: usually resolves with disease control, can use statins
  • Immunosuppresion for primary causes
  • Treat underlying secondary causes

Differential Diagnosis


Source: Grepmed

The three most commonly encountered causes, besides diabetic nephropathy, are:


Minimal Change Disease

As seen in this patient, is typically seen in pediatric population and it is the most common cause of nephrotic syndrome in kids < 8-10 years old. It only accounts for 10% of cases of nephrotic syndrome in adults.


  • Acute onset edema
  • Higher incidences of thrombotic events in adults
  • AKI common, at higher risk for ATN


  • Biopsy, electron microscopy with podocyte effacement


  • Corticosteroids: initial course of 6-8 weeks in adults, 1.5mg/kg/day
  • Cyclosporine for non-responders
  • Other options: mycophenolate (Cellcept), azathioprine (but pt is already on this, Imuran!)


  • 80-90% of patients respond to initial corticosteroid therapy
  • Up to 50% can recur

Focal Segmental Glomerulosclerosis (FSGS)


  • Higher incidence among African Americans (5 times more likely than White)
  • Associated with HIV (collapsing variant), heroin (30x risk)


  • Biopsy: focal and segmental hyalinization of the glomeruli, often with immunostaining showing IgM and complement (C3) deposits in a nodular and coarse granular patter


  • Primary: Immunosuppression, corticosteroids +/- cyclosporine, tacrolimus + plasma exchange
  • Secondary: Treat underlying cause

Prognosis: Poor

  • > 50% develop renal failure within 10 years of diagnosis, and 20% develop ESRD within 2 years despite treatment
  • May recur after kidney transplantation.
  • Heroin addicts with FSGS: can experience complete remission if they STOP EARLY.

Membranous Nephropathy


  • Associated with malignancy i.e. lymphoma, colon cancer, lung cancer
  • Most cases are idiopathic


  • Biopsy
  • Microscopy: Thickened capillary loops
  • Immunoassay: Granular IgG & C3 depositions in the subepithelial layer


  • Immunosuppression similar to above, treat any secondary causes


  • Generally pretty god, 30-40% treated go into complete remission, 30-50% go into partial remission. Treatment can be prolonged.
  • Treating secondary causes also can induce remission.

Note that there are some other causes that can present with both nephrotic and nephritc features, i.e. membranoproliferative glomerulonephritis. Complement levels are NORMAL in MCD, FSGS, and MN, while complement levels are low in MPGN.

Primary anticoagulation for patients with nephrotic syndrome can be considered in some cases but not routinely done. Please refer to this article for reference.


GPA – 10/1/18

Yours truly presented a case of a middle-aged woman with a recent history of otitis, sore throat, conjunctivitis, photophobia, and arthralgias who presented with chronic and progressive decline in functional status and AMS, found to be uremic with work up revealing c-ANCA associated ESRD.

Clinical Pearls

  • Remember that oval fat bodies are specific for glomerular pathology (more commonly nephrotic syndrome but can be seen in nephritic disease as well).
  • ANCA-associated vasculitides include GPA, MPA, eGPA (and renal-limited vasculitis).
  • All have similar features on renal histology (focal necrotizing, crescentic, pauci-immune glomerulonephritis).
  • They can affect multiple organ systems (see breakdown below) which makes their clinical diagnosis challenging apart from the following differences:
    • c-ANCA is associated with GPA, p-ANCA is seen in MPA and eGPA
    • Granulomas are seen in GPA and eGPA
    • Eosinophilia and asthma are associated with eGPA

ANCA-associated vasculitides


Chart above adapted from this paper by Koldingsnes et al.

Granulomatosis with polyangiitis (GPA)

Diagnostic criteria (two or more has 88% sensitivity and 92% specificity):

  • Nasal or oral inflammation (painful/painless oral ulcers, or purulent or bloody nasal discharge)
  • Abnormal chest radiograph showing nodules, fixed infiltrates, or cavities
  • Abnormal urinary sediment (microscopic hematuria w/w/o red cell casts)
  • Granulomatous inflammation on bx of artery or perivascular area

Clinical presentation:

  • Most commonly in older adults, M=F
  • More common among white individuals (~89%)
  • S/s
    • Fatigue, fever, weight loss, arthralgias, rhinosinusitis, cough, dyspnea, urinary abnormalities, purpura, and neurologic dysfunction.
    • ENT
      • 90% of GPA cases, only 35% of MPA
      • Nasal crusting, sinusitis, otitis media, earache, polychondritis, ulcers, discharge
      • Conductive and/or sensorineural hearing loss
      • Saddle nose deformity
    • Tracheal and pulmonary disease
      • Airways or parenchyma
    • Renal
      • ~18% at presentation but subsequently develops in 77-85% of patients within the first 2 years of disease onset
      • High risk of progression to ESRD
      • Asymptomatic hematuria
      • Subnephrotic range proteinuria
      • Rapidly progressive GN
    • Cutaneous
      • ~50% of patients
      • Leukocytoclastic angiitis is most common which causes purpura of lower extremities
      • Other findings: urticarial, livedo reticularis, nodules, erythema nodosum, pyoderma gangrenosum, and Sweet syndrome
    • Ophthalmic/orbital
      • Conjunctivitis, corneal ulcers, episcleritis/scleritis, optic neuropathy, retinal vasculitis, and uveitis.
    • Other organs
      • CNS: neuropathy, CN abnormalities, mass lesions, hearing loss, granulomatous inflammation of the CNS
      • GI tract, heart, lower GU, parotids, thyroid, liver, or breast
      • High incidence of DVT (unclear mechanism)
    • Can progress slowly over months or explosively over days
    • Relapses can manifest differently than original presentation

Diagnosis requires biopsy!


  • Prompt initiation of therapy can be life and organ sparing
  • Induction therapy: Steroids +-Cyclophosphamide +-Rituximab
  • Maintenance therapy: multiple options-Azathioprine, MTX, Rituximab, Leflunomide

Hyponatremia – 9/18/18

Thanks to Joe for presenting the case of a young man with no known medical history who presented with acute onset of generalized weakness, found to have symptomatic hyponatremia to 120 resulting from psychogenic polydipsia!

Clinical Pearls

  • Hyponatremia is largely a problem of too much free water (sometimes compounded by too little solute) and defined as a Na <135
  • Pick a systematic approach to solving the underlying diagnosis for any patient with hyponatremia (see below for one possible outline).
  • The term “pseudohyponatremia” refers to the presence of substances that interfere with laboratory measurement of sodium concentration in the blood, specifically high triglycerides and paraproteins.
    • Hyperglycemia does NOT fall into this category because glucose is osmotically active and pulls water into the intravascular space, resulting in a dilutional and true hyponatremia.
  • Chronic hyponatremia (>72 hours) must be corrected slowly to avoid osmotic demyelinating syndrome (ODS).  Acute hyponatremia (<48 hours) can be corrected more rapidly.  That said, we rarely have a Na value within 48 hours prior to patient presentation to determine acuity.  As a result, and given the neurologic risks, most patients are treated as if they have chronic hyponatremia.
  • ADH leads to increased uric acid excretion through the kidneys so low serum uric acid levels have been associated with SIADH.  But this test is not very specific.
  • Osmolarity of normal saline is 308 compared to human serum which is normally 280-295.  In a hyponatremic patient, NS infusion becomes a relatively hypertonic (rather than isotonic) solution!


For more detailed information, refer to this prior post and this review article.

Metformin Associated Lactic Acidosis (MALA) 9/17/2018

Thanks to doctor-in-training Emma who presented a case of an elderly woman, on dialysis, who came in with SEVERE lactic acidosis due to a variety of factors, but largely contributed by being prescribed metformin 2 weeks prior to presentation.

We will use this case to illustrate several concepts:

On initial presentation, pt was in a state of shock. If you remember from medical school, there are mainly 4 types:

  • Cardiogenic
    • Myopathic (DCM, acute MI)
    • Mechanical (Acute MR, VSD, severe AS)
    • Arrhythmia
  • Hypovolemic
    • Hemorrhage, volume depletion
  • Distributive
    • Sepsis
    • Anaphylaxis
    • Neurogenic (spinal cord injury)
    • Endocrine (myxedema, Addison’s)
  • Obstructive
    • Pericardial tamponade
    • PE
    • Pneumothorax

Shock can also be approached from a cardiac output standpoint to help differentiate the potential causes:


If someone is hypovolemic, but he/she is found to be hypotensive but bradycardic (instead of tachycardic), remember from physiology:

MAP = CO x SVR, where CO is cardiac output, SVR is systemic vascular resistance

CO = SV x HR, SV is stroke volume, and HR is heart rate.

Hence in a state of hypovolemia, the body will attempt to maximize CO by increasing HR to maintain adequate MAP. If you see the opposite though, there could be something else going on…

  • Cardiac: MI, conduction abnormalities, infectious (Lyme, Charga’s)
  • Toxic/Meds: CCB, Beta blocker, Dig, Alpha 2, organophosphate
  • Lytes: Hyperkalemia -> heart block -> sinus arrest
  • Endocrine: Hypothyroidism (myxema coma), adrenal insufficiency
  • Environmental: Hypothermia
  • Neurogenic shock


Acid-Base: Acid-base disorders can appear daunting, but the following algorithm can make things simpler if followed consistently. We will work through this patient’s acid/base disorder together. Her HCO3 is 6, AG of 52, with an ABG of 6.83/13/170.

  1. Look at the pH: < 7.4 automatically means some sort of acidosis is going on.
  2. Next look at the PCO2, if it is in the same direction as the pH (low PCO2 in this case, and low pH), then it is suggestive of a primary metabolic rather than a respiratory issue causing the acidosis. If pH is low and PCO2 is high, then there is high suspicions for a respiratory process driving the acidosis.
  3. Look at the Anion Gap, which in this case in 52. Go through your differential for AGMA.
  4. Calculate the Delta Gap. This basically is a way to assess whether a mix acid/base disorder exists after taking into account the AG. To help illustrate:Capture2
  5. Delta gap = calculated AG – normal AG = 52 – 12 = 40. Now there are several ways to do this, but one method that’s quick and simple is to simply add this delta gap to the measured bicarb and see what other metabolic acid/base disorders can be hiding beneath the anion gap. In this case, 40 + 6 = 46, which is suggestive of an underlying metabolic alkalosis.
  6. Lastly, calculate compensation. For AGMA, use Winter’s Formula = 1.5 (HCO3) + 8 +/-2. The calculated PCO2 should be 15-19. Since our measured PCO2 is 13, which is lower than expected, then this is suggestive of an underlying respiratory alkalosis as well, probably due to sepsis.
  7. Our final answer for the acid/base disorder for this patient is: AGMA with metabolic alkalosis and concurrent respiratory alkalosis!


Lactic Acidosis: Traditionally we view this as a sign of sepsis, or a marker of tissue hypoperfusion. However this is not always the case!

  • Type A: Inadequate oxygen delivery
    • Rule of thumb: Tissue hypoperfusion, tissue ischemia
    • Can also be seen with increased anaerobic muscular activity, like generalized convulsions in a seizure
    • Can also be seen in hypoxemia, severe anemia
    • Cryptic shock (elevated lactate, okay BP), similar to overt septic shock in terms of mortality in setting of severe sepsis.
  • Type B: altered physiology, others
    • B1: Underlying disease, malignancy, hepatic & renal failure
    • B2: Drugs, toxins
    • B3: Inborn errors of metabolism, enzyme deficiency
  • Management: Tx the underlying cause, bicarb controversial, studies have shown no benefits? But most experts would agree with usage in critically ill patients with profound acidemia.


MALA: Lastly, this case illustrates the dangers of metformin, in the right setting, can lead to severe acid/base disturbance (MALA).

  • Do NOT use metformin if GFR < 30, be careful in CKD patients.
  • If suspecting metformin toxicity and pt is hyperglycemic, this is a sign of severe toxicity.
  • Always do a thorough med reconciliation on every single patient!

Lupus nephritis – 7/26/18

Thanks to Naina for presenting an interesting case of a young woman presenting with fever, nausea/vomiting, and R flank pain found to have pyelonephritis and lupus nephritis!

Clinical Pearls

  • Renal involvement is noted in ~50% of patients with SLE and can present as nephrotic or nephritic syndromes.
  • The most common and severe form is diffuse proliferative lupus nephritis (class IV)
  • It is important to distinguish SLE flare from an infection. When infection is present, it must be treated first before starting immunosuppression.
    • SLE flare is associated with a normal WBC, low CRP (because CRP production by hepatocytes is down-regulated by type 1 IFN release in lupus flare), and absence of fever
  • Lab findings suggestive of flare include elevated anti-dsDNA (correlates with disease activity), low complement levels (predominantly C3 decline), worsening proteinuria, and elevated creatinine.


* Membranoproliferative GN can present with mixed nephrotic/nephritic picture.

SLE and renal disease:

  • Renal involvement is common and eventually occurs in ~50% of SLE patients
  • 10% progress to ESRD
  • High mortality compared to SLE w/o nephritis
  • More common and severe in African Americans, Hispanics, Asians and can be the only manifestation of lupus on presentation!
  • Classifications of GN:
    • Can evolve from one to another
    • Minimal mesangial lupus nephritis (class I)
      • Earliest and mildest form
      • Rarely diagnosed b/c pts have a normal U/A, no or minimal proteinuria, and normal Cr
    • Mesangial proliferative lupus nephritis (class II)
      • Microscopic hematuria and/or proteinuria
      • Light microscopy would show mesangial hypercellularity or mesangial matrix expansion
    • Focal lupus nephritis (class III)
      • Hematuria, proteinuria, some HTN, decreased GFR
      • Less than 50% glomeruli affected by light microscopy
      • Segmental glomerulonephritis
    • Diffuse lupus nephritis (class IV)
      • Most common and most severe
      • Hematuria, proteinuria, nephrotic syndrome, HTN, reduced GFR
      • Hypocomplementemia (esp C3) and elevated anti-dsDNA during active disease
      • >50% of glomeruli are affected
    • Lupus membranous nephropathy (class V)
      • nephrotic syndrome, Cr normal or slightly elevated
      • Diffuse thickening of the glomerular capillary wall and subepithelial deposits
      • Can present without any other clinical or serologic manifestations of SLE
    • Advanced sclerosing lupus nephritis (class VI)
      • Slow, progressive renal dysfunction with proteinuria and relatively bland urine sediment
      • Global sclerosis >90% of glomeruli
      • Active GN no longer observed
  • Treatment:
    • Best to initiate early but AFTER treatment of active infection:

      • Cyclophosphamide or Mycophenolate PLUS solumedrol 250-1 g/day x 3 days (former takes 10-14 days to have an effect so the latter is much faster) or prednisone 60 mg/day
      • Mycophenolate is the preferred choice to preserve fertility in women of reproductive age
    • Goals of therapy:
      • substantial reduction in urine protein excretion  to <0.33 g/day
      • improvement or stabilization of serum creatinine
      • improvement of urinary sediment

Acute Kidney Injury – 11/7/17

Definition of AKI

1) Increase in Cr by greater or equal to 0.3 in 48 hours
2) Increase in Cr 1.5 x baseline within 7 days
3) UOP < 0.5 mL/kg/hr x 6 hours

Causes of elevated Cr without drop in GFR

Medications that block secretion – cimetidine, TMP, and HIV medications
Increased muscle mass

Causes of elevated BUN without drop in GFR

Albumin infusions
Steroid use
Tetracycline antibiotics

Urine sediment

Pre-renal azotemia = hyaline casts
ATN = muddy brown granular casts
AIN = sterile pyuria (+/- eosinophils)
GN = protein, dysmorphic RBCS, RBC casts

Indications for dialysis

A = acidosis
E = electrolyte abnormalities refractory to medical therapy
I = intoxicants
O = overload refractory to diuretics
U = uremia