Nephrotic & Nephritic Syndrome

Question 1

what is the urine protein excretion in healthy individuals?

Answer 1

In healthy individuals, urine protein excretion is usually <150mg/day
(0.15g/day).
 2/3 of these proteins are Tamm-Horsfall proteins (also known as uromodulin
is a glycoprotein produced excessively by the renal tubular epithelial cells of
the distal loop of Henle).
 1/3 are albumin.

Question 2

list the medical states with regard to protein loss within 24 hrs

Answer 2

With 24 hours:
 Albumin Protein loss <30 mg is normal
 Protein loss between 30-300mg (not detectable on dipstick) is termed
microalbuminuria
 Protein loss between 300-3000mg is termed macroalbuminuria.
 Protein loss > 3.5g is termed a nephrotic syndrome

Question 3

what is nephrotic syndrome?

Answer 3

Nephrotic syndrome is a clinical complex characterized by:
 Significant proteinuria of >3.5g per 24h (most important clinical feature).
 Hypoalbuminemia-pitting edema (lower extremities, periorbital, ascites,
pleural effusion) (decreased oncotic pressure).
 Hypogammaglobinemia- increased risk of infection.
 Hyperlipidemia and lipiduria (fat casts in urine) and hypercholesterolemia
 Hypercoagulability- due to loss of anti-thrombin III.

Question 4

causes of nephrotic syndrome

Answer 4

PRIMARY NEPHROTIC SYNDROME
 Primary glomerulopathies (idiopathic): account for 30-50% of adult nephrotic
syndrome.
 These are not a consequence of systemic disease.
 They include:
 Minimal change disease/nephropathy
 Focal segmental glomerulosclerosis
 Membranous glomerulonephritis
 Membranoproliferative glomerulonephritis

SECONDARY NEPHROTIC SYNDROME
 Multisystem disease: accounts for 50-70% of adult nephrotic syndrome
 Causes include:
 Endocrine disorders: Diabetes mellitus (diabetic nephropathy)
 Cardiovascular diseases: Hypertension, Pre-eclampsia
 Autoimmune: Systemic lupus erythematosus, vasculitis
 Infiltrative: Amyloidosis, sarcoidosis, myeloma, light chain deposition and
fibrillary immunotactoid disease
 Collagen vascular diseases
 Infectious: infectious endocarditis, HBV, HCV, HIV, Malaria, EBV, leprosy,
syphilis
 Drugs
 Neoplasms: leukemias, lymphomas and solid tumors

Question 5

C/F of nephrotic syndrome

Answer 5

 Clinical features include:
 Peri-orbital edema which is mostly seen early morning, may also present with
a puffy face or generalized edema or scrotal swelling.
o Differential diagnosis for generalized edema includes: chronic liver
disease, Right ventricular heart failure, Adult malnutrition
 Production of frothy urine (protein in urine)
 Accelerated atherosclerosis
 Recurrent infections especially with pneumococcus (due loss of C3b
complement)
 Iron deficiency anemia (loss of transferrin in urine)
 DVT (hypercoagulable state- loss of antithrombin III and over production of
fibrinogen).
 Note: most patients are normotensive however patients can develop
hypertension (from fluid retention, this is much commoner in nephritic
syndrome) or hypotension (due to fluid loss from vessels, commoner in kids)
The urine produced is froathy due to the presence of proteins.

Question 6

how does proteinuria occur in nephrotic syndrome?

Answer 6

leading to an increase in size and number of
pores, allowing passage of more and larger molecules.
 Fixed negatively charged components are present in the glomerular capillary wall
which repel negatively charged protein molecules. Reduction of this fixed charge
occurs in glomerular disease and appears to be a key factor in the genesis of heavy
proteinuria.

Question 7

C/F suggestive of acute renal vein thrombosis

Answer 7

Clinical features that suggest acute renal vein thrombosis include sudden
onset of flank or abdominal pain, gross hematuria, a left-sided varicocele (the
left testicular vein drains into the renal vein), increased proteinuria and an
acute decline in GFR.

Question 8

how does hypoalbuminemia occur in nephrotic syndrome?

Answer 8

The normal dietary protein intake is around 70g daily and the liver can synthesize
albumin at a rate of 10-12g daily. How then does a urinary protein loss of the
order of 3.5g daily result in hypoproteinemia?
 There is increased catabolism of reabsorbed albumin in the proximal tubules
during nephrotic syndrome even though there is an actual increase in the
albumin synthesized. The loss of protein is thus more and only 3.5g is seen
in urine causing the liver to fail to match up the synthesis.

Question 9

how does hyperlipidemia occur in nephrotic syndrome?

Answer 9

 Hyperlipidemia- is believed to be a consequence of increased hepatic lipoprotein
synthesis and decreased clearance. Hyperlipidemia may accelerate
atherosclerosis and progression of renal disease.
 There is an increase in LDL, IDL and triglycerides but no change or decrease in
HDL.
 There is an increase in the LDL/HDL cholesterol ratio.
 Lipids are also passed in urine. Urine may contain fat oval bodies (which are
proximal convoluted cells filled with fats).

Question 10

COMPLICATIONS OF NEPHROTIC SYNDROME

Answer 10

1. Recurrent infections: loss of globulins and low molecular weight complements.
2. Thrombosis: most commonly in renal artery (may present as acute abdomen)
    Loss of anticoagulant proteins e.g. anti-thrombin III
    Hyperlipidemia-disturbs platelet membrane as well as endothelium cause
   platelet activation and aggregation
    Stasis of blood: since it is concentrated as vascular compartment cannot hold
   water due to low oncotic pressure caused by hypoproteinemia.
    Over production of fibrinogen by the liver
3. Iron deficiency anemia: due to loss of transferrin
4. Protein malnutrition
5. Hypocalcemia: Vitamin D deficiency due to enhanced urinary excretion of
   cholecalciferol-binding protein.

Question 11

what are the histological subtypes of nephrotic syndrome?

Answer 11

MINIMAL CHANGE DISEASE/NEPHROPATHY
FOCAL SEGMENTAL GLOMERUOSCLEROSIS
MEMBRANOUS NEPHROPATHY
MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Question 12

MINIMAL CHANGE DISEASE/NEPHROPATHY

Answer 12

 Most common cause of nephrotic syndrome in children.
 Usually idiopathic or secondary to infection, may be associated with Hodgkin
lymphoma (Due to release of cytokines by Reed-Steinburg cells).

Question 13

etiology of MINIMAL CHANGE DISEASE/NEPHROPATHY

Answer 13

 Many implicated drugs include NSAIDs, Lithium, antibiotics
(Cephalosporins, rifampicin, ampicillin), bisphosphonates and sulfasalazine.
 Atopy is present in 30% of cases and allergic reactions can trigger nephrotic
syndrome.
 Infections e.g. HCV, HIV and TB are rarer causes.

Question 14

MINIMAL CHANGE DISEASE/NEPHROPATHY microscopic findings

Answer 14

 Normal glomeruli can be seen under light microscopy on H & E stain, lipids may
be seen in proximal tubule cells.
 Effacement (flattening) of foot processes is seen on electron microscopy.
 Recall the glomerular filtration membranes consists of the endothelial cells,
basement membrane and the foot processes of the podocytes (epithelial
cells).
 No immune complex deposits are seen (negative immunofluorescence (IF))

Question 15

MINIMAL CHANGE DISEASE/NEPHROPATHY Tx

Answer 15

 It carries an excellent response to steroids (damage is mediated by cytokines from
T-cells) and cytotoxic drugs. It often relapses.
 High dose corticosteroid therapy with prednisolone 60mg/m2 daily (up to a
maximum of 80mg/day) for a maximum of 4-6 weeks followed by 40 mg/m2
every other day for a further 4-6 weeks
 When there is relapse on steroid withdrawal, cyclophosphamide should be
added after repeat induction with steroids. A course of cyclophosphamide
1.5-2.0 mg/kg daily is given for 8-12 weeks with concomitant prednisolone
7.5-15 mg/day.
 Steroid unresponsive patient may also respond to cyclophosphamide. No
more than two courses of cyclophosphamide should be prescribed in children
because of the risk of side-effects which include azoospermia.
 An alternative to cyclophosphamide is ciclosporin 3-5mg/kg per day.
 It is often regarded as a condition that does not lead to CKD.

Question 16

FOCAL SEGMENTAL GLOMERUOSCLEROSIS

Answer 16

 Most common cause of nephrotic syndrome in Hispanics and African Americans.
 All age groups are affected.
 Usually idiopathic, may be associated with HIV, heroin use and sickle cell
disease.
 It also recurs in transplanted kidneys, sometimes within days of transplantation,
particularly in patients with aggressive renal disease.

Question 17

FOCAL SEGMENTAL GLOMERUOSCLEROSIS microscopy findings

Answer 17

 Focal (some glomeruli) and segmental (involving only part of the glomerulus)
sclerosis (thickening-deposition of collagen) on H&E stain.
 Damage tends to occur at junction between the cortex and medulla.
 Glomerulosclerosis-deposition of collagen
 Effacement of foot process is seen on electron microscopy.
 No immune complex deposits (negative IF).

Question 18

FOCAL SEGMENTAL GLOMERUOSCLEROSIS presentation

Answer 18

 Presentation:
 Massive proteinuria (non-selective)
 Hematuria
 Hypertension
 Renal impairment

Question 19

FOCAL SEGMENTAL GLOMERUOSCLEROSIS Tx

Answer 19

 Treatment: steroids, cyclosporine A; cyclophosphamide.
 Poor response to steroids, progresses to chronic renal failure

Question 20

MEMBRANOUS NEPHROPATHY

Answer 20

 Most common cause of nephrotic syndrome in Caucasian adults. Occurs more in
males.
 May present as asymptomatic proteinuria or frank nephrotic syndrome.
 Microscopic hematuria, hypertension and/or renal impairment may accompany
the nephrotic syndrome. There is a predilection to clotting (Renal vein
thrombosis)
 Usually idiopathic, may be associated with hepatitis B or C, solid tumors, SLE
or drugs e.g. NSAIDs and penicillamine

Question 21

MEMBRANOUS NEPHROPATHY microscopic findings

Answer 21

 Thick glomerular basement membrane is seen on H & E.
 Due to immune complex deposition (granular IF), sub-epithelial deposits with
‘spike and dome’ appearance on EM.

Question 22

MEMBRANOUS NEPHROPATHY Tx

Answer 22

 Treatment: Observation if slow progression. Steroids alternating with either
cyclophosphamide or chlorambucil.
 Poor response to steroids, progresses slowly to chronic renal failure. 25%
spontaneously remit

Question 23

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS on microscopy

Answer 23

 This can present with either nephritic or nephrotic syndrome or both.
 Thick glomerular basement membrane on H&E often with ‘tram-track’
appearance.
 Due to immune complex deposition (granular IF).
 Electron-microscopy shows sub-endothelial deposits

Question 24

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS types

Answer 24

 Divided into 2 types based on location of deposits:
 Type I- subendothelial, associated with HBV and HCV. Is more often
associated with the formation of tram-tracks.
 Type II (dense deposit disease)- intramembranous associated with C3
nephritic factor (autoantibody that stabilizes C3 convertase, leading to
overactivation of complement, inflammation and low levels of circulating
C3).

Question 25

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS Tx

Answer 25

 Treatment:  Non-nephrotic: observe  Nephrotic or worsening renal function: steroids.  Poor response to steroids, progresses to chronic renal failure. 50% die within 5 years of renal biopsy.

Question 26

how does diabetes mellitus cause nephrotic syndrome?

Answer 26

 This is one of the common systemic causes of nephrotic syndrome  High serum glucose leads to non-enzymatic glycosylation of the vascular basement membrane resulting in hyaline arteriolosclerosis (microvascular damage).  Glomerular efferent arteriole is more affected than the afferent arteriole, leading to high glomerular filtration pressure.  Hyperfiltration injury leads to microalbuminuria.  Eventually progresses to nephrotic syndrome  Characterized by sclerosis of the mesangium with formation of KimmelstielWilson nodules.  Retinopathy should be present as eyes are usually affected before kidneys.  It can definitively be diagnosed by biopsy though rarely needed.  ACE inhibitors slow progression of hyperfiltration induced damage

Question 27

how does systemic amylodosis cause nephrotic syndrome?

Answer 27

 Kidney is the most commonly involved organ in systemic amyloidosis.  Amyloid deposits in the mesangium, resulting in nephrotic syndrome.  Characterized by apple-green birefringence under polarize light after staining with Congo red.  Glomerular deposition diseases include: multiple myeloma (in adults), amyloidosis (common because of HIV and infection)

Question 28

how is proteinuria confirmed in the diagnosis of nephrotic syndrome?

Answer 28

 Confirming significant proteinuria  If protein detected on dipstick rule out benign temporary causes e.g. orthostatic, fever, exercise. Dipstick only detects albumin >100mg/L so in patient with CKD, ACR (Urine albumin to creatinine ratio) is used to screen for proteinuria.  If persistent, quantify proteinuria and do bloods.  If nephrotic syndrome is confirmed, renal biopsy may be needed to find or confirm the cause. Not required if specific diagnosis is very likely e.g. minimal change disease in kids.

Question 29

which investigations are used to diagnose nephrotic syndrome?

Answer 29

1. Urinalysis: (To quantify proteinuria)  4+ protein in urine  Microscopy, culture and sensitivity to exclude UTIs  Look for cell casts  Protein electrophoresis 2. 24-hour urine collection (proteins >3.5g/day)- rarely done and instead a spot sample is taken ideally in the morning for ACR or PCR. 3. Urine Albumin-creatinine ratio (ACR):  Microalbuminuria: >2.5mg/mmol (men) and >3mg/mmol (women)  Proteinuria >30mg/mmol  Nephrotic syndrome >250mg/mmol  Note: ACR is more sensitive than PCR at lower protein levels (ACR<70 mg/mmol) 4. Urine protein-creatinine ratio (PCR)  Proteinuria >45mg/mmol  Nephrotic syndrome >300mg/mol 5. Bloods  Serum albumin (decreased)  Serum cholesterol (increased)  Glucose: to rule out diabetes mellitus  U and E to assess renal function  LFTs: may show other causes of decreased albumin or fluid retention  Clotting panel: for clotting abnormalities  C-reactive protein: may be elevated in autoimmune disease.  Immunological: complement, dsDNA, ANCA, RF  Serum Ig and electrophoresis  Microbiology: Syphilis, HBV, HCV and HIV tests 6. Imaging:  Kidney ultrasound is often useful, especially if there is abnormal kidney function. It is needed before biopsy  Chest X-ray- for pleural effusions 7. Renal biopsy  Microscopy  Immunochemical test

Question 30

management of nephrotic syndrome

Answer 30

General measures:  Control proteinuria o Dietary protein restriction: the potential value of dietary protein restriction for reducing proteinuria must be balanced against risk of contributing to malnutrition o ACE inhibitors/Angiotensin II receptors antagonists: to decrease proteinuria by decreasing glomerular filtration pressure. (monitor blood pressure and renal function) o Controlling hypertension: keeping BP below 130/80 reduces proteinuria  Specific treatment of underlying morphologic entity  Minimal change disease- steroids  Focal segmental glomerulosclerosis: steroids, cyclosporin A; cyclophosphamide.  Membranous nephropathy: Observation if slow progression. Steroids alternating with either cyclophosphamide or chlorambucil.  Membranoproliferative glomerulonephritis: o Non-nephrotic: observe o Nephrotic or worsening renal function: steroids

Question 31

Tx of nephrotic syndrome complications

Answer 31

 Treatment of complications: o Edema: should be managed cautiously  Moderate salt restriction: usually 1 to 2 g/day  Loop diuretics: can be given in higher doses. It is unwise to remove >1.0 kg of edema per day as more aggressive diuresis may precipitate intravascular volume depletion and prerenal azotemia.  Start with bendroflumethiazide 5mg daily and add furosemide 40-120mg daily  Unresponsive patients require furosemide 40-120 mg daily with addition of amiloride (5mg daily) with serum potassium concentration being monitored regularly.  Nephrotic patients may malabsorb diuretics (as well as other drugs) owing to gut mucosal edema and parenteral administration is then required initially.  Albumin infusion can be given to patients who are diureticresistant as well as oliguric and uremic in absence of severe glomerular damage. o Sepsis (e.g. Pneumococcal infection): pneumococcal vaccine should be given. There should be early detection and aggressive treatment of infections, rather than long-term antibiotic prophylaxis. o Thromboembolism: anticoagulation is indicated for patients with deep venous thrombosis, arterial thrombosis and pulmonary embolism. Heparin may not be effective because of urinary loss of anti-thrombin III. o Hyperlipidemia: may need lipid lowering agents (statins-HMG CoA reductase inhibitors) o Vitamin D deficiency- Vitamin D supplementation

Question 32

NEPHRITIC SYNDROME

Answer 32

 These are a group of diseases were damage to the glomeruli is mediated by immune complex deposition and inflammatory processes.  They are characterized by:  Sub-nephrotic range proteinuria (<3.5g/day): mild to moderate proteinuria  Sudden onset (days to weeks) of acute renal failure  Oliguria (<400ml of urine per day) and Azotemia  Hypertension, periorbital edema and salt retention.  Macroscopic Hematuria (with recurrent red blood cell cast)  Pyuria (white blood cells in urine)  Presence of urinary sediment.

Question 33

NEPHRITIC SYNDROME causes

Answer 33

 Postinfectious glomerulonephritis (including post-streptococcal)  Subacute bacterial endocarditis  Lupus nephritis  Anti-glomerular basement membrane disease  IgA nephropathy  ANCA small vessels vasculitis (Wegener’s granulomatosis, microscopic polyangitis, Churg-strauss Syndrome)  Membranoproliferative glomerulonephritis  Mesangioproliferative glomerulonephritis

Question 34

NEPHRITIC SYNDROME diagnosis

Answer 34

 Definitive diagnosis is by renal biopsy  If biopsy is not available, use clinical signs/symptoms  Urinalysis  Urine microscopy, culture and sensitivity  U+Es, creatinine

Question 35

NEPHRITIC SYNDROME Tx

Answer 35

 Use ACEi if there is component of proteinuria and the creatinine is stable  Consider corticosteroids therapy or other immunosuppressive agents (although benefit depends on histologic type)  Specific treatments:  Post-streptococcal glomerulonephritis and subacute bacterial endocarditis o Supportive care o Treat infectious etiologies  Others o Treat with some combination of steroids, cytotoxic agents and plasmapheresis.

Question 36

ACUTE GLOMERULONEPHRITIS (ACUTE NEPHRITIC SYNDROME)

Answer 36

 This is a clinical correlate of acute glomerular inflammation.  The hallmark of nephritic syndrome is glomerular inflammation and bleeding from the glomeruli.  In its most dramatic form it is characterized by:  Sub-nephrotic range proteinuria (<3.5g/day)  Sudden onset (days to weeks) of acute renal failure  Oliguria (<400ml of urine per day) and Azotemia  Hypertension, periorbital edema and salt retention.  Macroscopic Hematuria  Presence of urinary sediment.

Question 37

ACUTE GLOMERULONEPHRITIS (ACUTE NEPHRITIC SYNDROME) etiology

Answer 37

 Acute nephritic syndrome can result from renal-limited primary glomerulopathy or from secondary glomerulopathy complicating systemic disease.  Immune-complex glomerulonephritis may be:  Idiopathic  Represent a response to known antigen stimulus (e.g. post infectious glomerulonephritis)  Part of a multisystem immune complex disorder (e.g. lupus nephritis, Henoch-Schonlein purpura/Allergic pupura, cryoglobulinemia, bacterial endocarditis).

Question 38

ACUTE GLOMERULONEPHRITIS (ACUTE NEPHRITIC SYNDROME) C/F

Answer 38

 Subnephrotic range proteinuria (<3.5g/day)  Periorbital edema  Hypertension (due to impaired GFR and salt retention)  Macroscopic Hematuria: with RBC casts and dysmorphic RBCs in urine.  Oliguria (<400ml of urine per day)  Azotemia

Question 39

ACUTE GLOMERULONEPHRITIS (ACUTE NEPHRITIC SYNDROME) investigations

Answer 39

 Urinalysis: as a result of injury to the glomerular capillary wall, urinalysis typically reveals red blood cell casts, dysmorphic red blood cells, leukocytes and subnephrotic proteinuria of <3.5g/day (nephritic urinary sediment)  Hematuria is often macroscopic  Renal function test: elevated serum creatinine  Serology: immunologic assays suggesting the underlying disease.  Renal biopsy:  Reveals hypercellular inflamed glomeruli  Immune-complex deposition activate complement  C5a attracts neutrophils which mediate damage

Question 40

POSTSTREPTOCOCCAL GLOMERULONEPHRITIS

Answer 40

 This is the prototypical post-infectious glomerulonephritis and leading cause of acute nephritic syndrome.  Most cases are sporadic but can also occur as an epidemic.  Glomerulonephritis develops on average 10 days after pharyngitis or 2 weeks after a skin infection (impetigo) with a nephritogenic strain of group A betahemolytic streptococcus (Carrying M protein virulence factor).  Epidemic poststreptococcal glomerulonephritis is most commonly encountered in children of 2 to 6 years of age with pharyngitis during the winter months.  Poststreptococcal glomerulonephritis in association with cutaneous infection usually occurs in a setting of poor personal hygiene or streptococcal superinfection of another skin disease.

Question 41

POSTSTREPTOCOCCAL GLOMERULONEPHRITIS C/F

Answer 41

 Classical presentation (2-3 weeks after infection):  Full-blown nephritic syndrome with oliguric acute renal failure  Gross hematuria (red or ‘smoky’ urine)- cola colored urine.  Headache and generalized symptoms such as anorexia, nausea, vomiting and malaise.  Swelling of the renal capsule can cause flank or back pain.  Physical examination:  Hypertension  Periorbital Edema  Hypovolemia  Usually seen in children but may occur in adults

Question 42

POSTSTREPTOCOCCAL GLOMERULONEPHRITIS lab findings

Answer 42

 Urinalysis: as a result of injury to the glomerular capillary wall, urinalysis typically reveals red blood cell casts, dysmorphic red blood cells, leukocytes and subnephrotic proteinuria of <3.5g/day (nephritic urinary sediment).  Renal function test: the serum creatinine is often mildly elevated at presentation.  Serology: most patients have circulating antibodies against streptococcal exoenzymes such as ASO, and DNAase.  Renal biopsy:  Hypercellular inflamed glomeruli on H & E.  Mediated by immune complex deposition (granular IF)  Subepithelial ‘humps’ on EM

Question 43

POSTSTREPTOCOCCAL GLOMERULONEPHRITIS management

Answer 43

 Eliminating the streptococcal infection with antibiotics.  Supportive therapy until spontaneous resolution of glomerular inflammation occurs:  Bed rest  Salt restriction  Diuretics to control ECF volume  Antihypertensive drugs to control high blood pressure  Dialysis: some patients may need dialysis.  Some adults develop rapidly progressive glomelomerulonephritis  This is a nephritic syndrome that progresses to renal failure in weeks to months.  Renal biopsy is characterized by crescents in Bowman space (H&E) comprised of fibrin and macrophages

Question 44

POSTSTREPTOCOCCAL GLOMERULONEPHRITIS complications

Answer 44

 Congestive heart failure  Pulmonary edema  Acute renal failure  Severe hypertension with hypertensive encephalopathy

Question 45

RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

Answer 45

 This is a nephritic syndrome that progresses to renal failure in weeks to months.  Renal biopsy is characterized by crescents in Bowman space (H&E) comprised of fibrin and macrophages

Question 46

describe the immunofluorescence pattern of the diseases that cause RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

Answer 46

1. Goodpasture syndrome : Linear (anti-basement membrane antibody) 2. Post-streptococcal glomerulonephritis (most common) or diffuse proliferative glomerulonephritis : Granular (due to immune complex deposition) 3. Wegener granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome : Negative IF (pauci-immune)

Question 47

IgA NEPHROPATHY

Answer 47

 IgA immune complex deposition in mesangium of glomeruli.  Most common nephropathy worldwide.  Presents during childhood with:  Episodic gross or microscopic hematuria with RBC casts usually following mucosal infections.  IgA immune complex deposition in mesangium on IF (granular)  May slowly progress to renal failure.

Question 48

ALPORT SYNDROME

Answer 48

 Inherited defect in type IV collagen, most commonly X-linked  Results in thinning and splitting of glomerular basement membrane.  Presents as isolated hematuria, sensory hearing loss and ocular disturbances