|Multiple sclerosis; Kidney disease; Heart failure;
Demyelinating disease; Diabetes insipidus; Acquaporin
|Multiple sclerosis (MS)  and its variant, neuromyelitis optica ,
(NMO) are autoimmune diseases of the central nervous system that
typically cause progressively disabling symptoms involving the entire
nervous system. These diseases have rarely been associated with de
novo heart failure and only in the setting of bladder dysfunction have
they been linked to renal failure. The medications used to treat them
can have significant adverse effects on kidney and cardiovascular
system . We present a case of a patient with concomitant cervical
demyelinating disease and heart failure who was also found to be
suffering from chronic kidney disease of unclear etiology.
|A 31 year old -Yemeni male presented to the ED with gradually
worsening shortness of breath. He was diagnosed with Multiple
Sclerosis (MS) 1.5 months prior to admission and started on
Interferon-beta 1a and Fingolimod. There was no other significant
past medical or surgical history. The family history was significant for
a brother who died of unknown renal disease in his 40s but never
required dialysis. Social history was significant for 6 pack-year
smoking history, no alcohol or illicit drugs. Medication review was
negative for NSAIDS, antibiotics or herbal medication use.
Approximately 1.5 months prior to admission, he noted a sudden
sensation in his legs feeling extremely "heavy," and when he stood up,
he was unable to keep his balance. Associated with this, patient had
incontinence of urine and a sensation of "wiggling" in his arms, neck,
and legs (possible consistent with fasciculations). He had no visual loss
and no weakness of the arms. Pt was seen in a hospital in Yemen and
referred to a specialist in Jordan where he had a MRI of the brain,
cervical, and lumbar spine which showed multiple T2 lesions in deep
white matter, medulla, and cervical spine. Lumbar spine was
unremarkable. He was then given diagnosis of multiple sclerosis. The
MRI incidentally revealed a fracture/posterior displacement of odontoid bone, which was read as not causing stenosis. There were no
enhancing lesions. He underwent LP as well, which showed 2260 RBC,
2 WBC, 34 protein, 51 glucose and negative oligoclonal bands.
Serological workup had shown elevated ESR and CRP (25 and 14) so
rheumatologic workup was done, showing only borderline SSA
(negative anti-phospholipid, ANCA, lupus). Pt was treated with 5 days
of "cortisone" IV and discharged. Since then, gait has improved
minimally however it continues to be impaired, and he walks with a
cane. Patient was discharged with Rebif (Interferon beta-1b) and
|The admission clinical exam was significant for a blood pressure of
168/110 mm Hg, heart rate of 120bpm, crackles bilaterally on lung
exam and bilateral lower extremities edema. Neurological exam was
significant for diffusely increased spastic tone in both lower
extremities and wide based waddling gait with minimal knee flexion,
requiring a cane for ambulation.
|Diagnostic Work Up
|Significant labs: BUN/Creat- 40/2.71 mg/dl, normal sodium,
potassium, bicarbonate and chloride, PTH-121 mg/dl, Phosphorus-4.2
mg/dl, Calcium-7.9 mg/dl, Albumin-2.6 mg/dl,Hb-12.8 gm/dl, normal
WBCs and Platelets. Urinalysis: No RBC and ~ 2-3 gm proteinuria.
Serology: Negative ANA, ANCA, Hepatitis serology, HIV.
Complements, ESR, Rheumatoid factor, UPEP and SPEP were normal.
Chest x-ray: Mild pulmonary edema, CT head without contrast:
Normal, MRI head with and without contrast from Jordan 1.5 months
prior to admission: Multiple small white matter hyper intense lesion in
the cerebral white matter (some juxtacortical but not periventricular)
and increased signal at the ventral medulla; MRI C-spine with
longitudinally extensive cord hyper intensity and post displacement of
dens. There were no lesions in the MRI of the lumbar spine. Renal
Ultrasound: Atrophic right kidney 4.8 cm and a small left kidney 8.2
cm. Trans Thoracic Echocardiogram: Severe diffuse left ventricular
hypokinesis with severely reduced contractility (EF-30%) and LVH,
Nuclear stress test: Diffuse hypo kinesis and mild LV dysfunction.
|On initial presentation the immediate cause of kidney failure was
not clear. Differential diagnosis included primary kidney disease,
kidney disease secondary to heart failure (Cardiorenal syndrome) or
systemic inflammatory disease affecting heart, kidney and nervous
system at the same time. The small size of the kidneys on ultrasound
and proteinuria on urinalysis was supportive of either primary kidney
disease or systemic inflammatory disease. Patient was given Lasix to
achieve euvolemia. Lisinopril and Carvedilol were started for BP
control and titrated up with a target of <130/80. Urine Protein to
Creatinine ratio (UPC) came down to ~1.5 gm but renal function kept
worsening with peak creatinine of 3.4 mg/dl after 3 months of follow
up. Patient also had a follow up echocardiogram showing normal
ejection fraction which essentially excluded the diagnosis of kidney
failure secondary to heart failure. Follow up MRI after 3 month
showed persistent cervical spine lesion however brain lesions were
improving. Patient still has gait abnormality
|Kidney injury is Multiple Sclerosis and demyelinating spinal disease
is uncommon. Acute kidney injury is more often described than
chronic kidney disease in this group of patients. The most common
cause of kidney injury is post-renal due to bladder dysfunction leading
to recurrent UTI and renal stones . Glomerulonephritis is relatively
uncommon in MS patients. Treatment of MS with Interferon beta-1b
can lead to thrombotic microangiopathy, membranoproliferative GN
and FSGS-tip variant [4-7]. Apart from kidney injury a demyelinating
lesion in the hypothalamus can lead to central Diabetes Insipidus8.MS
patients are prone to get constipation, visual disturbances due to optic
neuritis and motor dysfunction which makes hemodialysis preferable
over peritoneal dialysis. Data for kidney transplant in MS patients is
very limited. This case is a unique presentation of a young man who
presents with MS, sudden onset of systolic heart failure and kidney
failure. Once a patient has kidney disease the focus of the management
is to diagnose and treat the cause of kidney disease. Many times the
cause is not identifiable which shifts the focus of management in
slowing the progression of kidney failure and treating complications of
kidney failure. Our patient had less than normal-sized kidneys
suggestive of advanced disease with significant scarring. One would be
tempted to perform a renal biopsy to find out the cause of renal failure
but the chance of getting viable glomeruli and interstitium are very
minimal with small sized kidney as compared to the risk of a kidney
biopsy. We did not find any treatable cause of renal failure in this
patient. Our goal then became to minimize urinary protein excretion
as much as we can and control BP in order to slow down progression
of kidney disease. This was achieved by adding Lisinopril which is an
Angiotensin Coverting Enzyme Inhibitor (ACEI). It works by
decreasing the intraglomerular pressure by dilating efferent arterioles
and thereby decreases perfusion pressure and proteinuria. It also
decreases BP and prevents left ventricular remodeling. It is uncertain if
this is a rare presentation of one disease, such as multiple sclerosis,
with an autoimmune component affecting the heart and kidney, which has been described, or the result of the medication given for his MS
with an unforeseen renal complication. A highly specific autoantibody
directed against the water channel protein aquaporin-4 is present in
the sera of 60–70% of patients who have a clinical diagnosis of NMO.
Aquaporin-4 is localized to the foot processes of astrocytes in close
apposition to endothelial surfaces . There is a diverse yet
characteristic distribution of aquaporins in the human body with
specific roles in each organ . AQP1 is found in the blood vessels,
kidney proximal tubules, eye, and ear. AQP2 is expressed in the kidney
collecting ducts, where it shuttles between the intracellular storage
sites and the plasma membrane under the control of antidiuretic
hormone (ADH). Mutations of AQP2 result in diabetes insipidus.
AQP3 is present in the kidney collecting ducts, epidermis, urinary,
respiratory, and digestive tracts. AQP3 in organs other than the kidney
may be involved in the supply of water to them. AQP4 is present in the
brain astrocytes, eye, ear, skeletal muscle, stomach parietal cells, and
kidney collecting ducts. AQP5 is in the secretory cells such as salivary,
lacrimal, and sweat glands. AQP5 is also expressed in the ear and eye.
AQP6 is localized intracellular vesicles in the kidney collecting duct
cells. AQP7 is expressed in the adipocytes, testis, and kidney. AQP8 is
expressed in the kidney, testis, and liver. AQP9 is present in the liver
and leukocytes. AQP10 is expressed in the intestine. One possible
explanation for our patient clinical presentation is antibody directed
against different aquaporin channels leading to central nervous system
findings and kidney failure. It is very difficult to extrapolate it from
one case report. We need further research studies in this area to
understand the possible disease process.
- Milo R, Miller A (2014) Revised diagnostic criteria of multiple sclerosis. 13: 518-24.
- Behjati M, Etemadifar M, AbdarEsfahani (2014) Cardiovascular effects of fingolimod: A review article. J Neurol 13: 119-126.
- Mahadeva A, Tanasescu R, Gran B (2014) Urinary tract infections in multiple sclerosis: under-diagnosed and under-treated? A clinical audit at a large University Hospital. Am J ClinExpImmunol 3: 57-67.
- Yuste C, Rapalai M, Pritchard BA, Jones TJ, Tucker B, Ramakrishna SB (2014) Nephrotic-range proteinuria on interferon-β treatment: immune-induced glomerulonephritis or other pathway? Clin Kidney J 7: 190-193.
- Kumasaka R, Nakamura N, Shirato K, et al. (2006) Nephrotic syndrome associated with interferonbeta- 1b therapy for multiple sclerosis. ClinExpNephrol 10: 222–225.
- Markowitz GS, Nasr SH, Barry Stokes M, et al. (2010) Treatment with IFN-α, -β, or -γ is associated with collapsing focal segmental glomerulosclerosis. Clin J Am SocNephrol 5: 607–615
- Noris M, Remuzzi G (2009) Atypical hemolytic–uremic syndrome. N Engl J Med 361: 1676–1687.
- Tiedje V, Schlamann M, Führer D, Moeller LC (2013) Diabetes insipidus as a rare cause of acute cognitive impairment in multiple sclerosis. MultScler 19: 1676-1678.
- Hinson SR, McKeon A, Lennon VA (2010) Neurological autoimmunity targeting aquaporin-4. Neuroscience 168: 1009-18.
- Takata K, Matsuzaki T, Tajika Y (2004) Aquaporins: water channel proteins of the cell membrane. ProgHistochemCytochem 39: 1-83.