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UTMJ Vol 79 No1

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					                                                                                                                    Morning Report

Accounting for Polyuria

Michelle Porepa, B.A. (0T4)
Xerxes Punthakee, B.Sc. (0T4)
Jordan Weinstein, MD

Case Presentation                                                        tion due to excessive protein intake, trauma, or a catabolic state
A 65 year-old man presented to the emergency department                  may also lead to solute polyuria. Iatrogenic causes of solute diure-
with malaise and frequent urination. He has had nocturia                 sis include administration of mannitol or radiocontrast media. In
and mild hesitancy for 4 years, although lately he has                   all cases the pressure of unabsorbed solutes will draw water and
noticed frequent urination during the day. He is otherwise               ions into the urine.
well, on no medications and followed regularly by his fam-
ily           doctor with yearly physical examinations. A                If a water diuresis is present, one must consider what underlies it.
screening exercise stress test was normal 2 years ago. He                Diabetes insipidus (DI), or the aberrant excretion of dilute urine
is a      lifetime non-smoker, consumes 3 glasses of wine                due to an anti-diuretic hormone (ADH) defect along the hypo-
per week and is a retired accountant.                                    thalamic-kidney axis, can be divided into central and nephrogenic
                                                                         types. Central DI is the inability to produce or release ADH from
What is the Definition of Polyuria?                                      the posterior pituitary. Common causes include head trauma or
Polyuria is frequently defined arbitrarily as urine output greater       infections such as meningitis or encephalitis, granulomatous dis-
than 3 L/day. However, volume of urine produced is dependent             ease, neoplastic causes and vascular problems such as aneurysms.
on a variety of factors including fluid intake, renal function and the   Idiopathic causes account for half of all central DI cases and they
physiologic demands of the individual. Thus, it is more appropri-        may have a hereditary component.
ate to define polyuria in the context of a given clinical setting. In
order to define polyuria, consider the following formula:                Nephrogenic DI can result from the failure of two mechanisms in
                                                                         the kidney: the inability to form a hyperosmotic renal medullary
                           Osmole Excretion Rate (mOsm/24 Hr)            interstitium, or the failure of the distal and collecting tubules and
Urine Volume (L/24 Hr) =
                              Urine Osmolality (mOsm/L)                  collecting ducts to respond to ADH. Numerous renal diseases can
                                                                         impair the concentrating mechanism, particularly the ones that
Therefore, urine flow rate could be increased by two factors:            affect the medulla. These include infiltrative diseases such as amy-
increased osmole excretion rate (especially with a fixed urine           loidosis, infections such as pyelonephritis, drug-induced damage
osmolality) or a low urine osmolality (with a fixed osmole excre-        due to analgesics or lithium, generalized polycystic disease,
tion rate). The average person consumes and excretes 900                 hypokalemia and hypoxic damage resulting from sickle cell anemia.
mOsm/day, primarily as urea and electrolytes, to remain in solute        Diuretics that impair the function of the Loop of Henle by inhibit-
balance. If a condition led to an osmole excretion rate exceeding        ing electrolyte reabsorption can also lead to a transient dysfunction
intake, then polyuria with solute rich urine would exist. Conversely,    of urine concentrating ability. Marked hypercalcemia impairs the
if a condition led to a fixed, low urine osmolality (e.g. 50-100         tubular response to ADH, as do various congenital conditions.
mOsm/L), polyuria with dilute urine would exist. Therefore, when
evaluating this condition the urine osmolality is a key decision         Finally, a large volume of dilute urine could be appropriate if a
point to determine the etiology of the polyuria; a low value (i.e. 50    large volume of water is ingested, usually on a psychiatric basis,
mOsm/L) represents a water diuresis, whereas a larger value rep-         such as in primary polydipsia. Hypothalamic disease and drugs
resents a mixed or solute diuresis.                                      such as thioridazine, chlorpromazine and anticholinergic agents
                                                                         may also lead to primary polydipsia.
What is the Differential Diagnosis of Polyuria?
If a solute diuresis is considered, then the osmotic diuretic must       How Can We Apply this Information to Our Patient?
be identified. Hyperglycemia in excess of the reabsorption               In the present case, we must determine whether Mr. E has a
threshold of the kidney, such as in diabetes mellitus, will lead         problem with solute or water excretion. A diagnosis of polyuria
to a solute diuresis with glucose as the solute. High urea excre-        cannot be determined conclusively from history alone; indeed,

                                                                                                  volume 79, number 1, December 2001       61
an examination of the urine volume and its components will be        Are we further ahead?
required when investigating this patient. Perhaps some clues         What investigations will clarify this presentation?
from the history would allow us to speculate on the cause of         To summarize at this point, our patient is a 60 year-old man with
his polyuria.                                                        possible polyuria, non-specific symptoms of poor concentration,
                                                                     fatigue and weight loss with signs of anemia, volume contraction
Case Presentation                                                    and point tenderness on a rib. The first investigations should be
Mr. E has no personal or family history of diabetes. His             aimed at excluding diabetes and evaluating the serum calcium. If
last fasting blood sugar was normal. He does not com-                hypercalcemia exists, we must determine its etiology, focusing, in
plain of blurred vision or polyphagia. Mr. E has no fami-            particular, on malignancies.
ly history of renal disease, and has no history of psychi-
atric disorders. He has no irritative voiding symptoms and           Case Presentation
his obstructive voiding symptoms have not worsened. He
also has no history of intracranial diseases or trauma. Over                           Investigations: Bloodwork
the last several months, Mr. E has complained of fatigue
and reduced exercise tolerance, owing to mild shortness of           Hgb                 95 g/dl (MCV 84 fL)
breath. He has had some difficulty concentrating on his              WBC                 7.4 (normal differential)
morning crossword puzzle. Finally, Mr. E has lost                    PLT                 155
10 pounds in the past year.                                          Na                  144 mmol/L
                                                                     K                   3.4 mmol/L
What is Our Working Diagnosis?                                       Cl                  111 mmol /L
Based on his history, a number of disorders leading to polyuria      HC03                28 mmol/L
seem less likely. Mr. E was not previously diabetic; neverthe-       BUN                 9.0 mmol /L
less, this could have evolved over the past year. Other causes       Cr                  130 umol/L
of purely solute diuresis, such as mannitol or radiocontrast         Ca                  3.8 mmol/L
administration, are not relevant here. However, Mr. E may well       Mg                  0.8 mmol/L
have a problem with his urinary concentrating mechanism. He          P04                 1.0 mmol/L
could have a brain tumor leading to central DI and other neu-        Albumin             32 g/dL
rologic manifestations. Congenital causes of nephrogenic DI are      TSH                 Normal
not relevant here but Mr. E could have an acquired form. Of          PSA                 Normal
these disorders, hypercalcemia or an infiltrative tubulopathy
could be the culprit. Especially given Mr. E’s other manifesta-
tions of difficulty concentrating, malaise and weight loss, hyper-   What is the Differential Diagnosis of Hypercalcemia?
calcemia and conditions leading to it might be underlying this       Hypercalcemia is defined as an abnormal elevation in serum ion-
presentation.                                                        ized calcium concentration. Total calcium, as opposed to ionized
                                                                     calcium, is generally measured (n = 2.25-2.62 mmol/L). Therefore
Case Presentation                                                    one must be aware of factors that influence the fraction of total
On physical examination, Mr. E has generalized pallor.               serum calcium that is ionized. For example, low serum pH increas-
Otherwise, he appears well nourished, in no apparent dis-            es the ionized fraction of calcium. Serum albumin is the major
tress, and was alert. Blood pressure was 150/90 in the               circulating calcium-binding protein, and when decreased does not
supine position, 120/95 while sitting. Heart rate was 90             usually affect the ionized quantity. Therefore, one could ‘correct’
and regular in the supine position and 110 while sitting.            the reported calcium to a number that accounts for the low albu-
Head and neck examination showed normal sclera but                   min in order to predict the corresponding ionized fraction.
conjunctival pallor. There was no cervical or axillary lym-          Generally, for each 10 g/dL decrease in serum albumin, one
phadenopathy. The thyroid was normal. There were no                  should increase the measured total calcium by 0.2 mmoL/L.
lesions in the mouth. Cardiovascular examination showed              Alternatively, one could measure the ionized fraction directly.
a low JVP. Pulmonary exam was normal. There was no
clubbing. Abdominal examination revealed no evidence of              The causes of hypercalcemia are numerous, but hyperparathy-
organomegaly or masses. Rectal exam showed a diffusely               roidism and cancer account for 90% of the cases. Primary hyper-
enlarged prostate with negative occult blood testing.                parathyroidism can occur as the result of a solitary adenoma or a
Neurologic examination showed no deficits with normal                multiple endocrine neoplasia syndrome. Malignant causes includ-
fundoscopy, visual field testing, or acuity. MSK examina-            ing solid tumors that metastasize to bone, solid tumors with
tion showed point tenderness on the angle of the 7th rib.            humoral-mediated hypercalcemia, and hematologic malignancies
The skin examination was normal. Urinalysis showed no                such as multiple myeloma, lymphoma and leukemia.
proteinuria, glucosuria or blood on dipstick and negative
microscopy. The addition of sulfosalicylic acid to the urine         A combination of clinical features and lab results can be used
did not change its appearance.                                       to differentiate between the numerous causes of hypercal-

62       University of Toronto Medical Journal
cemia. The duration of the hypercalcemia is a key factor used to        The latter effect leads to an inability to reabsorb large volumes of
distinguish between different etiologies. Hyperparathyroidism has a     water, even in the presence of ADH. It is as though a patient with
chronic course, with asymptomatic hypercalcemia often present for       hypercalcemia is on a loop diuretic leading to an osmotic diuresis
more than a year. The diagnosis is frequently made in patients          and a subsequent resistance to ADH. Therefore, hypercalcemia
without symptoms as a result of screening. Elevated PTH levels          leads to a mixture of solute diuresis and partial ADH resistance
further confirm this clinical picture.                                  (owing to a fixed, low medullary osmolality).

However, patients with malignancy related hypercalcemia present
quite differently. Malignant hypercalcemia is strikingly rapid and                                    Na
development of malignancy associated signs and symptoms are                                           K
evident when hypercalcemia is detected. Paraneoplastic signs that                                                              Ca
may heighten suspicion include weight loss, fatigue, muscle weak-
ness, unexplained skin rash, or symptoms specific for a particular                                              –                                     H2O
tumor. If PTH levels are not elevated, or the clinical situation dic-                                                            Na

tates as such, then a thorough workup must be undertaken for
malignancy.                                                                                                                      Cl

                                                                          Urine/Lumen                TAL Cell                   Medullary Intersitium
Some of the less frequent causes of hypercalcemia include
excessive intake of vitamin D or calcium supplements, endogenous
vitamin D action resulting from granulomatous diseases, high            Figure 1. Hypercalcemia and polyuria: Na/K/2Cl channel of the thick ascending limb
                                                                        (TAL) reabsorbs these solutes. NaCl (and area) then diffuses into the medullary inter-
bone turnover from any of several causes, or tertiary                   stitium, rendering it hypertonic. Water diffuses freely from the collecting tubule under
hyperparathyroidism of chronic renal failure.                           the presence of ADH from a region of lower to higher osmolality. Potassium is recy-
                                                                        cled to the lumen via the apical ROMK channel, allowing the Na/K/2Cl to continue
                                                                        reabsorption. Hypercalcemia negatively inhibits ROMK via activation of a basolateral
Case Presentation                                                       cation receptor, preventing K recycling and ultimately, Na/K/2Cl function. In this way,
                                                                        hypercalcemia simulates the actions of loop diuretics; electrolytes are wasted in the
                                                                        urine and the reduction of medullary hypertonicity reduces the kidney’s capacity to
                        Urine data (spot)                               reabsorb free water.

[Na]                75 mmol/L                                           Case Presentation
[K]                 15 mmol/L                                           Chest X-ray:              Normal lung fields
[Cl]                95 mmol/L                                                                     Lytic lesion on seventh rib at the angle
[Urea]              150 mmol/L
Osm                 340 (mOsm/Kg/L)                                     ECG:                      NSR @ 90
Glucose             Nil                                                                           Shortened QT interval

24 Hr urine volume: 3.6L                                                How do we integrate the rest of these laboratory
                                                                        findings? How should we proceed?
                                                                        Although not diagnostic, the lesion on his rib might well represent
                                                                        a bony metastasis or hematological malignancy. Of these, multi-
How do we interpret the urine data?                                     ple myeloma produces these characteristic lytic lesions. The short-
In terms of the patient's urinary complaint, he has a 3.6 L urine       ened QT on Mr. E’s ECG is likely due to hypercalcemia, owing
output containing a large quantity of solutes (3.6 L x 340 mOsm/L       to early membrane repolarization. Mr. E also has moderate renal
= 1224 mOsm), in excess of a presumed intake of 900                     failure with normal urinalysis and a normocytic anemia. Both
mOsm/day. The total osmolality of the electrolytes and urea close-      require attention in his work-up. In the meantime, this man should
ly approximate the measured osmolality, eliminating an unmea-           be treated for severe hypercalcemia. Ultimately, therapy should be
sured solute as the cause of polyuria. Therefore, Mr. E has solute      aimed at the treatment of his underlying condition.
polyuria on the basis of hypercalcemia. The urinary solute diuresis
contributed to significant volume contraction, evidenced by pos-        Case Presentation
tural hypotension and low JVP.                                          This man was admitted to the internal medicine service
                                                                        at a tertiary care teaching hospital. He was initially treat-
What is the relationship between this man’s                             ed with volume resuscitation (saline bolus 3 L over
hypercalcemia and polyuria?                                             4 hours) followed by forced saline diuresis (normal saline
Calcium stimulates the cation receptor on the basolateral surface       @ 200 cc/hr) in order to promote urinary excretion of
of thick ascending limb cells in the Loop of Henle (Figure 1). This     calcium. A single dose of pamidronate (60 mg IV x1) was
action leads to inhibition of the rat outer medulla K channel           used to inhibit bone turn-over. A repeat calcium after 48
(ROMK), an important regulator of the Na/K/2Cl channel.                 hours of treatment was 2.65 mmol/L. Given his response,
ROMK closure leads to inhibition of the Na/K/2Cl channel and            the use of steroids and calcitonin was not required.
results in saline diuresis and a reduction in medullary osmolality.

                                                                                                          volume 79, number 1, December 2001                63
Steroids might be effective if the underlying cause of              Epilogue
hypercalcemia was a malignancy that is sensitive to these           Mr. E began chemotherapy with an alkylating agent
medications (e.g. lymphoma). During his resuscitation,              (melphalan) and prednisone.          His hypercalcemia
the patient’s BUN and Cr returned to normal, likely                 resolved, and he experienced a clinical remission,
reflecting resolution of prerenal azotemia.                         remaining disease free for 6 months. Unfortunately, he
                                                                    relapsed within one year, suffering anemia and thrombo-
A serum protein electrophoresis showed a monoclonal spike           cytopenia. He is currently being evaluated for an autolo-
in the gamma region and immunoelectrophoresis confirmed             gous stem-cell transplant.
that this was indeed monoclonal of the IgG kappa type. A
complete skeletal survey showed lytic lesions in the lumbar
vertebrae and salt and pepper appearance on skull films. A                                    Clinical Pearls
bone marrow aspirate and biopsy showed 30% infiltration
with plasma cells. A 24 hour urine collection showed no evi-        1. Polyuria is not defined by volume alone but by volume and solute
dence of Bence-Jones proteinuria. The consulting oncology              excretion in a clinical context.
service felt that this man’s presentation was convincing for
multiple myeloma.                                                   2. In the absence of diabetes and medications, polyuria in an older
                                                                       person should heighten suspicion for hypercalcemia.
What is multiple myeloma and what are its clinical
manifestations?                                                     3. Hypercalcemia has many etiologies but 90% of cases can be
Multiple myeloma is a malignant condition characterized by             accounted for by malignancy and primary hyperparathyroidism.
the proliferation of a single plasma cell type producing a mon-
oclonal immunoglobulin. The growth of plasma cell clones            4. Multiple myeloma can present in a variety of ways. However,
results in extensive bony destruction, hypercalcemia, and              the constellation of bony pain and hypercalcemia in an
cytopenia. Large circulating quantities of monoclonal                  older male without other obvious malignancies is a classical
immunoglobulin lead to a variety of clinical syndromes, usu-           presentation.

ally on the basis of amyloidosis (protein deposition in various

The most common presenting complaints in patients with
                                                                    Bataille R and Harousseau J. (1997). Multiple Myeloma.
multiple myeloma are those related to anemia, bone pain, and
                                                                    NEJM. 336(23): 1657-1664.
infection. Anemia can manifest as weakness or fatigue, and
                                                                    Braunwald E, Fauci AS, Isselbacher KJ, et al. (eds). (2001).
pallor may be notable on exam. Bone pain occurs most com-
                                                                    Harrison’s Principles of Internal Medicine, 15th ed. McGraw-
monly in the back and the ribs. It is characterized by wors-
                                                                    Hill, New York.
ening of pain on movement and, in contrast to more typical
                                                                    Goldman L and Bennet JC. (eds). (2000). Cecil Textbook of
cancer pain, is not worse at night. Bone involvement may
                                                                    Medicine. 21st ed. W.B. Saunders Company, Toronto.
also present as a fracture, especially in the femoral neck.         Halperin ML and Goldstein MB. (1999). Fluid, Electrolyte
Bony damage and collapse may lead to spinal cord compres-           and Acid-Base Physiology: A Problem-Based Approach. 3rd
sion and its associated neurologic symptoms. Bacterial infec-       ed. W.B. Saunders Company, Toronto.
tions are also common in patients with myeloma. Lastly,             UpToDate ver. 9.2 (accessed via CD-ROM).
patients may present with renal failure. Tubular damage asso-
ciated with excretion of monoclonal light chains, or Bence-
Jones proteins, is often present with renal involvement in mul-
tiple myeloma. Conventional dipsticks that detect albumin do        Note: The above case, though realistic, is hypothetical.
not detect Bence-Jones proteinuria. However, the addition of
sulfosalicylic acid to urine will result in precipitation and
clouding if light chains are present. There are a variety of rare
renal manifestations including amyloidosis, plasma cell infil-
tration, and Fanconi’s Syndrome, to name a few.

Multiple myeloma accounts for 1% of all malignancies in the
United States, affecting 4/100,000 people annually. It is slight-
ly more frequent in men and its incidence in black people
is double that in caucasians. The median age of diagnosis
is 65 years.

64       University of Toronto Medical Journal