Polyuria: Simple and Mixed Disorders

VIGNETTE IN CLINICAL PATHOPHYSIOLOGY

Polyuria: Simple and Mixed Disorders Robert G. Narins, MD, and Louis J. Riley, Jr, MD INDEX WORDS: Polyuria; hypernatremia; diuresis; vasopressin.

T

HE CLINICAL conditions that spawn polyuria are usually obvious, making identification of its etiology and pathogenesis a simple matter. However, in more complex settings, the sorting of contributing pathologic forces requires closer clinical and chemical inspection. The "simple polyurias" are caused by diuresis of either solute or water, whereas the "mixed polyurias" derive from the simultaneous excessive excretion of both solute and water. Simple chemical analysis of the urine and plasma in the mixed disorders can quickly document the pathophysiologic basis of the increased urine volume and often helps to craft effective therapeutic regimens. The following case history illustrates how one can apply the physiologic concepts of osmolal (Cosm ) and free water (C HZO ) clearance to the assessment of a complex polyuric syndrome. Figure 1 outlines the pathophysiologic approach to the differential diagnosis of polyuria and is based on whether a water or solute diuresis is driving the urine flow. CASE REPORT A 27 -year-old white man with a lO-year history of idiopathic complete central diabetes insipidus (CDl) had been well controlled with vasopressin tannate in oil (VPTO) (5 U intramuscularly, every 2 days). Admission to the hospital following a motorcycle accident showed a disoriented male without focal neurologic signs who had an obvious compound fracture of the left humerus. Vital signs were normal and apart from several superficial cuts and abrasions the remainder of his physical examination was unrevealing. Relevant initial and subsequent laboratory data are shown in Table 1. Routine urinalysis was negative, including the dipstick for glucose. After resetting and casting the fracture under anesthesia, he was transferred to the surgical intensive care unit where he was to receive intramuscular injections of 5 U of VPTO every 2 to 3 days. Normal saline was infused parenterally at a rate that matched urine output. Hourly urine volumes progressively increased (Table 1). The polyuria was interpreted as resistance to the hormone and orders were rewritten for hourly injections of 10 U ofVPTO.

Questions

1. How can one prove whether a simple or a mixed polyuria is occurring?

2. What is the pathophysiologic basis for the increasing polyuria developing postoperatively? 3. What are the guidelines for hormonal and water replacement when patients with CDI are hospitalized with a severe intercurrent illness? DISCUSSION

Question 1

Regulation of serum sodium concentration requires that the kidney excrete electrolytes with a variable amount of water. When challenged by dilute fluids, sodium must be excreted with increased amounts of water, thereby preventing the occurrence of hyponatremia. Conversely, during periods of thirsting, sodium must be excreted in a reduced volume of urine thereby conserving water and minimizing the risk of developing hypernatremia. Thus, in a given clinical setting there is a "correct" proportionality between the excretion of water and electrolytes. The use of free CHZO illld Cosm enables one to define whether the observed proportionality between excreted water and electrolytes is indeed appropriate to the needs of the host. Unfortunately, in many clinical settings the standard clearance formulas used for these calculations can be misleading. Standard formulas use terms for urinary and plasma osmolality that include not only the relevant electrolytic, but also the irrelevant nonelectrolytic components of osmolality. Total urinary osmolality, as measured by the clinical laboratory, reflects all the solute excreted per unit volume of urine. Sodium, potassium, and their accompanying anions account for almost the entire ionic portion, while urea normally forms the vast bulk of the excreted nonelectrolyte solute. However, urea is an ineffective osmole, ie, it freely penetrates cell membranes, does From the Department of Medicine, Temple University Health Sciences Center, Philadelphia, PA. Address reprint requests to Robert G. Narins, MD, Professor of Medicine, Temple University Health Sciences Center, Broad and Ontario Sts, Philadelphia, PA 19140. © 1991 by the National Kidney Foundation, Inc. 0272-638619111702-0027$3.0010

American Journal of Kidney Diseases, Vol XVII, No 2 (February), 1991: pp 237-241

237

238

NARINS AND RILEY

I POLYURIA I I INCREASED SOLUTE EXCRETION

INCREASED WATER EXCRETION

I

~

I

I

SODIUM 1. VOMITING

1. DIURETIC

2. RENAL SALT WASTING

2. ALKALI INGESTION

2. BLADDER LAVAGE (PROSTATEC' TOMY) 3. TREAT eNS EDEMA

3. EXCESS SALT INGESTION

GLUCOSE

UREA

MANNITOL

He03

1. DIURETICS

1. CATABOLIC STATES

2. PROTEIN

LOADING 3. TREAT eNS

DRUGS CHEMICALS

1. DIABETES 1. RADIOGRAPH Ie MELLITUS DYES 2. I.V. FlUIDS 2. CARBENICILLIN 3. HHNK COMA

EDEMA

EXCESSIVE WATER INGESTION

1. PSYCHOGENIC POLYDIPISIA 2. THIRST CENTER DEFECT 3. HYPERRENINEMIA A. K' DEPLETION B. RENAL VASCULAR DISEASE C. RENAL TUMORS O. RENAL HYPQPERFUSIOH

DIMINISHED WATER REABSORPTION

,

DIABETES INSIPIDUS

CENTRAL

RENAL

A. IDIOPATHIC (50%)

A. CONGENITALI FAMILIAL B. OBSTRUCTION C. AMYLOID D. SJOGRENS E. ATN·DIURETIC PHASE F. POST-RENAL TRANSPLANTATION G. SICKLE CELL NEPHROPATHY H. K' DEPLETION I. HYPERCALCEMIA J. LITHIUM K. DEMECLOCYCLINE L. METHOXYFLURANE

B. POST-HYPQX C. BASAL SKULL FRACTURE D. TUMORS E. HISTIOCYTOSIS F. GRANULOMATOUS DISEASE G. VASCULAR DISEASE H. CNS INFECTION I. CNS HEMORRHAGE J. FAMILIAL

Fig 1. Pathophysiologic approach to polyuria. Urine volume may be increased by excessive excretion. of solute (increased osmolal clearance [Cos m]) or by excessive water excretion (increased free water clearance [CH20]). The clinical disorders that cause polyuria by increasing either Coom or CH20 are illustrated.

not establish sustained transcellular osmotic gradients, does not displace water from one fluid compartment to another, and its excretion leaves serum sodium concentration unchanged.! Because the proportionality between the excretion of electrolytes and water is not influenced by urea, measurements of total urinary and total plasma osmolality should not be used in the calculation of CH20 and Cosmo For clinical purposes, the electrolyte portion of urinary osmolality can be approximated by doubling the sum of the concentrations of excreted sodium and potassium, thereby accounting for the contribution of both cations and anions. It must be appreciated that urinary potassium losses influence serum sodium concentraTable 1. Laboratory Data

Laboratory Data

Admission to Emergency Room

Serum studies Na (mmoI/L) K (mmoI/L) CI (mmoI/L) CO2 (mmoI/L) Osmolality (mOsm/L) BUN (mmoI/L) Creatinine (pmoI/L) Urine studies Volume (Uh) Na (mmoI/L) K (mmol/L) CI (mmoI/L) Osmolality (mOsm/L)

First 4 Hours Postoperatively

2

144 4.0 107 25 290 5.0 88 0.2 30 10 50 100

3

150

4

160

3.6 80 0.4

200

1.05 80 5 230

1.4

275

1.6 130 10 300

tion. The basis for this effect is as follows. 5 Intracellular and extracellular osmolalities are always equal, since water freely moves between compartments, dissipating osmotic gradients.! Sodium, potassium, and their counterbalancing anions account for the effective osmolalities of the extracellular and intracellular fluid spaces, respectively. Selective loss of potassium, the key intracellular osmole, dilutes the intracellular fluid causing electrolyte-free water to move extracellularly, thereby reducing serum sodium concentration. The contribution of electrolytes to serum osmolality may be obtained by simply doubling the serum sodium concentration. Serum potassium concentration can be ignored, since its contribution to serum osmolality is trivial. In contrast, urinary potassium concentrations are often 50 to 100 mEq/L. As shown below, use of the electrolyte osmolality of serum and urine allows one to accurately define the proportionality between excreted electrolytes and electrolyte-free water. A common clinical example is given to illustrate how the use of total urinary osmolality may confuse one's understanding of the pathophysiology of saIt and water disorders. A thirsting subject not ingesting salt excretes 700 mL of urine that is almost totally devoid of electrolytes, but contains enough urea to yield an osmolality of 300 mOsm. Loss of these 700 mL of water without electrolytes will cause serum sodium concentration to increase and this fact would have been disguised if CH20

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POLYURIA: SIMPLE AND MIXED DISORDERS

and not electrolyte-free water clearance (CH20(E») were used in the calculation. Thus, calculation of CH20(E) codifies the contribution of water excretion to a given patient's polyuria. The contribution of solute excretion to polyuria has traditionally made use of the Cosmo The concept of Cosm can be developed as follows. The Cosm is defined as the volume of urine required to excrete urinary solute isoosmotically. Knowing the quantity of solute excreted allows calculation of the volume of urine required to excrete this solute isoosmotically, ie, at a concentration equal to that in plasma (eg, 300 mmol). If, for example, 600 mmol of solute were excreted, 2 L of urine would be required to excrete it isoosmotically, and the Cosm would be 2 L. Thus, one could view dilute urine as a composite of two virtual volumes, the electrolyte-free water portion and the isoosmotic portion. It therefore follows that: Total urine volume (V) = CH20(E) + Cosmo It also follows that as solute excretion increases, a larger volume of urine is required to excrete the solute, ie, the Cosm must increase. Thus, the Cosm codifies the contribution of solute excretion to a given patient's polyuna. Separating electrolyte osmolal clearance from total Cos m allows for a clearer diagnostic approach to a solute diuresis (Fig 1) and also allows for the calculation of CH20(E). The standard clearance formula for Cosm is: Cosm = (Uosm V)/Pos m. By using the total osmolality of urine and plasma, one defines the total solute contribution to Cosmo The electrolyte component is defined by using only the electrolyte components of plasma and urinary osmolalities, as previously defined: COsm(E) = (Uosm(E) [2(Na + K)] V)/(2PNa). The difference between the total Cosm and the electrolyte osmolal clearance CoSm(E) identifies the contribution of nonelectrolytes (eg, urea, glucose, mannitol) to a solute diuresis. By using the COSm(E), one can now define the calculation for CH20(E): CH20(E) = V - Cosm(E). A normal subject, for example, with a serum sodium of 140 mmollL (mEq/L), excreting 50 mEq/L of sodium and 20 mEq/L of potassium with a urine volume of 2 Lid, is excreting 1 L of CH20(E) plus 1 L of Cosm (E): COsm(E) = (2[50 mEq/L + 20 mEq/L] x 2 Lld)/2[140 mEq/L] = 1 Lid. Since V = CH20(E) + COSm(E), it follows that: CH20(E) = 2 Lid - 1 Lid = 1 Lid.

Applying these concepts to the case presented above, reveals the following: Admission values for

C

osm(E)

-

Casm(E)

and

CHZO(E)

were:

2(UNa + UK) x V 2(PNa )

2(40 mEq/L) X 0.2 Llh 2(144 mEq/L)

0.056 Llh

V = Cosm(E) + CH20(E) 0.2 Llh = 0.056 Llh + CH20(E) CH20(E) = 0.144 Llh Excretion of 0.144 Llh of electrolyte-free water would result in loss of 3.46 L of CH20(E) in 24 hours, suggesting that at the time of admission the effect of the patient's VPTO was wearing off. Two Hours Postoperatively: Cosm(E): 0.60 Llh CH20(E): 0.45 Llh Four Hours Postoperatively: Cosm(E): 1.4 Llh CH20(E): 0.2 Llh Question 2

The rising Cosm(E) from the time of admission reflects the inappropriate infusion of normal saline in replacement of the increasing urinary volume. Extracellular fluid volume expansion resulted from the hourly infusion of more salt than was being excreted. Progressive inhibition of tubular sodium reabsorption eventually allowed for the matching of the hourly rates of sodium infusion with those of urinary excretion. Since all postoperative urines were more dilute than the increasingly more hypertonic plasma, an inappropriate CH20(E) diuresis must also have been occurring. Hypernatremia should stimulate ADH release, which, in turn, should cause the urine to become progressively more concentrated. The increased CH20(E) is consistent with the patient's untreated CD!. Pitressin tannate is a waterinsoluble extract from animal posterior pituitaries. It is dispersed in peanut oil and unless vigorously shaken and warmed, the active fraction remains in the bottom of the ampule and the syringe aspirates only the inactive oil. The above-described patient

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received hourly injections of vehicle without the hormone. Replacement of the patient's hourly urine volume with normal saline modestly expanded his extracellular fluid (ECF) volume, accounting for the decreases in BUN and serum creatinine. The resulting sodium diuresis caused his Cosm (E) to progressively increase. While the absence of circulating vasopressin accounted for the water diuresis, the contemporaneous sodium diuresis actually limited the amount of electrolyte-free water that could have been excreted. The ECF volume expansion impaired sodium reabsorption, which, of course, impaired distal electrolyte-free water generation and the increased distal flow of solute and water, by limiting contact time with transporting epithelium, further limited solute uptake. Urinary loss of CH20(E)' along with insensible water loss, obviously accounted for the patient's increasing serum sodium concentration. A mixed polyuria (free water and osmotic diuresis) resulted from failure to treat effectively his cm and by iatrogenically creating a sodium osmotic diuresis.

Question 3 Fluid and hormonal replacement therapy in the uncomplicated patient with cm requiring hospitalization should be guided by urine output. In the absence of a solute diuresis (ie, no glycosuria, urea excess, etc; Fig I) urine volume in such patients will reflect CH20(E)' In addition to urine volume, the serum sodium concentration serves as a prime guide to net water balance. Use of hormonal preparations with long half-lives renders patients vulnerable to developing hyponatremia, the therapy of which requires use of complex regimens. Preparations with short half-lives are advantageous in that simple discontinuation of the hormone rapidly allows water diuresis to develop, enabling one to shed excess fluid. Measurements of urinary electrolytes and osmolality are usually unnecessary in the uncomplicated case; body weight, urine volume, and serum sodium concentration usually suffice to convey needed information regarding water balance. Should a superimposed solute diuresis be suspected, assessment of COSm(IOI)' Cosm(E)' and CH20(E) can be useful. Vasopressin and its analogues are the principal

NARINS AND RILEY

agents used in the treatment of CD!. The pharmacokinetic differences among the various preparations compel familiarity with those differences as a precondition to efficient use. Aqueous vasopressin is a water-soluble, posterior hypophyseal extract that can be administered by intravenous, subcutaneous, or intramuscular route. 2 The onset of effect occurs within approximately 30 to 60 minutes, with a duration of action of 4 to 6 hours. It is the ideal preparation for management of transient CDI or acute management of chronic CDI, as in this case. The pharmacokinetic characteristics of aqueous vasopressin allow frequent reevaluations of polyuria in the acute setting where fluctuations in magnitude are likely to occur. Ideally, doses of 5 to 10 U (0.25 to 0.5 mL) should be administered just as polyuria recurs (awaiting the return o( polyuria minimizes the chance of accidental water intoxication). Vasopressin tannate in oil requires intramuscular injection and had been standard therapy for chronic complete cm in the past because of its conveniently long duration of action, 24 to 72 hours.2 Its onset of action occurs between 2 to 4 hours after injection and, therefore, it is not useful in the acute setting. There is certainly no justification for hourly injections as was given in this case. Desmopressin (l-desamino-8-o-arginine vasopressin) or DDAVP is a long-acting, 12- to 24hour duration, nasal spray synthetic preparation that is presently considered the drug of choice for the routine management of complete CD!. 2 Twice daily nasal inhalations (5 to 20 Ilg) are usually required. DDAVP also has the additional attractive feature of probably being the least vasoconstrictive of the vasopressin analogues. Synthetic 8-lysinevasopressin (LVP) is a nasal spray preparation with clinical activity lasting approximately 4 to 6 hours. 2 Like DDAVP and aqueous vasopressin, the time for onset of effect is approximately 30 to 60 minutes. Thus, the half-life and rapid onset of action of aqueous vasopressin and LVP make them the replacement therapies of choice for patients with CDI suffering acute intercurrent illnesses. Finally, there are nonhormonal agents that have also been used in the treatment of polyuria. 2 However, they are used either adjunctively in the treatment of complete and incomplete CDI or in nephrogenic diabetes insipidus. As such, they offer little in the clinical setting discussed.

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POLYURIA: SIMPLE AND MIXED DISORDERS

REFERENCES 1. Fanestil DD: Compartmentation of body water, in Maxwell MH, Kleeman CR, Narins RG (eds): Clinical Disorders of Fluid and Electrolyte Metabolism. New York, NY, McGraw Hill, 1987, pp 1-14 2. Robertson GL, Ber! T: Water metabolism, in Brenner BM, Rector FC Jr (eds): The Kidney. Philadelphia, PA, Saunders, 1986, pp 385-432

3. Gennari FJ, Kassirer JP: Osmotic diuresis. N Engl J Med 291:714-719, 1974 4. Rose BD: New approach to disturbances in the plasma sodium concentration. Am J Med 81: 1033-1038, 1986 5. Edelman IS, Leibman J, O'Meara MP: Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J Clin Invest 37: 1236-1245, 1958