NEPHROGENIC DIABETES INSIPIDUS
In diabetes insipidus (DI), abnormalities in ADH signaling prevent patients from appropriately concentrating tubular ﬂuid, leading to the continuous production of large volumes of dilute urine. DI is termed “central” if there is diminished production of ADH, usually because of abnormalities in the hypothalamus or posterior pituitary, or “nephrogenic” if there is diminished renal response to ADH. Nephrogenic DI (NDI) can occur because of inherited mutations or, more commonly, acquired insults to the renal tubules.
A detailed description of ADH physiology is available on Plate 3-17. In brief, elevations in serum osmolality trigger release of ADH from the posterior pituitary. In the kidneys, ADH binds to V2 receptors on the basolateral surface of principal cells, located in the collecting duct, which triggers translocation of aquaporin 2 (AQP-2) channels from endosomes to apical cell membranes. As a result, water is reabsorbed through a transcellular route from the tubule lumen into the interstitium. In addition, ADH up-regulates apical ENaC and urea transporters in the collecting duct, as well as Na+/K+/2Cl- cotransporters (NKCC2) in the thick ascending limb, to increase the concentration of solute in the interstitium and draw more water out of the collecting duct.
Inherited NDI, which is the major cause of NDI in children, typically results from mutations in either the V2 receptor or AQP-2 channel. V2 mutations account for 90% of cases and are inherited in an X-linked recessive pattern. Females may exhibit a variable level of disease depending on their particular pattern of X-inactivation (lyonization). AQP-2 mutations account for most of the remaining cases and can be inherited in an autosomal recessive or dominant pattern. Other tubular disorders, such as Bartter syndrome, can also feature increased urine production because of failure to establish an adequate concentration of solutes in the medullary interstitium; thus, even though ADH is present and functional, there is a diminished transcellular gradient for water transport.
Acquired NDI, which is more common in adults, is most frequently the result of long-term lithium usage, commonly employed to treat bipolar disorder. About 40% to 50% of patients who take lithium will experience this complication to some degree; among them, about half will experience signiﬁcant polyuria, starting as early as 8 weeks after therapy begins. Lithium is freely ﬁltered at the glomerulus and primarily reabsorbed in the proximal tubule. A small amount, however, is reabsorbed through apical ENaC in principle cells of the collecting duct. It accumulates within the cell, where it appears to interfere with the second messenger cascade that connects V2 activation to luminal insertion of AQP-2 channels. For reasons that are poorly under-stood, but which may involve a selective toxic effect on principal cells, these effects can persist even after lithium is discontinued.
Other drugs that may cause diabetes insipidus include demeclocycline, amphotericin B, and orlistat. The mechanisms are diverse and not completely under-stood. V2 receptor antagonists, such as tolvaptan, may cause transient NDI. Finally, acquired NDI may also occur in the setting of normal aging, which causes a decreased density of collecting duct transporters; hypercalcemia and hypokalemia because these states interfere with reabsorption in the thick ascending limb and therefore decrease the medullary solute gradient; release of bilateral ureteral obstructions because of tubular injury; and amyloidosis, if there is extensive tubular deposition.
PRESENTATION AND DIAGNOSIS
The major symptom of both central and nephrogenic DI is polyuria, arbitrarily deﬁned as greater than 3 L/ day of urine production in adults and 2 L/day in children. Additional features often include constant thirst (polydipsia) and fatigue. In children with inherited NDI, failure to thrive and mental retardation may occur secondary to repeated episodes of severe dehydration, if diagnosis and treatment have been delayed. Patients with polyuria should be questioned regarding their water intake to assess for possible primary polydipsia (i.e., compulsive water consumption, which leads by necessity to polyuria). In addition, their medications should be carefully reviewed to determine if they are taking diuretics or medications (such as lithium) known to cause DI. A prior history of trans-sphenoidal neurologic surgery strongly suggests central DI. Finally, family history should be assessed for possible inherited disease.
On serum chemistries, hypernatremia is suggestive of severe dehydration secondary to polyuria, whereas hyponatremia indicates primary polydipsia. Hypokalemia and hypercalcemia may cause NDI, as previously stated, and should be noted if present. Fasting glucose levels should be normal to exclude hyperglycemia as a cause of osmotic diuresis. Serum creatinine concentration may be slightly elevated in the setting of severe dehydration, with an elevated BUN:creatinine ratio and bland urine sediment suggestive of a prerenal state (see Plate 4-1).
In children and adults, a water deprivation test is the gold standard for diagnosis. This procedure tests the urine-concentrating capabilities of the kidneys in response to dehydration. In normal individuals, there will be an appropriate increase in urine osmolality as the body attempts to conserve free water. In patients with DI, in contrast, the urine osmolality remains depressed, with the exact level depending on various testing parameters and whether the DI is complete or partial. The distinction between central and nephrogenic DI may be established by assessing the response to exogenous vasopressin agonists, such as desmopressin, which will lead to urine concentration in central DI but have no effect in nephrogenic DI.
Of note, patients with primary polydipsia may have ﬁndings that resemble those of partial NDI because their urine-concentrating abilities are frequently impaired (as a result of medullary wash-out) but the addition of desmopressin has no effect (since they have intact secretion of endogenous ADH). Thus a careful history may be required to make the distinction.
All potentially modiﬁable causes of NDI should be reversed. Lithium, for example, should be discontinued, and hypokalemia or hypercalcemia should be corrected. These measures may lead to complete recovery of renal function, although lithi m-associated NDI may be irreversible in some cases.
It is important for all patients to maintain adequate hydration. If young children cannot obtain their own water, it must regularly be offered to them. A low-salt diet should be instituted to promote solute and water reabsorption in the proximal tubule.
In addition, a diuretic can be offered because it can paradoxically reduce urine output by causing a slight volume depletion, which up-regulates salt and water reabsorption in the proximal tubule. Thiazide diuretics are preferred over loop diuretics because the latter impair creation of the solute gradient in the medulla, which interferes with urine concentration. In addition, amiloride has been proposed as a potentially preventative measure in patients taking lithium, because this agent appears to limit lithium inﬂux into principal cells. Its efﬁcacy, however, remains unknown.