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Nephrogenic diabetes insipidus
Classification and external resources
ICD-10 N25.1
ICD-9 588.1
OMIM 304800 125800
MeSH D018500

Nephrogenic diabetes insipidus is a form of diabetes insipidus due primarily to pathology of the kidney.

Contents

Causes

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Acquired

Nephrogenic DI is most common in its acquired forms, meaning that the defect was not present at birth. These acquired forms have numerous potential causes. The most obvious cause is a kidney or systemic disorder, including amyloidosis [1], polycystic kidney disease [2], electrolyte imbalance,[3][4] or some other kidney defect.[1]

In addition to kidney and systemic disorders, nephrogenic DI can present itself as a side-effect to some medications. The most common and well known of these drugs is lithium,[5] although there are numerous other medications that cause this effect with lesser frequency.[1]

Hereditary

This form of DI can also be hereditary.

  • Usually, the hereditary form of nephrogenic DI is the result of an X-linked genetic defect which causes the vasopressin receptor (also called the V2 receptor) in the kidney to not function correctly.[1][6]
  • In more rare cases, a mutation in the "aquaporin 2" gene can cause a break in the kidney water channel, which results in the kidney being unable to absorb water.[1][7]

Presentation

The clinical manifestation is similar to neurogenic diabetes insipidus, presenting with excessive thirst and excretion of a large amount of dilute urine. Dehydration is common, and incontinence can occur secondary to chronic bladder distension.[8] On investigation, there will be an increased plasma osmolarity and descreased urine osmolarity. As pituitary function is normal, ADH levels are likely to be a normal or raised.

Treatment

Treat any underlying cause, allow the patient to drink as much as required. Correct metabolic abnormalities. The first line of treatment is hydrochlorothiazide and amiloride. [9]

External Links

References

  1. ^ a b c d e Wildin, Robert (2006), What is NDI?, The Diabetes Inspidus Foundation   http://www.diabetesinsipidus.org/4_types_nephrogenic_di.htm
  2. ^ http://kidney.niddk.nih.gov/kudiseases/pubs/insipidus/index.htm
  3. ^ Marples D, Frøkiaer J, Dørup J, Knepper MA, Nielsen S (April 1996). "Hypokalemia-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla and cortex". J. Clin. Invest. 97 (8): 1960–8. doi:10.1172/JCI118628. PMID 8621781.  
  4. ^ Carney S, Rayson B, Morgan T (October 1976). "A study in vitro of the concentrating defect associated with hypokalaemia and hypercalcaemia". Pflugers Arch. 366 (1): 11–7. PMID 185584.  
  5. ^ Christensen S, Kusano E, Yusufi AN, Murayama N, Dousa TP (June 1985). "Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats". J. Clin. Invest. 75 (6): 1869–79. doi:10.1172/JCI111901. PMID 2989335.  
  6. ^ Online 'Mendelian Inheritance in Man' (OMIM) DIABETES INSIPIDUS, NEPHROGENIC, X-LINKED -304800
  7. ^ Online 'Mendelian Inheritance in Man' (OMIM) DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL -125800
  8. ^ Kavanagh, Sean (20 Jun 2007). "Nephrogenic Diabetes Insipidus". Patient UK. http://www.patient.co.uk/showdoc/40001780/. Retrieved 22 Jun 2009.  
  9. ^ Kirchlechner V, Koller DY, Seidl R, Waldhauser F (June 1999). "Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride". Arch. Dis. Child. 80 (6): 548–52. PMID 10332005. PMC 1717946. http://adc.bmj.com/cgi/pmidlookup?view=long&pmid=10332005.  

TREATMENT — The urine output in patients with nephrogenic DI can be lowered with a low salt, low protein diet, diuretics, and nonsteroidal antiinflammatory drugs (NSAIDs). In infants, early recognition is of immediate clinical significance because treatment can avert the physical and mental retardation that results from repeated episodes of dehydration and hypernatremia. (See "Diagnosis of polyuria and diabetes insipidus").

In adults, the decision to undertake treatment must be based upon the individual patient's intolerance of the polyuria and polydipsia since, in almost all patients, the thirst mechanism is sufficient to maintain the plasma sodium in the high-normal range. The treatment of patients with hypernatremia is discussed separately. (See "Treatment of hypernatremia").

Special considerations in hereditary disease — Given their inability to independently respond to increased thirst, infants and very young children should be offered water every two hours during the day and night. In severe cases, continuous gastric feeding may be required. However, the ingestion of large quantities of water may exacerbate physiologic gastrointestinal reflux in infants and toddlers, which may require treatment. Appetite and growth should be monitored closely. (See "Management of gastroesophageal reflux disease in children and adolescents").

The high urine flow associated with hereditary nephrogenic DI induces dilatation of the urinary tract (hydronephrosis) and bladder in ≥50 percent of cases [4-6]. A rare complication is progressive loss of renal function and possible end-stage renal disease, probably related to voluntary retention of urine leading to bladder dysfunction [7-9]. These problems may also occur with other causes of massive urine volumes, most commonly seen with primary polydipsia [7].

Decreasing urine flow with the interventions discussed below, and frequent voiding and "double voiding" (to empty the bladder entirely) are important preventive measures. This approach should be taught to children once they are old enough, and should be continued in adulthood, to prevent severe dilatation of the urinary tract.

Decreased dietary solute — When the urine osmolality is fixed, as in nephrogenic DI, the urine output is determined by solute excretion. Suppose that the maximum urine osmolality is 150 mosmol/kg. In this setting, the daily urine volume will be 5 liters if solute excretion is in the normal range at 750 mosmol/day, but only 3 liters if solute excretion is lowered to 450 mosmol/day by dietary modification.

These observations provide the rationale for the use of a low salt, low protein diet to diminish the urine output in nephrogenic DI [1,10]. The reduction in urine output will be directly proportional to the decrease in solute intake and excretion. Restriction of salt intake to ≤100 meq/day (2.3 g sodium) and protein intake to ≤1.0 g/kg may be reasonable goals, but such diets are not easy to achieve and maintain. Furthermore, protein restriction in infants and young children may be harmful and is not advised. (See "Patient information: Low sodium diet").

Although most children with nephrogenic DI are underweight and relatively short during the first years of life, their height and weight become progressively normal during school-age years [11]. These growth observations could be related in part to limited caloric intake and decreased dietary solute during the first years of life.

Diuretics — Thiazide diuretics in combination with a low solute diet can diminish the degree of polyuria in patients with nephrogenic DI [1,12-14]. The potassium-sparing diuretic amiloride also may be helpful, both by its additive effect with the thiazide diuretic [15] and, with reversible lithium-induced disease, by possibly allowing lithium to be continued (see below) [16].

A thiazide diuretic (such as hydrochlorothiazide, 25 mg once or twice daily) acts by inducing mild volume depletion. As little as a 1 to 1.5 kg weight loss can reduce the urine output by more than 50 percent (eg, from 10 L/day to below 3.5 L/day in a study of patients with nephrogenic DI on a severely sodium-restricted diet [9 meq/day]) [12].

This effect is presumably mediated by a hypovolemia-induced increase in proximal sodium and water reabsorption, thereby diminishing water delivery to the ADH-sensitive sites in the collecting tubules and reducing the urine output. Diuretic therapy can lead to a variety of usually mild electrolyte complications (See "Time course of diuretic-induced electrolyte complications" and see "Diuretic-induced hypokalemia" and see "Diuretic-induced hyperuricemia and gout").

The initial natriuresis and therefore the later antipolyuric response can be enhanced by combination therapy with amiloride (or other potassium-sparing diuretic) [16]. This regimen has an additional benefit, since amiloride partially blocks the potassium wasting induced by the thiazide.

Amiloride may be particularly beneficial in patients with reversible lithium nephrotoxicity, given its site and mechanism of action [17]. If amiloride is used, a small contraction of extracellular fluid volume may ensue, and it may be necessary to decrease the dose of lithium chronically administered and to measure plasma concentrations at frequent intervals until a new steady state is achieved. This drug closes the sodium channels in the luminal membrane of the collecting tubule cells. These channels constitute the mechanism by which filtered lithium normally enters these cells and then interferes with their response to ADH [15]. The permeability for lithium of the epithelial sodium channel (ENaC) is 1.5- to twofold higher than that for sodium. Whereas sodium is extruded from the interior of the cell to the blood compartment by the sodium pump (Na,K-ATPase) located at the basolateral membrane, lithium is a poor substrate for the sodium pump. As a consequence, toxic intracellular levels could build up quickly in all cells expressing ENaC at their plasma membrane and exposed to therapeutic concentrations of lithium (0.6 to 1.2 mmole/L). (See "Renal toxicity of lithium"). Glycogen synthase kinase 3 (GSK-3 beta) is inhibited by lithium and is likely the common molecular target for the primary and secondary toxic effects of lithium [18].

A loop diuretic, although also capable of inducing mild volume depletion, is not as likely to lower the urine output in nephrogenic DI. These agents decrease sodium chloride reabsorption in the medullary thick ascending limb of the loop of Henle, thereby decreasing the accumulation of NaCl in the medullary interstitium that is essential for the production of a concentrated urine. Thus, a loop diuretic induces relative ADH resistance, an effect that is counterproductive in nephrogenic DI.

Nonsteroidal antiinflammatory drugs — The efficacy of NSAIDs in this setting is dependent upon inhibition of renal prostaglandin synthesis. In normal subjects, prostaglandins antagonize the action of ADH and NSAIDs increase concentrating ability [19,20]. If, for example, normal subjects are given a submaximal dose of ADH, the ensuing rise in urine osmolality can be increased by more than 200 mosmol/kg if the patient has been pretreated with a NSAID [19]. The net effect in patients with DI may be a 25 to 50 percent reduction in urine output [13,14,21], a response that is partially additive to that of a thiazide diuretic [14,16].

This approach is particularly beneficial in patients polyuria due to complex congenital polyuric-polydipsic Bartter-like syndromes, in whom prostaglandins appear to be pathogenetically important. (See "Bartter's and Gitelman's syndromes", section on Role of prostaglandins).

Not all NSAIDs are equally effective in a given patient; as an example, indomethacin appears to have a greater effect than ibuprofen [13]. A variety of complications may ensue with long-term use of NSAIDs. (See "NSAIDs: Overview of adverse effects").

Exogenous ADH — Most patients with nephrogenic DI have partial rather than complete resistance to ADH. It is therefore possible that attaining supraphysiologic hormone levels will increase the renal effect of ADH to a clinically important degree. In some patients with nephrogenic DI, exogenous ADH has been found to increase the urine osmolality by 40 to 45 percent, an effect which would be expected to produce a similar decline in urine volume [22,23].

Thus, desmopressin (dDAVP) may be tried in patients who have persistent symptomatic polyuria after implementation of the above regimen. One case report of a patient with lithium-induced nephrogenic DI suggested that benefit may be more likely if desmopressin is combined with a NSAID [24].

Experimental approaches — Most patients with congenital X-linked nephrogenic DI have defective V2 vasopressin receptors that are unable to properly fold intracellularly and, as a consequence, correctly transfer to the cell surface. (See "Causes of nephrogenic diabetes insipidus").

In in vitro systems, the administration of selective, cell permeable nonpeptide V2 and V1a receptor antagonists were able to rescue mutant V2 receptors by promoting their proper folding and maturation [25,26]. This resulted in the expression of functional cell surface V2 receptors, suggesting that such a therapeutic approach may eventually be fruitful.

In a pilot study, a nonpeptide V1a receptor antagonist was administered to five men with nephrogenic DI (each with one of three identified mutations in the AVPR2 gene that codes for the V2 receptor) [26]. This resulted in an increase in urine osmolality from a mean of 100 to 150 mosm/kg, and reductions in urine volume from 12 to 8 L/day and in water intake from 11 to 7 L/day.

Most aquaporin-2 mutations associated with nephrogenic DI also result in proteins being retained in the intracellular space [10]. Research to find chaperone-like molecules to help direct these proteins to the cell surface is ongoing [27].

SUMMARY AND RECOMMENDATIONS — Nephrogenic DI results from partial or complete resistance of the kidney to the effects of antidiuretic hormone. In adults, a concentrating defect severe enough to produce polyuria due to nephrogenic DI is most often due to chronic lithium use or hypercalcemia, and less frequently to other conditions that impair tubular function, such as Sjögren's syndrome. In infants, congenital nephrogenic DI is most common. (See "Causes of nephrogenic diabetes insipidus").

If a cause can be identified, we recommend correcting the underlying disorder (eg, hypercalcemia) or discontinuing the offending drug, if feasible. Lithium-induced nephrogenic DI may be irreversible if tubular injury is severe, and there is a marked concentrating defect. (See "Renal toxicity of lithium").

There are usually no adverse medical effects of polyuria although, as noted above, the functional hydronephrosis in congenital nephrogenic DI rarely leads to significant renal injury [7]. As a result, the only indication for therapy in adults is to relieve the patient's symptoms.

Initial therapy — Therapy of the polyuria in nephrogenic DI consists of the following sequential approach:

All adult patients should be instructed to take a low sodium-low protein diet as tolerated, and all infants and young children should be provided a low sodium diet. The reduction in urine output will be directly proportional to the fall in solute excretion. As a result, the efficacy of solute restriction will depend directly upon patient compliance. (See "Decreased dietary solute" above). In all patients who have significant polyuria, we recommend frequent and "double-voiding" to avoid bladder dilatation and dysfunction. In all children, and in adults with symptomatic polyuria persisting despite a low solute diet, we recommend starting a thiazide diuretic (eg, hydrochlorothiazide 25 mg once daily to a usual maximum of 25 mg twice daily in adults, and appropriate dosing in children) (Grade 1A). (See "Diuretics" above). An exception to this are children with polyuria due to complex congenital polyuric-polydipsic Bartter-like syndromes, in whom we recommend NSAIDs as initial therapy (Grade 1B). "(See "Bartter's and Gitelman's syndromes", section on Treatment).

We suggest adding amiloride if the urine output is insufficiently reduced (Grade 2B). We recommend amiloride as part of primary therapy to prevent progression of, or possibly improve, lithium-induced DI in patients in whom lithium is continued (Grade 1B). (See "Diuretics" above). If symptomatic polyuria persists, we suggest adding indomethacin if there are no contraindications (Grade 2B). (See "Nonsteroidal antiinflammatory drugs" above). In patients who cannot be treated with NSAIDs or who have persistent symptomatic polyuria after the addition of NSAIDs, we suggest a trial of desmopressin (Grade 2B). (See "Exogenous ADH" above). Hereditary disease — There are special considerations in the management of hereditary nephrogenic DI, particularly in infants and young children. (See "Special considerations in hereditary disease" above).

In infants and very young children, we recommend offering water every two hours, with the goal of avoiding severe dehydration and hypernatremia (Grade 1B). If gastroesophageal reflux becomes problematic, we recommend appropriate management. (See "Management of gastroesophageal reflux disease in children and adolescents"). In all children, we recommend implementation of measures to decrease urine flow as discussed above, and frequent and "double voiding," with the goal of avoiding dilatation of the urinary tract and bladder (Grade 1C). We suggest continuing these preventive measures to avoid dilatation of the urinary tract in adulthood.


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