Nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus is a form of diabetes insipidus primarily due to pathology of the kidney. This is in contrast to central/neurogenic diabetes insipidus, which is caused by insufficient levels of antidiuretic hormone (ADH, that is, arginine vasopressin or AVP). Nephrogenic diabetes insipidus is caused by an improper response of the kidney to ADH, leading to a decrease in the ability of the kidney to concentrate the urine by removing free water.

Not to be confused with Neurogenic diabetes insipidus.
Nephrogenic diabetes insipidus
Other namesRenal diabetes insipidus
SpecialtyNephrology 

Signs and symptoms

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.[1] On investigation, there will be an increased plasma osmolarity and decreased urine osmolarity. As pituitary function is normal, ADH levels are likely to be abnormal or raised. Polyuria will continue as long as the patient is able to drink. If the patient is unable to drink and is still unable to concentrate the urine, then hypernatremia will ensue with its neurologic symptoms.

Causes

Acquired

Nephrogenic DI (NDI) 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,[2] polycystic kidney disease,[3] electrolyte imbalance,[4][5] or some other kidney defect.[2]

The major causes of acquired NDI that produce clinical symptoms (e.g. polyuria) in the adult are lithium toxicity and high blood calcium.

Chronic lithium ingestion – appears to affect the tubules by entering the collecting tubule cells through sodium channels, accumulating and interfering with the normal response to ADH (ADH resistance) in a mechanism that is not yet fully understood.

High blood calcium causes natriuresis (increased sodium loss in the urine) and water diuresis, in part by its effect through the calcium-sensing receptor (CaSR).

Osmotic

Other causes of acquired NDI include: low blood potassium, post-obstructive polyuria, sickle cell disease/trait, amyloidosis, Sjögren syndrome, renal cystic disease, Bartter syndrome, and various medications (Amphotericin B, Orlistat, Ifosfamide, Ofloxacin, Cidofovir, Vaptanes).

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 medications is lithium,[6] although there are many other medications that cause this effect with lesser frequency.[2]

Hereditary

This form of DI can also be hereditary due to defects in either of the following genes:

Type OMIM Gene Locus
NDI1 304800 AVPR2 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.[2][7]
NDI2 125800 AQP2 In more rare cases, a mutation in the "aquaporin 2" gene impede the normal functionality of the kidney water channel, which results in the kidney being unable to absorb water. This mutation is often inherited in an autosomal recessive manner although dominant mutations are reported from time to time [2][8]

Diagnosis

Differential diagnosis includes nephrogenic diabetes insipidus, neurogenic/central diabetes insipidus and psychogenic polydipsia. They may be differentiated by using the water deprivation test. Recently, lab assays for ADH are available and can aid in diagnosis.

If able to rehydrate properly, sodium concentration should be nearer to the maximum of the normal range. This, however, is not a diagnostic finding, as it depends on patient hydration.

DDAVP can also be used; if the patient is able to concentrate urine following administration of DDAVP, then the cause of the diabetes insipidus is neurogenic (central diabetes insipidus); if no response occurs to DDAVP administration, then the cause is likely to be nephrogenic.

Treatment

Persons with nephrogenic diabetes insipidus will need to consume enough fluids to equal the amount of urine produced. Any underlying cause such as high blood calcium must be corrected to treat NDI. The first line of treatment is hydrochlorothiazide and amiloride.[9] Patients may also consider a low-salt and low-protein diet.

Thiazide is used in treatment because diabetes insipidus causes the excretion of more water than sodium (i.e. dilute urine). This condition results in a net concentrating effect on the serum (increasing its osmolarity). This high serum osmolarity stimulates excessive thirst in an attempt to dilute the serum back to normal and provide free water for excreting the excess serum solutes. However, since the patient is unable to concentrate urine to excrete the excess solutes, the resulting urine fails to decrease serum osmolarity and the cycle repeats itself, hence excessive urination. Thiazide diuretics allow increased excretion of Na+ and water, thereby reducing the serum osmolarity and eliminating volume excess. Therefore, thiazides allow increased solute excretion in the urine, breaking the polydipsia-polyuria cycle.

Etymology

The name of the disease comes from:

  • Diabetes - from L. diabetes, from Gk. diabetes "excessive discharge of urine," lit. "a passer-through, siphon," from diabainein "to pass through," from dia- "through" + bainein "to go"
  • Insipidus - "without taste or perceptible flavor," from Fr. insipide, from L.L. inspidus "tasteless," from L. in- "not" + sapidus "tasty," from sapere "have a taste"

This is because patients experience polyuria (an excretion of over 2.5 liters of urine per day), and that the urine content does not have an elevated glucose concentration, as opposed to diabetes mellitus. The two diseases were named (in ancient times) for the fact that one is excessive urination in which the urine tastes sweet (diabetes mellitus) whereas the other is excessive urination in which the urine tastes unremarkable (diabetes insipidus).

Although they shared a name, diabetes mellitus and diabetes insipidus are two separate conditions. Both cause excessive urination (hence the similarity in name), but whereas diabetes insipidus is a problem with the production of antidiuretic hormone (central diabetes insipidus) or the kidneys' response to antidiuretic hormone (nephrogenic diabetes insipidus), diabetes mellitus causes polyuria via osmotic diuresis, due to the high blood sugar leaking into the urine, taking excess water along with it.

References
  1. "Diabetes Insipidus. Diabetes symptoms and information". www.patient.co.uk. Retrieved 2018-05-18.
  2. Wildin, Robert (2006). "What is NDI?". The Diabetes Inspidus Foundation. Cite journal requires |journal= (help) "Archived copy". Archived from the original on 2009-04-01. Retrieved 2009-04-04.CS1 maint: archived copy as title (link)
  3. "Diabetes Insipidus | NIDDK". National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved 2018-05-18.
  4. 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. PMC 507266. PMID 8621781.
  5. Carney S, Rayson B, Morgan T (October 1976). "A study in vitro of the concentrating defect associated with hypokalaemia and hypercalcaemia". Pflügers Arch. 366 (1): 11–7. doi:10.1007/BF02486556. PMID 185584.
  6. 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. PMC 425543. PMID 2989335.
  7. Online Mendelian Inheritance in Man (OMIM) DIABETES INSIPIDUS, NEPHROGENIC, X-LINKED -304800
  8. Online Mendelian Inheritance in Man (OMIM) DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL -125800
  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. doi:10.1136/adc.80.6.548. PMC 1717946. PMID 10332005.
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