Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus is a condition characterized by polyuria and polydipsia, resulting from the inability of the kidneys to concentrate urine.

Nephrogenic Diabetes Insipidus arises due to this process: congenital.

Presentation

Moderate to severe cases are characterized by polyuria, polydipsia, and nocturia. Polyuria is defined as urine output greater than 3L/day in adults or 2L/m2 in children.

Patients usually have good thirst response which allows for proper rehydration and, therefore, maintenance of normal serum levels. However, children and elderly patients with critical illness or dementia who may not communicate thirst effectively may present with hypernatremia. In turn, hypernatremia causes confusion, coma, and uninhibited neuromuscular excitation leading to convulsions. Infants with NDI may present with cognitive impairments, failure to thrive, and growth retardation.

Differential diagnoses of NDI include primary polydipsia, diabetes mellitus, and post-obstructive diuresis, all of which are characterized by a significant increase in urine osmolality.

Workup

If nephrogenic diabetes insipidus is suspected in a patient, investigations required to confirm the diagnosis include a 24-hour urine collection for volume and osmolality, serum electrolyte levels, and a water deprivation test.

If urine osmolality is < 300 mOsm/kg after a 24-hour collection, diabetic insipidus (central or nephrogenic) is likely. If osmolality is greater than 300mOsm/kg, solute diuresis is likely and the causes of solute diuresis such as diabetes mellitus should be investigated and excluded.

Serum sodium levels are elevated in patients with diabetes insipidus who are severely dehydrated. Patients who have been rehydrated may present with mild hypernatremia.

The diagnosis can be confirmed by a water deprivation test. Water deprivation tests assess the maximum concentrating ability of the kidneys and their response to ADH. The test involves depriving a patient of water for 3 to 6 hours, within which period the urine is collected for measurement of volume every hour and osmolality every 2 hours. In nephrogenic diabetes insipidus, the maximal urine osmolality is usually low (<300 mOsm/kg).

Distinguishing nephrogenic diabetes insipidus from central diabetes insipidus involves the administration of exogenous ADH, such as desmopressin 10 mcg intranasally or aqueous vasopressin 5 units subcutaneously. After two hours of administering exogenous ADH, urine osmolality is measured. In central diabetes insipidus, urine osmolality increases by 50-100%, while minimal increase in urine osmolality is recorded in nephrogenic diabetes insipidus.

Treatment

Treatment consists of adequate intake of free water, treatment of the underlying etiology and dietary salt and protein restriction. Diuretics and NSAIDs are supportive treatment options.

In infants, young children, and the elderly, who may not respond well to thirst, adequate free water intake should be ensured. Additionally, adequate nutrition should be ensured in these patients because of the risk of malnutrition.

A reduction in urine volume can be achieved by reducing dietary solute intake. Therefore, a low-salt and low-protein diet is recommended for patients with nephrogenic diabetes insipidus [11] [12]. However, a low protein diet is not recommended in infants and young children. The reduced caloric and dietary solute intake may cause weight reduction and short stature in children in the first few years of treatment [13].

Thiazide diuretics are also indicated in treatment. Thiazide diuretics used in combination with dietary solute restriction reduces polyuria in nephrogenic diabetes insipidus [11] [14] [15] [16]. Additionally, amiloride, a potassium-sparing diuretic is indicated in the treatment of nephrogenic diabetes insipidus. Amiloride is employed for its synergistic effects with thiazide diuretics (both prevent potassium depletion caused by thiazides) and for its beneficial effects in patients with reversible lithium-induced NDI [17] [18] [19] [20]. However, with amiloride, the dose of lithium being administered should be reduced since there is a little chance of reduction of extracellular fluid volume.

Amiloride acts by closing the luminal sodium channels in the collecting tubules [21]. These sodium channels usually allow for the entry of lithium into cells, causing a defective response of the cells to ADH [17]. These channels are up to two times more permeable to lithium than sodium [22]. Lithium in the cells primarily targets and inhibits glycogen synthase kinase 3, so this inhibition mediates the toxic effects of lithium use [23].

Loop diuretics are contraindicated in nephrogenic diabetes insipidus because of their counterproductive effects. Loop diuretics inhibit sodium reabsorption in the thick ascending limb of the loop of Henle, thereby reducing the sodium chloride gradient in the medullary interstitium responsible for water reabsorption.

Prostaglandins counter the effects of ADH and NSAIDs inhibit prostaglandin synthesis, hence the indication of NSAIDs in the treatment of nephrogenic diabetes insipidus [24] [25]. Treatment of patients with NSAIDs before the administration of ADH achieves a net reduction in urine output of 25-50% [15] [16] [26]. Patients with polyuria resulting from congenital polyuric-polydipsic Bartter-like syndromes benefit most from NSAID therapy because these conditions have prostaglandin as a key pathogenic entity. The NSAIDs vary in their effects on urine output reduction; indomethacin is more efficient than ibuprofen in reducing urine output [15].

Prognosis

The clinical outcome of nephrogenic diabetes insipidus is generally good, however, it depends on the underlying etiology. In some cases of prolonged lithium use, certain irreversible features may occur.

A common complication of NDI is dilatation of the urinary tract (dilatation of the ureter and hydronephrosis) [5] [6] [7]. Rarely, the disease may ultimately result in renal failure and end-stage renal disease [8] [9] [10].

Mortality occurs most commonly among children and the elderly and may be a result of severe dehydration, fever, cardiovascular collapse, and hypernatremia. Mortality is rare in adults because of the ease of rehydration.

Etiology

Nephrogenic diabetes insipidus may be acquired or genetic. The most common hereditary form is an X-linked disease characterized by a mutation of the arginine vasopressin (AVP) receptor 2 gene. Other genetic forms involve the autosomal recessive or dominant inheritance of genetic mutations of the aquaporin-2 genes. Excluding the autosomal dominant disease, all homozygous forms of these genetic disorders present with complete unresponsiveness to ADH, while the heterozygous forms show no clinical manifestations.

Acquired causes of the disease include diseases and drugs which impair the concentrating ability of the kidneys. These disorders include the autosomal dominant polycystic kidney disease, sickle cell nephropathy, pyelonephritis, hypercalcemia, amyloidosis, myeloma, sarcoma, medullary sponge kidney, chronic hypokalemic nephropathy, and drugs such as lithium, demeclocycline, ofloxacin, amphotericin B, dopamine, dexamethasone, and orlistat. NDI may also be idiopathic.

Certain clinical syndromes mimic neurogenic diabetes insipidus and include gestational diabetes insipidus (in which the placenta secretes vasopressinase which degrades ADH) and post-pituitary surgery, whereby a functionally ineffective ADH precursor is secreted instead of ADH.

Childhood-onset disease is mostly due to genetic defects, the most common of which include the X-linked hereditary NDI resulting from defects in the AVPR2 gene, and the autosomal dominant and recessive disorders due to mutations in the aquaporin-2 genes. Adult-onset disease is almost always acquired and most commonly results from hypercalcemia and lithium toxicity.

Epidemiology

The prevalence of diabetes insipidus in the United States is about 3 in 100,000 population [3]. Both central and nephrogenic diabetes insipidus show no sexual or ethnic predilections. The inherited forms constitute 1-2% of all cases of diabetes insipidus (central and nephrogenic). Furthermore, there is an estimated incidence rate of 1 in 20 million births for genetic nephrogenic diabetes insipidus caused by a mutation in the aquaporin-2 genes [4].

Sex distribution
Age distribution

Pathophysiology

The hallmark of nephrogenic diabetes insipidus is an impaired response of the kidneys to ADH; however, ADH secretion remains normal. The problem is usually due to a defective response to ADH of the collecting tubules or a defect in the renal countercurrent mechanism.

In elderly individuals and critically ill patients, there may be a mild reduction in renal concentrating ability. However, the symptoms are milder compared to the manifestations of NDI.

Prevention

The acquired forms of nephrogenic diabetes insipidus can be prevented by eliminating the risk factors for the underlying disease or prescribing alternative medications or lower doses of the offending drugs.

Lithium, for example, causes NDI in a dose-dependent pattern, therefore, the lowest therapeutic dose of lithium is prescribed to prevent it. Additionally, patients on lithium should undergo baseline and routine renal function, thyroid function, electrolyte, and liver function tests.

Summary

Diabetes insipidus (DI) is defined as the excessive passage of dilute (<300mOsm/kg) urine in large volumes (>3 L/24 h).

Diabetes insipidus can be classified into central and nephrogenic diabetes insipidus. Central or neurogenic diabetes insipidus is characterized by an impaired secretion of antidiuretic hormone (ADH), also called arginine vasopressin. This results in an impaired urine-concentrating ability of the kidney. Nephrogenic diabetes insipidus (NDI) is characterized by an impaired response or resistance to ADH by the kidney cells [1] in the presence of normal ADH secretion.

Nephrogenic DI can result from genetic disorders or may occur following certain acquired diseases. Hereditary forms of NDI are rare and include mutations in the genes coding for aquaporin receptor-2 and arginine vasopressin receptors [2]. The hereditary forms of the disease usually have an early onset, presenting as early as the first few days of neonatal life.

Common secondary causes of NDI include polycystic kidney disease, sickle cell nephropathy, amyloidosis, and chronic hypokalemic nephropathy. Medications such as lithium and orlistat are also implicated in NDI.

The clinical features include polyuria, polydipsia, and nocturia. The severe dehydration which may result from the excessive fluid loss may cause confusion, coma, and renal impairment. Death usually results from cardiovascular compromise.

Diagnosis requires the exclusion of differential diagnoses such as primary polydipsia and glycosuria, and diabetes mellitus. Tests necessary for the diagnosis include serum electrolytes, 24-hour urine collection for volume and osmolality, and a water deprivation test. The water deprivation test is the confirmatory test for nephrogenic diabetes insipidus.

Treatment involves the correction or treatment of the underlying disease, reduction of urine output, and rehydration. Rehydration may be via the intravenous route in severe dehydration or by adequate oral intake of free water. Reduction of urine output can be attained by maintaining a low-salt, low-protein diet with pharmacologic intervention, including the administration of thiazide diuretics, amiloride, and non-steroidal antiinflammatory drugs (NSAIDs).

Patient Information

Diabetes insipidus is a condition characterized by excessive urination and thirst. It is caused by a problem in the ability of the kidneys to absorb excess water from the urine.

Diabetes insipidus can be classified into two types, based on the organ from which the problem emanates. These are central diabetes insipidus and nephrogenic diabetes insipidus (NDI). Central diabetes insipidus is caused by the brain's inability to produce and secrete a hormone called anti-diuretic hormone (ADH). This hormone is responsible for the absorption of excess water from the urine. Nephrogenic diabetes insipidus implies that the problem is not from the brain, but the kidneys. In this condition, ADH is produced, but the kidneys are unresponsive to it, therefore causing excess urine production and water loss.

Nephrogenic diabetes insipidus can be caused by genetic disorders or other diseases or drugs. The genetic disorders involved cause defects in the genes which code for the ADH receptors and the water channels in the kidneys. Diseases which could cause NDI include pyelonephritis, multiple myeloma, and polycycystic kidney disease. Drugs which could cause the disease include lithium, amphoterin B, dexamethasone, dopamine, and ofloxacin. Lithium is the most common drug which causes the disease.

Generally, once the underlying factor is controlled, NDI can be successfully treated. However, in some cases of chronic lithium use, a permanent damage might have been established. Death results from severe dehydration and heart failure and it usually occurs among children and the elderly because of the difficulty in communicating dehydration.

The cardinal features include excessive urination (polyuria), excessive thirst (polydipsia), and frequent urination at night (nocturia). There is a critical chemical in the blood called sodium: excess sodium in the blood occurs in dehydrated patients and when it is severe, it may cause confusion and coma.

Additionally, children with NDI may present with failure to thrive, mental impairment, constipation, and malnutrition.

Because there are a number of conditions which could present similarly to diabetes insipidus, several investigations are necessary to confirm the diagnosis. These include measurement of urine volume and its solute content after a 24-hour urine collection, measurement of blood levels of certain chemicals called electrolytes including potassium and sodium, and assessing the volume and solute content of urine after the patient has been deprived of water for about 6 hours; the latter is referred to as the water-deprivation test.

Treatment involves the correction or treatment of the underlying disease, adequate intake of free water, and restriction of salt and protein in diet.

Certain drugs are administered to reduce urine volume, thirst, and to improve the kidney's ability to concentrate the urine. Rehydration is very important in the management of a patient with NDI to prevent the complications of dehydration.

Self-assessment

References

  1. Earley LE, Orloff J. The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin-resistant diabetes insipidus. J Clin Invest. Nov 1962; 41(11):1988-97.
  2. Babey M, Kopp P, Robertson GL. Familial forms of diabetes insipidus: clinical and molecular characteristics. Nat Rev Endocrinol. 2011 Jul 5. 7(12):701-14.
  3. Saborio P, Tipton GA, Chan JC. Diabetes insipidus. Pediatr Rev. 2000 Apr. 21(4):122-9; quiz 129.
  4. Verkman AS. Aquaporins in clinical medicine. Annu Rev Med. 2012. 63:303-16.
  5. Ulinski T, Grapin C, Forin V, et al. Severe bladder dysfunction in a family with ADH receptor gene mutation responsible for X-linked nephrogenic diabetes insipidus. Nephrol Dial Transplant 2004; 19:2928.
  6. Shalev H, Romanovsky I, Knoers NV, et al. Bladder function impairment in aquaporin-2 defective nephrogenic diabetes insipidus. Nephrol Dial Transplant 2004; 19:608.
  7. Uribarri J, Kaskas M. Hereditary nephrogenic diabetes insipidus and bilateral nonobstructive hydronephrosis. Nephron 1993; 65:346.
  8. Streitz JM Jr, Streitz JM. Polyuric urinary tract dilatation with renal damage. J Urol 1988; 139:784.
  9. Zender HO, Ruedin P, Moser F, et al. Traumatic rupture of the urinary tract in a patient presenting nephrogenic diabetes insipidus associated with hydronephrosis and chronic renal failure: case report and review of the literature. Clin Nephrol 1992; 38:196.
  10. Higuchi A, Kawamura T, Nakai H, Hasegawa Y. Infrequent voiding in nephrogenic diabetes insipidus as a cause of renal failure. Pediatr Int 2002; 44:540.
  11. Rose, BD, Post, TW, Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York, 2001, pp. 754-759,782-783.
  12. Sasaki S. Nephrogenic diabetes insipidus: update of genetic and clinical aspects. Nephrol Dial Transplant 2004; 19:1351.
  13. van Lieburg AF, Knoers NV, Monnens LA. Clinical presentation and follow-up of 30 patients with congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 1999; 10:1958.
  14. Earley LE, Orloff J. The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin-resistant diabetes insipidus. J Clin Invest 1962; 41:1988.
  15. Libber S, Harrison H, Spector D. Treatment of nephrogenic diabetes insipidus with prostaglandin synthesis inhibitors. J Pediatr 1986; 108:305.
  16. Monnens L, Jonkman A, Thomas C. Response to indomethacin and hydrochlorothiazide in nephrogenic diabetes insipidus. Clin Sci (Lond) 1984; 66:709.
  17. Batlle DC, von Riotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med 1985; 312:408.
  18. Knoers N, Monnens LA. Amiloride-hydrochlorothiazide versus indomethacin-hydrochlorothiazide in the treatment of nephrogenic diabetes insipidus. J Pediatr 1990; 117:499.
  19. Bedford JJ, Weggery S, Ellis G, et al. Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. Clin J Am Soc Nephrol 2008; 3:1324.
  20. Christensen BM, Zuber AM, Loffing J, et al. alphaENaC-mediated lithium absorption promotes nephrogenic diabetes insipidus. J Am Soc Nephrol 2011; 22:253.
  21. Kortenoeven ML, Li Y, Shaw S, et al. Amiloride blocks lithium entry through the sodium channel thereby attenuating the resultant nephrogenic diabetes insipidus. Kidney Int 2009; 76:44.
  22. Grünfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol 2009; 5:270.
  23. O'Brien WT, Harper AD, Jové F, et al. Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 2004; 24:6791.
  24. Berl T, Raz A, Wald H, et al. Prostaglandin synthesis inhibition and the action of vasopressin: studies in man and rat. Am J Physiol 1977; 232:F529.
  25. Stokes JB. Integrated actions of renal medullary prostaglandins in the control of water excretion. Am J Physiol 1981; 240:F471.
  26. Allen HM, Jackson RL, Winchester MD, et al. Indomethacin in the treatment of lithium-induced nephrogenic diabetes insipidus. Arch Intern Med 1989; 149:1123.

  • A micropuncture study of the early phase of acute urate nephropathy. - JD Conger, SA Falk, SJ Guggenheim - Journal of Clinical , 1976 - ncbi.nlm.nih.gov
  • Of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium - GH Kim, JW Lee, YK Oh, HR Chang - Journal of the , 2004 - Am Soc Nephrol
  • Absent factor VIII response to synthetic vasopressin analogue (DDAVP) in nephrogenic diabetes insipidus - NL Kobrinsky, ED Israels, MS Cheang, JJ Doyle - The Lancet, 1985 - Elsevier
  • Causes of reversible nephrogenic diabetes insipidus: a systematic review - CG Garofeanu, M Weir, MP Rosas-Arellano - American journal of , 2005 - Elsevier
  • Of an Aquaporin-2 mutant with wild-type Aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus - N Marr, DG Bichet, M Lonergan - Human molecular , 2002 - Oxford Univ Press
  • Clinical manifestations and management of acute lithium intoxication - MD Okusa, LJT Crystal - The American journal of medicine, 1994 - Elsevier
  • Diabetes insipidus - PH Baylis, T Cheetham - Archives of disease in childhood, 1998 - adc.bmj.com
  • Causes of reversible nephrogenic diabetes insipidus: a systematic review - CG Garofeanu, M Weir, MP Rosas-Arellano - American journal of , 2005 - Elsevier
  • Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy - P Vylet'al, H Hůlková, M Živná, L Berna - Journal of inherited , 2008 - Springer
  • A mutation in the vasopressin V2-receptor gene in a kindred with X-linked nephrogenic diabetes insipidus - JJ Merendino Jr, AM Spiegel - England Journal of , 1993 - Mass Medical Soc
  • Neonatal mortality in an aquaporin-2 knock-in mouse model of recessive nephrogenic diabetes insipidus - B Yang, A Gillespie, EJ Carlson, CJ Epstein - Journal of Biological , 2001 - ASBMB
  • A molecular defect in the vasopressin V2-receptor gene causing nephrogenic diabetes insipidus - EJ Holtzman, HW Harris Jr - England Journal of , 1993 - Mass Medical Soc
  • Autosomal recessive inheritance of vasopressin‐resistant diabetes insipidus - JM Langley, JW Balfe, T Selander - American journal of , 1991 - Wiley Online Library
  • Of an Aquaporin-2 mutant with wild-type Aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus - N Marr, DG Bichet, M Lonergan - Human molecular , 2002 - Oxford Univ Press
  • Amelioration of polyuria in nephrogenic diabetes insipidus due to aquaporin‐2 deficiency - Z Hochberg, L Even, A Danon - Clinical endocrinology, 1998 - Wiley Online Library
  • Author index Volume 53, 1978 - PJ AGGETT, HT DELVES - Archives of Disease in , 1978 - europepmc.org
  • An aetiological profile of short stature in the Indian subcontinent - AH Zargar, BA Laway, SR Masoodi - paediatrics and child , 1998 - Wiley Online Library
  • -related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus - A Karras, M Lafaurie, A Furco - Clinical infectious , 2003 - cid.oxfordjournals.org
Self-assessment