- Nephrogenic diabetes insipidus
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. This is in contrast to central/neurogenic diabetes insipidus, which is caused by insufficient levels of antidiuretic hormone (ADH)/Argenine Vasopressin (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.
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.
Although they shared a name, diabetes mellitus and diabetes insipidus are two entirely separate conditions with a separate pathogenesis. Both cause polyuria (hence the similarity in name) but whereas diabetes insipidus is a problem with the production of antidiuretic hormone (Cranial diabetes insipidus) or renal 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.
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, polycystic kidney disease, electrolyte imbalance, or some other kidney defect.
The major causes of acquired NDI that produce clinical symptoms (e.g. polyuria) in the adult are lithium toxicity and hypercalcemia.
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.
Hypercalcemia causes natriuresis (increased sodium loss in the urine) and water diuresis, in part by its effect through the calcium sensing receptor (CaR).
Other causes of acquired NDI include: hypokalemia, post-obstructive polyuria, sickle cell disease/trait, amyloidosis, Sjogren syndrome, renal cystic disease, Barter syndrome and various drugs (Amphotericin B, Orlistat, Ifosfomide, 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 drugs is lithium, although there are numerous other medications that cause this effect with lesser frequency.
This form of DI can also be hereditary:
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. 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 
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. On investigation, there will be an increased plasma osmolarity and decreased urine osmolarity. As pituitary function is normal, ADH levels are likely to be a normal or raised. polyuria will continue as long as the patient is able to drink. if the patient is unable to drink, but still is unable to concentrate the urine - hypernatremia will ensue with its neurologic symptoms.
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; if no response occurs to DDAVP administration, then the cause is likely to be nephrogenic.
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. Consider a low-salt and low-protein diet.
In nephrogenic Diabetes Inspidus caused by Lithium (seen in Bipolar patients for example), K-sparing diuretics such as Amiloride would be used. The goal in this case is to excrete Lithium. Using Hydrochlorothiazide in this case would increase aldosterone, which would lead to increased Sodium retention (and Lithium as well).
- ^ a b c d e Wildin, Robert (2006). What is NDI?. The Diabetes Inspidus Foundation. http://www.diabetesinsipidus.org/4_types_nephrogenic_di.htm
- ^ http://kidney.niddk.nih.gov/kudiseases/pubs/insipidus/index.htm
- ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=507266.
- ^ 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. doi:10.1007/BF02486556. PMID 185584.
- ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=425543.
- ^ Online 'Mendelian Inheritance in Man' (OMIM) DIABETES INSIPIDUS, NEPHROGENIC, X-LINKED -304800
- ^ Online 'Mendelian Inheritance in Man' (OMIM) DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL -125800
- ^ Kavanagh, Sean (20 Jun 2007). "Nephrogenic Diabetes Insipidus". Patient UK. http://www.patient.co.uk/showdoc/40001780/. Retrieved 22 Jun 2009.
- ^ 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. http://adc.bmj.com/cgi/pmidlookup?view=long&pmid=10332005.
Urinary system · Pathology · Urologic disease / Uropathy (N00–N39, 580–599) AbdominalGlomerulopathy/
nephroticBy conditionType III RPG/Pauci-immuneTubulopathy/
PelvicUrethra Any/all Sex linkage: X-linked disorders X-linked recessive Immune Hematologic Endocrine Metabolicmineral: Menkes disease/Occipital horn syndrome Nervous system
X-Linked mental retardation: Coffin–Lowry syndrome · MASA syndrome · X-linked alpha thalassemia mental retardation syndrome · Siderius X-linked mental retardation syndromeCharcot–Marie–Tooth disease (CMTX2-3) · Pelizaeus–Merzbacher disease · SMAX2
Skin and related tissue Neuromuscular Urologic Bone/tooth No primary system X-linked dominant Genetic disorder, membrane: cell surface receptor deficiencies G protein-coupled receptor
(including hormone)Class AClass BClass CCASR (Familial hypocalciuric hypercalcemia)Class FFZD4 (Familial exudative vitreoretinopathy 1)
growth factor)ROR2 (Robinow syndrome) · FGFR1 (Pfeiffer syndrome, KAL2 Kallmann syndrome) · FGFR2 (Apert syndrome, Antley-Bixler syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson-Weiss syndrome) · FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome) · INSR (Donohue syndrome · Rabson–Mendenhall syndrome) · NTRK1 (Congenital insensitivity to pain with anhidrosis) · KIT (KIT Piebaldism, Gastrointestinal stromal tumor)
JAK-STAT TNF receptor Lipid receptor Other/ungroupedEDAR (EDAR Hypohidrotic ectodermal dysplasia) · PTCH1 (Nevoid basal cell carcinoma syndrome) · BMPR1A (BMPR1A Juvenile polyposis syndrome) · IL2RG (X-linked severe combined immunodeficiency)
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