Nephrogenic diabetes insipidus

Not to be confused with Neurogenic diabetes insipidus.

Nephrogenic diabetes insipidus
Classification and external resources
Specialty	urology
ICD-10	N25.1
ICD-9-CM	588.1
OMIM	304800 125800
MedlinePlus	000511
MeSH	D018500
GeneReviews	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)/Arginine 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.

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.

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.

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 a normal 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, Sjogren 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:

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; 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] 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. Basically, thiazides allow increased solute excretion in the urine, breaking the polydipsia-polyuria cycle.

References

↑ Kavanagh, Sean (20 Jun 2007). "Nephrogenic Diabetes Insipidus". Patient UK. Retrieved 22 Jun 2009.
1 2 3 4 5 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.
↑ 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.
↑ Online 'Mendelian Inheritance in Man' (OMIM) DIABETES INSIPIDUS, NEPHROGENIC, X-LINKED -304800
↑ Online 'Mendelian Inheritance in Man' (OMIM) DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL -125800
↑ 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.

Diseases of the urinary system (N00–N39, 580–599)

Kidney disease

Glomerules

Primarily
nephrotic

Non-proliferative	Minimal change Focal segmental Membranous

Proliferative	Mesangial proliferative Endocapillary proliferative Membranoproliferative/mesangiocapillary

By condition	Diabetic Amyloidosis

Primarily
nephritic,
RPG

Type I RPG/Type II hypersensitivity	Goodpasture's syndrome

Type II RPG/Type III hypersensitivity	Post-streptococcal Lupus DPGN IgA/Berger's

Type III RPG/Pauci-immune	Granulomatosis with polyangiitis Microscopic polyangiitis Churg–Strauss syndrome

General

Tubules

Interstitium

Interstitial nephritis
- Pyelonephritis
- Danubian endemic familial nephropathy

General

General syndromes	Nephritis Nephrosis) Renal failure Acute renal failure Chronic kidney disease Uremic pericarditis Uremia Diabetes insipidus Nephrogenic Renal papilla Renal papillary necrosis Major calyx/pelvis Hydronephrosis Pyonephrosis Reflux nephropathy

Vascular	Renal artery stenosis Renal ischemia Hypertensive nephropathy Renovascular hypertension Renal cortical necrosis

Other	Analgesic nephropathy Renal osteodystrophy Nephroptosis Abderhalden–Kaufmann–Lignac syndrome

Urinary tract

Ureter	Ureteritis Ureterocele Megaureter

Bladder	Cystitis Interstitial cystitis Hunner's ulcer Trigonitis Hemorrhagic cystitis Neurogenic bladder dysfunction Bladder sphincter dyssynergia Vesicointestinal fistula Vesicoureteral reflux

Urethra	Urethritis Non-gonococcal urethritis Urethral syndrome Urethral stricture/Meatal stenosis Urethral caruncle

Any/all	Obstructive uropathy Urinary tract infection Retroperitoneal fibrosis Urolithiasis Bladder stone Kidney stone Renal colic Malakoplakia Urinary incontinence Stress Urge Overflow

Sex linkage: X-linked disorders

X-linked recessive

Immune	Chronic granulomatous disease (CYBB) Wiskott–Aldrich syndrome X-linked severe combined immunodeficiency X-linked agammaglobulinemia Hyper-IgM syndrome type 1 IPEX X-linked lymphoproliferative disease Properdin deficiency

Hematologic	Haemophilia A Haemophilia B X-linked sideroblastic anemia

Endocrine	Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy KAL1 Kallmann syndrome X-linked adrenal hypoplasia congenita

Metabolic	Amino acid: Ornithine transcarbamylase deficiency Oculocerebrorenal syndrome Dyslipidemia: Adrenoleukodystrophy Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency Pyruvate dehydrogenase deficiency Danon disease/glycogen storage disease Type IIb Lipid storage disorder: Fabry's disease Mucopolysaccharidosis: Hunter syndrome Purine-pyrimidine metabolism: Lesch–Nyhan syndrome Mineral: 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 syndrome Eye disorders: Color blindness (red and green, but not blue) Ocular albinism (1) Norrie disease Choroideremia Other: Charcot–Marie–Tooth disease (CMTX2-3) Pelizaeus–Merzbacher disease SMAX2

Skin and related tissue	Dyskeratosis congenita Hypohidrotic ectodermal dysplasia (EDA) X-linked ichthyosis X-linked endothelial corneal dystrophy

Neuromuscular	Becker's muscular dystrophy/Duchenne Centronuclear myopathy (MTM1) Conradi–Hünermann syndrome Emery–Dreifuss muscular dystrophy 1

Urologic	Alport syndrome Dent's disease X-linked nephrogenic diabetes insipidus

Bone/tooth	AMELX Amelogenesis imperfecta

No primary system	Barth syndrome McLeod syndrome Smith–Fineman–Myers syndrome Simpson–Golabi–Behmel syndrome Mohr–Tranebjærg syndrome Nasodigitoacoustic syndrome

X-linked dominant

X-linked hypophosphatemia Focal dermal hypoplasia Fragile X syndrome Aicardi syndrome Incontinentia pigmenti Rett syndrome CHILD syndrome Lujan–Fryns syndrome Orofaciodigital syndrome 1 Craniofrontonasal dysplasia

Diseases of ion channels

Calcium channel

Voltage-gated	CACNA1A Familial hemiplegic migraine 1 Episodic ataxia 2 Spinocerebellar ataxia type-6 CACNA1C Timothy syndrome Brugada syndrome 3 Long QT syndrome 8 CACNA1F Ocular albinism 2 CSNB2A CACNA1S Hypokalemic periodic paralysis 1 Thyrotoxic periodic paralysis 1 CACNB2 Brugada syndrome 4

Ligand gated	RYR1 Malignant hyperthermia Central core disease RYR2 CPVT1 ARVD2

Sodium channel

Voltage-gated	SCN1A Familial hemiplegic migraine 3 GEFS+ 2 Febrile seizure 3A SCN1B Brugada syndrome 6 GEFS+ 1 SCN4A Hypokalemic periodic paralysis 2 Hyperkalemic periodic paralysis Paramyotonia congenita Potassium-aggravated myotonia SCN4B Long QT syndrome 10 SCN5A Brugada syndrome 1 Long QT syndrome 3 SCN9A Erythromelalgia Febrile seizure 3B Paroxysmal extreme pain disorder Congenital insensitivity to pain

Constitutively active	SCNN1B/SCNN1G Liddle's syndrome SCNN1A/SCNN1B/SCNN1G Pseudohypoaldosteronism 1AR

Potassium channel

Voltage-gated	KCNA1 Episodic ataxia 1 KCNA5 Familial atrial fibrillation 7 KCNC3 Spinocerebellar ataxia type-13 KCNE1 Jervell and Lange-Nielsen syndrome Long QT syndrome 5 KCNE2 Long QT syndrome 6 KCNE3 Brugada syndrome 5 KCNH2 Short QT syndrome KCNQ1 Jervell and Lange-Nielsen syndrome Romano–Ward syndrome Short QT syndrome Long QT syndrome 1 Familial atrial fibrillation 3 KCNQ2 BFNS1

Inward-rectifier	KCNJ1 Bartter syndrome 2 KCNJ2 Andersen–Tawil syndrome Long QT syndrome 7 Short QT syndrome) KCNJ11 TNDM3 KCNJ18 Thyrotoxic periodic paralysis 2

Chloride channel

TRP channel

TRPC6
- FSGS2
TRPML1
- Mucolipidosis type IV

Connexin

Porin

AQP2
- Nephrogenic diabetes insipidus 2

See also: ion channels

Cell surface receptor deficiencies

G protein-coupled receptor
(including hormone)

Class A	TSHR (Congenital hypothyroidism 1) LHCGR (Luteinizing hormone insensitivity, Leydig cell hypoplasia, Male-limited precocious puberty) FSHR (Follicle-stimulating hormone insensitivity, XX gonadal dysgenesis) GnRHR (Gonadotropin-releasing hormone insensitivity) EDNRB (ABCD syndrome, Waardenburg syndrome 4a, Hirschsprung's disease 2) AVPR2 (Nephrogenic diabetes insipidus 1) PTGER2 (Aspirin-induced asthma)

Class B	PTH1R (Jansen's metaphyseal chondrodysplasia)

Class C	CASR (Familial hypocalciuric hypercalcemia)

Class F	FZD4 (Familial exudative vitreoretinopathy 1)

Enzyme-linked receptor
(including
growth factor)

RTK	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)

STPK	AMHR2 (Persistent Müllerian duct syndrome II) TGF beta receptors: Endoglin/Alk-1/SMAD4 (Hereditary hemorrhagic telangiectasia) TGFBR1/TGFBR2 (Loeys–Dietz syndrome)

GC	GUCY2D (Leber's congenital amaurosis 1)

JAK-STAT

MPL (Congenital amegakaryocytic thrombocytopenia)

TNF receptor

TNFRSF1A (TNF receptor associated periodic syndrome)
TNFRSF13B (Selective immunoglobulin A deficiency 2)
TNFRSF5 (Hyper-IgM syndrome type 3)
TNFRSF13C (CVID4)
TNFRSF13B (CVID2)
TNFRSF6 (Autoimmune lymphoproliferative syndrome 1A)

Lipid receptor

LRP: LRP2 (Donnai–Barrow syndrome)
LRP4 (Cenani–Lenz syndactylism)
LRP5 (Worth syndrome, Familial exudative vitreoretinopathy 4, Osteopetrosis 1)

LDLR (LDLR Familial hypercholesterolemia)

Other/ungrouped

Immunoglobulin superfamily: AGM3, 6

EDAR (EDAR hypohidrotic ectodermal dysplasia)

See also: cell surface receptors

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