Diabetes insipidus, nephrogenic E25.1

In 1590, the Dutch anatomist Pieter Pauw (1564 - 1617) was the first to describe the clinical picture of diabetes insipidus in an 18-year-old girl who died in the course of the disease (Kivelä 1998).

Nephrogenic diabetes insipidus (NDI) is a disease in which sufficient antidiuretic hormone (ADH = arginine vasopressin [Steinbeck 2013]) is produced - in contrast to central D.i. - but this cannot exert its effect (Striebel 2014).

As a result, the kidneys are not sufficiently able to produce concentrated urine under water deprivation (Herold 2021).

The urine volume comprises > 50 ml / kg bw per day (corresponds to > 3500 ml at 70 kg).

(Kasper 2015)

NDI represents a form of diabetes insipidus, which also includes:

• central diabetes insipidus (ZDI)
• gestational diabetes insipidus
• primary polydipsia (see diabetes insipidus)(Kasper 2015).

According to Siegenthaler (2006), NDI is etiologically divided into:

• hereditary NDI
• acquired NDI

NDI is a rare disease and affects both sexes equally frequently (Lehnert 2010).

Nephrogenic D.I. - in contrast to central D.I. - is the less common form (Herold 2021).

The acquired form of an NDI is far more common than the congenital one. Congenital x- chromosomal D.I. exclusively affects boys (Lehnert 2010).

The most common causes of acquired NDI are hypercalcemia, hypokalemia, and lithium therapy (30 %) (Kuhlmann 2015).

Causes of an NDI can be:

Hereditary forms due to genetic alterations. The congenital form is differentiated into 2 variants:

• x- chromosomal recessive form: the mutated gene for the vasopressin type 2 receptor is found on Xq28.
• autosomal recessive form: a defective water transport channel (aquaporin 2) of the renal collecting tube is present (Herold 2021).

The hereditary form of NDI can also occur in the context of a:

• Barrter syndrome
• cystinosis (Bichet 2020).

Acquired form. Causes of acquired NDI may include:

• Renal diseases with tubular damage such as analgesic nephropathy, familial renal cysts, obstructive nephropathy, advanced renal failure etc. (Risler 2008), interstitial nephritis (Siegenthaler 2006)
• metabolically induced by e.g. hypercalcemia, hypokalemia
• drug-induced by e.g. amphotericin, colchicine, lithium carbonate, methoxyflurane, propoxyphene, tolazamide, vinblastine (Risler 2008) or loop diuretics (Kuhlmann 2015)
• following diseases: amyloidosis, plasmocytoma, sarcoidosis, sickle cell anemia, Sjögren' s syndrome (Risler 2008).

Pathophysiologically, NDI results in a lack of response to ADH in the distal tubule due to destruction or defect of ADH receptors (Herold 2021).

Typical of NDI is the clinical triad of:

• 1. polydipsia
• 2. polyuria (50 % of patients have an excretion of 4 - 8 l / d, 25 % > 12 l / d and in individual cases up to 40 l / d [Siegenthaler 2006])
• 3. hypernatremia

In addition, there may be:

• Daytime sleepiness (due to nocturnal polyuria)
• Enuresis (Kasper 2015)
• nocturia (if this is absent, a D.i. is practically excluded)
• Asthenuria (lack of ability to concentrate urine [Herold 2021]).

In congenital NDI, although the disease begins immediately after birth, it is often not initially recognizable as such due to immature renal function. Polyuria usually does not set in until after the neonatal period following sodium and protein intake (Lentze 2014).

Especially in congenital N.I., early diagnosis is important to prevent severe dehydration states and hypernatremia, as these can otherwise lead to serious damage such as:

• psychomotor development disorders
• cerebral calcifications
• vomiting
• diarrhoea in children < 2 years of age (Herold 2021)
• Febrile episodes
• failure to thrive
• strongly fluctuating body weight (Lentze 2014)

In cases of marked polyuria, the following may develop:

• Dilatation of the urinary tract
• hydronephrosis
• megacystis (Lentze 2014)

In the case of the above symptoms, glucosuria should first be ruled out (Kasper 2015). Subsequently, further diagnostic measures are required (see below).

MRI

The posterior pituitary lobe appears on cerebral MRI in healthy adults and children as a hyperintense signal called a "bright spot". This is reduced in size or absent in patients with nephrogenic diabetes insipidus (Kasper 2015).

• with water loss are found:
  • Hypernatremia (> 150 mmol / l)
  • Hyperchloridemia (> 110 mmol / l)
  • Increase of
    • Serum osmolality (> 310 mosmol / kg)
    • Hematocrit
    • Total protein
    • if necessary urea
    • if necessary creatinine (Kröner 2010)
• Urine osmolality: This is normal at < 100 mosmol / l (in contrast to central diabetes insipidus, in which osmolality is increased [Kasper 2015]).
• Specific gravity < 1005
• even in severe dehydration, urine osmolality never exceeds serum osmolality (typical symptom in nephrogenic D.I.; normal values in healthy individuals 270 - 303 mosmol / l in serum and 500 - 1170 mosmol / l in urine [Striebel 2014])
• With adequate fluid intake, normal values for serum sodium are found (Lentze 2014).

Measurement of copeptin: The measurement of copeptin is best suited for further differentiation. This test method has a higher sensitivity and specificity than the previously performed thirst test with ADH- measurement.

Test procedure: The determination of copeptin should be performed as a stress test with hypertonic NaCl solution in cases of suspected nephrogenic D.I..

Stress test with NaCl: Copeptin is determined first, followed by infusion of a hypertonic 3 % NaCl solution, and copeptin is measured again.

Test results indicative of an NDI:

• Urine osmolarity is low
• Plasma osmolarity increases
• Copeptin i. S. rises

The NaCl test is 95% more reliable than the dehydration test (Herold 2021).

• Dehydration: Copeptin levels are measured after 8 hours of dehydration in the morning fasting.
• In renal diabetes insipidus, the value is > 20 pmol / l. (Kasper 2015)

ADH- test: The ADH- test is used to differentiate between central and nephrogenic D.I.. After ADH administration, the urine osmolality does not increase and the serum osmolality does not decrease in nephrogenic D.I. (Kröner 2010).

• central diabetes insipidus
• primary polydipsia (see diabetes insipidus)
• diabetes mellitus (in this case there is osmotic diuresis)
• diuretic abuse
• hypercalcemic crisis
• dry mouth (indicated by medications such as anticholinergics)
• chronic renal failure
• interstitial nephritis
• vesicoureteral reflux
• obstructive uropathies
• Lithium therapy
• hypokalemia
• hypercalcaemia (Kröner 2010)

The causal therapy of NDI consists of treating the triggering cause. Symptomatically, thiazide diuretics or NSAIDs can be used on a trial basis (Herold 2021). These improve polyuria and polydipsia by 30%-70% (Kasper 2015).

Desmopressin is ineffective in NDI (Kasper 2015).

In acquired NDI, the prognosis depends on the underlying disease.

In children, the prognosis depends very much on whether it was possible in the first years of life to maintain the water balance without dehydration and without severe exsiccosis with extreme hypernatremia. If this should be the case, the prognosis is good under lifelong therapy (Lentze 2014).

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