ADTKD

Synonyms

Medullary cystic kidney disease; MCKD; medullary cystic kidney disease; medullary cystic disease type 1; medullary cystic disease type 2; MCKD 1; ADMCKD1; MCKD 2; ADMCKD2;

First described by

Thorn et al. were the first to describe a "medullary cystic disease- familial juvenile nephronophthisis- complex" in 1944. Just one year later, Smith and Graham wrote about a chronic kidney disease, which they first labeled "medullary cystic disease (MCD)" (Zalewski 2005).

In recent years, the term "autosomal dominant tubulointerstitial kidney disease (ADTKD)" has been introduced, which seems to make more sense, since not all patients show renal cysts (Sauerbruch 2018).

ADTKD is a hereditary tubulointerstitial nephropathy that typically leads to progressive loss of renal function in adults with unremarkable urine status and sediment (Risler 2008). The often accompanying hyperuricemia may occur earlier in life (Sauerbruch 2018).

ADTKD belongs to the group of cystic nephropathies (Herold 2021) and can hardly be distinguished clinically-pathologically from nephronophthisis (Zalewski 2005).

ADTKD is differentiated into 6 different subtypes:

• 1. ADTKD- UMOD:

In this case, there is an alteration of the uromodulin protein, also known as "Tamm- Horsfall protein". The patients preferentially develop hyperuricemia with accompanying gout attacks. Renal cysts occasionally occur (Herold 2021).

• 2. ADTKD- MUC:

In type 2, the mucin1 protein is altered. Kidney cysts are sometimes found in affected patients (Herold 2021).

• 3. ADTKD- REN:

Type 3 affects the renin protein. The mutation causes childhood anemia, hypotension, hyperkalemia, and it can lead to acute renal failure (Herold 2021).

• 4. ADTKD- HNF1B:

Hepatocyte nuclear factor 1 beta is altered in this. This can result in electrolyte disturbances, urogenic malformations, bilateral renal cysts, and a genetic defect in insulin production, Maturity Onset Diabetes of the Young (MODY 5) (Herold 2021 / Kalyani 2018).

• 5. ADTKD- SEC 61A1:

In type 5, the protein alteration is found in SEC 61A1. Affected individuals often present with a cleft palate, congenital neutropenia, and anemia (Herold 2021).

• 6. ADTKD- NOS;

In this case, the altered gene has not yet been identified (Herold 2021).

The term "medullary cystic kidney disease (MCKD)", used until recently, differentiates between type I and type II (Kasper 2015).

• MCKD I:

In type I, the mutation is found in the mucin I gene. This leads to a change in the repeat region in the gene, which gives rise to a large neoprotein fragment. This has toxic effects on the renal tubule (Kasper 2015).

Clinically, there is minimal proteinuria in these patients. Sonographically, cysts are sometimes detectable. In adulthood, there is a slow, progressive renal failure (Kasper 2015).

• MCKD II:

In type II, the mutation is in the so-called UMOT gene, which encodes the protein uromodulin. This leads clinically to hyperuricemia. The urine sediment is usually benign. The risk of chronic renal failure is only moderately increased (Kasper 2015).

ADTKD is a rare disorder (Sauerbruch 2018), although it represents the largest heterogeneous group of hereditary disorders that do not manifest until adulthood (Knaup 2019).

Risler (2008) describes the incidence as 1: 1,000,000, and only 55 affected families were known worldwide by 2001, according to Hegele (2015).

• ADTKD- UMOD:

Type 1 is the most common, accounting for 70%.

• ADTKD- MUC:

Type 2 is found between 25 % - 30 %.

• ADTKD- REN:

Type 3 is the rarest form at 5 %.

(Wolf 2020)

The disease is inherited in an autosomal dominant manner. In the meantime, several gene loci could be differentiated (Sauerbruch 2018).

ADTKD can manifest in childhood, but usually does not become manifest until adulthood (Sauerbruch 2018) in the 3rd decade of life (Zivna 2020).

The disease usually begins insidiously and is asymptomatic. Blood pressure is normal (Herold 2021).

Recurrent attacks of gout may occur (Risler 2008).

Only patients with a renin mutation exhibit pronounced hypotension, especially in childhood (Sauerbruch 2018).

Family anamnesis is not infrequently found clustered over generations:

• Hyperuricemia
• chronic renal insufficiency of unclear origin

(Risler 2008)

Only molecular genetic analysis ultimately leads to a reliable diagnosis (Knaup 2019).

Sonography

The kidneys appear rather small sonographically and predominantly - but not always - show multiple cortico-medullary cysts (Sauerbruch 2018).

Urine:

Inconspicuous urine sediment (Herold 2021), at most mild proteinuria (Kasper 2015).

In case of manifestation in childhood:

• GFR decreased
• Osmolality ≤ 800 mosmol / kg H2O (Zalewski 2005).
• metabolic acidosis
• hyperkalemia
• renal anemia (especially in patients with renin mutation [Sauerbruch 2018])
• Hyperuricemia

(Zivna 2020)

In adults:

• Hyperuricemia (Zivna 2020)

Histologically, the kidney tissue usually shows fibrotic changes (Kasper 2015).

• Nephronophthisis (already occurring in childhood or adolescence)
• Alport syndrome (microhematuria)
• ADPKD = autosomal dominant polycystic nephropathy large cysts
• Fabry disease (marked proteinuria)

(Zivna 2020)

Only the symptoms of ADTKD can be treated appropriately with medication (see "Internal therapy").

(Zivna 2020)

The patient should be presented to a nephrologist promptly after the diagnosis is confirmed (Zivna 2020).

Hyperuricemia

Hyperuricemia should be treated with a uric acid reducer (Kasper 2015) such as:

• Allopurinol

Dosage recommendation: 200 mg - 300 mg / d (the dose should be reduced from a creatinine- clearance of 80 ml / min).

• Febuxostat

Dosage recommendation: 80 mg - 120 mg / d. In mild to moderate renal impairment, dose adjustment is not required.

(Actories 2017)

Arterial Hypotension

Patients with renin mutation exhibit pronounced hypotension, especially in childhood (Sauerbruch 2018). Fludrocortisone, for example, can be used as a medication in this case.

Dosage recommendation: initial dose 0.5 mg p. o., then 0.1 mg - 0.2 mg p. o. (Paumgartner 2013).

Anemia

Renal anemia, which often occurs in patients with renin mutation, can be treated with erythropoiesis-stimulating agents (ESA) (Sauerbruch 2018).

ESA therapy is recommended from a Hb between 9.0 - 10.0 g / dl. The target value should be 10.0 and 11.5 g / dl or 12.0 g / dl.

The following drugs can be used:

• Epoetin alfa

Dosage recommendation: 20 - 50 I. E. / kg KG i. v., 3 x / week

or

• Darbepoetin

Dosage recommendation: 0.45 µg / kg bw i. v., 1 x / week

(Kuhlmann 2015)

The increasing renal insufficiency may require dialysis or a kidney transplant. No recurrence occurs in the transplant itself (Risler 2008).

Children with ADTKD should be checked every 6 months:

• Hb- concentration
• Potassium
• Uric acid
• Bicarbonate
• Creatinine
• GFR

In adulthood, it is sufficient to perform the above tests every 12 months.

(Zivna 2020)

In ADTKD, renal ins ufficiency usually occurs between the ages of 30-50 (Herold 2021).

Terminal renal failure occurs after:

• 5 years in 14 %
• 10 years in 29 %
• 20 years in 58 % of cases

(Risler 2008)

If transplantation should become necessary, there is no recurrence of the disease (Risler 2008).

Children of affected individuals have a 50% risk of also developing ADTKD. Prenatal testing is now possible (Zivna 2020).

1. Aktories K et al (2017) General and special pharmacology and toxicology. Elsevier Urban and Fischer Publishers 525
2. Hegele A et al. (2015) Urology: intensive course for continuing education. Thieme Verlag 120 - 121
3. Herold G et al (2021) Internal medicine. Herold Publishers 631
4. Kalyani R R et al (2018) Diabetes Head to Toe: Everything You Need to Know about Diagnosis, Treatment, and Living with Diabetes. John Hopkins University Press Baltimore 22 - 23
5. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 1854
6. Kasper D L et al (2015) Harrison's internal medicine. Georg Thieme Publishers 2283 - 2284
7. Knaup K X et al (2019) Autosomal dominant tubulointerstitial kidney disease (ADTKD). The Nephrologist (2) 112 - 119
8. Kuhlmann U et al. (2015) Nephrology: pathophysiology - clinic - renal replacement procedures. Thieme Verlag 416 - 418
9. Manski D (2019) The urology textbook. Dirk Manski Publishers 499
10. Paumgartner G et al (2013) Therapy of internal diseases. Springer Verlag 232
11. Risler T et al (2008) Specialist nephrology. Elsevier Urban and Fischer Publishers 720 - 722
12. Sauerbruch T et al. (2018) Therapy handbook: yearbook 2018. elsevier publishers 66.1.4
13. Wolf G et al (2020) Nephrology: the essentials for physicians of all specialties. Elsevier Urban and Fischer Publishing 62
14. Zalewski Isabella (2005) Phenotype-genotype correlation for autosomal dominant medullary cystic kidney disease on chromosome 1q21. INAUGURAL - DISSERTATION for the award of the medical doctorate degree of the Medical Faculty of the Albert-Ludwigs-University Freiburg im Breisgau.
15. Zivna M et al (2020) Autosomal dominant tubulointerstitial kidney disease- REN. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK53700/