Adpkd Q61.2

As early as 460 BCE, Hippocrates described what was probably a polycystic kidney disease. The first comprehensive description of a cyst was made by Cruveilhier in the years 1829 - 1835. Marquardt was the first to differentiate between two different modes of inheritance in 1934. In 1971, Blyth and Ockenden comprehensively described the clinical variability of the autosomal dominant form in childhood.

In 1988, Romeo et al. and Kimberling et al. obtained evidence for the genetic heterogeneity of ADPKD. The first mapping of the PKD1 gene (chromosome 16p13.3, also known as polycytic breakpoint gene with the gene product polycystin 1) was achieved by Reeders et al. in 1985 and in 1993 Kimberling et al. and Peters et al. mapped the PKD2 gene locus (chromosome 4q21-q3; gene product polycystin 2) (Ganten 2013).

Autosomal dominant polycystic nephropathy (ADPKD) is a disease in which cysts progressively form in both nephrons and collecting tubules (Risler 2008). Although the cysts affect only about 5% of the renal tubules, the cysts, which are several centimeters in size, cause the surrounding tissues to perish and ultimately lead to a loss of renal function (Kasper 2015). Additionally, other organ systems are involved in the disease such as vasculature, heart, liver, cerebral vessels (Risler 2008). ADPKD ultimately leads to terminal renal failure (Hegele 2015).

Because of the different gene loci, a distinction is made between ADPKD 1 (with the gene product polycystin 1), which occurs in 85 % of cases, and ADPKD 2 (with the gene product TRPP2-polycystin2), which is found in only 15 % of cases. Another novel disease gene affects ALG 9 (Herold 2021). With regard to inheritance, almost 100 % penetrance is typical, so that in children of affected individuals 50 % also develop the disease (Hegele 2015). In ADPKD, cysts are predominantly found bilaterally (Herold 2021).

ADPKD is one of the most common autosomal dominant diseases and affects all ethnic groups (Kasper 2015). The gene frequency is 1: 400 to 1: 2,000 (Herold 2021). The prevalence in dialysis patients is about 10 %. In up to 30 % of cases, however, the family history is negative (Herold 2021).

It is a genetic disorder with autosomal dominant inheritance (Herold 2021).

Numerous transport pathways at the subcellular level probably play a role in the pathogenesis. Of particular note is the disruption of ciliary proteins (Kuhlmann 2015).

In the area of signal transduction and in the formation of the primary cilium of the tubule epithelial cell, the glycoproteins polycystin 1 and polycystin 2 play an important role.

If a mutation occurs in this process, cell polarity is disturbed, as is the proliferation of the tubular epithelium, and ultimately cysts form.

Although any section of the nephron can be affected (Hegele 2015), cysts only form in a few nephrons. These cysts probably ultimately cause renal failure by compressing the surrounding tissue (Risler 2008).

In most cases, the disease manifests itself after the age of 20 (Herold 2021). Only 10 % of those affected already show symptoms in childhood (Kuhlmann 2015).

In ADPKD, there is typically a progressive formation of cysts, usually occurring before the age of 30 (Kasper 2015) and progressing to terminal renal failure in the 5th decade of life in ADPKD 1, and in the 7th decade of life in ADPKD 2 (Herold 2021).

The following symptoms may be present:

• Hematuria: Rupture of a cyst may result in hematuria. This often occurs in the context of a urinary tract infection or after major exertion (Risler 2008).
• Pain in the flank area: Pain is found in about 60% of patients. It results from hemorrhage into the cyst or infection of the cyst (Kasper 2015). There is typically no hematuria in this case (Risler 2008).
• Colic in nephrolithiasis: Calcium oxalate or uric acid stones occur in approximately 20% of affected individuals (Risler 2008).
• Kidney infection: Kidney infections occur in up to 50% of patients at least 1 time in their lifetime. These include acute pyelonephritis and infections of the cysts (Kasper 2015).

The symptomatology varies greatly. Many patients are often asymptomatic until the age of 30 - 40 years and the disease is diagnosed by chance by a palpable tumor or hypertension (Kasper 2015).

If there is a genetic predisposition, the family history should include 3 generations (Hegele 2015).

ADPKD 1

The following age-dependent criteria apply to confirm the diagnosis in case of a positive history:

- 15 - 29 years: Detection of 2 renal cysts uni- or bilaterally achieves a sensitivity of 96% and a specificity of 100% in patients at increased risk.

- 30 - 59 years: At least 2 cysts are detectable in each kidney (both sensitivity and specificity are 100 %).

- > 60 years: At least 4 cysts are found in each kidney (sensitivity and specificity also 100 %).

ADPKD 2

In patients with ADPKD 2, in which the symptomatology manifests later, the sensitivity is lower. (Kasper 2015)

- Physical examination

- Palpable tumor

Kidneys can enlarge up to 4 times and weigh up to 20 times more than normal (Kasper 2015).

Sonography: Sonography is the diagnostic method of first choice in ADPKD. The individual cysts can have a diameter of 5 cm or more. Echogenic material is sometimes found inside the cyst. Since it is not possible to differentiate sonographically between pus, hematoma or detritus, further diagnostics should follow in such cases (Hofmann 2005).

In addition, examination of possibly existing extrarenal manifestations (see also:

• Liver
• Pancreas
• Spleen
• Echocardiogram of the heart (Kasper 2015 / Hofmann 2005)CT or MRT

CT or MRI are generally not required for diagnostic confirmation of ADPKD (Risler 2008).

In the case of sonographically unclear findings, such as echogenic material within the cyst, a CT or MRI is always recommended for further differentiation (Hofmann 2005).

Another indication is the determination of the total kidney volume (TKV), which can be used to measure the growth rate of the cysts.

There are 2 classifications to TKV(Herold 2021):

1. PROPKD score: This is a prognostic model to calculate the probability of End Stage Renal Disease (ESRD).

• Male: 1 point
• hypertension before the age of 35: 2 points
• first urological event before the age of 35: 2 points
• PKD2- mutation: 0 points
• non-shortening PKD1- mutation: 2 points
• truncation of the PKD1- mutation: 4 points

Evaluation (Cornec- Le Gall 2016)

• 0 - 3 points: low risk (onset of ESRD 81.4% after age 60; mean age: 70.6 years).
• 4 - 6 points: medium risk (average age for ESRD: 56.9 years).
• 7 - 9 points: high risk (onset of ESRD in 90.9 % before the age of 60; average age: 49 years)

2. mayo clinic classification : the mayo classification predicts the loss of glomerular filtration fraction per year

using kidney volume adjusted for height (HtTKV) in relation to age, differentiating between class A - E (Serra 2017):

• A man: - 0.23 woman: 0.03
• B - 1,33 - 1,13
• C. - 2,63 - 2,43
• D - 3,48 - 3,29
• E. - 4,78 - 4,58

Cranial CT: Cranial CT should be used for risk assessment in familial cerebral hemorrhage and clinical symptoms such as severe headache, intracranial pressure symptoms (Risler 2008).

Genetic diagnostics: If there is a clinical suspicion of ADPKD, genetic testing is recommended for early and severe courses (Kemper 2020).

• Urine sediment: This is pathological in up to 90 % (Herold 2021).
• Hematuria in the case of rupture of a cyst (see also "Clinical symptoms")
• Moderate proteinuria (< 1 g / d/Risler 2008)
• Decreased urine osmolality (Striebel 2008) due to decreased urine concentrating ability (Risler 2008)
• Glomerular filtration rate (GFR): This may be reduced in arterial hypertension (Kasper 2015).

• multiple simple renal cysts
• autosomal recessive polycystic nephropathy
• familial juvenile nephronophthisis
• Acquired cystic nephropathy
• medullary sponge kidney
• tuberculous sclerosis
• von Hippel- Landau- syndrome
• Uromodulin-associated nephropathy (Ferri 2021)

• frequent urinary tract infections (Risler 2008)
• acute pyelonephritis 50 % (Kasper 2015)
• arterial hypertension up to 90 % (Hegele 2015)
• nephrolithiasis 20 % (Risler 2008)
• Renal cell car cinoma: although renal cell carcinoma is not more common than in the general population, it is often bilateral, multicentric and sarcomatoid (Kasper 2015).

Extrarenal manifestations (Herold 2021 / Hofmann 2005):

• Liver cysts 40 % - 90 %
• Pancreatic cysts 5 % - 10 %
• Spleen 5 %
• Brain base aneurysms 40 %
• Heart valve changes 50 % (most common is mitral valve prolapse with about 30 % [Kasper 2015]).

The treatment of ADPKD is exclusively symptomatic.

Arterial hypertension: Blood pressure levels should be well controlled, otherwise renal function will deteriorate further. The target value is an RR of ≤ 120 / 80 mmHg and in patients with an eGFR < 30 ml / min ≤ 140 / 90 mmHg.

Medication options include ACE inhibitors such as captopril, enalapril, ramipril or angiotensin receptor blockers (ARBs) = sartans such as candesartan, losartan, valsartan (Herold 2021).

• Urinary tract infection: Any urinary tract infection should be treated promptly with appropriate medication (Herold 2021).
• Renal insufficiency: Similarly, symptomatic treatment of renal insufficiency (see d.) is indicated (Herold 2021).
• Tolvaptan: Tolvaptan (trade name Jinarc) is a vasopressin V2 receptor antagonist that was approved in 2015 for the treatment of stage 1-3 ADPKD with chronic renal failure (s. d.). Tolvaptan slows the progression of both cysts and renal failure, as shown in a placebo-controlled phase 3 study in 1445 patients. Side effects may include: liver enzymes (0.9%). The discontinuation rate is relatively high due to side effects and was 23% in the study. Dosage recommendation: 95 mg tolvaptan / d (Herold 2021 / Kasper 2015 / Schwabe 2016).
• Infection of the cyst: In about 8.5 % (Kuhlmann 2015), infection of a cyst occurs during the course of the disease. This should be treated with fat-soluble antibiotics that can penetrate the cyst wall, since the vast majority of cysts are not connected to the glomerular filtration. Suitable agents include trimethoprim- sulfamethoxazole, quinolones, chloramphenicol , etc. The duration of treatment should be between 4 - 6 weeks (Kasper 2015). A treatment alternative to drug therapy is percutaneous puncture with subsequent drainage. After healing of the inflammation, sclerotherapy should be performed (Hegele 2015).

Pain: Patients with large cysts often complain of pain in the flank or abdomen. Non-opioids and also opioids are suitable analgesics. Often transcutaneous electrical nerve stimulation, acupuncture etc. have also been found to be helpful (Kasper 2015).

Pain in the context of renal colic: Suitable for this purpose are (Seitz 2018):

• Metamizol: 1 g - 2 g i. v. is the drug of 1st choice, as it has an additional spasmolytic and antinociceptive effect on the ureter
• Paracetamol: 1 g i. v.
• Diclofenac: 75 mg / kg bw i. v.
• Morphine: 0.1 mg / kg bw i. v.

ASA is contraindicated in planned extracorporeal shock wave lithotripsy (ESWL) because of the risk of renal hematoma (Herold 2020). In a randomized trial, the combination of paracetamol and diclofenac was shown to be superior to the administration of morphine for pain relief (Seitz 2018).

Screening of patients at risk for cerebral aneurysm: Genetic counselling: Genetic counselling should be offered if the patient wishes to have a child (Herold 2021).

In patients with very large and/or frequently infected cysts, unilateral or bilateral nephrectomy or renal transplantation is indicated in individual cases (Kasper 2015).

In ADPKD 1, terminal renal failure is predominantly present from the 5th decade of life, in contrast to ADPKD 2, in which it often does not occur until the 7th decade of life (Herold 2021).

More than 50% of patients with ADPKD become dialysis dependent or require kidney transplantation as the disease progresses with age (Kasper 2015). This is 2% in 40 year olds, 23% in 50 year olds and 48% in 73 year olds (Hegele 2015).

The main cause of death in ADPKD is cardiovascular infections (Kasper 2015), followed by renal failure and aneurysm bleeding (Herold 2021).

In patients without a classic family history, close relatives should be examined for ADPKD if necessary, although an inconspicuous sonographic finding in childhood does not exclude ADPKD (Kemper 2020).

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