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EDITORIAL Table of Contents   
Year : 1999  |  Volume : 10  |  Issue : 1  |  Page : 7-20
Autosomal Dominant Polycystic Kidney Disease

Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany

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How to cite this article:
Schwenger V, Zeier M. Autosomal Dominant Polycystic Kidney Disease. Saudi J Kidney Dis Transpl 1999;10:7-20

How to cite this URL:
Schwenger V, Zeier M. Autosomal Dominant Polycystic Kidney Disease. Saudi J Kidney Dis Transpl [serial online] 1999 [cited 2020 Jun 1];10:7-20. Available from: http://www.sjkdt.org/text.asp?1999/10/1/7/37296
Autosomal dominant polycystic kidney disease (ADPKD) accounts for approxi­mately 8 to 10% of individuals with end­stage renal disease (ESRD) in Europe and in USA and is thus, the most common hereditary disorder which leads to end-stage renal failure (ESRF). [1] Extreme expansion from multiple bilateral renal cysts leads to enormous enlargement of the kidneys [Figure - 1] and in some patients to progre­ssive renal failure. Manifestation of ESRF is usually between the 40 and 70 years of life, although earlier ages of onset of terminal renal failure are sometimes observed.

Renal cysts and renal failure are the major manifestations of ADPKD. Extra-renal manifestations of ADPKD indicates that it is a systemic disease with multiple connective tissue abnormalities. [2] This paper describes the renal manifestations of ADPKD, but also the extra renal participation, genetic background, the pathogenesis currently discussed, recent diagnostic tools and therapeutic modalities.

   Genetics Top

At least two different genetic forms of hereditary cystic disease are distinguish­able. [3],[4],[5],[6],[7],[8] In 1985, Reeders identified the causative gene for the most common form of the disease, ADPKD1. It is localized to the short arm (16 p 13.3) of chromosome 16(3) [Figure - 2] and ADPKD1 has been completely sequenced. [9]

In addition, families were identified with no linkage to chromosome 16 and thus a second causative gene was considered localized to chromosome 4 (ADPKD2). [4],[5],[10] In nearly 85 to 90% of cases, ADPKD1 is responsible for polycystic kidney disease. [7] Newer investigations shows that there is at least one additional genetic side unlinked to chromosome 16 or chromosome 4. [6],[7],[8],[9],[10],[11] The identification and sequencing of ADPKD1 made the identification of the gene product polycystin possible [Figure - 3]. Polycystin is a 4304 amino acid containing protein encoded on chromosome 16. [2],[12],[13],[14],[15] It is a multifunctional surface protein, which participates in cell-to-cell or cell-to matrix ineraction. [12] Western blot analysis and immunofluorescence studies showed that polycystin expression is temporary regulated during renal development. [13] In fetal kidneys, polycystin is localized on plasma membranes, in epithelial cells of distal nephron and vascular endothelial cells.[13],[15] while in adult kidneys, it is localized intra-cellularly. [13] Polycystin has also been localized in biliary epithelium, pancreas, mammary gland and in brain astroytes. [15] Temporary regulated expression of polycystin during renal development indicates that polycystin may play a role in nephrogenesis. [13]

The protein product of ADPKD2 gene contains 268 amino acids and exhibits structural similarity to polycystin. [4],[5],[16],[17],[18] C­-terminal end of polycystin binds specifically to C-terminal end of ADPKD 2 protein products. [14],[15] This is possibly due to a common signal transaction way of ADPKD 1 and APKD 2. [12]

   Pathogenesis Top

In principle any pat of the nephron, particularly Bowman's capsule and Henle's loop may undergo cystic transformation. [19] In the past, different theories had been proposed to account for this formation, e.g. renal cysts derive form obstruction of nephrons by intraluminal polypoids which are readily demonstrable by lightly and electron microscopy. [20] It is very unlikely that it is obstruction which accounts for cyst formation, since renal cysts without intra­luminal obstruction were readily demon­strable in a fetal kidney [Figure - 4]. [21]

Animal models of cyst formation show specific characteristics for differentiation of cyst epithelial cells from other "normal cells". For example, cyst epithelial cells from patients with ADPKD are associated with hyperproliferation. [22] Furthermore, abnormal expression of epithelial cell growth factor (EGF) and calpactin is demonstrable. Epithelial cells are more sensitive to growth factors and less sensitive against inhibitory factors. [23][,24] These observations point to an increased proliferation of tubular cells. Although increased proliferation is involved, this does not seem to be the only defect. It has been suggested that fluid secretion into the cysts is necessary for cyst enlargement. [25],[26] The dislocation of the Na-K-ATPase from the basolateral membrane to the apical membrane may play a crucial role in increased secretion.[27],[28] The reversed direction of transepithelial sodium transport results in cyst expansion due to sodium and fluid transport into cells. [24]

   Renal Manifestations Top

Progression of renal failure

It is not entirely apparent why cystic transformation of a minority of nephrons, less that 5%, should cause renal failure. Although there are few repots about early manifestation of renal failure in childhood. [29] only one half of ADPKD patients reach ESRF before the sixth decade. ESRF occurs earlier in males than in females [Figure - 5] [30],[31]

The earliest abnormality of cystic kidney is a functional decrease of concentrating ability. [32] Renal failure cannot be entirely explained on the basis of compression atrophy.[33] Deroofing of cysts fails to prevent deterioration of renal function, causes no improvement of hypertension and thus argues against a primary role of compression atrophy. Other explanations offered to explain renal failure include glomerular overperfusion and progressive loss of renal function as in diabetes or glomerulonephritis. The histomorphological equivalent of glomerular overperfusion is focal glomerulosclerosis (FSGS). In a morphological study, we found no evidence for FSGS but instead found global sclerosis, which is a marker for glomerular ischemia. [33] One further argument against a pathogenetic role of glomerular heper­perfusion is the observation that progression of renal failure is not exaggerated after uni­nephrectomy with the resultant hyperper­fusion of the remaining kidney. [34] Further­more, cystic kidneys from patients with severe renal failure and from patients with less severe renal failure can be distinguished by the presence of pronounced vascular sclerosis and advanced interstitial fibrosis in the former group. [19] Vascular is more pronounced in the kidney than in extra­renal tissue (e.g. liver, pancreas). Accele­rated intrarenal atherosclerosis may reflect the interaction of high blood pressure with an abnormal vascular tissue (polycystin?). As has been amply demonstrated, hypertension plays a major role in the progression of renal failure in patients with ADPKD. [35] Presumable additional factors are involved, e.g. increased activation of intrarenal rennin system. The genesis of increased interstitial fibrosis has not been completely clarified. One possibility is the increases stimulation of interstitial fibroblasts through ODGF.36 Newer data suggest that apoptosis may play a major role in deterioration of renal function. [37],[38]

   Hypertension Top

High blood pressure is the most common clinical manifestation of patient with ADPKD. Two mechanisms have been shown to be responsible for hypertension in ADPKD. Inappropriate sodium excretion on the one hand. [39],[40] and inappropriate rennin secretion on the other.[41],[42] Hypertension in ADPKD patients is sodium sernstive. [19]

Recent studies have shown higher levels or plasma rennin activity in ADPKD. [42] We further demonstrated outside of the juxta­glomerular appatatus. [33] ADPKD patients with arterial hypertension shows a more rapid progression to ESRF that patients with normal blood pressure. [35],[43]

Urinary tract infection

Approximately 50% of ADPKD patients suffer at least one or more infections of the urinary tract seen more commonly in women that in men. Cyst infection is due either to previous urinary tract infection or hematogenous spread. Most infections are caused by gram negative organisms. Treatment of infected cysts is somewhat complicated, because the antibiotic should be able to penetrate the cysts. Agent which are lipophilic are recommended, e.g. ciprofloxacin, trimethoprim, sulfamethoxazole, or clindamycin [44],[45],[46],[47],[48] In severe infections, ultrasound guided puncture and aspiration can be useful. This may be difficult because the ultrasound image does not reveal the whole kidney. MRI is a useful tool to distinguish older form newer hemorrhages and also purulent exudates. For further diagnostic accuracy leucocytes scintigraphy may be helpful [Figure - 6]. Surgical nephroctomy is the treatment of last resort.

Reduction of cyst volume and nephrectomy

Total renal size as well as the size of the cysts increase progressively over time. The affected kidney can reach over 40 cm in length and over 8 kg in weight. [49] In this setting, some patients suffer from disabling symptoms, including chronic abdominal pain and anorexia due to increases intra-abdominal pressure. The symptoms may be relieved by nephrectomy. After surgical decompression there is no significant worsening or renal function. [50] Surgical cyst decompression is sometimes employed in the treatment of chronic pain. [51] Pre­transplant nephrectomy should only be considered in individuals with large cystic kidney or recurrent infections. [49]

   Nephrolithiasis Top

Frequency of occurrence of nephroli­thiasis in ADPKD is approximately 20% with no preponderance of gender. The composition of the calculi (uric acid, calcium-oxalate, calcium phosphate and struvite) suggests that metabolic disorders together with mechanical factors are responsible for the information. Relevant factors are low urinary citrate and less often hyperuricemia and hypercalcuuria. [52]

   Proteinuria Top

Proteinuria in ADPKD is typically mild, less than one gram per day. [22] Other glomerular diseases (e.g. diabetic nephropathy, lupus erythematosus) have to be excluded. If proteinuria is in the nephritic range.

   Renal cell carcinoma Top

In our data, we have no definite evidence for increased prevalence of renal cell carcinoma in DPKD. There are few reports about bilateral renal cell carcinoma, possibly due to cellular hyperproliferation.[49],[53],[54],[55] Presumably, these cases represent misdiagnosed forms of Hipper-Lindau disease. Ultrasound scanning and computer tomography are very sensitive and specific diagnostic procedures to detect renal cell carcinoma.

   Renal replacement therapy Top

Eight to 10 percent of all patients on chronic renal replacement therapy suffer from polycystic kidney disease. Survival of patients with ADPKD is better that for other renal disease, despite having similar cardiovascular risk profile.[56],[57],[58] There is a possible beneficial effect of better hemo­globin levels, because of secondary endogenous erythropoietin production.[58],[59] ADPKD patients have been shown to have significantly higher hemoglobin and EPO levels than yatients with other primary renal diseases.[60],[61]

   Kidney transplantation Top

There is no significant difference in graft and patient survival between patients with ADPKD and other non-diabetic primary renal disease. In principle, kidney transplantation in patients with ADPKD is possible. Prior to renal transplantation infectious foci must be excluded. Some­times unilateral nephrectomy is necessary, because of enormous cysts enlargement.

   Extra-renal Manifestations Top

ADPKD is a systemic disease with multiple extra-renal and renal manifesta­tions, involving both cystic and non-cystic lesions. Extra-renal cysts occure in liver, pancreas, spleen, thyroid gland, ovary and in the central nervous system. Additionally, inguinal hernia, diverticular disease, valvular heart abnormalities, intracranial aneurysms and dissection of arteries have been noticed.[2],[62],[63],[64],[65]

   Hepatic cysts Top

Hepatic cysts are a common extra-renal manifestation in patients with ADPKD, with a prevalence of up to 90%.[66],[67],[68],[70] Hepatic cysts in patients with ADPKD derive from the intra-hepatic biliary epithelium.[68],[71],[72]

Normally biliary epithelium secretes a bicarbonate-rich fluid while in ADPKD, bicarbonate is replaced by chloride,[68],[69] Massive secretion of fluids with abnormal composition may followed by duct expansion and cystogenesis. [69],[72],[73] Additionally polycystin is expressed both in hepatocytes and in biliary epithelium and might be involved in development of intrahepatic bile ducts. [74] There is evidence that polycystin is involved in the development of liver cysts as well.

Hepatic cystic disease is more severe in female than in male, possibly influenced by female sex hormones. [67],[70] Normally liver function is well preserved. [75] Liver enzymes and bilirubin are in the normal range but enormous enlargement of hepatic cysts frequently elevates alkaline phosphatase levels. [76] Elevated portal pressure is observed in some patients. [77],[78] Complications due to enlargement of liver cysts for example cyst infection (frequently) or malignancy (rare) are responsible for a mortality up to 10%. [79] More commonly, hepatic cysts are asymptomatic. Occasionally female patients suffer from disabling abdominal pain secondary to massive partial hepatectomy, surgical fenestration, [76] cystectomy (cyst deroofing), percutaneous drainage [80] or alcohol instillation [81] may be required. [76],[77],[78],[79],[80],[81],[82] The typical symptoms of hepatic cyst infection are fever, leuco­cytosis, abdominal pain in the right upper quadrant, elevation of transaminases, or bilirubin. The first diagnostic choice is ultrasound [Figure - 7], followed by computer tomography or magnetic resonance tomo­graphy. Leucocytes scanning is also helpful in the diagnosis of cyst infection. [75] As a therapeutic possibility lipid soluble anti­biotics are recommended, nevertheless there is only less information about penetration of antibiotics in infected liver cysts. [75]

   Diverticular disease Top

Another common non-cystic extrarenal manifestation in patients with ADPKD are diverticular disease of the colon. Pre­valences from 30 to 80% were noted.[83],[84],[85] Diverticular disease is of clinical import­ance. Complications such as infection or rupture are not uncommon. Prior to trans­plantation or CAPD-treatment, colon exami­nations (x-ray or endoscopy) are required, particularly in patient with previous complications from diverticular disese. [83]

   Cerebrovascular disease Top

One of the most serious and in consequence disabling complications in ADPKD patients is rupture of intracranial aneurysms and subarachnoidal haemorrhage. One of the most serious and in consequence disabling complications in ADPKD patients is rupture of intracranial aneurysms and subarachnoidal haemorrhage. There is strong evidence suggesting a correlation between ADPKD and intracranial aneurysms.[78],[86],[87] The observed prevalence is increased up to 10% of what is seen in the general population.[88],[89],[90] In patients with positive family history of intracranial aneurysm (ICA) prevalence is somewhat higher. Asymptomatic intracranial aneurysms can be identified very early with magnetic resonance imaging. [91] The most important determinant whether ICA may rupture is the size (diameter). If the diameter of aneurysm is greater than 10 mm, there is increases risk for fupture. [92] Most ICA occur in the anterior circulation [Figure - 8]. [93] In case of rupture of aneurysm, mortality can rise up to 50% and morbidity up 50-70%. [2],[90]

Rupture of ICA in patients with ADPKD is a complication of the younger patient, [93] frequently under age 50 year. ICA causes neurological symptoms through different mechanisms: compression due to extreme dilation of aneurysm, immobilization and cerebral ischemia and subarachnoidal bleeding.

Screening of small asymptomatic ICA in patients with ADPKD is a conflicting issue. Patients with ADPKD are on a high risk for a neurological event on the one hand and acute renal failure through contrast medium due to cerebral angiography on the other hand. Magnetic resonance angiography (MR) is therefore a highly sensitive and specific non-invasive screening test, which could detect ICA with a size less than 5 mm. [94],[95]

Different follow-up observation have suggested that there is no significant increase in the size of the aneurysms with time. [88],[91],[95],[96],[97],[98] We recommend MR screening for ADPKD patients with a positive family history of ruptured ICA, and patients with high-risk occupations. Surgical intervention must be considered when the aneurysms are greater that 10 mm in diameter.

   Cardiovascular abnormalities Top

Numerous studies have reported an association between ADPKD and ectasias, aneurysms of thoracic and abdominal aorta, dissection of aorta and aneurysms of coronary arteries. [65],[83],[99],[100] There is also a higher prevalence of valvular abnormalities. Since the initial report of Leier on valvular abnormalities, mitral and aortic actasia, as well as mitral and aortic valve incompe­tence have been reported in association with ADPKD.[65],[101],[102],[103],[104] The most common abnormalities are mitral valve prolapse in up to 22%, [18],[102],[104] in competence of mitral valve in 8-31% [101],[102],[104] and incompetence of aortic valve in 5-36%. [101],[104]

Although polycystin is expressed in normal fetal and childhood myocardium, [72] its relationship to valvular heart disease remains not fully understood. Some observations indicate that mild cardiac expression may be responsible for left ventricular hypertrophy. [105] Left ventricular hypertrophy remains independent of arterial hypertension and valvular abnormalities. Our own observations do not indicate that left ventricular hypertrophy is an independent feature in patients with ADPKD. In patients without valvular lesions, no difference of left ventricular mass index was found between ADPKD and matched controls. [56]

   Diagnostic and therapeutic possibilities Top

In overt disease the diagnosis is easy to establish. Affected patients typically present with renal failure, flank pain, positive family history and sonographically enlarged kidneys with multiple bilateral cysts. In addition cysts may also be seen in other organs. Although ADPKD I is frequently associated with a more excessive enlargement of the kidneys it is not possible to distinguish cystic kidney disease type 1 from type 2 disease by ultrasound. [7] As a rule the diagnosis in ADPKD I is earlier to establish that in type2 disease,27.4 years versus 41.1 years of age in average. [106]

In some cases however, especially in patients with negative family history, patients may present with an unclarified hematuria and advance renal failure. This can either represent a new genetic mutation or, more likely, late development of renal failure in which affected other family members are not any more informative.

Ravine and coworkers suggested that in patients under 30 years of life with positive family history at lest two renal cysts (unilateral or bilateral) are sufficient to establish the diagnosis, from age 30 to 59 two cysts in each kidney are required and in patients over 60 years of life t lest 4 cysts in each kidney are required. [107]

Ultrasonographic diagnosis of ADPKD is more difficult to establish in children of affectedparents. [108] Cystic formation begins in the fetus21 and, rarely can be diagnosed in the first years of life. Nevertheless, in our experience this is very uncommon. It is very difficult to establish the correct diagnosis in children and young adults, because the enlargement of the kidneys frequently begins above the age of 25. In patients with ADPKD1 disease the probability of a positive utrasonography in affected children below the age of 10 years is estimated to be 8%, in approximately 60­65% of affected adults below 20, and in approximately 85% of cases between 20 and 30 years, and virtually 100% in adults above the age of 30 years. [108],[109] Thus a negative utrasounography in patients below 30 years does not exclude the eventual development of ADPKD disease. This is of interest if family members are willing to donate a kidney.

If diagnosis is established, regular monitoring of renal function is necessary. The major interest is to prevent deterioration of renal function. The most important measure in this regard is to control systemic blood pressure to prevent progression of renal failure.

   References Top

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Vedat Schwenger
Department Internal Medicine, University of Heidelberg, Bergheimer Strabe 56a, 69115 Heidelberg
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