Disease classification
Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) can be classified according to the mode of inheritance. Autosomal recessive polycystic kidney disease, which develops in infancy, is rare; autosomal dominant polycystic kidney disease, which is often detected in young and middle age, can also develop at any age.
ADPKD is the most common monogenic hereditary kidney disease, with an incidence rate of 1/1000~1/4000, and the age of onset is mostly 30~50 years old, so it is also called “adult-type polycystic kidney disease” in the past, but in fact, the disease can occur at any age, even in fetus, so the term “adult-type “In addition to the kidney, ADPKD can also be associated with liver cysts, pancreatic cysts, intracranial aneurysms, heart valve abnormalities, etc. Therefore, it is also a systemic disease. The two main mutated genes that have been identified to cause polycystic kidney disease are PKD1HE PKD2. 50% of patients over 60 years of age will develop end-stage renal failure, accounting for 5-10% of the causes of end-stage renal failure.
ARPKD is a recessive hereditary nephropathy, which usually manifests itself in infancy, so it used to be called “infantile polycystic kidney disease”, with a small percentage occurring in children or adolescents. The incidence is about 1/10,000 to 1/4,000, and is often associated with liver involvement, manifesting as liver cysts. Among children with ARPKD, 50% die of respiratory failure or renal failure within hours to days after birth, while those who survive to adulthood are characterized by fusiform dilatation of the renal collecting ducts and progression to renal failure with intrahepatic bile duct dilatation, congenital hepatic fibrosis, and clinical manifestations of portal hypertension. Since ARPKD is a rare disease, mostly occurring in children, this article only describes ADPKD.
Causes
The disease is inherited in an autosomal dominant manner, and according to its inheritance pattern, the disease occurs from generation to generation, with equal incidence in both sexes. If one parent has the disease, there is a 50% chance that the child will develop the disease. However, about 40% of patients have no family transmission, which may be due to the mutation of the patient’s own genes.
PKD1 is located on the short wall of chromosome 16 (16p13.3), with a gene length of 52kb, 46 exons and 14kb mRNA. PKD2 is located on the long arm of chromosome 4 (4q22-23), with a gene length of 68kb, 15 exons and 2.9kb mRNA. A third gene (PKD3) may exist but has not been localized and cloned on the chromosome. the protein expression products of PKD1 and PKD2 become polycystin 1 and polycystin 2, respectively. 81 and 41 mutations have been reported so far in PKD1 and PKD2 genes, including missense mutations, nonsense mutations, shearing errors, deletions, insertions and duplications. The mutations in PKD1 and PKD2 genes have been reported in 81 and 41 forms respectively, including missense mutations, nonsense mutations, shearing errors, deletions, insertions and duplications.
Pathogenesis
The second strike theory
In 1996, Qian et al. proposed the “two-hit” theory of somatic allele mutations. This theory suggests that the tubular epithelial cells in polycystic kidney disease inherit the PKD mutation gene (reproductive mutation) from the father, and the genotype is heterozygous, which does not cause polycystic kidney disease at this time. Only when the normal haploid is lost, the individual develops polycystic kidney disease. According to the “second strike” theory, the time and location of the second mutation determines the time and location of the renal cysts. It is believed that PKD1 gene is more prone to mutation than PKD2, therefore, PKD1 gene mutation causes high incidence and early onset of polycystic kidney disease. In addition, it is also possible to have mutations in both PKD1 and PKD2 genes, a phenomenon called “cross heterozygosity”, in which mutations in PKD1 gene in germ cells are accompanied by mutations in PKD2 gene in somatic cells or mutations in both PKD1 and PKD2 genes in a single individual. Patients with this cross-hybrid mutation are more severely affected than those with a single gene mutation.
Helical region-helix interaction hypothesis
Polycystin 1 is distributed on the surface of the cell membrane and has a region in the extracellular region that is homologous to the oocyte glue receptor of sea urchin sperm. through a common pathway to the nucleus, regulating cell proliferation, differentiation and migration, and ensuring the production and maintenance of normal renal tubule morphology. Therefore, mutations in either of the two polycystins lead to abnormalities in signal production and transmission pathways, causing pathologically identical polycystic kidney disease in humans and mice, which is the doctrine of helix-helical zone interactions.
The role of cilia in the pathogenesis of polycystic kidney disease
Cilia are elongated tubular structures found on the surface of most cells and are divided into primary cilia and motor cilia according to their structure and function, which have the function of movement and sensing external signals. Studies have shown that polycystic kidney disease is a group of cilia-related diseases. Renal cilia extend from tubular epithelial cells into the tubular lumen and come into direct contact with urine, and their function is mainly as mechanical sensing of urine flow stimulation. Polycystin 1 and polycystin 2 are co-expressed in renal cilia and form a polycystin complex that translates mechanical stimuli into chemical signals, increases intracellular calcium ion flow, and regulates cell cycle and division. Abnormal renal cilium structure and architecture or PC1 and PC2 structure and dysfunction can lead to the development of renal cystic disease.
In summary, genetic mutation genes are heterozygous, and under the “second strike” of environmental factors such as toxins and infections, somatic cell mutations occur, causing abnormal structure and function of cilia or polycystins, cell cycle regulation and intracellular metabolism disorders, epithelial proliferation, formation of micro-polyps and obstruction of renal tubular lumen; abnormal basement membrane components, cell polarity The basement membrane composition is abnormal, cell polarity is changed, and the luminal membrane surface of tubular cells secrete more fluid; at the same time, the formation of neovascularization increases, providing nutrition for the proliferating cells. These phenotypic abnormalities cause the epithelial cells lining the cyst to proliferate and the cyst to increase progressively, producing a biological behavior similar to that of a benign tumor and eventually leading to disease progression and loss of renal function.
Clinical manifestations
ADPKD is a disease that involves multiple systems throughout the body, and its clinical manifestations include renal manifestations and extra-renal manifestations.
Renal manifestations
(1), renal cysts: Many symptoms of ADPKD patients are closely related to the development of renal cysts. There are multiple fluid cysts in the kidney cortex and medulla, ranging from several millimeters to several centimeters in diameter, and the size and number of cysts gradually increase with the progression of the disease. The degree of enlargement of renal cysts is higher in male patients than in female patients.
(2), pain: back or ribbed abdominal pain is the most common symptom in patients with ADPKD. The symptoms become more pronounced with age and cyst enlargement, and are more common in women. Acute pain or sudden increase in pain often indicates cyst rupture and bleeding, urinary tract obstruction and co-infection caused by stones or blood clots. Chronic pain is mostly caused by the enlarged kidney or cyst pulling on the renal peritoneum and the kidney tip and compressing the adjacent organs. Giant liver cysts can also cause pain under the right rib cage.
(3), bleeding: more than 90% of patients have intracapsular hemorrhage or meatus hematuria. It is mostly spontaneous, but can also occur after strenuous exercise or trauma. Causes of hematuria include rupture of cystic vessels, stones, infection or cancer. Generally, hematuria is self-limiting and can disappear on its own in 2-7 days. If the bleeding lasts for more than 1 week or the patient is older than 50 years old, the possibility of cancer needs to be excluded.
(4), Hypertension: It is one of the most common early manifestations of ADPKD patients. Among young ADPKD patients with normal renal function, 50% have blood pressure higher than 140/90 mmHg, while almost 100% of patients with end-stage renal disease suffer from hypertension. The blood pressure is positively related to the size of the kidney and the number of cysts, and it keeps increasing with age.
(5), renal function impairment: early renal function impairment is often manifested as a decrease in renal concentration function. Most patients can maintain normal renal function in 40~60 years of cyst growth; once renal function starts to decline, its glomerular filtration rate decreases at a rate of about 4.4~5.5 ml/min per year, and the development time from impaired renal function to end-stage renal disease is about 10 years.
(6) Other: 20% of ADPKD patients are often combined with kidney stones, mostly uric acid and/or calcium oxalate stones. Urinary tract and cystic infections are common complications, with retrograde infection being the main route. Compared to the general population, patients with ADPKD have an earlier age of onset of renal cell carcinoma, are symptomatic, and are prone to bilateral sarcomatoid multicentric metastases.
Extra-renal manifestations
In addition to the kidney, ADPKD can also involve the gastrointestinal tract, cardiovascular, central nervous and reproductive systems. Extra-renal lesions can be classified as cystic or non-cystic.
Cystic lesions refer to cysts involving the liver, pancreas, spleen, ovaries, arachnoid and pineal gland, among which liver cysts have the highest incidence. Liver cysts gradually increase with age and rarely affect liver function, but excessive cyst size can cause pain.
Non-cystic lesions include heart valve abnormalities, colonic diverticula, and intracranial aneurysms. Among them, intracranial aneurysms are the most dangerous and are the main cause of early death in patients, seen in 8% of ADPKD patients, with an incidence of up to 22% in patients with positive family history. Most patients are asymptomatic, and a few patients develop vasospastic headache. As the aneurysm increases in size, the risk of aneurysm rupture increases.
Diagnosis
The diagnosis is established mainly on the basis of family history, clinical manifestations and ancillary tests. 60% of ADPKD patients have a clear family history and clinical manifestations as described above, and imaging and genetic diagnosis are required to confirm the diagnosis.
Family history
ADPKD has autosomal dominant genetic characteristics, i.e. the disease occurs from generation to generation with equal incidence in men and women, and the patients are heterozygous with 100% epistasis, but only 60% of patients have a clear family history.
Clinical diagnostic criteria
Primary criteria: ① diffusely scattered fluid-filled cysts in the dermis of the kidney; ② clear family history of polycystic kidney.
Secondary criteria: ① polycystic liver; ② renal failure; ③ abdominal wall hernia; ④ heart valve lesion; ⑤ pancreatic cyst; ⑥ cerebral aneurysm; ⑦ seminiferous gland cyst; ⑧ ptosis.
If two major criteria and one minor criterion are present, the clinical diagnosis of ADPKD can be confirmed. if only the first major criterion is present and there is no family history of ADPKD, three or more minor criteria are required to confirm the diagnosis of ADPKD.
Imaging examinations
1. Ultrasonography: It is the preferred diagnostic method for ADPKD. Its main ultrasound manifestations are obvious increase in kidney volume, multiple cysts of different sizes in the kidney with echogenic enhancement of renal parenchyma. Color Doppler ultrasound manifestation: there is flowery blood flow between the cyst walls of the kidney with disorganized distribution. Renal blood flow is reduced and the resistance index is elevated. Enough high-sensitivity ultrasound can detect tiny cysts of 0.2 cm in diameter, so ultrasound is also often used as a method of prenatal diagnosis and screening for ADPKD in the immediate family. Regular use of ultrasound to detect renal volume size, vascular blood flow and resistance index in patients with ADPKD is useful for clinical monitoring of disease progression, determining the timing of treatment, evaluating efficacy, and predicting disease regression.
In 1994, Ravine et al. proposed the following ultrasound diagnostic criteria: two cysts in unilateral or bilateral kidneys in patients under 30 years of age with family history, at least two cysts in bilateral kidneys in patients 30-59 years of age, and at least four cysts in each bilateral kidney in patients over 60 years of age; if there are other extra-renal manifestations, such as liver cysts, the diagnostic criteria can be relaxed. This diagnostic criterion has 97% sensitivity and 90% specificity, and can be diagnosed if there is no family genetic history, more than 10 cysts in each kidney, and other renal cystic diseases are excluded.
(2) Computed tomography (CT) and magnetic resonance imaging (MRI) examinations: high accuracy, cysts of 0.3~0.5 cm can be detected. MRI examination of kidney volume and calculation of the ratio of cyst to normal kidney tissue cross-sectional area sensitively reflects the disease progression of ADPKD and can be used as an indicator to observe the efficacy of drugs.
(3) Genetic diagnosis Currently, it is mostly used for pre-cyst and prenatal diagnosis, and for those who have no family history of ADPKD and have difficulty in differentiating it from other cystic-type diseases. It mainly includes techniques such as gene chain analysis, microsatellite DNA testing and direct detection of gene mutations.
Differential diagnosis
Hereditary cystic kidney disease
1. ARPKD usually has an early onset, mostly in infancy, combined with congenital liver fibrosis, leading to portal hypertension and biliary dysplasia. When it occurs in adults, it is often clinically difficult to distinguish from ADPKD, and liver ultrasound and liver biopsy are feasible to distinguish, and mutation gene testing can determine the distinction.
2. Medullary cystic kidney disease (MCKD) is an autosomal dominant disorder with a low incidence. Ultrasound and CT examinations are helpful for diagnosis.
3, tuberous sclerosis complex (TSC) autosomal dominant inheritance, in addition to bilateral kidney and liver cysts, skin and central nervous system damage may also appear, such as vascular smooth muscle lipoma, malignant epithelial vascular smooth muscle lipoma, facial angiofibroma and hypopigmented spots. The main clinical manifestations are convulsions and unresponsiveness, which can be differentiated from ADPKD.
4. von Hippel-Lindau disease (VHL) is an autosomal dominant disease with multiple cysts in both kidneys, often associated with solid tumors of the kidney (such as renal cell carcinoma, pheochromocytoma, etc.), optic nerve and central neuroma, and can be differentiated from ADPKD. VHL disease without solid tumors is similar to ADPKD and needs to be differentiated by testing for mutated genes.
5. type I orofacial-finger syndrome (orofaciodigital syndrome type 1) This is a common X-linked dominant disease. Patients with type I orofacial-finger syndrome have oral abnormalities: widened tongue band, cleft tongue, cleft palate, cleft lip, disordered tooth alignment, facial abnormalities such as widened nasal root, sinus, zygomatic dysplasia and finger abnormalities.
Non-genetic cystic kidney disease
1. Polycystic kidney dysplasia is the most common cystic kidney disease in infants. Infants with bilateral lesions do not survive, and those who do survive tend to have unilateral lesions. It is usually easier to differentiate from ADPKD. One kidney with dysplasia is not full of cysts and has no urinary function, while the contralateral kidney has no cysts and often has compensatory hypertrophy or hydronephrosis due to ureteral obstruction.
2.Multi-room cyst Multi-room cyst is a rare disease with unilateral involvement, in which there are isolated, separated into multi-room cysts in normal renal tissue, with the possibility of malignant transformation. It is characterized by a cyst that is divided into multiple ultrasound-permeable atrial compartments.
3.Medullary spongy kidney The medullary collecting ducts are dilated to form cysts, and the typical manifestation of excretory urography is brush streaks and small cysts in front of the renal calyces, which can be distinguished from ADPKD.
4, simple renal cyst The incidence of simple renal cyst increases with age, there is no family history of this disease, the kidney family volume is normal, the typical renal cyst is single chamber, located in the cortex, there is usually no small cyst distribution around the cyst, there is no extra-renal manifestations such as liver cysts. It is usually asymptomatic, benign passing and usually does not require treatment.
5. Acquired renal cysts are seen in long-term hemodialysis patients with renal failure, 90% of those on dialysis for more than 10 years are complicated by renal cysts, without family history and generally without clinical symptoms. Acquired cysts must be alerted to the complication of malignant tumor.
Disease Treatment
Although the research on the pathogenesis of ADPKD has made great progress this year, there is no effective treatment method so far. The principles of treatment for ADPKD are to reduce the birth rate of individuals with the disease, early diagnosis, patient education, regular checkups, active control of complications, and timely renal replacement therapy for patients with end-stage renal disease.
General treatment
Pay attention to rest, avoid smoking, tea, coffee and ethanol-containing beverages, chocolate, low-salt diet in case of hypertension, and low-protein diet is recommended in the late stage of the disease. Most patients do not need to change their lifestyle or restrict physical activity in the early stage. When the cyst is large, strenuous physical activity and abdominal trauma should be avoided. Patients should be followed up regularly.
Management of complications
1. Pain Pain in some patients is transient and can be observed first. If the pain is persistent or severe, analgesics can be given, but generally analgesics are less effective. If the pain is severe and cannot be relieved by painkillers and affects the patient’s life, surgery can be carefully considered.
2. Hemorrhage There are 3 kinds of cases: First, intracapsular hemorrhage, the patient has sudden pain, but no physical hematuria. Second, the cyst bleeding and the urinary tract want to connect, bleeding to a certain extent is broken into the urinary tract, discharged out of the body, appearing in the carnal hematuria; third, subcapsular bleeding, large amount, no hematuria, blood pressure can drop. In addition to active treatment for the causes of hematuria such as enlarged cysts, hypertension, urinary system and urinary tract stones, bed rest is very important. Commonly used hemostatic drugs have little effect and may even form blood clots, leading to urinary tract obstruction or inducing infection. Very few patients with large amounts of bleeding need blood transfusion therapy. Patients already on hemodialysis who have recurrent episodes of hematuria should be treated with small molecule or heparin-free dialysis. For those with large bleeding and ineffective medical treatment, angiography can be carefully considered for selective renal artery embolization or nephrectomy.
3. Hypertension is one of the common complications of ADPKD and one of the factors promoting the deterioration of renal function. The target value is 130/80 mmHg. The early stage of hypertension should be salt limitation (2-4g/d), maintaining proper weight and moderate exercise. Pharmacological treatment is preferred to ACEI, ARB and calcium channel blockers. For hypertension that cannot be controlled by medication, cyst decompression surgery, renal artery embolization or nephrectomy can be considered.
4. Infection: Urinary tract and cyst infection is a common complication. Water-soluble antibiotics are secreted through glomerular filtration and proximal tubule, and fat-soluble antibiotics are diffused through the cyst wall to the cyst. Therefore a combination of water- and fat-soluble antibiotics is used. Early culture of the causative organism and selection of sensitive antibiotics can achieve better efficacy. The course of treatment is 1-2 weeks, with longer courses needed for renal cyst infections.
Management of extra-renal symptoms
1. polycystic liver Based on the principle of reducing the volume of liver cyst, ultrasound-guided cyst puncture and aspiration with injection of sclerosing agent can be used, and surgical treatment, such as laparoscopic cyst depanalization and decompression as well as hepatic lobectomy, can be used. Cyst infection is treated with cyst fluid puncture and drainage combined with antibiotics (cotrimoxazole and quinolone) for 2-3 weeks.
2. Intracranial aneurysm MRI or angiography should be performed for patients aged 18-35 years with a family history of aneurysm. If there is no positive finding, the review will be done after 5 years. If there is a positive finding, the size of the aneurysm should be determined by angiography. Aneurysms less than 6 mm in diameter with low risk of rupture can be treated conservatively with an annual follow-up. Aneurysms larger than 6mm require surgical treatment. In principle, to prevent rebleeding and cerebral ischemia, codeine can be applied for pain relief, aspirin is prohibited, and surgery is performed as early as possible, preferably within 72 hours of bleeding. 25% of patients will have cerebral ischemia 5-14 days after aneurysm rupture, and vasoactive drugs or calcium antagonists can be used as appropriate.
Surgical treatment
Surgical treatment can be used to remove enlarged cysts if conservative treatment fails. The option chosen for different patients should depend on the severity of the symptoms, the extent of the lesion and the number and location of the cysts, the level of renal function and the complications. It has been reported that surgery can stimulate the growth of cysts and promote the progression of renal insufficiency, so the indications should be strictly controlled and limited to severe pain and intractable hypertension where drug therapy is ineffective, infection that is difficult to control or for placement of the transplanted kidney before kidney transplantation. Methods such as ultrasound-guided cyst puncture and aspiration, cyst decompression, laparoscopic decompression of the apex, and highly selective intravascular renal embolization.
Renal replacement therapy
Renal replacement therapy is required when ADPKD progresses to end-stage renal disease. Hemodialysis is preferred, but peritoneal dialysis is also an option, but enlarged kidneys are effective peritoneal dialysis area decreases and can affect the effectiveness of peritoneal dialysis. Kidney transplantation is another treatment option for ADPKD end-stage renal disease, and the kidney survival rate after transplantation as well as the complication rate is similar to other kidney transplant populations. Nephrectomy is feasible in patients with cystic infection, recurrent cystic bleeding, severe hypertension and giant kidney protruding into the pelvis prior to renal transplantation. one of the major complications after renal transplantation in ADPKD patients is infection, with urinary tract infection being the most common. Therefore, infection should be carefully monitored and treated early after transplantation.
Disease prognosis
Factors affecting the prognosis of patients with ADPKD include genotype, gender, age, time of onset, hypertension, hematuria, proteinuria, urinary tract infections, kidney and cyst size, pregnancy, and hormones. About 50% of patients enter end-stage renal disease at the age of 57-73 years. Risk factors for entering end-stage renal disease are PKD1 gene mutation, male, onset of disease before 30 years of age, 1st episode of hematuria before 30 years of age, and hypertension before 35 years of age. The most common cause of death in patients with end-stage ADPKD is cardiovascular complications, followed by infections.
Disease prevention
Early diagnosis and eugenics.
Disease care
Diet for ADPKD patients: ① Drink more water (4000ml), it is recommended that ADPKD patients drink about 4000ml and keep the urine volume at 2000-2500ml. ② Lemon juice is especially recommended to be added to the warm water drunk. Avoid drinking drinks with excessive caffeine because caffeine aggravates cell proliferation and cyst fluid secretion; ③ less salt, low salt diet can keep more urine volume, reduce renal cyst proliferation and cyst fluid secretion and reduce the occurrence of infection and stones, as well as strongly control hypertension and reduce the damage of hypertension. ④Fruit: early and middle section of potassium-containing fruits (such as oranges and bananas), but if there is obvious hyperkalemia, the intake of high-potassium fruits must be restricted. ⑤ Protein: the content in the diet should be controlled at 0.7~1g/kg.d. CKD stage 3 should be low protein diet, i.e. daily protein intake of 0.6kg/d. ⑥ Other: avoid strong tea and coffee and spicy food.
In addition, long walks on flat roads, swimming, jogging, Tai Chi and yoga are recommended; avoid strenuous exercise and competitive confrontational body-slamming sports; maintain a normal state of mind and avoid conflict, overexcitement and pessimism.