Polyvisceral Polycystic Disease-a Case Study And Review
Apr 19, 2023
Abstract
Polycystic kidney disease (PKD) occurs in about one in 20,000 births. It is even rarer to have cysts in other organs such as the adrenal glands, liver, and bladder. Reviewing the literature, there is evidence that PKD occurs in combination with polycystic liver disease, but to date, no multiorgan cysts have been reported. An autopsy of a 36-week fetus showed multiple cysts in the kidneys, liver, adrenal glands, and bladder. Further histopathological reports confirmed the diagnosis of polycystic kidney disease. A history of previous in-utero death of another child at 28 weeks of gestation suggested the presence of a familial phenotype. Consecutive prenatal ultrasounds did not reveal abnormalities, emphasizing the important role of fetal autopsy in the context of incomplete obstetric history. The diagnosis of fetal anomalies is helpful in counseling parents about the possible recurrence of a new pregnancy.
Keywords
Polycystic kidney disease; Autopsy; Chromosomal microarray; Cistanche's effects.
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Introduction
Fetal development is a complex process that is organized in time and hierarchy. Disruptions in mutual signaling during embryogenesis are responsible for a variety of developmental defects. Congenital anomalies of the kidney and urinary tract (CAKUT) account for one-third of all congenital malformations and are estimated to occur in 3-6 cases per 1000 live births. Fetal kidney anomalies alone account for 20% of fetal congenital defects. Common renal anomalies include a wide variety of disorders with complex pathophysiology, different clinical outcomes, and management implications. These renal disorders have a significant impact on neonatal and infant morbidity and mortality.
Polycystic kidney disease (PKD) is a clinically and genetically diverse disease that includes various hereditary and non-hereditary types, i.e., unilateral or bilateral; isolated or disseminated cysts; renal or extrarenal involvement. PKD is a sensory ciliopathy with elevated proliferation rates and increased apoptosis. PKD has a complex pathogenesis involving multiple molecular pathways that overlap, complement, or oppose each other. Renal abnormalities can occur either alone or in combination with other abnormalities or syndromes. They commonly occur in infancy and childhood and include autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), polycystic dysplasia, glomeruli cystic kidney, Bardet-Biedl, beckwith_wiedemann, Ivemark, Jeune, juvenile nephropathy, Von Hippel- Lindau disease and tumor cysts, among other diseases. The genetic patterns, prognosis, and presentation of these disorders vary widely, making accurate diagnosis essential for proper management and genetic counseling. Recent advances have mapped many genes associated with PKD, thus increasing the challenge for proper identification.
Case report
A 23-year-old female, living in a rural area, presented to the obstetric hospital with 36 weeks of gestation and fetal loss. She was gestation 2, 1st trimester, miscarriage 1 at 28 weeks of gestation;- non-consanguineous marriage. She underwent four antenatal examinations at a nearby hospital, and three antenatal ultrasound examinations at weeks 12, 18, and 24, which showed normal fetal growth pattern and adequate amniotic fluid volume, but the last examination showed decreased amniotic fluid volume. Otherwise, her prenatal period was uneventful. There was no history of any illness, drug intake, or fever. There was a previous history of intrauterine death at 28 weeks due to small bowel abnormalities. The patient was from a rural area and did not have any birth records. She had neither genetic studies for fetal miscarriage nor genetic counseling for future pregnancies. She presented to an obstetrician in an urban center complaining of fetal loss of fetal movement and an ultrasound (USG) showed intrauterine death of the fetus. Due to her multiple miscarriages, the fetus was sent to our laboratory in 10% neutral buffered formalin for fetal autopsy and a bit of thigh tissue was taken for microarray. The above medical history was provided by the attending obstetrician. A family genealogy analysis was not performed by the physician and therefore was not provided to us. Due to the patient's lack of cooperation, no further investigation could be performed.
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Autopsy findings
A systematic autopsy was performed and all organs were fixed in formalin and then examined histopathologically, with paraffin-embedded tissue blocks cut to 4 microns thickness and stained with conventional hematoxylin and eosin stain (H&E). This was a female fetus weighing 3 kg and 43 cm long; the anthropometric measurements of the fetus were equivalent to 36 weeks of gestational age. The fetus had a short, wide, bulbous nose and a thick upper lip. No other significant external abnormalities were found. Internal examination revealed cysts in several organs. The liver section revealed multiple cysts between 0.75 - 1 cm in diameter filled with clear fluid, consistent with the diagnosis of polycystic liver disease. Microscopic examination revealed multiple cystic interstitial spaces with a single cubic lining in some places (Figure 1a, b).
Fig. 1 a.Gross appearance showing liver with multiple cysts of varying size; b. microscopic low-power view with partially autolyzed normal hepatic parenchyma and adjacent cysts spaces partly lined by cuboidal epithelium (H&E, 100×)
External examination of the kidney showed partial maintenance of the right renal-shaped structure and congestive changes in the left renal-shaped structure. Multiple cysts, 0.6-0.2 cm in diameter, occupying the cortex and medulla, were seen in the right renal section, while small left renal sections revealed 1- 0.3 cm-sized cysts covering the entire renal parenchyma. Microscopic sections confirmed the presence of a large number of glomerular cysts arranged by a single layer of cuboidal epithelium, consistent with bilateral polycystic kidney disease (Figure 2a-d).
Fig. 2 a.Gross appearance showing right kidney with maintained reniform shape and multiple cysts within the renal parenchyma; b. gross appearance showing more affected left kidney with loss of reniform shape and more number of cysts compared to the right side; c, d low-power microscopy showing normal renal parenchyma with clustered glomeruli and several cysts lined by a single layer of cuboidal epithelium (H&E, 100×)
Adrenal examination revealed a normal right adrenal gland; however, the left gland exhibited a large cystic structure covering the left lateral border of the kidney measuring 6 cm × 5 cm × 4.3 cm. Upon further dissection, it was easily separated from the renal surface. The section showed a completely replaced thin-walled cyst filled with clear fluid and foci showing compressed adrenal parenchyma as hypertrophic yellowish structures (Figure 3a, b). Multiple small cysts (0.2-0.3 cm) were distributed on the surface of the bladder and microscopically showed cysts lined with hypertrophied epithelium on the plasma membrane aspect, while the subsurface muscular layer was histologically normal. The heart, brain, and lungs were normal in gross and histomorphology. Based on these findings, a final diagnosis of multi-visceral polycystic disease was made, based on the gross and morphological findings, confirmed by autopsy, in a rare case of severe and early detection of polycystic kidney disease.
Fig. 3 a. Gross findings of left adrenal showing a cut open, thin-walled, uninoculated cyst with fattened yellowish areas of compressed normal adrenal parenchyma (arrow); b. low power microscopy showing a portion of primitive adrenal parenchyma with adjacent cystic structures lined by fattened cuboidal epithelium (H&E, 100×)
Chromosome microarray analysis (CMA) was performed using Affymetrix CytoScan 750K arrays on fetal thigh tissue and fetal portions of the placenta delivered from saline-soaked gauze slices. The data were analyzed using the Chromosome Analysis Suite. The analysis was based on the human reference genome (GRCh37/hg 19). No obvious regions of purity change or replication-neutral long contiguous purity stretches were detected in the samples.
Discussion
Medical termination of pregnancy is usually recommended in cases identified by USG or genetic studies that are not consistent with a vital anomaly. In these cases, an autopsy helps to reach the correct diagnosis of the abnormality and also helps to determine the accuracy of the ultrasound examination. Fetal autopsies add key information and alter the risk of recurrence in 2.3% of cases. For example, a case with an ultrasound report of autosomal recessive polycystic kidney disease was terminated and an autopsy revealed bladder outlet obstruction with posterior urethral valves and secondary cystic changes in both kidneys. Here, the two diseases have completely different inheritance patterns and are sporadic with minimal risk of recurrence compared to the polycystic kidney which has a 25% recurrence rate.
Polycystic kidney disease
Common presentations of PKD include numerous renal cysts and enlarged kidneys in childhood or adolescence. On this basis, it is classified into four different types:1. Porter's syndrome type I- ARPKD; 2. cystic dysplasia of the kidney; 3. ADPKD and 4. hydronephrosis or renal capsule. The differences observed in the clinical and pathological presentation help us to describe the type of disease. Fluid-filled focal cysts develop due to dysregulation of several pathways, namely increased cell proliferation, abnormal epithelial polarity, apoptosis, and fluid secretion, leading to symptoms such as abdominal pain, hematuria, cardiovascular malformations, and renal calculi. Recurrent urinary tract infections with eventual loss of renal function occur later in the life of ADPKD, collecting tubular shuttle dilation, enlarged and fibrotic portal area, bile duct hyperplasia, and portal vein branch hypoplasia leading to portal hypertension in ARPKD with early childhood end-stage renal disease and congenital hepatic fibrosis compared to the echogenic renal enlargement detected in utero or in the neonatal period [13]. Depending on the type of disease, genetic testing will vary. Clinical presentation and spectrum will help us to make a diagnosis. This further implies the importance of accurate classification of the disease for appropriate treatment.
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Genetics of PKD
The PKD1 gene on the short arm of chromosome 16 (4304 amino acids) and the PKD2 gene on the long arm of chromosome 4 (969 amino acids) were associated with ADPKD in 85% and 15% of cases, respectively. In addition to hemizygous variants of PKD1 and PKD2, ARPKD is also associated with double allelic variants of PKHD1 [13]. deletion or impairment of the protein products of PKD1 and PKD2 genes, polycystin-1 (PC-1) and polycystin-2 (PC-2), was found to be associated with renal cysts. PC-1 and PC-2, which are localized in the renal tubules, are responsible for the differentiation, maintenance, and repair of renal tubular cells. It is also involved in intracellular calcium transport and cell cycle regulation.PC-1 is the major integrin determining the multi-organ phenotype and is present in the cilia and plasma membrane of all cyst sites (kidney, liver, pancreas) and also in PKD cases; they were found to be overexpressed. The genetic pattern of ADPKD is nearly 100% epistatic, as a previous history of in-utero maternal death is associated with familial ADPKD, but could not be confirmed due to parental disagreement.
Hypertension is an early manifestation of PKD, manifesting in 50-62% of patients with normal renal function and in 100% of patients with chronic renal failure. Disruption of ductal plate reconstruction during late embryonic development is responsible for this condition. The onset of cysts begins in the embryonic stage of kidney development and progresses to adulthood,b as is evident from our case. The early onset of this disease is attributed to the co-inheritance of a variant or incompletely penetrant allele of the PKD1 gene with mutant 1. PKD causes the kidney to lose its shape, size, and weight, which is the main cause of progressive renal failure. The presence of a large number of cysts on the renal cortex or medulla is highly suggestive of severe cases of PKD, which is consistent with our report.
The left kidney is most affected in polycystic cases compared to the right kidney, which is consistent with our findings.PKD is a systemic ciliopathy that can cause renal and extra-renal cysts, and liver, pancreas, spleen, seminal vesicles, testes or ovaries and arachnoid cysts are present in about 5% of adult patients. However, the presence of additional renal cysts is less common in younger patients and therefore our case is rare. Hepatic cysts are the most common extra-renal manifestation of PKD, sometimes more prominent than extra-renal manifestations. Polycystic liver disease (PLD) is mostly asymptomatic, but cases have been reported with clinical problems due to hepatomegaly.
The incidence of isolated adrenal cysts in autopsy cases was 0.06-0.18%. These are a heterogeneous group of lesions, mostly unilateral, similar to our case, with cysts in the left adrenal region. Their predominance was higher in women than in men (3:1), which is consistent with our situation. In most cases, its etiology is unknown, but in some cases, it is associated with intracapsular hemorrhage or cystic deterioration of primary adrenal and vascular tumors. It is asymptomatic in most cases and will not be detected.
Bergmann et al reported eight families with multiple fetal loss due to PKD1 gene mutations. Some of our findings coincide with his study, but the presence of multiorgan cysts was not found in any of his autopsy reports. Thus, the presence of multiorgan cysts with PKD in our case suggests that there are other genes involved in the embryonic developmental pathway in combination with the PKD1 gene. The presence of aneurysms and heart valve disease was associated with PKD with a prevalence of 8% and 26%, respectively.
The development of CMA has led to a 12-15% increase in the detection rate of genetic diseases compared to conventional methods. In this multi-organ cyst sample, there were no significant regions of pure zygotes or replication-neutral long contiguous pure zygotes, which remain elusive and suggest the involvement of unidentified pathogenic variants or epigenetic influences.
In our case, there were no digital abnormalities, or cardiovascular, CNS, or respiratory abnormalities. Therefore, Meckel's, Di George, VACTERL abnormalities, BNAR, BOR, and CHARGE syndromes were excluded. Considering the signs, symptoms, and presentation, we believe this is a case of early and severe polycystic kidney disease combined with multi-organ cysts, including the adrenal glands, adding to its rarity. The presence of genetics cannot be determined, but its identification is essential to determine the origin and risk of recurrence
Conclusion
This case report will further emphasize the importance of fetal autopsy in the setting of incomplete obstetric history. In most cases, it also provides results regarding the origin and the risk of recurrence in future pregnancies. Appropriate guidance and kin-based genetic counseling should be provided to family members.
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How to improve polycystic kidney disease with Cistanche extract?
Polycystic kidney disease (PKD) is a genetic disorder that causes the growth of cysts in the kidneys, leading to impaired kidney function and possible kidney failure. Currently, there is no cure for PKD, but natural supplements such as Cistanche extract have shown promise in improving the condition.
Cistanche extract is derived from the Cistanche plant, which is known for its medicinal properties in Chinese medicine. It contains a variety of bioactive compounds such as echinacoside and Acteoside, which have been demonstrated to possess multiple pharmacological effects on the body, including antioxidant, anti-inflammatory, and immune-boosting properties.
Studies have shown that Cistanche extract can improve kidney function in patients with PKD. One study showed that rats with PKD that were given Cistanche extract had reduced levels of cyst growth and improved kidney function compared to rats that did not receive the extract. Another study found that administering Cistanche extract to patients with PKD led to a reduction in cyst size and improved renal function.
Cistanche extract can also help reduce oxidative stress, which plays a role in the progression of PKD. The antioxidant properties of Cistanche extract can help protect against damage to the kidneys caused by free radicals and other harmful substances.
In conclusion, Cistanche extract may be a promising natural supplement for individuals with PKD looking to improve their kidney function. However, it is important to consult with a healthcare professional before taking any new supplements, as they may interact with medications or have side effects.
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K. Indumathi1;G. Bhavani1; K. Sudha2; G. Srinivasaraman2; R. Manjunathan1.
1 Department of Pathology, Anderson Labs and Diagnostics, Chennai, Tamil Nadu 600084, India
2 Department of Radiology, Anderson Labs and Diagnostics, Chennai, Tamil Nadu 600084, India
