The renal lesion of congenital hepatic fibrosis: pathologic and morphometric analysis, with comparison to the renal lesion of infantile polycystic disease

The renal lesion of congenital hepatic fibrosis (CHF = Blyth and Ockenden's juvenile polycystic disease of liver and kidneys) was analyzed from 6 specimens from patients aged 3 3/12 to 19 3/12 years and compared with that of 5 patients with infantile polycystic disease (IPCD) aged 6 months to 14 4/12 years. Pathologic, microdissection, injection, and morphometric studies show that the predominantly medullary cystic lesion of CHF shows different distribution in medullary, cortico-medullary, and cortical zones of kidney from the lesion of IPCD, and shows a different time course, from early life to renal insufficiency, from that of IPCD. The renal cysts in CHF affect deep or central collecting tubules, in contrast to the involvement of more peripheral orders of collecting tubules in IPCD. Papillary pore counts, performed for 1 patient, gave significantly low values, in contrast to normal values reported for IPCD. The findings support the previously published conclusion, based on differences in the hepatic lesions of the two conditions, that CHF and IPCD are difference diseases, rather than different permissible manifestations of a single disease.     

Morphometric Studies of Cystic and Tubulointerstitial Kidney Diseases with Hepatic Fibrosis in Children

Portal tract fibrosis with biliary ductular enlargement or proliferation occurs in a number of genetic diseases that have cystic or tubulointerstitial renal lesions. These include some with renal cystic disease such as autosomal recessive diseases (e.g., infantile polycystic disease, juvenile polycystic disease, and Meckel's syndrome), autosomal dominant diseases (e.g., adult polycystic disease), and, rarely, tuberose sclerosis and dominant glomerulocystic disease. Portal tract fibrosis with biliary enlargement and proliferation occurs also with tubulointerstitial kidney diseases. These probably include at least three disorders in the category nephronophthisis-congenital hepatic fibrosis (one autosomal recessive disease and two either autosomal or X-linked recessive diseases) plus Jeune's syndrome (the tubulointerstitial diseases Fanconi's familial nephronophthisis and anti-tubular membrane antibody disease do not regularly cause hepatic fibrosis). Morphometric data on ratios of bile ductules to connective tissue in hepatic portal tracts show high values for infantile polycystic disease (mean, 0.616) compared to lower values for juvenile polycystic disease (mean, 0.286). That the cystic renal lesions of the first two diseases differ in type and time course is known. Similar data on ratios of glomeruli plus tubules to connective tissue in renal cortices and of tubules to connective tissue in outer medullary zones of kidneys, respectively, are as follows: for Fanconi's nephronophthisis, 0.445 and 0.197; for anti-tubular basement membrane antibody disease, 0.585 and 0.164; and for the three types of nephronophthisis-congenital hepatic fibrosis studied, 0.668 and 0.446, 1.39 and 0.921, and 1.18 and 0.12. These data support clinical impressions that the category nephrophthisis-congenital hepatic fibrosis includes more than one disease entity.     

Polycystic disease and hepatic fibrosis in children. Renal function studies.

Renal function studies were done in five children with infantile polycystic disease (IPCD)of kidneys and liver and in four with congenital hepatic fibrosis (CHF). Glomerular filtration rate was reduced in all IPCD patients and in two of four CHF patients. Urinary concentrating ability following water deprivation and vasopressin administration was impaired in all IPCD patients and in three of four CHF patients. During control period, all patients had asymptomatic metabolic acidosis with total carbon dioxide content less than or equal to 20.5 millimols/liter, and net acid excretion (NAE) was reduced in all but one. Ammonium chloride was administered to seven patients; NAE increased in all, but the increments were subnormal in four. The inability to excrete maximally concentrated urine and an adequate amount of net acid may best be explained by abnormal tubular structure or alterations in medullary architecture secondary to progressive scarring, or both.     

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF)

ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in congenital hepatic fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents.     

小儿囊肿性肾病47例

目的探讨小儿囊肿性肾病的常见病因及其临床特点。方法本院1995年1月～2006年12月共收治47例囊肿性肾病患儿。男31例,女16例;诊断时年龄1h～14岁;回顾分析其病因和临床特点。结果遗传性21例（44.68%）。包括常染色体隐性遗传多囊肾病（ARPKD）16例（34.04%）,肾单位肾痨（NPH）5例（10.64%）;发育异常24例（51.07%）。包括髓质海绵肾（MSK）13例（27.66%）,囊肿性肾发育不良（CRD）10例（21.28%）及孤立多房性肾囊肿（SMC）1例（2.13%）;获得性2例（4.25%）,均为单纯性肾囊肿（SRC）。16例ARPKD囊肿分布于皮质和髓质,肾衰竭12例（75%）,肾脏外损害9例（56.25%）。5例NPH囊肿分布于皮髓质交界处,肾衰竭5例（100%）,缺血性视网膜炎致盲1例（20%）。13例MSK囊肿局限于肾锥体,各有3例（23.08%）表现为继发性肾结石、泌尿系感染（UTI）和远端肾小管酸中毒,另2例（15.38%）表现为继发性肾积水,肾衰竭2例（15.38%）与病程长、结石并反复感染有关。10例CRD均为单肾囊性变,表现为腹部包块7例（70%）,宫内诊断5例（50%）。SRC2例和SMC1例均为局灶性肾囊肿,仅表现为腹部包块,手术切除后痊愈。结论小儿囊肿性肾病以遗传性及发育异常性疾病为主,常见病因有ARPKD、NPH、MSK和CRD;ARPKD和NPH为进行性肾衰竭或肾外病变,预后差;MSK和CRD属肾脏发育异常,尽早诊断和治疗,预后好。     

Impact of liver transplantation on renal function of patients with congenital hepatic fibrosis associated with autosomal recessive polycystic kidney disease

Congenital hepatic fibrosis (CHF) is an uncommon autosomal recessive malformation. It may be associated with extrahepatic manifestations such as polycystic kidney disease. The main consequence is portal hypertension and bleeding from varices. Despite liver transplantation as a therapeutic option for this patient, long-term impact of liver transplantation on renal functions of patients with autosomal recessive polycystic kidney disease with associated liver disease is not well known. In this study, we aimed to analyze the patient's renal function after liver transplantation by creatinine clearance, glomerular filtration rate, and renal resistive indexes. Between March 1997 and September 2002, three of 50 orthotopic liver transplantation (OLT) were performed because of CHF associated with ARPKD at Ege University Organ Transplantation and Research Center. Baseline immunosuppression consisted of prednisone and cyclosporine A (CSA). The mean follow-up of the patients was 2.1 yr. Blood urea and creatinine levels were decreased after operation in all patients and remained within the normal range at the sixth and 12th month, whereas the level of the third patient were increased at the 18th month. RRI values of patients were not found different at the sixth month whereas, RRI values of patients were decreased at the 12th month and remained unchanged at the 18th month of follow-up. During the study period hypertension developed in one patient at the 16th month and resolved with antihypertensive treatment and decreasing dosage of CSA. Kidney function has remained satisfactory in all of the patients despite the use of cyclosporine. OLT can provide good survival in patients with CHF associated with ARPKD.     

Labeled Lectin Studies of Renal Tubular Dysgenesis and Renal Tubular Atrophy of Postnatal Renal Ischemia and end-Stage Kidney Disease

Renal tubular dysgenesis (RTD), with hypoplasia especially of renal proximal convoluted tubules and clinical neonatal anuria or oliguria, has been reported as a congenital familial (autosomal recessive) disease, variably with features of oligohydramnios, Potter syndrome, or pulmonary hypoplasia. A similar tubular lesion due to antenatal tubular atrophy has been reported for conjoined twins with twin-twin transfusion syndrome or acardia and in infants of mothers given antihypertensive agents, including angiotensin-converting enzyme (ACE) inhibitors, during pregnancy, and it has been seen as a unilateral lesion in young infants with renal artery stenosis due to arteritis or medial arterial calcinosis. The renal tubular changes in RTD are very like those of the “endocrine kidney” in experimental animals and resemble those of the renal tubular atrophy of end-stage kidney diseases such as glomerulonephritis, tubulointerstitial kidney disease, obstructive uropathy/pyelonephritis, graft rejection of transplanted kidneys, or the renal parenchymal changes seen with protracted dialysis therapy. Labeled lectins that differentially mark proximal convoluted, distal convoluted and connecting, and collecting tubules showed no distinctive differences in stainingpatterns of the hypoplastic renal tubules of infants and children with RTD, postnatal renal artery obstruction, or the various types of end-stage renal disease with the lectins used (PNA, GSL1, UEA, and LTA). The findings suggest that the renal tubular changes in some if not all the conditions studied are the result of renal ischemia. The reported familial RTD with hypernephronic nephromegaly may be a specific disorder, but other forms could reflect renal ischemia acquired in utero or in early or later postnatal life.     

Clinicopathologic Spectrum of Glomerulocystic Kidneys: Report of Two Cases and a Brief Review of Literature

Two cases of glomerulocystic kidneys (GK) are described and 35 cases are reviewed from the literature. Glomerular cysts formed by dilatation of Bowman's space are the basic and predominant lesion of GK. GK can occur in two different settings: (1) cases in which GK are the only major anomaly or are associated with variable types of anomalies that do not constitute a well-defined syndrome and (2) as part of a well-defined syndrome such as Zellweger's, trisomy 13, short-rib-polydactyly or oral-facial-digital syndrome. The genetic heterogeneity of GK is reflected in the different modes of inheritance of these syndromes. With one exception, no familial incidence is reported for GK unassociated with a syndrome. The morphologic heterogeneity is reflected in those cases in which the cysts show epithelial hyperplasia and/or presence of primitive/dysplastic glomeruli. It is not certain that these histologic variations represent different subtypes of GK. GK is characterized by bilaterality, renal enlargement, absence of urinary tract obstruction, presence of 2-3 mm cortical cysts lined by flattened to cuboidal epithelium and containing a glomerular tuft. GK cannot be distinguished morphologically from adult polycystic kidney disease (APKD) manifesting in the neonatal period. Familial incidence and autosomal dominant pattern of inheritance are the only clues to the correct diagnosis of APKD in such instances.     

Morphometric studies of cystic and tubulointerstitial kidney diseases with hepatic fibrosis in children

Portal tract fibrosis with biliary ductular enlargement or proliferation occurs in a number of genetic diseases that have cystic or tubulointerstitial renal lesions. These include some with renal cystic disease such as autosomal recessive diseases (e.g., infantile polycystic disease, juvenile polycystic disease, and Meckel's syndrome), autosomal dominant diseases (e.g., adult polycystic disease) and, rarely, tuberose sclerosis and dominant glomerulocystic disease. Portal tract fibrosis with biliary enlargement and proliferation occurs also with tubulointerstitial kidney diseases. These probably include at least three disorders in the category nephronophthisis-congenital hepatic fibrosis (one autosomal recessive disease and two either autosomal or X-linked recessive diseases) plus Jeune's syndrome (the tubulointerstitial diseases Fanconi's familial nephronophthisis and anti-tubular membrane antibody disease do not regularly cause hepatic fibrosis). Morphometric data on ratios of bile ductules to connective tissue in hepatic portal tracts show high values for infantile polycystic disease (mean, 0.616) compared to lower values for juvenile polycystic disease (mean, 0.286). That the cystic renal lesions of the first two diseases differ in type and time course is known. Similar data on ratios of glomeruli plus tubules to connective tissue in renal cortices and of tubules to connective tissue in outer medullary zones of kidneys, respectively, are as follows: for Fanconi's nephronophthisis, 0.445 and 0.197; for anti-tubular basement membrane antibody disease, 0.585 and 0.164; and for the three types of nephronophthisis-congenital hepatic fibrosis studied, 0.668 and 0.446, 1.39 and 0.921, and 1.18 and 0.12. These data support clinical impressions that the category nephrophthisis-congenital hepatic fibrosis includes more than one disease entity.     

Immunocytochemical Studies of the Distribution of Alpha and PI Isoforms of Glutathione S-Transferase in Cystic Renal Diseases

We describe immunohistochemical studies of the expression of alpha and pi class glutathione S-transferases (GSTs) in normal fetal kidneys. These define, in greater detail, changes in expression of alpha isoforms in the proximal tubule. At about 36 weeks of gestation expression of alpha isoforms was down-regulated in the distal tubules and collecting ducts while pi was expressed throughout the nephron. Tubular expression of alpha isoforms was restricted to the part adjacent to the glomerulus; cells farthest from the glomerulus were negative. After 40 weeks of gestation, alpha isoforms were expressed along the entire proximal tubule, while pi was restricted to the distal tubule and collecting ducts. GST expression was also studied in multicystic renal dysplasia, autosomal recessive polycystic kidney disease, and autosomal dominant polycystic kidney disease to determine whether the patterns of expression of alpha and pi isoforms allow identification of the origin of the cysts that characterize these diseases. Cysts were lined by epithelia that were strongly positive for alpha and pi isoforms. The epithelia of noncystic nephrons in renal cystic dysplasia demonstrated delayed maturity, suggesting that GST expression was dependent on the stage of development and not length of gestation.     

Radiologic features of “adult type” polycystic kidney disease in the neonate

Two cases are reported of adult type polycystic renal disease (autosomal dominant) presenting in the newborn as a unilateral abdominal mass. The radiographic findings in the involved kidney simulated the ectatic tubules of infantile polycystic disease, yet histologic examination was consistent with the adult variety and both infants had other family members with adult type polycystic kidneys. These cases emphasize some of the ambiguities that exist in the definition and classification of polycystic renal disease.     

小儿多囊肾19例临床分析

目的探讨小儿多囊肾的临床特点及诊断情况。方法回顾性分析1978年1月～2003年11月收治的19例多囊肾患儿的临床特点及诊疗情况。结果19例中男12例,女7例,年龄中位数为6．5岁,均无父母多囊肾证据。起病时的临床表现为尿异常6例、发热6例、腹部包块2例,余为苍白伴鼻衄、纳差、乏力、腹痛、多发畸形及抽搐。明确诊断时11例已存在不同程度的肾功能异常。均经影像学（主要是B超）诊断为多囊肾。6例经长期随访,2例死亡,3例因终末期肾病而接受透析,1例肾功能正常。结论多囊肾患儿多为常染色体隐性遗传多囊肾,临床表现多样,明确诊断时多已有不同程度的肾功能损害。对尿常规异常的患儿应行B超以及早发现多囊肾。     

Predominant extrahepatic biliary disease in autosomal recessive polycystic kidney disease: a new association

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of ectatic renal collecting ducts, intrahepatic biliary dysgenesis, and portal fibrosis. Portal hypertension and recurrent bacterial cholangitis can dominate the clinical picture in long-term survivors. Predominant extrahepatic bile duct disease was revealed in four patients who underwent magnetic resonance cholangiopancreatography. All four patients had portal hypertension, although liver biochemistries did not suggest biliary disease. In two of the patients, cholangitis was clinically ascribed to the bile duct disease. Western blot analysis of plasma membranes from normal rat extrahepatic bile duct and kidney revealed the presence of polyductin as a single approximately 440 kDa protein. Although the exact function of polyductin in the extrahepatic duct is unknown, it may have a role in the development and control of lumenal size. Clinical management of patients with ARPKD should include consideration of potential problems related to extrahepatic bile duct disease.     

Body growth in children with polycystic kidney disease

We analysed the body growth of 121 prepubertal children with polycystic kidney disease participating in a longitudinal multicentre study. The patients were followed from an age of 1 to 9 years in girls and 1 to 10 years in boys over a mean period of 3.6 years. Children with end-stage renal disease were excluded. Fifty-four patients had the autosomal dominant form of the disease and 67 the autosomal recessive form. At last observation, 2% of patients with the dominant form and 28% of those with the recessive form had an estimated glomerular filtration rate of < 60 ml/(min 1.73 m²). At first observation, the mean height SD score (SDS) in patients with the dominant form was almost the same as in controls, whilst in those with the recessive form it was significantly decreased (girls –0.82 SDS, boys -0.68 SDS, p < 0.001). During the follow-up the height SDS decreased slightly in both groups (NS). In patients with autosomal recessive kidney disease the degree of growth retardation appeared to be related to renal function: at last observation the height of girls with an estimated glomerular filtration rate of < 60ml/(min 1.73 m²) was more retarded than that of boys (mean -2.1 SDS versus -1.5 SDS, NS). The height SDS and renal function at last observation correlated in girls ( r = 0.83, p < 0.001) but not in boys ( r = 0.55) with the recessive form. No correlation was found between the height SDS and hypertension. The weight-for-height SDS at onset was significantly reduced in patients with the recessive form with decreased renal function. Our data suggest that the autosomal recessive, but not the dominant, form of polycystic kidney disease is associated with early growth retardation, which seems to be more severe in girls, probably due to the more rapid deterioration of renal function.     

Familial Renal Tubular Dysgenesis: A Disorder Not Isolated to Proximal Convoluted Tubules

The autopsy findings of a newborn with renal tubular dysgenesis, born to first cousins of Moslim Arob descent, are described. Hypocalvaria and hyperflexible joints were noted in addition to the renal lesion. A microdissection study demonstrated marked shortening of all the nephron segments from the glomeruli to the collecting tubules, rather than an isolated abnormality of the proximal convoluted tubules.     

Spectrum of pediatric developmental and genetic renal lesions and associated congenital malformations--an autopsy study from north India

Pediatric developmental and genetic renal lesions are a known cause of mortality in the perinatal/neonatal period. These lesions are associated with a wide range of extrarenal congenital malformations that influence the outcome of the patients. In this autopsy study, we have analyzed the spectrum of pediatric developmental and genetic renal lesions and their associated congenital malformations. A total of 4,099 autopsies (20 weeks of gestation to 1 year of life) were reviewed, of which 158 cases (3.85%) of pediatric developmental (143 cases) and genetic renal lesions (15 cases) were found. Autosomal recessive polycystic kidney disease was the commonest genetic lesion. Primitive ducts with cuffing of immature mesenchyme—the sine qua non of renal dysplasia—was found in all cases of dysplasia. Associated congenital malformations were seen in all cases and thus a thorough search for them is mandatory. Ductal plate malformation was found in all cases of autosomal recessive polycystic kidney disease and in 1 case of bilateral multicystic dysplasia.     

Glomerulocystic renal disease: ultrasound appearances

Renal and hepatic sonography were performed in 2 neonates with glomerulocystic renal disease. One neonate had ultrasound findings of normal hypoechoic medullary pyramids, enabling differentiation from infantile polycystic renal disease. Previous case reports have highlighted the similarity of renal ultrasound findings in these two conditions.     

Hemihypertrophy in a boy with renal polycystic disease: Varied patterns of presentation of renal polycystic disease in his family

Hemihypertrophy is a condition that has been described in association with a variety of other malformations and diseases; quite often these have had a renal origin. — It is the purpose of this paper to record and discuss the occurrence of polycystic disease in a family, to note that the disease was manifest as either the adult or the infantile form, and detail the fact that one member of the family who had infantile type polycystic disease also had hemihypertrophy. —The pattern of inheritance of renal polycystic disease, its age at presentation and the variation in the boy of its manifestation with the passage of time are discussed. The need for caution in offering a prognosis and genetic counselling is stressed.     

New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney–liver complications

Improved neonatal medical care and renal replacement technology have improved the long‐term survival of patients with ARPKD. Ten‐yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra‐ and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto‐systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat‐soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato‐biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age‐matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64–80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato‐biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to <10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver–kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver–kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.     

Transjugular intrahepatic portosystemic shunt prior to renal transplantation in a child with autosomal-recessive polycystic kidney disease and portal hypertension: A case report

Autosomal-recessive polycystic kidney disease (ARPKD) can cause renal failure and portal hypertension in children. Portal hypertension may complicate the course of renal transplantation (Tx). We report the successful outcome of a patient with end-stage renal disease (ESRD) and portal hypertension treated with transjugular intrahepatic portosystemic shunt (TIPS), a minimally invasive endovascular technique of portosystemic shunt, prior to renal Tx.