Biventricular diastolic dysfunction in patients with autosomal-dominant polycystic kidney disease

BACKGROUND: Left ventricular diastolic dysfunction has been shown in patients with autosomal-dominant polycystic kidney disease (ADPKD). However, there is no study evaluating right ventricular functions in these patients. METHODS: In the present study, diastolic functions of both ventricles in normotensive and hypertensive ADPKD patients with well-preserved renal function were investigated. Fifteen hypertensive and 16 normotensive patients with ADPKD with well-preserved renal function, 16 patients with essential hypertension, and 24 healthy subjects were included in the study. Conventional left and right ventricular echocardiographic measurements were performed in all subjects. Left and right ventricular functions were investigated both by myocardial performance index (MPI) [calculated by dividing the sum of isovolumic contraction time and isovolumic relaxation time (IVRT) by ejection time] and by tissue Doppler imaging (TDI). RESULTS: Left ventricular deceleration time and IVRT were significantly prolonged in hypertensive patients with ADPKD compared with patients with essential hypertension and even in normotensive patients with ADPKD compared with healthy subjects. Left and right MPIs were significantly higher in patients with ADPKD compared with healthy subjects, showing systolic and diastolic dysfunction. Moreover, by using TDI, the peak early diastolic mitral annular velocity (Em) to peak late diastolic mitral annular velocity (Am) ratio and the peak early diastolic tricuspid annular velocity (Et) to peak late diastolic tricuspid annular velocity (At) ratio were decreased in patients with ADPKD, suggesting biventricular diastolic dysfunction. CONCLUSION: Both hypertensive and normotensive patients with ADPKD show significant biventricular diastolic dysfunction, suggesting cardiac involvement very early in the course of ADPKD.     

Determinants of renal volume in autosomal-dominant polycystic kidney disease

The Consortium of Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) recently showed that renal enlargement in autosomal-dominant polycystic kidney disease mimicked exponential growth. We determined the effects of cyst initiation rate, total number, and growth rate on the time-dependent change of total cyst volume (TCV). Mathematical models with equations integrating cyst surface area, volume, and an invariant growth rate constant were used to compute the time-dependent change in volume of solitary and multiple cysts. Multiple expanding cysts increased TCV in an exponential-like pattern even when individual cysts formed at different rates or exhibited different but constant growth rates. TCV depended on the rate of cyst initiation and on the total number of cysts; however, the compounding effect of exponential-like growth was the most powerful determinant of long-term cyst expansion. Extrapolation of TCV data plots for individual subjects back to an age of 18 predicted TCV values within an established range. We conclude that cysts started early in life were the main contributor to eventual TCV while their growth rate primarily determined renal size; although the rate of formation and the ultimate number of cysts also contributed. The good fit between the exponential models and the extrapolated CRISP data indicates that the TCV growth rate is a defining trait for individual patients and may be used as a prognostic marker.     

Transplantation for polycystic kidney disease

Twenty-four patients with end stage renal failure due to polycystic renal disease have been treated with hemodialysis and transplantation. While on dialysis, the incidence of complications did not differ from a similar group of patients with other causes of renal failure. Bilateral pretransplant nephrectomy is not mandatory except in cases of persistent infection or hemorrhage. A much higher incidence of HLA A3 and HLA B7 was noted in patients with polycystic disease when compared with the general population. Following cadaver renal transplantation, kidney function was significantly better in patients with polycystic disease when compared with those with other forms of renal failure. Patient survival was the same in both groups. We conclude that hemodialysis and transplantation are acceptable forms of treatment for a patient with end stage polycystic renal disease.     

Transplantation for polycystic kidney disease

During the 4-year period from June 1977 to May 1981, a total of 108 patients with polycystic kidney disease and 2440 nonpolycystic patients received cadaver renal allografts in the Southeastern Organ Procurement Foundation (SEOPF) Prospective Study. There were no significant differences between the groups with and without polycystic disease in terms of recipient blood group, history of splenectomy, or preformed antibody status. As a group, transplanted polycystic patients underwent native nephrectomy more often, had a better HLA match, received less antilymphocyte serum (ALS), and were slightly older than nonpolycystic patients. Although proportionately fewer polycystic patients received pretransplant transfusions than nonpolycystic patients (P = .002), transfusion was associated with a significant increase in graft survival in the polycystic group (P less than .05), as well as in the nonpolycystic group (P less than .0001). Gene frequency analysis showed no HLA-A, or -B antigen linkage with polycystic disease. No significant differences existed between the polycystic and nonpolycystic groups in terms of overall graft and patient survival. However, transplanted polycystic patients died more frequently from bacterial sepsis (P less than .05), especially from gram-positive organisms (P = .01). Pretransplant bilateral nephrectomy did not affect the incidence of sepsis. However, following graft failure, patients with bilateral native nephrectomy had a greater incidence of severe anemia (50% versus 39%) and death (58% versus 25%; P less than .05) than those with unilateral nephrectomy or no nephrectomy. Treatment with ALS did not significantly improve graft survival in those with polycystic disease. A strong positive correlation was found between patient death and treatment with ALS only in the polycystic group (P less than .01). These findings indicate that the use of pretransplant bilateral native nephrectomy and posttransplant ALS should be judicious in the polycystic patient because they may be associated with increased morbidity and mortality.     

Clinical aspects of renal transplantation in polycystic kidney disease

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) as a systemic disorder represents a special subgroup among patients with end-stage renal disease (ESRD). The different organ manifestations are potential risk factors for cardiovascular events or infections in the course after renal transplantation. Therefore, a long-term evaluation of ADPKD patients and of a control group was done. PATIENTS AND METHODS: 80 ADPKD patients were compared with 88 non-diabetic patients in a retrospective follow-up after renal transplantation. Patient and graft survival (1, 5 and 10 years after transplantation) as well as complications such as infections and cardiovascular events were evaluated. RESULTS: A comparable overall transplant (1 year, 5 years, 10 years: 83%, 73%, 67% ADPKD vs. 84%, 70%, 51% controls) and patient survival rate (1 year, 5 years, 10 years: 96%, 84%, 73% ADPKD vs. 91%, 79%, 58% controls) was found in both groups. Infectious complications with the exception of urinary tract infections (UTIs: ADPKD 42.5% vs. 26%) were diagnosed in similar frequency in the graft recipients. ADPKD patients were significantly more affected by UTIs than their control group (p < 0.05) and tended to suffer more often from lethal infections (ADPKD 7 vs. controls 3), but without statistical significance. Cardiovascular events were not observed to be significantly different between both groups (ADPKD 3 vs. controls 4). An obvious difference was found in patient (p < 0.01) and transplant survival rates (p < 0.05) of male and female ADPKD patients. The female group showed a significantly better outcome. CONCLUSIONS: The overall patient and graft survival rates did not differ between the ADPKD and control groups. The better outcome of female ADPKD graft recipients compared to the male group may be related to a gender-dependent disease severity, possibly due to hormonal effects. As UTIs and lethal septicemia were the leading complications in ADPKD patients, a careful monitoring for infections is important in the post-transplant follow-up.     

Autosomal dominant polycystic kidney disease--more than a renal disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease, affecting a half million Americans. The clinical phenotype can result from at least two different gene defects. One gene that can cause ADPKD has been located on the short arm of chromosome 16. This discovery has made possible new methods for diagnosing the disorder in gene carriers prior to the development of renal cysts. Although renal cysts are clearly an important manifestation of the gene defect, other systemic manifestations are both common and clinically important. Cardiac valvular lesions, intracranial aneurysms, hepatic cysts, and diverticula are included in the array of systemic manifestations. Moreover, renal cysts are only one of a myriad of renal manifestations. Although ADPKD was long considered an adult cystic disease, it is also a common cause of childhood cystic disease and must be considered in the differential diagnosis in that setting.     

多囊肾患者肾移植术后的临床效果

目的:探讨多囊肾患者肾移植的特点、并发症及其对移植效果的影响。方法:回顾性分析了42例多囊肾患者和80例非多囊肾患者肾移植的临床资料。对两组患者的术后并发症以及1年和5年的人、肾存活率进行比较。同时对多囊肾组术前切除原肾和不切除原肾的患者进行比较。结果:两组患者在术后移植肾功能延迟恢复,急性排斥反应,心脑血管并发症以及肺部感染的发生率上均无显著性差异。多囊肾组患者术后的泌尿系感染的发生率高于对照组(P<0.05)。多囊肾组和对照组患者,1年和5年人存活率分别为95.24%与97.50%和83.81%与88.92%;1年和5年肾存活率分别为90.48%与94.97%和69.55%与66.54%。多囊肾组术前切除原肾和不切除原肾的两组患者间,上述并发症以及人、肾存活率差异均无统计学意义。结论:多囊肾患者接受肾移植是可行的,术后的人肾存活率与对照组比较差异无统计学意义,不切除原病变肾脏能收到满意的移植效果。多囊肾患者肾移植术后易发生泌尿系感染,应积极采取有效的防治措施。     

Hypertension and renal injury in experimental polycystic kidney disease

Hypertension and renal injury in experimental polycystic kidney disease. BACKGROUND: Hypertension accelerates renal failure in autosomal dominant polycystic kidney disease (ADPKD), and evidence suggests a role for the renin-angiotensin system (RAS) in the functional and structural changes. To explore the hypothesis that RAS adaptations contribute to disease progression, we examined RAS activity and the long-term consequences of antihypertensive drugs, which suppress (enalapril) or stimulate (hydralazine) the RAS, in experimental polycystic kidney disease. METHODS: Studies were conducted in male heterozygous cystic Han:SPRD rats (Cy/+) and in unaffected littermates (controls). In protocol 1, either angiotensin II (Ang II), enalaprilat, or saline vehicle was acutely infused into cystic and control rats, which were aged 10 to 12 weeks. The mean arterial pressure (MAP), glomerular filtration rate (GFR), and renal plasma flow (RPF) were measured at baseline and after an infusion of test substances. In protocol 2, cystic rats received chronic therapy with either enalapril, hydralazine, or no therapy for 10 to 12 weeks of age and then underwent renal function and RAS studies. In protocol 3, similar cohorts were followed for 40 weeks to assess the effects of therapy on blood pressure, proteinuria, serum creatinine, RAS parameters, and renal morphology. RESULTS: In protocol 1, cystic rats had massive kidneys, slightly elevated blood pressure, and profound renal vasoconstriction and reduced GFR. Ang II induced similar changes in MAP and renal function in control and cystic rats. Enalaprilat induced little effect on MAP but more striking increases in GFR and RPF in cystic rats. In protocol 2, at 10 weeks of age, enalapril was superior in preserving renal function, but neither drug limited the expansion of the tubulointerstitium. In protocol 3, at 40 weeks of age, both drugs ameliorated the increase in serum creatinine, although only enalapril reduced proteinuria and kidney size. CONCLUSIONS: In polycystic rats, acute RAS suppression markedly ameliorates renal dysfunction. However, although chronic enalapril and hydralazine protect against the loss of renal function, only enalapril limits renal growth and proteinuria, and neither significantly limits tubulointerstitial fibrosis. The long-term studies give clear support to the importance of blood pressure control, per se, but only partial support to the importance of the particular agent used. As in clinical studies, angiotensin-converting enzyme inhibition may be less beneficial in ADPKD than in renal diseases characterized by predominant glomerular injury.     

多囊肾囊内感染与肾移植

常染色体显性多囊肾病（ADPKD）是一种常见的单基因遗传性肾病,可进展为终末期肾病（ESRD）。ADPKD患者常反复发生囊内感染,抗生素治疗所产生的耐药性问题日益突出,肾移植手术方式也需根据多囊肾的感染情况进行选择。本文从肾囊肿起源、囊肿的分类及囊液的来源、囊液内细菌类型及其耐药性、ADPKD患者囊内感染与肾移植治疗等方面进行综述,为ADPKD患者囊内感染的诊治提供参考。     

多囊肾患者肾移植的临床研究

目的　分析多囊肾病 (PKD)患者肾移植术后移植效果 ,并探讨影响因素。方法　选取19 78年至 2 0 0 2年 46例PKD肾移植患者 (PKD组 )和 46例其它肾脏病 (非糖尿病肾病 )肾移植患者(对照组 )进行回顾性分析。评估人、肾存活率 (肾移植后 1、3和 5年 ) ,以及术后并发症 ,如感染和心血管疾病等情况。结果　两组患者 1、3、5年人存活率 :PKD组为 95.7%、91.3 %、91.3 % ;对照组为97.8%、95.7%、93 .5% ;肾存活率 :PKD组为 93 .5%、89.1%、87.0 % ;对照组为 95.7%、89.1%、87.0 %。PKD组中 ,女性患者 5年移植人、肾存活率达到 10 0 %、10 0 % ,男性只有 88.2 %、82 .4% ,差异有显著性 (P <0 .0 5)。PKD组患者比对照组更易发生尿路感染 (P <0 .0 5) ;其它部位的感染发生率相似。两组心血管并发症差异无显著性 (PKD组 3例 ,对照组 4例 )。结论　PKD组和对照组总的人、肾存活率差异无显著性。PKD组的女性患者肾移植后存活率高于男性 ,可能与性激素的影响有关。尿路感染和严重的肺部感染可能是PKD患者术后主要的并发症。     

Therapies to slow polycystic kidney disease

Advances in the understanding of cystogenesis and availability of animal models orthologous to human autosomal dominant polycystic kidney disease (ADPKD) and recessive polycystic kidney disease (ARPKD) will likely facilitate the development of treatments for these diseases. Proteins mutated in ADPKD and ARPKD, as well as in several animal models, are localized to renal primary cilia. These are thought to have a sensory function and contribute to the regulation of the intracellular calcium ([Ca2+]i). It seems likely that the maintenance of a differentiated renal epithelial phenotype, characterized by controlled fluid secretion and cell proliferation, requires precise functional coordination of cAMP and Ras/Raf/MEK/ERK signaling by [Ca2+]i. [Ca2+]i alterations, linked to genetic defects causing polycystic kidney disease, may hinder negative feedback mechanisms that control cAMP and Ras/Raf/MEK/ERK signaling, and result in increased fluid secretion and cell proliferation. cAMP levels, Raf kinase activities and ERK phosphorylation are increased in polycystic kidneys. There is also evidence of abnormal cross-talk between cAMP and MAPK pathways, that can be reproduced in wild-type cells by altering [Ca2+]i. While cAMP inhibits Ras-Raf-1-stimulated phosphorylation of ERK in normal kidney cells, it markedly increases B-Raf kinase activity and ERK phosphorylation in polycystic kidney cells. Treatment strategies should probably be aimed at increasing [Ca2+]i, inhibiting Ras/Raf/MEK/ERK signaling or lowering cAMP in the distal nephron and collecting duct. Vasopressin is the major adenylyl cyclase agonist in the collecting duct principal cells via a V2 receptor. OPC31260, a V2 receptor antagonist, lowers renal cAMP and markedly inhibits cystogenesis in four animal models of polycystic kidney disease, three of which are orthologous to human diseases (PCK rat, ARPKD; pcy mouse, adolescent nephronophthisis; Pkd2WS25/- mouse, ADPKD). The renal selectivity and safety profile of this class of drugs make it an excellent candidate for clinical trials.     

A hereditary model of slowly progressive polycystic kidney disease in the mouse

There are two known forms of hereditary polycystic kidney disease (PKD) in humans. Although both forms initiate early in life, autosomal recessive PKD is rapidly progressive to kidney failure shortly after birth whereas autosomal dominant PKD is slowly progressive, taking many years to end stage. Research in this field has been limited by the availability of suitable animal models of PKD. Recently the C57BL/6J-cpk mouse has been used to study the pathogenesis of rapidly progressive hereditary PKD. The study presented here describes a slowly progressive PKD in the DBA/2-pcy mouse. The disease trait is transmitted in an autosomal recessive pattern and was localized to chromosome 9 through linkage to the dilute coat color and transferrin genes. Whereas some cystic changes were seen in fetal and newborn affected mice, renal enlargement did not develop until after 8 weeks of age and azotemia did not develop until after 18 weeks of age. Renal cysts were identified in all segments of the nephron and collecting duct and progressively enlarged with age. Individual cysts were found to be lined by a single layer of epithelial cells in most areas, with focal polyps and mounds of cells principally in collecting duct cysts. Early stages of cyst formation were associated with some abnormalities of tubular and glomerular basement membranes and accelerated eruption of incisors. Late stages of the disease were characterized by azotemia and chronic renal interstitial inflammatory infiltrates in all affected animals and cerebral vascular aneurysms in a few. We conclude that the DBA/2-pcy mouse has a form of renal cystic disease that appears similar in many respects to that seen in the dominant form of human PKD.     

Genetics of progressive renal failure in diabetic kidney disease

Diabetic kidney disease is a microvascular complication that is observed in a minority of patients with long-standing hyperglycemia. Diabetic nephropathy (DN) is associated with shortened patient survival, severe morbidity, and increased health care costs. Unfortunately, the incidence rates of DN continue to increase in Western societies, and DN is now the most common reported cause of end-stage renal disease in developed nations. DN results from a complex interplay between inherited and environmental factors. This article reviews the data that support an inherited basis for susceptibility to DN by summarizing familial aggregation studies, genome-wide linkage, and population-based association analyses in diabetic and nondiabetic kidney disease. Recent evidence linking genes involved in the regulation of endothelial function with genetic predisposition to albuminuria is presented. The integration of carefully designed genetic linkage and association studies with gene expression experiments in human and animal models of diabetic kidney disease appear to offer great promise for detecting the molecular mechanisms underlying susceptibility to DN.     

Adrenal insufficiency due to isolated adrenocorticotropin deficiency complicated by autosomal recessive polycystic kidney disease

We describe a 29-old-year Japanese man with autosomal recessive polycystic kidney disease who was frequently hypoglycemic. Insulinoma as a cause of hypoglycemia was denied because the ratio of plasma immunoreactive insulin to glucose was low. Adrenal insufficiency was diagnosed because of the low urinary excretion of 17-hydroxycorticosteroids, and both blunted responses of plasma cortisol to an intravenous injection of adrenocorticotropin and of plasma adrenocorticotropin to an intravenous injection of human corticotropin releasing hormone were observed, although basal plasma concentrations of cortisol and adrenocorticotropin were normal. The elusion profile of plasma sample from our patient chromatographed on a Sephadex G-75 column showed two peaks of (1-39)-ACTH and beta-lipotropin, with no evidence of high molecular weight form of ACTH. The plasma concentrations of thyroid stimulating hormone and growth hormone were within the normal range. These findings indicated that this patient with autosomal recessive polycystic kidney disease was associated with adrenal insufficiency due to isolated adrenocorticotropin deficiency.