Diseases causing end-stage renal failure in New South Wales.

The nature of the original renal disease was determined in 403 consecutive cases of end-stage renal failure, in 317 of which the clinical diagnosis was corroborated by histological examination of the kidney. Five diseases accounted for 20 or more cases--glomerulonephritis (31% of the total), analgesic nephropathy (29%), primary vesicoureteral reflux (8%), essential hypertension (6%), and polycystic kidneys (5%). In only four cases did renal failure result from chronic pyelonephritis without a demonstrable primary cause. Greater use of micturating cystography and cystoscopy and routine urine testing for salicylate are advocated for earlier diagnosis of the major causes of "pyelonephritis". The incidence of end-stage renal failure in people aged 15-55 in New South Wales was estimated to be at least 34 new cases per million of total population each year.     

A Bedouin kindred with infantile nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping.

A novel type of infantile nephronophthisis was identified in an extended Bedouin family from Israel. This disease has an autosomal recessive mode of inheritance, with the phenotypic presentation ranging from a Potter-like syndrome to hyperechogenic kidneys, renal insufficiency, hypertension, and hyperkalemia. Affected individuals show rapid deterioration of kidney function, leading to end-stage renal failure within 3 years. Histopathologic examination of renal tissue revealed variable findings, ranging from infantile polycystic kidneys to chronic tubulointerstitial nephritis, fibrosis, and cortical microcysts. A known familial juvenile nephronophthisis locus on chromosome 2q13 and autosomal recessive polycystic kidney disease on chromosome 6p21.1-p12 were excluded by genetic linkage analysis. A genomewide screen for linkage was conducted by searching for a locus inherited by descent in all affected individuals. Pooled DNA samples from parents and unaffected siblings and individual DNA samples from four affected individuals were used as PCR templates with trinucleotide- and tetranucleotide-repeat polymorphic markers. Using this approach, we identified linkage to infantile nephronophthisis for markers on chromosome 9q22-31. The disorder maps to a 12.9-cM region flanked by markers D9S280 and GGAT3G09.     

Molecular pathogenesis of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest inherited human disorders yet remains relatively unknown to the wider medical, scientific and public audience. ADPKD is characterised by the development of bilateral enlarged kidneys containing multiple fluid-filled cysts and is a leading cause of end-stage renal failure (ESRF). ADPKD is caused by mutations in two genes: PKD1 and PKD2. The protein products of the PKD genes, polycystin-1 and polycystin-2, form a calcium-regulated, calcium-permeable ion channel. The polycystin complex is implicated in regulation of the cell cycle via multiple signal transduction pathways as well as the mechanosensory function of the renal primary cilium, an enigmatic cellular organelle whose role in normal physiology is still poorly understood. Defects in cilial function are now documented in several other human diseases including autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome and many animal models of polycystic kidney disease. Therapeutic trials in these animal models of polycystic kidney disease have identified several promising drugs that ameliorate disease severity. However, elucidation of the function of the polycystins and the primary cilium will have a major impact on our understanding of renal cystic diseases and will create exciting new opportunities for the design of disease-specific therapies.     

Prospective trial of operative versus non-operative treatment of severe vesicoureteric reflux in children: five years' observation. Birmingham Reflux Study Group.

Children with severe vesicoureteric reflux were allocated randomly to either operative or non-operative treatment and followed up. Altogether 161 children were observed for two years, of whom 104 were followed up for five years. Reflux was abolished in 98% of ureters reimplanted, but more than half of the patients treated non-operatively continued to show severe reflux at five years. Two patients progressed to end stage renal failure, and a further four with extensive bilateral renal scarring became hypertensive. There were no significant differences between treatment groups in the incidence of breakthrough urinary infection, renal excretory function and concentrating ability, renal growth, progression of existing renal scars, or new scar formation. Progressive scarring occurred at all ages but was significantly more common during the first two years'' observation. Furthermore, new scars developed exclusively during the first two years'' observation, affecting 10 children aged 2-7 at allocation. Neither treatment can claim superiority or fully protect the kidneys from further damage, and efforts must continue to be directed towards identifying those at risk before scarring develops.     

Renal Transplantation: An Analysis of 33 Cases

Thirty-three patients with end-stage renal failure have had transplants over a three-year period, four patients receiving kidneys from siblings and the remainder cadaver organs. Twenty-seven kidneys survived with stable function for periods of six months to three years. Graft survival at one year was 85% and at two years 82%. One patient died and five were returned to dialysis. Complications included rejection episodes, technical problems, respiratory and wound infections, gastrointestinal disorders, and side effects of steroids.     

Regular short haemodialysis in end-stage renal failure.

A study was made of thrice weekly haemodialysis of 3-3 1/2 hours'' duration using a large surface area dialyser in patients with end-stage renal failure. Body water, potassium, and blood pressure control were satisfactory and comparable with the more widely used long dialysis schedules (6-9 hours thrice weekly). Patient rehabilitation was improved overall and the regimen enabled the dialysis unit to treat more patients despite a reduction in technical and nursing staff. The technique proved inadequate, however, in two patients with an intercurrent infection, and more intensive dialysis in recommended in such cases.     

多囊肾病动物模型的研究进展

多囊肾病(Polycystic kidney disease,PKD)是以肾脏充满多个液性囊泡,细胞增殖异常,间质炎细胞浸润及细胞外基质重塑等病理特点为主的遗传性疾病。主要分为常染色体显性多囊肾病(Autosomal dominant polycystic kidney disease,ADPKD)及常染色体隐性多囊肾病(Autosomal recessive polycystic kidney disease,ARPKD)。ADPKD更为常见,发病率约为1:500-1000,约50%的患者到60岁会发展为终末期肾脏病。ARPKD较少见,发病率约为1:20000-1:40000,患者多在婴幼儿时期死亡。目前,一旦多囊肾发展为终末期肾脏病,除了肾脏移植和透析外没有更有效的治疗方法,因此,早期的诊治对延缓多囊肾进展及防止其发展为终末期肾脏病是至关重要的。多囊肾动物模型的建立在研究多囊肾疾病具体发病机制及新药研发中具有重要意义。本文介绍了PKD疾病动物模型的研究进展,包括经典PKD自发模型、化学诱导模型及基因修饰模型。     

Survival of patients treated for end-stage renal disease by dialysis and transplantation.

The results of treatment in 213 patients with end-stage renal disease who underwent hemodialysis, peritoneal dialysis or transplantation, or a combination, between 1962 and 1975 were analysed. Comparison by censored survival analysis showed significantly better (P less than 0.01) patient survival with the integrated therapy of dialysis and transplantation than with either form of dialysis alone. There was no significant difference in survival of males and females but survival at the extremes of age was poorer. Analysis of survival by major cause of renal failure indicated best survival in patients with congenital renal disease. Graft and patient survival rates at 1 year after the first transplantation were 42% and 69%. The major cause of death in this series was vascular disease but infection was responsible for 50% of deaths after transplantation. While integration of dialysis with transplantation produces best patient survival, this course is possible only when sufficient cadaver kidneys are available.     

Stem-cell approaches for kidney repair: choosing the right cells

With the increasing rate of end-stage renal failure and limited alternatives for its treatment, stem cell (SC) therapy for kidney injury is urgently needed. Choosing the right SC type is the critical step in realizing the potential of this therapeutic approach. Four possible sources of SCs are envisioned for the development of this type of treatment: (i) bone-marrow-derived SCs (BMSCs), (ii) renal adult SCs, (iii) embryonic SCs and (iv) fetal renal SCs. We suggest that resident SCs recently identified in the Bowman's capsule of adult human kidneys might prospectively be the ideal cell type for treatment of both acute and chronic renal injury because they display the potential to differentiate into multiple types of renal cells. However, BMSCs also represent an attractive alternative, especially for the treatment of patients affected by acute renal failure.     

Free tissue transfer in patients with renal disease

Several authors have cited renal disease as a risk factor for free flap failure. The authors performed a retrospective analysis of all patients who underwent free tissue transfer with concomitant renal disease, including acute renal failure, end-stage renal disease, chronic renal insufficiency, and functional kidney transplants, to determine what effect renal disease has on flap survival and overall reconstructive outcome. More than 1053 free flaps were examined. Renal disease was identified in 32 patients who underwent 33 free tissue transfers. Average patient age was 57 years (range, 36 to 80 years). Twelve patients (38 percent) were on chronic dialysis (end-stage renal disease), 18 patients (56 percent) had chronic renal insufficiency, and three patients (9 percent) had the diagnosis of acute renal failure at the time of surgery. Three patients in the chronic renal insufficiency group had a functioning renal transplant. Average follow-up was 16 months. Immediate postoperative complications occurred in 14 patients (42 percent of the 33 flaps). Overall perioperative mortality was 3 percent. Within the first 30 days there were two cases (6 percent) of primary flap failure; an additional four legs were lost as the result of complications related to their bypass grafts. There were no primary flap failures after 30 days; however, within the first year after surgery an additional seven limbs were lost as the result of progressive ischemia or infection, and an additional three patients died. This resulted in a 52 percent incidence of major morbidity or mortality during the first year and a 55 percent reconstructive success rate in survivors at 1 year. No significant difference was seen in postoperative morbidity or mortality when comparing the end-stage renal disease group to the chronic renal insufficiency group; however, patients with renal disease and diabetes tended to have poorer outcomes. Renal disease, especially renal disease associated with diabetes and peripheral vascular disease, can be a strong indicator of possible reconstructive failure. The surgeon and patient should be aware of the medical and surgical complications associated with this procedure at the outset.     

Adult Polycystic Kidney Disease in a Rhesus Monkey (Macaca mulatta)

Adult polycystic kidney disease was diagnosed at necropsy in a 16-year-old rhesus monkey dead from renal failure. Both kidneys were enlarged and contained multiple cysts ranging from 0.1 to 4.0 cm in diameter. The age of onset of the clinical signs, terminal uremia, and the gross and histologic findings in this macaque were consistent with adult (type III) polycystic kidney disease of man.     

Donation of kidneys. Medical Services Study Group of the Royal College of Physicians.

A survey of deaths from medical causes among hospital inpatients aged under 50 years in three health regions provided details of 1168 such deaths not caused by renal failure. Kidneys for transplantation were obtained from only 20 of these patients. In another 18 cases permission was refused or donation was impracticable. Ninety-eight of the deaths were due to subarachnoid haemorrhage and 38 to primary cerebral tumour, yet kidneys were obtained from only 11 and one of these patients respectively. Patients dying from subarachnoid haemorrhage are particularly suitable for donating their kidneys, but there is still a shortage of kidneys for transplantation because they are not harvested efficiently. Doctors seem to be reluctant to ask relatives'' permission to remove kidneys, and the arrangement of a donation is time consuming. Because transplant surgery is recognised as a specialist sphere, surgeons in other specialties may be reluctant to remove kidneys and come to rely on one transplant team covering a wide area. In an area such as Grampian, where a small population is served by one hospital containing all the major units, including accident and emergency and renal departments, it may be easier to arrange prompt donation and transplantation.     

低剂量多巴胺对急性心衰合并肾功能不全患者的影响

目的:探讨低剂量多巴胺能否通过利尿作用改善急性左心衰患者的充血症状以及肾功能。方法:将2013年9月至2013年12月我院收治的80例急性心衰合并肾功能不全的患者随机分为对照组和治疗组,每组各40例。对照组给予常规治疗,治疗组在常规治疗的基础上加用小剂量多巴胺静脉泵入48小时。观察和比较两组患者48小时内的总尿量及血清胱抑素C的变化、充血症状、肾功能及临床疗效的差异。结果:与对照组相比,治疗组48小时总尿量、血清胱抑素C的变化、体重变化、BNP变化、肌酐变化、进展性心衰发生率、死亡率、治疗失败患者比例均无明显差异(P0.05)。结论:低剂量多巴胺不能在利尿治疗基础上减轻急性心力衰竭并发肾功能不全患者的充血症状或改善肾功能。     

Erythropoietin therapy in patients with chronic renal failure.

Symptomatic anemia is a common complication of chronic renal failure. Treatment is now possible with the availability of recombinant human erythropoietin (epoetin alfa). Previous experimental studies have suggested that correcting the anemia of chronic renal failure may be harmful in that renal failure may be accelerated. Although experience with this drug has been primarily restricted to its use in patients with end-stage renal disease, several recent trials have been reported in patients with varying degrees of chronic renal failure. We review these studies with particular reference to the progression of renal failure and the drug''s reported side effects. We conclude that the use of epoetin is beneficial and well tolerated and that there is no compelling evidence for the acceleration of renal failure associated with its use in patients.     

Overexpression of PKD1 causes polycystic kidney disease

The pathogenetic mechanisms underlying autosomal dominant polycystic kidney disease (ADPKD) remain to be elucidated. While there is evidence that Pkd1 gene haploinsufficiency and loss of heterozygosity can cause cyst formation in mice, paradoxically high levels of Pkd1 expression have been detected in the kidneys of ADPKD patients. To determine whether Pkd1 gain of function can be a pathogenetic process, a Pkd1 bacterial artificial chromosome (Pkd1-BAC) was modified by homologous recombination to solely target a sustained Pkd1 expression preferentially to the adult kidney. Several transgenic lines were generated that specifically overexpressed the Pkd1 transgene in the kidneys 2- to 15-fold over Pkd1 endogenous levels. All transgenic mice reproducibly developed tubular and glomerular cysts and renal insufficiency and died of renal failure. This model demonstrates that overexpression of wild-type Pkd1 alone is sufficient to trigger cystogenesis resembling human ADPKD. Our results also uncovered a striking increased renal c-myc expression in mice from all transgenic lines, indicating that c-myc is a critical in vivo downstream effector of Pkd1 molecular pathways. This study not only produced an invaluable and first PKD model to evaluate molecular pathogenesis and therapies but also provides evidence that gain of function could be a pathogenetic mechanism in ADPKD.     

Lack of association of ACE/angiotensinogen genotype with renal function in autosomal dominant polycystic kidney disease

ACE polymorphisms have recently been shown to associate with worse renal and or cardiovascular outcome, with the D allele widely reported as a risk factor for cardiovascular disease. In autosomal dominant polycystic kidney disease (ADPKD), there are conflicting reports of an association between ACE polymorphisms and disease phenotype. There are no previous reports of any association between angiotensinogen polymorphisms and clinical phenotype in ADPKD. We examined the ACE I/D and angiotensinogen M235T polymorphisms in 176 patients with ADPKD. Patients are categorized into three groups according to the reason for initial investigation. Clinical history and examination findings were recorded at the time of first referral. A cohort of 17 patients had progressive renal impairment observed after 3 or more years of follow-up. Reciprocal creatinine against time was plotted in this group. From the patient population of 176, a total of 33 patients reached end-stage renal failure (ESRF) or a serum creatinine greater than 500 microm/liter. ACE genotype and M235T polymorphism frequencies were compared across groups. Serum creatinine and presence of hypertension and onset of ESRF were taken as outcome variables; age and source of referral were taken as confounding variables. There was no association of any genotype or allele with either creatinine, inverse creatinine, hypertension, or age at end-stage renal failure. These findings do not support the proposition that ACE genotype or angiotensinogen polymorphisms are associated with a worse prognosis in patients with ADPKD.     

磺达肝癸钠应用于冠心病合并肾功能不全患者的临床研究

目的:观察磺达肝癸钠应用于冠心病急性冠脉综合征合并肾功能不全患者抗凝治疗的疗效及安全性。方法:216例急性冠脉综合征患者分为肾功能正常组及肾功能不全组,皮下注射磺达肝癸钠2.5毫克,一日一次,连用8天,比较两组治疗9天内主要不良心脏事件(MACE)及出血并发症的发生率和30天及180天的随访情况。结果:治疗9天内及随访30天、180天期间,两组患者主要不良心脏事件发生率无统计学差异(P0.05),治疗及随访期间两组均未出现严重出血及中度出血,肾功能不全组轻微出血8例,肾功能正常组轻微出血5例,两组间比较差异无统计学意义(P0.05)。结论:磺达肝癸钠对于冠心病合并肾功能不全患者的抗凝治疗是一种安全有效的药物。     

CUBN as a novel locus for end-stage renal disease: insights from renal transplantation

Chronic kidney disease (CKD) is a complex disorder. As genome-wide association studies identified cubilin gene CUBN as a locus for albuminuria, and urinary protein loss is a risk factor for progressive CKD, we tested the hypothesis that common genetic variants in CUBN are associated with end-stage renal disease (ESRD) and proteinuria. First, a total of 1142 patients with ESRD, admitted for renal transplantation, and 1186 donors were genotyped for SNPs rs7918972 and rs1801239 (case-control study). The rs7918972 minor allele frequency (MAF) was higher in ESRD patients comparing to kidney donors, implicating an increased risk for ESRD (OR 1.39, p?=?0.0004) in native kidneys. Second, after transplantation recipients were followed for 5.8 [3.8-9.2] years (longitudinal study) documenting ESRD in transplanted kidneys--graft failure (GF). During post-transplant follow-up 92 (9.6%) cases of death-censored GF occurred. Donor rs7918972 MAF, representing genotype of the transplanted kidney, was 16.3% in GF vs 10.7% in cases with functioning graft. Consistently, a multivariate Cox regression analysis showed that donor rs7918972 is a predictor of GF, although statistical significance was not reached (HR 1.53, p?=?0.055). There was no association of recipient rs7918972 with GF. Rs1801239 was not associated with ESRD or GF. In line with an association with the outcome, donor rs7918972 was associated with elevated proteinuria levels cross-sectionally at 1 year after transplantation. Thus, we identified CUBN rs7918972 as a novel risk variant for renal function loss in two independent settings: ESRD in native kidneys and GF in transplanted kidneys.