Why kidneys fail in autosomal dominant polycystic kidney disease

The weight of evidence gathered from studies in humans with hereditary polycystic kidney disease (PKD)1 and PKD2 disorders, as well as from experimental animal models, indicates that cysts are primarily responsible for the decline in glomerular filtration rate that occurs fairly late in the course of the disease. The processes underlying this decline include anatomic disruption of glomerular filtration and urinary concentration mechanisms on a massive scale, coupled with compression and obstruction by cysts of adjacent nephrons in the cortex, medulla and papilla. Cysts prevent the drainage of urine from upstream tributaries, which leads to tubule atrophy and loss of functioning kidney parenchyma by mechanisms similar to those found in ureteral obstruction. Cyst-derived chemokines, cytokines and growth factors result in a progression to fibrosis that is comparable with the development of other progressive end-stage renal diseases. Treatment of renal cystic disorders early enough to prevent or reduce cyst formation or slow cyst growth, before the secondary changes become widespread, is a reasonable strategy to prolong the useful function of kidneys in patients with autosomal dominant polycystic kidney disease.     

Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

Summary  Uromodulin (UMOD) malfunction has been found in a range of autosomal dominant tubulointerstitial nephropathies associated with hyperuricaemia, gouty arthritis, medullary cysts and renal failure—labelled as familial juvenile hyperuricaemic nephropathy, medullary cystic disease type 2 and glomerulocystic kidney disease. To gain knowledge of the spectrum of UMOD changes in various genetic diseases with renal involvement we examined urinary UMOD excretion and found significant quantitative and qualitative changes in 15 male patients at various clinical stages of Fabry disease. In untreated patients, the changes ranged from normal to a marked decrease, or even absence of urinary UMOD. This was accompanied frequently by the presence of aberrantly processed UMOD lacking the C-terminal part following the K432 residue. The abnormal patterns normalized in all patients on enzyme replacement therapy and in some patients on substrate reduction therapy. Immunohistochemical analysis of the affected kidney revealed abnormal UMOD localization in the thick ascending limb of Henle’s loop and the distal convoluted tubule, with UMOD expression inversely proportional to the degree of storage. Our observations warrant evaluation of tubular functions in Fabry disease and suggest UMOD as a potential biochemical marker of therapeutic response of the kidney to therapy. Extended comparative studies of UMOD expression in kidney specimens obtained during individual types of therapies are therefore of great interest. Competing interests: None declared References to electronic databases: Fabry disease: OMIM 301500. α-Galactosidase A: EC 3.2.1.22. Uromodulin, OMIM 191845.     

A Novel Mutation of the HNF1B Gene Associated With Hypoplastic Glomerulocystic Kidney Disease and Neonatal Renal Failure: A Case Report and Mutation Update

Hepatocyte nuclear factor 1 beta (HNF1B) plays an important role in embryonic development, namely in the kidney, pancreas, liver, genital tract, and gut. Heterozygous germline mutations of HNF1B are associated with the renal cysts and diabetes syndrome (RCAD). Affected individuals may present a variety of renal developmental abnormalities and/or maturity-onset diabetes of the young (MODY).A Portuguese 19-month-old male infant was evaluated due to hypoplastic glomerulocystic kidney disease and renal dysfunction diagnosed in the neonatal period that progressed to stage 5 chronic renal disease during the first year of life. His mother was diagnosed with a solitary hypoplastic microcystic left kidney at age 20, with stage 2 chronic renal disease established at age 35, and presented bicornuate uterus, pancreatic atrophy, and gestational diabetes. DNA sequence analysis of HNF1B revealed a novel germline frameshift insertion (c.110_111insC or c.110dupC) in both the child and the mother. A review of the literature revealed a total of 106 different HNF1B mutations, in 236 mutation-positive families, comprising gross deletions (34%), missense mutations (31%), frameshift deletions or insertions (15%), nonsense mutations (11%), and splice-site mutations (8%).The study of this family with an unusual presentation of hypoplastic glomerulocystic kidney disease with neonatal renal dysfunction identified a previously unreported mutation of the HNF1B gene, thereby expanding the spectrum of known mutations associated with renal developmental disorders.     

Erworbene zystische Nierenerkrankung

Acquired cystic kidney disease (ACKD) develops from regenerating dilated tubular epithelium in patients with renal insufficiency and ends up in the cystic degeneration of the kidney in 30%–90% of patients with end-stage renal disease, depending on the length of time on dialysis, but regardless of type of renal disease. Bleeding, rupture or infection of the cysts are rare. The real problem posed by this cystic degeneration is the transition to complicated cysts and then to renal cell carcinoma. Patients with ACKD after renal transplantation developed renal cell carcinoma in 20% of cases (own experience). The tumour is more often a papillary than a clear cell carcinoma and, in contrast to sporadic renal cell carcinoma, usually has a more benign course; its genetic background is also different. Patients with end-stage renal disease should be checked by ultrasound of the kidneys annually and, if cysts are present, every six months to exclude renal cell carcinoma.     

Functional similarities of hepatic cystic and biliary epithelium: studies of fluid constituents and in vivo secretion in response to secretin

Hepatic cysts are a frequent manifestation of autosomal dominant polycystic kidney disease, but little is known about their functional characteristics. The goals of our study were to define the composition of hepatic cyst fluid and to determine whether hepatic cysts secrete in response to intravenously administered secretin. We percutaneously punctured five hepatic cysts and one proximal renal cyst from six subjects with autosomal dominant polycystic kidney disease and one solitary hepatic cyst from a subject without autosomal dominant polycystic kidney disease. Most fluids had an electrolyte composition similar to serum. Fluid from all hepatic cysts had glutamyltranspeptidase concentrations above those found in serum [( cyst]/[serum] = 4.93 +/- 5.92), contained secretory component (the epithelial receptor for polymeric IgA) and had glucose concentrations less than 15 mg/dl. Fluid from both hepatic and renal cysts of subjects with autosomal dominant polycystic kidney disease, but not from the subject with the solitary hepatic cyst, demonstrated extensive changes in the electrophoretic mobility of several serum proteins. Initial intracystic pressures ranged from 16 to 40 cm H2O, were reduced 57% to 97% after aspiration of a portion of cyst fluid and were held constant during the secretion study. Within 8 min of the intravenous administration of secretin, secretion of fluid increased in two of three hepatic cysts and in the renal cyst. The electrolyte composition of cyst fluids was not altered by secretin. These data suggest that hepatic cystic epithelium has functional characteristics of biliary epithelium and that secretion by both hepatic and renal cysts may be hormonally regulated.     

Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic syndrome with an incidence of 1:500 in the population, arising from inherited mutations in the genes for polycystic kidney disease 1 (PKD1) or polycystic kidney disease 2 (PKD2). Typical onset is in middle age, with gradual replacement of renal tissue with thousands of fluid-filled cysts, resulting in end-stage renal disease requiring dialysis or kidney transplantation. There currently are no approved therapies to slow or cure ADPKD. Mutations in the PKD1 and PKD2 genes abnormally activate multiple signaling proteins and pathways regulating cell proliferation, many of which we observe, through network construction, to be regulated by heat shock protein 90 (HSP90). Inhibiting HSP90 with a small molecule, STA-2842, induces the degradation of many ADPKD-relevant HSP90 client proteins in Pkd1^−/− primary kidney cells and in vivo. Using a conditional Cre-mediated mouse model to inactivate Pkd1 in vivo, we find that weekly administration of STA-2842 over 10 wk significantly reduces initial formation of renal cysts and kidney growth and slows the progression of these phenotypes in mice with preexisting cysts. These improved disease phenotypes are accompanied by improved indicators of kidney function and reduced expression and activity of HSP90 clients and their effectors, with the degree of inhibition correlating with cystic expansion in individual animals. Pharmacokinetic analysis indicates that HSP90 is overexpressed and HSP90 inhibitors are selectively retained in cystic versus normal kidney tissue, analogous to the situation observed in solid tumors. These results provide an initial justification for evaluating HSP90 inhibitors as therapeutic agents for ADPKD.     

Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease

Hepatic cysts are a major manifestation of autosomal dominant polycystic kidney disease. This study examined 239 autosomal dominant polycystic kidney disease patients and 189 unaffected family members to define the factors that influence the presence and severity of hepatic cysts. Autosomal dominant polycystic kidney disease patients with hepatic cysts were older than autosomal dominant polycystic kidney disease patients without such cysts (44.6 +/- 1.1 yr vs. 32.9 +/- 1.1 yr; p less than 0.0001). The number of hepatic cysts increased with age (r = 0.43; p less than 0.0001). Women were more likely to have massive hepatic cystic disease (greater than 15 cysts) than men (p less than 0.04). Women also had larger maximal cyst size (4.2 +/- 0.4 cm vs. 2.7 +/- 0.3 cm; p less than 0.004). Women with hepatic cysts were more likely to have been pregnant (p less than 0.001) and to have had more pregnancies (2.9 +/- 0.3 pregnancies vs. 1.6 +/- 0.2 pregnancies; p less than 0.0009). Kidney volume (p less than 0.0001), number of cysts (p less than 0.004), percentage of cystic parenchyma (p less than 0.001) and predominant cyst size (p less than 0.001) were greater and creatinine clearance was lower (64.5 +/- 3.1 ml/min/1.73 m2 vs. 94.5 +/- 3.4 ml/min/1.73 m2; p less than 0.001) in autosomal dominant polycystic kidney disease patients with hepatic cysts. By logistic regression, the frequency of hepatic cysts was related to increased age, increased severity of renal cystic disease and decreased creatinine clearance. Number and size of hepatic cysts correlated with the occurrence of pregnancy, female gender, increased age and severity of the renal lesion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma erythropoietin levels and acquired cystic disease of the kidney in patients receiving regular haemodialysis treatment

Acquired cystic disease of the kidney (ACDK) in patients with end-stage renal failure can be associated with development of polycythaemia. The relationship between plasma erythropoietin levels and ACDK in 17 patients on long-term haemodialysis treatment was studied. There was a significantly higher level of plasma erythropoietin in patients with multiple renal cysts than in those patients with less than five cysts or no cysts. Haemoglobin tended to be higher in the ACDK group, but the difference was not significant. These results indicate that the development of renal cysts results in increased secretion of erythropoietin.     

Glomerular hyperfiltration: definitions, mechanisms and clinical implications

Glomerular hyperfiltration is a phenomenon that can occur in various clinical conditions including kidney disease. No single definition of glomerular hyperfiltration has been agreed upon, and the pathophysiological mechanisms, which are likely to vary with the underlying disease, are not well explored. Glomerular hyperfiltration can be caused by afferent arteriolar vasodilation as seen in patients with diabetes or after a high-protein meal, and/or by efferent arteriolar vasoconstriction owing to activation of the renin-angiotensin-aldosterone system, thus leading to glomerular hypertension. Glomerular hypertrophy and increased glomerular pressure might be both a cause and a consequence of renal injury; understanding the renal adaptations to injury is therefore important to prevent further damage. In this Review, we discuss the current concepts of glomerular hyperfiltration and the renal hemodynamic changes associated with this condition. A physiological state of glomerular hyperfiltration occurs during pregnancy and after consumption of high-protein meals. The various diseases that have been associated with glomerular hyperfiltration, either per nephron or per total kidney, include diabetes mellitus, polycystic kidney disease, secondary focal segmental glomerulosclerosis caused by a reduction in renal mass, sickle cell anemia, high altitude renal syndrome and obesity. A better understanding of the mechanisms involved in glomerular hyperfiltration could enable the development of new strategies to prevent progression of kidney disease.     

Acquired cystic disease of the end-stage kidney

The development of multiple cysts in the previously noncystic chronically diseased kidneys of patients undergoing long-term dialysis appears to be associated with spontaneous renal bleeding and benign and malignant renal tumors. Two cases of acquired cystic disease with renal hemorrhage and adenocarcinoma are presented; metastases occurred in one patient and the other had bilateral carcinoma requiring bilateral nephrectomy. Combined data from 13 studies indicate acquired cystic disease occurs in one third of patients undergoing maintenance hemodialysis and is associated with adenocarcinoma in 4 percent of cases. Four cases of metastases and five deaths linked to acquired cystic disease have been reported. Eight of 24 patients with acquired cystic disease and clinical manifestations of renal bleeding had renal adenocarcinoma. Autopsy series indicate tumors associated with acquired cystic disease are usually benign but commonly bilateral and multiple. Cystic transformation of the end-stage kidney is more frequent after several years of hemodialysis. It is suggested that patients receiving dialysis treatments for more than three years have a baseline radiologic examination of the kidneys so that subsequent problems can be more easily identified and evaluated.     

Calcified hepatic and renal cysts in adult dominant polycystic kidney disease

Summary We report the case of a 56-year-old woman suffering from adult dominant polycystic kidney disease, treated by hemodialysis, in whom calcifications of the wall of hepatic and renal cysts developed. The possibility that cystic calcifications might be the consequence of secondary hyperparthyroidism is discussed.     

Liver cysts in patients with autosomal dominant polycystic kidney disease

Liver cysts were found in 46 (29 per cent) of 158 patients over 10 years of age with documented autosomal dominant-type polycystic kidney disease (PKD) from 62 unrelated families. Hepatic cysts were not found in any patient at risk for PKD in whom renal cysts were not detected. The prevalence of liver cysts increased with advancing age and with declining rate of glomerular filtration. Results of clinical and laboratory studies indicate that polycystic liver disease in patients with autosomal dominant-type PKD is a benign condition, rarely, if ever, causing impaired liver function or portal hypertension.     

The spectrum of cystic kidney disease in adulthood: differential diagnosis and complications

Simple renal cysts are the most common renal masses, accounting for roughly 65 to 70% of cases. They most often occur in patients over the age of 50 as determined from post-mortem examination or renal ultrasonography. The major concern with simple renal cysts is differentiating them from more serious disorders, such as polycystic kidney disease and solid masses such as a renal carcinoma or abscess. Renal arteriovenous malformations may present with ultrasound picture mimicking simple parapelvic cyst. Ultrasound, doppler ultrasound, computed tomography and magnetic resonance imaging are effective in documenting the underlying lesions non-invasively. Arteriography may be useful to characterise vascular lesion. We report here the spectrum of cystic kidney disease in adulthood in a group of patient with different disorders. The differential diagnosis, complications and associated process are discussed.     

Immunolocalization of ion transport proteins in human autosomal dominant polycystic kidney epithelial cells.

The kidneys of patients with autosomal dominant polycystic kidney disease become massively enlarged due to the progressive expansion of myriad fluid-filled cysts. The epithelial cells that line the cyst walls are responsible for secreting the cyst fluid, but the mechanism through which this secretion occurs is not well established. Recent studies suggest that renal cyst epithelial cells actively secrete Cl across their apical membranes, which in turn drives the transepithelial movement of Na and water. The characteristics of this secretory flux suggest that it is dependent upon the participation of an apical cystic fibrosis transmembrane conductance regulator (CFTR)-like Cl channel and basolateral Na,K-ATPase. To test this hypothesis, we have immunolocalized the CFTR and Na,K-ATPase proteins in intact cysts and in cyst epithelial cells cultured in vitro on permeable filter supports. In both settings, cyst epithelial cells were found to possess Na,K-ATPase exclusively at their basolateral surfaces; apical labeling was not detected. The CFTR protein was present at the apical surfaces of cyst epithelial cells that had been stimulated to secrete through incubation in forskolin. CFTR was detected in intracellular structures in cultured cyst epithelial cells that had not received the forskolin treatment. These results demonstrate that the renal epithelial cells that line cysts in autosomal dominant polycystic kidney disease express transport systems with the appropriate polarity to mediate active Cl and fluid secretion.     

Polycystic liver disease: quantitation of parenchymal and cyst volumes from computed tomography images and clinical correlates of hepatic cysts

Polycystic liver disease is a common manifestation of autosomal dominant polycystic kidney disease. However, factors that regulate hepatic cystogenesis have not been defined, and the effect of cyst formation on hepatic parenchymal mass has not been studied. We validated computed tomographic methods for measuring volumes from computed tomographic images using plastic-agar models and demonstrated that measured volumes were within 10% of actual volumes. The validated methods were used to measure hepatic parenchymal, hepatic cyst and kidney volumes in 25 subjects with polycystic liver disease and nine controls without autosomal dominant polycystic kidney disease. Hepatic cyst volume varied considerably in the 25 subjects with polycystic liver disease (20 to 7,148 ml), but hepatic parenchymal volume was not altered by hepatic cysts and was similar to that of controls (polycystic liver disease vs. controls: 1,357 +/- 185 vs. 1,319 + 340 ml). Total liver volume increased linearly as cyst volume increased (slope = 1.02 +/- 0.05, r = 0.994). Nine of 18 women with polycystic liver disease had massive hepatic cysts (cyst: parenchymal volume greater than 1; range of cyst volumes from 1,354 to 7,148 ml), and the other nine had cyst volumes (20 to 399 ml) similar to men with polycystic liver disease (25 to 1,107 ml). Total kidney volume, a measure of renal cystic disease, did not correlate with either total liver volume or the volume of hepatic cysts. The data indicate that hepatic parenchymal volume is preserved in polycystic liver disease despite massive cystic involvement and that women are uniquely susceptible to massive hepatic cystic disease.     

Pulmonary renal syndrome in childhood: a report of twenty-one cases and a review of the literature

In adults, the term specific pulmonary renal syndrome describes disorders with pulmonary and glomerular manifestations and includes Wegener's granulomatosis, Goodpasture disease, and systemic lupus erythematosus. Nonspecific pulmonary renal syndrome refers to either pulmonary disease complicating glomerular disease, or glomerular diseases following pulmonary disease. Since little is known regarding pulmonary renal syndrome in childhood, we reviewed the charts of 21 pediatric patients with pulmonary renal syndromes treated by the Department of Pediatrics, University of Bern between 1991 and 1998; we also reviewed the pediatric literature that deals with specific pulmonary renal syndromes. Specific pulmonary renal syndrome was noted in 3 children with systemic vasculitis (Wegener granulomatosis, N = 2; microscopic polyangiitis, N = 1) and 2 with systemic lupus erythematosus. Nonspecific pulmonary renal syndrome was observed in 12 patients with pulmonary edema (N = 9), pulmonary thromboembolism (N = 2), and pulmonary infection (N = 1) complicating the course of a glomerular disease, and in 4 children with a pulmonary disease followed by a glomerular disease. Review of the literature disclosed 52 cases of specific pulmonary renal syndrome other than systemic lupus erythematosus: Wegener granulomatosis (N = 28), Goodpasture disease (N = 13), and Henoch-Sch?nlein purpura (N = 11). In addition, hemolytic uremic syndrome complicated pneumococcal pneumonia in 32 cases. We conclude that pulmonary renal syndromes need to be looked for in childhood. Apart from Wegener granulomatosis, Goodpasture disease, and systemic lupus erythematosus, Henoch-Sch?nlein purpura and hemolytic-uremic syndrome occasionally have both pulmonary and renal features.     

Heterozygosity loss and somatic mutations in type I and II dominant autosomal renal polycystic kidney disease: evidence of a recessive mechanism at a cell level in cystogenesis

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder mainly characterized by renal cyst formation. Cysts in ADPKD are focal in nature, since only a small fraction of nephrons become cystic. The hypothesis that a second hit may be required for cyst formation has been proposed. This hypothesis suggests that inactivation of the inherited wild-type allele by a somatic mutation triggers cyst formation. In some cases, this second hit eliminates the normal allele and the affected cells remain with a single allele, which is the inherited mutated copy, and we only visualize one allele after the amplification by polymerase chain reaction; this is called loss of heterozygosity (LOH). In this study we have analysed the DNA isolated from epitehlial cells from 164 cysts of 8 kidneys affected by ADPKD type I and 30 cysts form a kidney affected by ADPKD type II. We have demonstrated the presence of LOH in 20.1% of PKD1 cysts and in 10% of PKD2 cysts. We have also found eight other different mutations in PKD2 cysts without LOH; so the percentage of somatic mutations in the PKD2 kidney reaches 36.6% of cysts. In conclusion, our data suggest that a recessive mechanism at the cellular level is implicated in cyst formation in the PKD1 and the PKD2 disease. The loss of both copies of the gene triggers the proliferation of a single cell, resulting in the cyst formation.     

Simultaneous clinical resolution of focal segmental glomerulosclerosis associated with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab

Background

Severe hypokalemia is known to cause muscle paralysis, and renal tubular acidosis is a recognized cause. Cystic disease of the kidney is associated with severe hypokalemia.

Case presentation

We report a 33-year-old male patient who presented with generalized limb weakness caused by severe hypokalemia due to renal tubular acidosis, who was found to have renal medullary cysts.

Conclusion

The association of cystic renal disease with hypokalemia, and the possible pathophysiological basis of the development of renal cysts in patients with severe hypokalemia, are discussed.     

Impact of calcium entry blockers on glomerular injury in experimental hypertension

Summary A major problem for patients with kidney disease and their physicians is that most chronic renal diseases progress to global glomerular sclerosis and end-stage renal failure. Studies in experimental models of hypertension and renal insufficiency have advanced our understanding of the pathogenesis of progressive kidney damage. In a number of settings, sclerosis has been related to the presence of intrarenal hypertension, a consequence of the hemodynamic adaptation to a reduction in the number of functioning nephrons. A growing body of evidence also supports the hypothesis that kidney and glomerular hypetrophy constitute an independent risk factor for glomerular sclerosis. Recent studies suggest that calcium antagonists can reduce glomerular injury in experimental hypertension. Renal protection may be related to the ability of these agents to inhibit compensatory renal growth.