cAMP activates ERK and increases proliferation of ADPKD epithelial cells, but not cells from normal human kidney cortex, through the sequential phosphorylation of PKA, B-Raf and MAPK in a pathway separate from, but complementary to, the classical receptor tyrosine kinase cascade. Consequently, cAMP and EGF have great potential to accelerate the progressive enlargement of renal cysts.

Kaspareit-Rittinghausen described a rodent model of inherited polycystic kidney disease (PKD), the Han:SPRD rat [1, 2], in which heterozygotes develop renal cysts and renal failure (in males) over several months, whereas homozygous animals develop rapidly progressive renal enlargement that leads to death in a few weeks. In this study, we examined selected elements of the pathogenesis of this disease in heterozygotes and homozygotes from birth to advanced disease. Heterozygous male rats developed slowly progressive renal cystic disease with interstitial fibrosis and azotemia seen by six months of age. Female heterozygotes developed slowly progressive renal cystic disease, but did not develop interstitial fibrosis or azotemia. Epithelial cells lining cyst cavities showed various degrees of morphologic immaturity. Cyst walls also developed basement membrane thickening, especially in areas of cellular immaturity, suggesting an interrelationship between this basement membrane thickening and cellular dedifferentiation. Thickened basement membranes were associated with increased immunoreactivity for type IV collagen, laminin, and fibronectin. Homozygous rats developed massive renal enlargement, marked azotemia, and died near three weeks of age. Renal c-myc proto-oncogene expression was elevated in homozygous cystic infants and in adult heterozygotes. In situ hybridization showed high levels of c-myc mRNA in cyst epithelia, suggesting abnormal regulation of cellular proliferation in the cells lining cysts, as seen in other models of PKD. The Han:SPRD rat is the only well-documented animal model of inherited PKD with an autosomal-dominant inheritance pattern and appears to have several features which resemble human ADPKD.

Purple urine bag syndrome (PUBS) is a unique disease entity characterized by an alarming purple discoloration of the urine secondary to recurrent urinary tract infections with indigo- and indirubin-producing bacteria. It is usually associated with prolonged urinary catheterization and chronic debilitated states. We hereby present a concise review of this rare phenomenon with historic perspectives, epidemiology, emphasizing on current concepts of etiology, pathogenesis, relevant clinical associations, treatment modalities, prognosis, and future directions in PUBS. In addition, we highlight an interesting occurrence of this intriguing phenomenon in a 39-year-old gentleman at our institution.

Abstract. Autosomal dominant polycystic kidney disease (AD-PKD) progresses to renal insufficiency in Ͼ50% of patients and is characterized by interstitial inflammation and fibrosis in the end stage. In a rat model of ADPKD, monocytes accumulate within the renal interstitium in association with increased levels of monocyte chemoattractant protein-1 (MCP-1) in cyst mural cells and increased excretion of this chemokine into the urine. For determining the extent to which this chemokine is abnormally expressed in patients with ADPKD, a cross-section study was performed of MCP-1 in urine, serum, and cyst fluid and MCP-1 production by mural epithelial cells cultured from the cysts of human patients with ADPKD. Upper boundaries for urinary MCP-1 excretion (Ͼ263 pg/mg creatinine) and serum creatinine concentration (Ͼ1.5 mg/dl) determined in 19 normal individuals were used to sort 55 ADPKD patients into three groups. In group 1 (n ϭ 13), urine MCP-1 excretion (136 Ϯ 14 pg/mg creatinine) was not different from normal volunteers (152 Ϯ 16 pg/mg); serum creatinine levels and urine total protein excretion were normal as well. In group 2 (n ϭ 27), urine MCP-1 excretion was increased (525 Ϯ 39 pg/mg creatinine), but serum creatinine levels and urine protein excretion were not different from normal. In group 3 (n ϭ 15), urine MCP-1 excretion increased further (1221 Ϯ 171 pg/mg), serum creatinine levels increased to 4.3 Ϯ 0.8 mg/dl, and urine protein excretion rose to 0.64 Ϯ 0.28 mg/mg creatinine. Serum MCP-1 levels of ADPKD patients (84 Ϯ 9.9 pg/ml; n ϭ 15) did not differ from normal. Levels of MCP-1 much higher than in serum or urine were found in cyst fluids obtained from nephrectomy specimens (range, 767 to 40,860 pg/ml; mean, 6434 Ϯ 841 pg/ml; n ϭ 73). Polarized, confluent cultures of ADPKD cyst epithelial cells secreted MCP-1 into the apical fluid to levels eightfold greater than in the basolateral medium. Similar results were obtained with tubule epithelial cells cultured from normal human renal cortex. On the basis of these results, it is concluded that urinary excretion of MCP-1 is increased in the majority of adult patients with ADPKD and that the source of some of this chemokine may be the mural epithelium of cysts. Furthermore, it seemed that urinary MCP-1 excretion may have increased in these ADPKD patients before appreciable increases in serum creatinine concentration or urine protein excretion were detected. It is reasonable to include urine MCP-1 excretion among candidate surrogate markers in controlled, longitudinal studies of ADPKD.Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder in which renal tubules develop in fluid-filled cysts in childhood that progressively enlarge for decades (1,2). In approximately one half of the patients, the progressive enlargement of the kidneys leads to the loss of renal function manifested in the early stages by hypertension and later by proteinuria and progressive azotemia. How to account for the fact that only a portion of the patients with ADPKD prog...

We conclude that the MAP kinase pathway is activated to the level of ERK in the abnormal mural epithelial cells lining cysts in animals with a dominantly inherited type of polycystic kidney disease. We suggest that cAMP, acting through PKA, Rap-1 and B-Raf, may contribute to the activation of ERK in a way that complements receptor tyrosine kinase-mediated agonists in the promotion of cyst enlargement.