Transient renal tubulopathy: a case report

A five-year-old boy was evaluated for fever, abdominal pain, vomiting, and diarrhea lasting two days. Chest radiograph revealed a left bronchopneumonia. Metabolic work-up demonstrated phosphaturia, glucosuria, calciuria, proteinuria, profound hypophosphatemia, hypouricemia, borderline hypomagnesemia, and normoglycemia. Creatine phosphokinase values were elevated, a finding consistent with rhabdomyolysis. Serum pH was normal and urine pH was 5. Serum urea and creatinine levels were normal. The child was treated with ceftriaxone and azithromycin. Oral phosphate was administered, followed by a rapid normalization of its serum level. Re-evaluation one and three months after discharge, while being off any therapy, showed the resolution of all metabolic abnormalities. We believe that the metabolic disturbances in this child were due to an acute and transient tubular dysfunction, possibly secondary to inflammatory/infectious induced tubulointerstitial nephritis (TIN). TIN presenting with an isolated tubular functional impairment, in the absence of any evidence of functional glomerular impairment, does not appear to have been described before.     

Overexpression of PKD2 in the mouse is associated with renal tubulopathy.

Polycystin-2 (PC-2), a cation channel of the Trp family, is involved in autosomal dominant polycystic kidney disease (ADPKD) type 2 (ADPKD2). This protein has recently been localized to the primary cilium where its channel function seems to be involved in a mechanosensory phenomenon. However, its biological function is not totally understood, especially in tubule formation. In the present paper, we describe a mouse model for human PC-2 overexpression, obtained by inserting a human bacterial artificial chromosome (BAC) containing the PKD2 gene. Three lines were generated, expressing different levels of PKD2. One line, PKD2-Y, has been explored in more detail and we will present physiological and molecular exploration of these transgenic animals. Our data demonstrate that transgenic animals older than 12 months present tubulopathy with proteinuria and failure to concentrate urine. Moreover, the kidney cortex has been found disorganized. Finally, we observe that extracellular matrix protein expression is downregulated in these animals. In conclusion, overexpression of human PKD2 leads to anomalies in tubular function, probably due to abnormalities in tubule morphogenesis.     

Aldosterone in progressive renal disease.

Blockade of the renin-angiotensin-aldosterone system has proven effective in retarding progression of renal disease in the remnant kidney model, as well as other experimental diseases, and, most importantly, in a range of progressive human renal diseases. Attention has focused on the role of angiotensin II (Ang II) in propagating progression both by its hemodynamic and nonhemodynamic actions. Recent evidence, predominately in the remnant kidney model, indicates that the drugs used to block this hormone system, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, also lower aldosterone levels. Thus, aldosterone, as well as angiotensin II, appears to be instrumental in sustaining the hypertension and fibroproliferative destruction of the residual kidney.     

Familial renal adysplasia

Renal dysplasia and agenesis as isolated findings are usually considered sporadic, noninherited abnormalities. We report three kindreds with familial renal adysplasia. Two or more children were affected in each of the families and at least one member--whether proband, sibling, or parent--had a clinically silent anomaly. Normal kidneys in the parents did not preclude the occurrence of renal adysplasia in more than one child. The empiric risks for offspring and first-degree relatives were 50% and 25%, respectively, suggesting a strong genetic factor such as a major dominant gene with variable expression. Because the disease appears to be genetic in some cases of renal adysplasia, careful screening of the proband's family, subsequent children, and pregnancies is important for the purpose of accurate genetic counseling.     

Mouse model for Lowe syndrome/Dent Disease 2 renal tubulopathy

The Lowe oculocerebrorenal syndrome is an X-linked disorder characterized by congenital cataracts, cognitive disability, and proximal tubular dysfunction. Both this syndrome and Dent Disease 2 result from loss-of-function mutations in the OCRL gene, which encodes a type II phosphatidylinositol bisphosphate 5-phosphatase. Ocrl-deficient mice are unaffected, however, which we believe reflects a difference in how humans and mice cope with the enzyme deficiency. Inpp5b and INPP5B, paralogous autosomal genes that encode another type II phosphoinositide 5-phosphatase in mice and humans, respectively, might explain the distinct phenotype in the two species because they are the closest paralogs to Ocrl and OCRL in their respective genomes yet differ between the two species with regard to expression and splicing. Here, we generated Ocrl(-/-) mice that express INPP5B but not Inpp5b. Similar to the human syndromes, all showed reduced postnatal growth, low molecular weight proteinuria, and aminoaciduria. Thus, we created an animal model for OCRL and Dent Disease 2 tubulopathy by humanizing a modifier paralog in mice already carrying the mutant disease gene.     

Familial Mediterranean fever triggered by renal transplantation.

Sir, Hereditary periodic fever syndromes are a group of non-autoimmunediseases characterized by episodic fever, and include familialmediterranean fever (FMF), hyper-immunoglobulin-D syndrome,tumour necrosis factor receptor-1-associated periodic syndromeand Muckle–Wells syndrome [1,2]. Of these, FMF is themost common and best known [1]. FMF mainly affects patientsof Mediterranean descent, namely Turks, Jews, Armenians andArabs [3]. However, the     

Light chain tubulopathy without Fanconi syndrome.

A 59-year-old white male was found to have mild proteinuriaand renal insufficiency during a life insurance test in 2003.His serum creatinine has been stable at 1.6 mg/dl since then.His 24 h urine protein was 720 mg in 2003 and 861     

Familial and sporadic renal oncocytomas--a comparative molecular-genetic analysis.

OBJECTIVES: Genetic causes of sporadic and familial renal oncocytomas are not known. We analyzed these tumors genetically in order to detect tumor-specific chromosome alterations. METHODS: DNA from 26 sporadic and 31 familial renal oncocytomas were screened by comparative genomic hybridization according to standard protocols including degenerate oligonucleotide-primed PCR. RESULTS: Chromosome alterations were detected in 19/26 sporadic (73%) and in 4/31 familial renal oncocytomas (13%). Partial or complete losses of chromosome 1 were most frequently found in both sporadic (15/26) and familial tumors (2/4). Less frequently, loss of chromosome 14 (3/26) was detected in sporadic renal oncocytomas as well as losses of 2p, 2q, 4q, 10 and 18 and gains of 1q and 17q in individual sporadic tumors. Inter-tumor variation of chromosome aberrations was prominent in 1 patient, where 1 tumor showed gains of chromosomes 5, 6q, 7, 10p, 12 and 13q, whereas the second tumor exhibited gains of chromosomes 5 and 7 and loss of 10q. In contrast to sporadic renal oncocytomas, most familial tumors (87%) were devoid of chromosome instabilities. CONCLUSION: Our results demonstrate that partial or complete loss of chromosome 1 is the most common alteration in renal oncocytomas, sporadic and familial. However, chromosome changes are much rarer in familial than in sporadic renal oncocytomas.     

Inconsistency in radiographic evaluation of progressive renal osteodystrophy.

Five radiologists graded 49 series of bone X-rays of 20 patients with chronic renal failure treated by hemodialysis. There was a high incidence of osteodystrophy which progressed identifiably over intervals exceeding 12 months. The severity grade of osteodystrophy was poorly reproducible among patients, among radiologists, and even between interpretations by the same radiologist after an interval of 10 months. Although the severity of osteodystrophy correlated with serum alkaline phosphatase values, the latter was not an accurate predictor of the severity of the bone lesions. Radiographic reassessment at intervals of one year or less in the asymptomatic patient has less reproducibility than the anticipated changes. More sensitive and reliable techniques are recommended.     

Familial juvenile nephronophthisis and renal transplantation in two siblings.

Familial juvenile nephronophthisis (FJN) is a hereditary renal disease, characterized by a juvenile onset and the development of medullary cysts and progressive renal damage. The pathogenesis of FJN remains unknown, and at present, no rational therapy other than renal transplantation is available. We describe two cases in siblings in whom there were no extrarenal complications, such as retinopathy or central nervous system involvement. Both patients display juvenile onset of the disease and end-stage renal failure. The brother received a kidney from his father, and the sister received a kidney from her mother. Recurrence of the underlying disease has not so far been found in the transplanted kidney.     

Familial and hereditary renal cancer syndromes

Hereditary and familial forms of kidney cancer are encountered routinely in urologic practice. Discoveries in the genetic and molecular biology of these diseases have had a critical impact on the understanding of kidney cancer pathogenesis in nearly all subtypes of renal cortical neoplasms and their clinical features. Developing knowledge in the field has helped formulate new diagnostic and molecular therapeutic strategies for patients who have kidney cancer. This article aims to familiarize the reader with the current understanding of identified syndromes, their biology, and approaches to treatment.     

Anemia ameliorates progressive renal injury in experimental DOCA-salt hypertension.

To explore the role of systemic hematocrit in the vascular adaptations which characterize desoxycorticosterone-salt hypertension, studies were performed in three groups of rats with uninephrectomy, desoxycorticosterone administration, and 1% saline in the drinking water. One group received recombinant human erythropoietin to increase hematocrit, and another group was subjected to phlebotomy and fed a low-iron diet to induce anemia. Control rats exhibited systemic and glomerular capillary hypertension, proteinuria, and substantial glomerular sclerosis at 8 wk. Erythropoietin modestly increased hematocrit and blood pressure and substantially aggravated glomerular capillary pressure, proteinuria, and glomerular sclerosis. In contrast, reduction of hematocrit with a low-iron diet significantly attenuated systemic and glomerular hypertension, proteinuria, and sclerosis. It was concluded that the pace of progression of glomerular injury can be limited by chronic reduction in hematocrit, which effectively ameliorates both systemic and glomerular hypertension in this model of salt-sensitive hypertensive renal disease.     

Familial pure proximal renal tubular acidosis--a clinical and genetic study.

BACKGROUND: Inherited proximal renal tubular acidosis (pRTA) is commonly associated with more generalized proximal tubular dysfunctions and occasionally with other organ system defects. Inherited combined pRTA and distal RTA with osteopetrosis and pure pRTA associated with ocular abnormalities, a rare disease which has been recently described. Only one family with pure isolated pRTA has been reported so far and the genetic cause for this disease is unknown. Objectives. We report a unique family with isolated pRTA. The aim of the project was to define the phenotype and to try to find the gene defect causing the disease. METHODS: Clinical and metabolic evaluation of all family members was performed and a family pedigree was constructed. DNA was extracted from blood samples of affected and unaffected family members. We amplified by PCR and sequenced the coding areas and splice-sites of the genes that contribute to HCO(-)(3) reclamation in the proximal tubule. The genes studied were as follows: CA II, CA IV, CA XIV, NCB1, Na(+)/H(+) exchanger (NHE)-3, NHE-8, the regulatory proteins of NHE3, NHRF1 and NHRF2 and the Cl(-)/HCO(-)(3) exchanger, SLC26A6. RESULTS: The father and all four children had RTA with blood HCO(-)(3) levels of 11-14 meq/l and urine pH of 5.3-5.4. Increased HCO(-)(3) fractional excretion after bicarbonate loading to 40-60% confirmed the diagnosis pRTA. No other tubular dysfunction was found, and no organ system dysfunction was detected, besides short stature. No mutation was found in all candidate genes studied. CONCLUSIONS: We presented a second family in the literature with familial isolated pure pRTA. The mode of inheritance is compatible with an autosomal dominant disease. Because of the small size of the family, wide genome search was not applicable and the gene candidate approach was chosen. Nine important candidate genes were extensively studied but the molecular basis of the disease was not yet found and genotyping nine important gene candidates were negative.     

低氧与慢性进展性肾脏疾病

多数慢性肾脏病存在着进行性发展，即所谓的进展性肾脏病（PRD），最终进展至终末期肾衰竭。目前关于PRD进展机制的学说很多。上世纪末英国学者Fine提出的“慢性低氧学说”正日益受到重视．它强调了肾脏小管间质的慢性氧缺失在肾脏疾病进展中的重要作用。低氧可诱导肾脏固有细胞产生多种细胞因子和炎症介导素，在肾脏病的发生和发展中可能起重要作用。我们现对近期PRD与低氧关系的研究进展作一综述。