Familial juvenile hyperuricemic nephropathy as rare cause of dialysis-dependent chronic kidney disease—a series of cases in two families

Hyperuricemia is a common symptom in adult population. It usually accompanies the chronic kidney disease. Less frequently, it is a primary phenomenon causing later serious clinical consequences. Familial juvenile hyperuricemic nephropathy (FJHN) is one of the hereditary conditions associated with high levels of serum uric acid and leading to dialysis in young adult age. It results from mutation in the UMOD gene, encoding the uromodulin protein, that is, Tamm–Horsfall protein. The aim of this paper was to present two families (7 affected members) with FJHN, in whom standard nephrological diagnostics did not provide clear cause of dialysis-dependent chronic kidney disease, until genetic testing was performed.     

Does type 2 diabetes mellitus delay renal failure in autosomal dominant polycystic kidney disease?

Autosomal dominant polycystic kidney disease (ADPKD) is a common renal disease without an effective therapeutic intervention to delay renal failure. Within kindreds, renal dysfunction often develops at a similar age in affected individuals, although there are known modifying factors. Two kindreds with ADPKD have shown a striking pattern of delayed onset of renal insufficiency in those individuals also suffering from type 2 diabetes mellitus. Eight nondiabetic patients with ADPKD had onset of dialysis or renal death at ages 38-52 years, (mean +/- SEM 46 +/- 1.9, n = 7) as compared with four diabetics who started dialysis or are still off dialysis at the age of 61 +/- 2.8 years (p < 0.01). Two of the four diabetics still have reasonable renal function at age 61 and 66. The diabetes was diagnosed at age 32 +/- 2 years and was treated with oral hypoglycemics for 19 +/- 2 years before institution of insulin. Cardiovascular disease dominated the clinical picture in the diabetics. In conclusion, onset of renal failure in ADPKD was delayed for over 15 years in individuals who also suffered from type 2 diabetes mellitus, in two ADPKD kindreds. Possible mechanisms are discussed, including glibenclamide inhibition of the cystic fibrosis transmembrane conductance regulator. The striking delay associated with type 2 diabetes mellitus in ADPKD induced renal failure should be evaluated further.     

Can progression of autosomal dominant or autosomal recessive polycystic kidney disease be prevented?

Data from animal and human studies suggest that the rate of progression of renal insufficiency can be retarded with careful control of blood pressure, institution of a low-protein diet, and the use of lipid-lowering agents. These therapeutic interventions become important when managing patients with renal insufficiency secondary to autosomal dominant polycystic kidney disease (PKD) and autosomal recessive polycystic kidney disease, in which end-stage renal disease is present in nearly 17,000 individuals per year. Several dietary and pharmacologic intervention strategies including blood pressure control, dietary modification, and the use of antioxidants as well as lipid-lowering agents have been studied in humans and animals with PKD in an effort to slow the rate of renal progression. This article reviews the current understanding of the effectiveness of these conventional therapies, as well as novel therapies that specifically target the mediators of cyst formation in PKD using tyrosine kinase inhibitors and gene therapy in an effort to identify potential strategies for retarding cyst formation and parenchymal injury in PKD. Current pharmacologic and dietary strategies fail to show any consistent benefits in preserving renal function and reducing renal injury in human PKD. The therapeutic potential for exciting new gene therapies and pharmacologic agents designed to target the pathophysiologic pathways involved in cyst formation are promising. Randomized, controlled trials in children and adults with early PKD are necessary to evaluate the effectiveness of these therapeutic interventions.     

Native nephrectomy for autosomal dominant polycystic kidney disease: before or after kidney transplantation?

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? The indications and timing of native nephrectomy in patients with autosomal dominant polycystic kidney disease (ADPKD) is controversial, especially for those undergoing renal transplantation. Post‐transplant unilateral native nephrectomy appears to be the preferred intervention compared to pre‐transplant native nephrectomy. There seems to be substantial additive risk to bilateral over unilateral nephrectomy, especially prior to transplantation. Pre‐transplant native nephrectomy should only be carried out when there are clear indications such as massive size preventing allograft placement, severe pain, early satiety, recurrent bleeding and infections, or suspected malignancy.

OBJECTIVE

To analyse indications, timing and outcomes of native nephrectomy in autosomal dominant polycystic kidney disease (ADPKD) patients listed for kidney transplantation.

PATIENTS AND METHODS

A retrospective analysis of all ADPKD patients who had a native nephrectomy prior to or following transplantation between January 2003 and December 2009 at a single centre, including those undergoing the sandwich technique (removal of the most severely affected native kidney prior to transplantation, and the other afterwards), was undertaken.

RESULTS

There were 35 individuals in our cohort (M : F = 16 : 19), with a median age of 51.5 years (range 43–65). Twenty patients were in the pre‐transplant nephrectomy group, 12 in the post‐transplant group, and three underwent the sandwich technique. Indications for nephrectomy varied but were most commonly pain/discomfort, space for transplantation, ongoing haematuria, recurrent infections, and gastrointestinal pressure symptoms (early satiety). Seven individuals in the pre‐transplant group and three in the post‐transplant group required critical care admission after nephrectomy. Transient renal graft dysfunction occurred in two post‐transplant bilateral nephrectomy patients. Two patients in the bilateral nephrectomy pre‐transplant group and one in the bilateral nephrectomy post‐transplant group died in the immediate post‐operative period. No complications were noted in the sandwich technique group.

CONCLUSION

Native nephrectomy in ADPKD is a major undertaking associated with significant morbidity especially in the pre‐transplant group. Post‐transplant unilateral nephrectomy appears to be the safest approach with fewest complications.     

Variable renal disease progression in autosomal dominant polycystic kidney disease: a role for nitric oxide?

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a variable renal disease progression, which is primarily due to genetic heterogeneity (PKD1 vs. PKD2). Evidence obtained in murine models and studies of variability in siblings and twins suggest that modifier genes influence renal disease progression in ADPKD. These modifier loci could affect cystogenesis and/or cyst progression, but also more general factors, i.e. endothelial dysfunction. The demonstration of endothelial dysfunction in Pkd1(+/-) mice and ADPKD patients, and the effect of the frequent Glu298Asp polymorphism of ENOS on renal disease progression in ADPKD suggest that an impaired release of nitric oxide (NO) by endothelial cells can accelerate renal function degradation. These results also suggest that polycystins can participate in the regulation of endothelial NO synthase (eNOS) and that addressing endothelial dysfunction in ADPKD can offer a new perspective to slow renal disease progression.     

The epidemics of cardiovascular disease in elderly patients with chronic kidney disease – Two facets of the same problem

There is increasing evidence that even mild renal dysfunction is a novel potent cardiovascular risk factor in the general elderly population. With more severe renal impairment, cardiovascular risk increases proportionately. This issue deserves attention, as chronic kidney disease (CKD) is predominantly a disease of the elderly, and the mean age of end-stage renal disease patients entering dialysis is growing constantly. In the dialysis population, when clinically significant cardiovascular disease (CVD) (particularly congestive heart failure) is present, survival is worse. Thus, every effort should be made to identify and treat cardiovascular risk factor in the early stages of CKD. However, elderly renal patients receive less proper cardiovascular therapy compared to non-renal subjects of the same age. This review deals briefly with the most significant data published in the last decade on CVD in elderly with CKD.     

Ventilator-induced lung injury and sepsis: two sides of the same coin?

Unequivocal evidence from both experimental and clinical research has shown that mechanical ventilation can damage the lungs and initiate an inflammatory response, possibly contributing to extrapulmonary organ dysfunction. This type of injury, referred to as ventilator-induced lung injury (VILI), resembles the syndromes of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). VILI can trigger a complex array of inflammatory mediators, resulting in a local and systemic inflammatory response. Substances produced in the lungs can be translocated into the systemic circulation as a result of injury to the pulmonary epithelium and to the capillary endothelium. This type of injury forms the basis for the use of low tidal volumes (5-7 mL/kg of predicted body weight) during mechanical ventilation of patients with ALI/ARDS. The recognition of VILI has prompted a number of investigators to suggest that ALI/ARDS may be, in part, a product of our efforts to mechanically ventilate patients rather than the progression of the underlying disease. On the other hand, current scientific evidence supports a link between VILI and the development of extrapulmonary organ dysfunction, similar to how most severe cases of sepsis are clinically manifested. In addition, functional genomics approaches using a gene array methodology to measure lung gene expression have identified differential patterns of gene expression in animal models of VILI, similar to those gene pathways activated during experimental and clinical sepsis. In this line of thought, we hypothesize that injurious mechanical ventilation could be responsible for the perpetuation and worsening of sepsis in some patients and for the development of a sepsis-like syndrome in others.     

Prehypertension and chronic kidney disease: the ox or the plow?

Nearly ten years ago, practice recommendations supported use of the clinical classification of 'prehypertension' for people with systolic blood pressure of 120-139 mm Hg or diastolic pressure of 80-89 mm Hg. This recommendation was based on observations that these ranges of blood pressure were associated with enhanced cardiovascular and cerebrovascular risks compared with blood pressure less than 120/80 mm Hg. Recent observations, including the report by Yano and colleagues, also suggest that prehypertension is an important risk factor for the development of chronic kidney disease.     

Review article: Risks of coronary artery calcification in chronic kidney disease: Do the same rules apply?

Atherosclerosis, once present, in the intimal and medial spaces of the blood vessel wall becomes calcified due to a variety of cellular and metabolic processes. Patients with chronic kidney disease (CKD) appear to have both accelerated and amplified vascular calcification compared with the general population. Calcium deposition within vascular tissue in the form of calcium hydroxyapatite crystals appears to be a permanent step in the mature atherosclerotic plaque, and to date has not been found to be reversible or modifiable with common treatments for atherosclerosis or dialysis management strategies. Densely calcified lesions with a circumferential arc of calcium around the vessel wall may be severely stenotic, however, are unlikely to develop symptomatic plaque rupture with an acute coronary syndrome. For that reason, the expected outcomes of atherosclerotic therapies in patients with CKD bone and mineral disorder have not followed the same rules of evidence. This paper will review the differences between the CKD and general population with respect to vascular calcification and the observed natural history in observational and interventional studies.     

Hashimoto's thyroiditis and medullary carcinoma in the same gland: a purely random occurrence?

In this paper the authors describe the case of 64-year-old woman who had been suffering from poorly defined thyroid disease for 30 years and Hashimoto's thyroiditis for 3 years, with recent detection of high serum calcitonin and CEA. Her family history was negative for endocrinological diseases and her general medical history was not significant for any diseases, except for mild hypertension. There were no pathological findings at physical examination. Cervical ultrasound showed 2 nodular lesions of the right lobe of the thyroid and the isthmus. FNABs of these nodules were performed under ultrasound control and proved non-diagnostic. The patient underwent total thyroidectomy. Intra-operative frozen sections were negative for cancer. Definitive histological examination was positive for medullary carcinoma of the right thyroid lobe (diameter 0.6 cm) in Hashimoto's thyroiditis. The association between thyroid cancers deriving from follicular cells and Hashimoto's thyroiditis is documented in the literature and would appear to determine a better prognosis. Cases such as the one presented in this paper, however, are rare and it is debated whether lymphocyte infiltration may predispose to the onset of medullary carcinoma or whether it is a defence against the tumour.     

Rheumatoid arthritis: Are ACPA-positive and ACPA-negative RA the same disease?

Seemingly contrasting genetic backgrounds in anti-citrullinated-protein antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis (RA) support the notion that these are in fact two distinct disease subsets, with different underlying pathogenesis, that might need tailored treatment strategies.     

Metabolic acidosis and kidney disease: does bicarbonate therapy slow the progression of CKD?

Metabolic acidosis is a common complication associated with progressive loss of kidney function. The diminishing ability of the kidneys to maintain acid-base homeostasis results in acid accumulation, leading to various complications such as impairment in nutritional status, worsened uremic bone disease and an association with increased mortality. In addition to these adverse effects which are related to acid retention, metabolic acidosis may also cause kidney damage, possibly through the stimulation of adaptive mechanisms aimed at maintaining acid-base homeostasis in the face of decreasing kidney function. Recent clinical trials have suggested that correction or prevention of metabolic acidosis by alkali administration is able to attenuate kidney damage and to slow progression of chronic kidney disease (CKD), and may hence offer an effective, safe and affordable renoprotective strategy. We review the physiology and pathophysiology of acid-base homeostasis in CKD, the mechanisms whereby metabolic acidosis may be deleterious to kidney function, and the results of clinical trials suggesting a benefit of alkali therapy, with special attention to details related to the practical implementation of the results of these trials.