Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece.

Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.

Control of proteinuria with increased doses of agalsidase alfa in a patient with Fabry disease with atypical genotype–phenotype expression / Control de la proteinuria con aumento de dosis de agalsidasa alfa en un paciente con enfermedad de Fabry y expresión de genotipo-fenotipo atípica

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Control of proteinuria with increased doses of agalsidase alfa in a patient with Fabry disease with atypical genotype-phenotype expression.

Fabry disease is a rare X-linked lysosomal storage disorder of glycosphingolipids, caused by the partial or complete deficiency of the lysosomal enzyme alpha-galactosidase A (a-Gal A). The missense mutation pN215S usually causes a milder form of the disease with isolated cardiac involvement. We report a case of a male Fabry patient with the pN215S mutation and a generalized disease. He suffered a relapse in proteinuria which responded to increased doses of the administered recombinant enzyme. Individualization of enzyme replacement therapy must be considered in selected cases characterized by clinical deterioration.

The role of melatonin in patients with chronic kidney disease undergoing haemodialysis.

Patients with chronic kidney disease including those undergoing haemodialysis have deranged sleep-wake pattern. In large part this is due to an abnormal circadian cycle of melatonin, a hormone secreted by the pineal gland in the evening and induces sleep. Subjects undergoing automated peritoneal dialysis or nocturnal haemodialysis have better sleep profile compared to those on daytime dialysis. Studies have shown that exogenous melatonin improves sleep-wake cycle in daytime haemodialysis patients. However, large randomised controlled trials are needed in order to establish its role in this patient population.

Relationship between depression, clinical and biochemical parameters in patients undergoing haemodialysis.

In this paper, we investigated the incidence of depression and its relation to clinical, laboratory parameters and sleep disorders in 45 haemodialysis (HD) patients. They were divided into two groups. Group A (n = 29) had no depression, whereas Group B (n = 16) had clinically assessed depression. Subjects were compared in terms of socioeconomic, clinical, laboratory parameters and presence of sleep disorders. Groups were matched for age, sex, family status, education, self-esteem, coffee and alcohol consumption, psychiatric history, time on HD and laboratory (serum urea, creatinine, electrolytes, iron, albumin and lipids) parameters. Group B demonstrated significantly lower haemoglobin levels (11.13 ± 1.69 and 12.23 ± 1.31 g/dl, respectively; p < 0.01) and higher C-Reactive Protein (CRP) levels (1.82 ± 1.73 and 0.83 ± 0.6 mg/dl, respectively; p < 0.005) compared to Group A. Additionally, strong correlation was observed when Hamilton Depression Scale scores were related to haemoglobin (r =-0.30, p < 0.05), CRP (r = 0.38, p < 0.001) and AIS scores (r = 0.54, p < 0.0001). In conclusion, depression seems to be related to high CRP, low haemoglobin levels and sleep disorders.

Slow continuous ultrafiltration in a patient with anomaly of a persistent left superior vena cava.

This paper describes an uncommon case of a patient with anomaly of a persistent left superior vena cava (PLSVC). A 54-year-old man with a history of chronic kidney disease, heart failure, diabetes mellitus and hypertension was admitted to the hospital for worsening dyspnoea. During his hospital stay, heart failure was further deteriorated and he became anuric. Renal replacement therapy was then required. After multiple unsuccessful attempts of right subclavian vein catheterisation, a catheter was placed in the left subclavian vein. Chest X-ray revealed the catheter in the left side of the thorax. Transthoracic cardiac ultrasound with agitated saline and chest MRI confirmed the diagnosis of PLSVC. The patient had nine sessions of slow continuous ultrafiltration. His heart and renal function were gradually improved. Nephrologists and health care professionals must be aware of this uncommon anatomic variant. Unnecessary manipulations can lead to serious complications, such as cardiac arrhythmias, cardiac arrest and venous sinus thrombosis.

Anacetrapib: a new weapon against dyslipidemia.

Anacetrapib is a cholesteryl-ester-transfer-protein (CETP) inhibitor, a new class of experimental drugs in the treatment of primary hypercholesterolemia and dyslipidaemia associated with the metabolic syndrome. One of the major advantages of this agent is, apart from the significant decrease in LDL-C it produces a substantial increase in HDL-C. Phase I, II, and III clinical trials have shown that anacetrapib is safe alone or in combination with statins. However, longterm clinical trials are required in order to assess whether it reduces mortality in individuals at high-risk of cardiovascular disease.

Posaconazole: a new antifungal weapon.

The last twenty years, the incidence of invasive fungal infections (IFI) has risen dramatically due to the prolongation of survival of patients with multiple risk factors for fungal infections. Amphotericin B was for more than 40 years the gold standard for almost all IFI, but toxicity and resistance, especially of new and emerging pathogens remained important issues. Fluconazole and itraconazole have also the same disadvantage of resistance. Voriconazole, a new triazole antifungal has offered an additional option, but the problem of resistant aspergillosis, and zygomycosis remains. Echinocandins (caspofungin, micafungin and anidulafungin) are active only against Candida and Aspergillus spp., but not against Fusarium, Scedosporium and Zygomycetes. Posaconazole is the most recently approved triazole with broad spectrum activity against Candida spp., Aspergillus spp., Cryptococcus neoformans, Zygomycetes, dermatiaceous, dimorphic, and other fungal pathogens. Interestingly, posaconazole is active against Candida spp., resistant to fluconazole and itraconazole, and Aspergillus fumigatus resistant to fluconazole itraconazole, amphotericin B, and voriconazole. The results from clinical trials of posaconazole as salvage treatment are encouraging. Multicenter clinical trials have also established its role in the prophylaxis of (IFI) in the severely immunocompromised patients such as those after hematopoietic stem cell transplantation (HSCT) who developed graft versus host disease (GVHD), as well as the neutropenic patients with an acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after myeloablative chemotherapy. Posaconazole has pharmacokinetic advantages and low side effect profile, which are very important, especially in the seriously ill population.

The role of paricalcitol on proteinuria.

Paricalcitol is a synthetic vitamin D analogue acting on vitamin D receptor (VDR). The result is inhibition of PTH synthesis and secretion. Paricalcitol appears also to block the renin-angiotensin-aldosterone system. We evaluated the role of paricalcitol in the management of proteinuria of various aetiology. A total of 19 patients participated. Most had diabetic nephropathy; however patients with other types of glomerulopathy leading to proteinuria were also included. Paricalcitol 1-2 µg daily, according to response, was administered for three months. Serum Ca, PO4, Ca × PO4, PTH, creatinine clearance and albumin, as well as 24 hour urine protein were measured before and after treatment. Five out of 19 patients did not respond to the treatment. The remaining 14 patients had an average 32.9% reduction of proteinuria. The drug was well tolerated. Paricalcitol appears to have a role in the treatment of proteinuria. However, our study raises a question regarding why some patients do not respond to paricalcitol. Patients with proteinuria due to diabetic nephropathy seem to respond better than patients with glomerulopathy.

Lactic acidosis after concomitant treatment with metformin and tenofovir in a patient with HIV infection.

We present an uncommon case of lactic acidosis after concomitant administration of Metformin and Tenofovir. This is a 74-year-old man with a history of diabetes mellitus receiving treatment with metformin. He had coronary artery disease and HIV infection treated with emtricitabine, tenofovir and recently started on efavirenz. He presented with zoster-like abdominal pain, tachypnoea, nausea and vomiting. On clinical examination, the patient was afebrile, hypotensive and tachycardic, he was markedly dehydrated and oliguric. The abdomen was soft, tender on palpation, not distended without rebound tenderness. The arterial blood gases revealed marked lactic acidosis and the laboratory tests on admission showed acute renal failure. The patient received nine treatments of slow continuous veno-venous hemofiltration (CVVHF). Despite the prolonged period of anuria, urine output progressively improved after 25 days and serum biochemical parameters of renal function returned to normal within 40 days. Health professionals must be aware of this uncommon effect in patients on antiretroviral treatment. Prompt initiation of CVVHF resulted in resolution of both lactic acidosis and renal failure.

Tolvaptan: a new therapeutic agent.

Tolvaptan is a new agent in the treatment of normovolemic and hypervolemic hyponatremia. It is a V(2) receptor antagonist inducing free water diuresis. It has been recently approved in USA and Europe for the treatment of hyponatremia associated with SIADH, cirrhosis as well as heart failure, while in hypovolemic hyponatremia its use is contraindicated. The drug also appears to be effective in the acute exacerbations of heart failure that need hospitalization. In the short-term tolvaptan seems to relieve acute congestive symptoms and improves mortality. However, the long-term effects on mortality are still controversial. The favorable short-term effects are ascribed to the selective V(2) receptor blocking, while the unopposed stimulation of V(1A) may give an explanation for the lack of long-term benefit. The drug should be initiated in the hospital setting because careful monitoring of fluid balance is recommended. It is administered orally giving the advantage of continuation in the outpatient setting. Moreover tolvaptan may have a role in the treatment of autosomal dominant polycystic kidney disease (ADPKD). Its effectiveness has been shown in animal models and Phase 3 clinical trial as well as an open-label study is now active. Since tolvaptan is metabolized by the cytochrome CYP3A4 in the liver physicians should be aware of possible drug to drug interactions. Resulting from large studies tolvaptan appears well tolerated. Common side effects are thirst, dry mouth and polyuria. Tolvaptan opens a new page not only in the treatment of normovolemic and hypervolemic hyponatremia but also in the treatment of acute decompensated heart failure and probably in ADPKD.

Reversal of refractory sulfasalazine-related renal failure after treatment with corticosteroids.

BACKGROUND: Sulfasalazine is a combination of sulfapyridine and 5-aminosalicylic acid and is used as a first-line treatment in inflammatory bowel disease. OBJECTIVE: We describe a case of acute interstitial nephritis that presented after 7 months of sulfasalazine therapy. Despite the discontinuation of the drug, the patient's renal function continued to deteriorate and recovered only when systemic corticosteroid treatment was initiated. CASE SUMMARY: A 19-year-old white male (weight, 65 kg) presented in November 2006 with upper abdominal pain, fever ≥38°C, bloody diarrhea, anorexia, and weight loss. Ulcerative colitis involving the left colon was diagnosed based on results of a colonoscopy and intestinal biopsy, and treatment was initiated with cefprozil 1 g/d, mesalamine 3 g/d, methylprednisolone 32 mg/d, and ranitidine 300 mg/d. All drugs were administered orally. Cefprozil and ranitidine were discontinued after 10 days. Mesalamine was discontinued 1 month later because of gastrointestinal adverse effects (vomiting and diarrhea), and methylprednisolone was tapered over the next 3 months to zero. The patient then had a relapse, and sulfasalazine 2 g/d orally was administered. Seven months after the initiation of sulfasalazine, the patient developed fatigue, nausea, fever more prominent in the afternoon (increased from 38°C to 40°C), and nocturia, and he was admitted to the hospital. He had no history of renal impairment. Laboratory test results showed elevated serum urea and creatinine levels (170 and 7 mg/dL, respectively), while kidney ultrasound showed normal kidneys without obstruction. The patient had a Naranjo Adverse Drug Reaction Probability scale score of 6, indicating a probable adverse drug reaction with sulfasalazine. Based on these findings, sulfasalazine-related nephrotoxicity was suspected, and the drug was discontinued. During the next 4 days, serum urea and creatinine values increased to 212 and 8.3 mg/dL, respectively, and then remained stable for 3 days. A renal biopsy was performed, which revealed changes compatible with granulomatous interstitial nephritis. The patient received methylprednisolone 500 mg IV for 3 days, followed by oral administration of methylprednisolone 16 mg/d for 1 month. Renal function recovered completely a few days after initiation of corticosteroids, and the patient's condition continued to be stable 1 year later (eg, serum urea, 34 mg/dL; creatinine level, 0.9 mg/dL). CONCLUSIONS: Although this isolated case of sulfasalazine- related interstitial nephritis cannot lead to definite conclusions, treatment with corticosteroids was effective in this patient and should be considered irrespective of the time of exposure to sulfasalazine. However, randomized controlled trials are needed to provide evidence regarding the efficacy and tolerability profile of corticosteroids.

The use of pregabalin in the treatment of uraemic pruritus in haemodialysis patients.

We evaluated the effect of pregabalin in the treatment of uraemic pruritus not due to secondary hyperparathyroidism. Sixteen haemodialysis patients suffering from uraemic pruritus resistant to conventional treatment started on pregabalin 25 mg/day orally. The parameters recorded were age, time on haemodialysis, haematocrit, Ca, PO4 , Ca × PO4 product, PTH, spKt/V, eosinophil counts and IgE. The effectiveness of pregabalin on uraemic pruritus was evaluated by using visual analogue scale before and after one month of treatment. Visual analogue scale consisted of a 10-cm horizontal line scored from 0 (no itch) to 10 (worst imaginable itch). Four patients discontinued treatment due to side effects and therefore were excluded from the study. The mean age of the remaining 12 patients was 61.2 ± 12.8 years, and the time on haemodialysis was 38 ± 39.1 months. The haematological and biochemical profile of the patients remained without significant change at the end of the observation period. There was a statistically significant difference between visual analogue scale values before and after the one month treatment period (7.44 ± 2.01 and 1.7 ± 1.31, respectively), p < 0.0003. Uraemic pruritus is a common and distressing symptom in patients undergoing haemodialysis. Pregabalin appears to be an effective alternative treatment.

Quality of life of Greek patients with end stage renal disease undergoing haemodialysis.

An evaluation of the quality of life of patients with end stage kidney disease undergoing haemodialysis in the Greek population was conducted to understand whether this quality could be improved. Comparisons were made with a similar study conducted in United States in regards to the effects of kidney disease in daily life, burden of kidney disease, work status, cognitive function, quality of social interaction, sexual function, social support, physical functioning, role physical on daily routine, pain, general health perceptions, role emotional, emotional well being, social function and energy/fatigue. Any differences are discussed and analysed. Sexual problems were found to be more prominent in this study, but the emotional status has greater influence in quality of life in the US study. The results were more positive in Greece with respect to dialysis staff encouragement, patient satisfaction, as well as acceptance and the understanding of illness. The results from our study reflect the differences of the health care systems in various countries as well as population-related beliefs and values.

Relation between insomnia mood disorders and clinical and biochemical parameters in patients undergoing chronic hemodialysis.

BACKGROUND: Sleep disturbances are usually the outcome of a complex interplay between intrinsic factors and environmental influences. Aim of this study was to investigate the incidence of insomnia and to assess its relation to clinical and laboratory parameters in hemodialysis patients. METHODS: Using Athens Insomnia Scale (AIS), sleeping profile of 45 subjects (32 male, 13 female, mean age 59+/-16.2 years) was evaluated. According to AIS, patients were divided into two groups. Group A comprised 32 patients with score 0-9 (absence of sleep disorders), whereas group B included 13 patients scoring higher than 9 (clinically assessed disorder). Subjects were compared in terms of socioeconomic, clinical, laboratory parameters and presence of depression (assessed by Hamilton Depression Scale, HAMD). RESULTS: No significant difference was observed with respect to age, sex, family status, education, self-esteem, coffee and alcohol consumption, time in hemodialysis and laboratory parameters. Group B demonstrated significantly lower albumin levels (3.65+/-0.38 and 3.9+/-0.24 g/dL respectively, p<0.01), higher CRP levels (1.88+/-1.9 and 0.92+/-0.64 mg/dL respectively, p<0.01) and exhibited depression (HAMD score 13.4+/-6.4 and 7.8+/-5.9 respectively, p<0.005). Moreover, significant correlation was observed when AIS scores were related to albumin (r=-0.29, p< 0.05), CRP (r=0.38, p<0.01) and HAMD scores (r=0.54, p<0.0001). CONCLUSIONS: Sleep disorders are common in hemodialysis patients. They seem to be related to high CRP and low albumin levels and demonstrate strong correlation to mood disorders, which are equally common to such patients.

Metformin-associated lactic acidosis treated with continuous renal replacement therapy.

INTRODUCTION: Lactic acidosis is an infrequent complication of metformin therapy for diabetes mellitus. The presence of clinical conditions, such as renal failure, increases the risk of metformin-associated lactic acidosis (MALA). We present a case of lactic acidosis in a patient with diabetes treated with metformin, complicated by acute renal failure in preexisting chronic nephropathy. CASE SUMMARY: A 70-year-old white male, weighing 77 kg, with diabetes mellitus, coronary heart disease, congestive heart failure (New York Heart Association class III), moderate essential hypertension (stage 2), and renal dysfunction (serum urea, 90 mg/dL; serum creatinine, 1.5 mg/dL; creatinine clearance, 49.8 mL/min/1.73 m2) presented to the emergency department of the General Hospital of Rhodes (Rhodes, Greece), complaining of malaise, respiratory distress, myalgias, disorientation, abdominal discomfort, and increasing somnolence of insidious onset. The patient's regimen included isosorbide mononitrate 60 mg QD, furosemide 40 mg QD, quinapril 20 mg QD, and metformin 850 mg TID. Before this hospitalization, he had received a 2-week course of oral diclofenac sodium 25 mg TID for low back pain. Preliminary laboratory evaluation found leukocytosis (27,300/mm3), severe renal failure (serum urea, 215 mg/dL; serum creatinine, 7.4 mg/dL; calculated creatinine clearance, 10.1 mL/min/1.73 m2), and a high anion gap metabolic acidosis (pH, 6.95; anion gap, 33 mEq/L) in arterial blood gas analysis. His medical and drug history, the clinical and laboratory findings, and the determination of lactate in samples of plasma (7.8 mEq/L), aroused the suspicion of MALA. The Naranjo algorithm scores for metformin and diclofenac sodium were 6 and 7, respectively. The patient received a single session of bicarbonate-buffered continuous venovenous hemodiafiltration (CWHDF) that lasted 16 hours. Ultimately, he was stabilized, and progressive restoration of acid-base balance and renal function was observed. DISCUSSION: We suspect that lactic acidosis may have been related to the use of metformin, the presence of heart and renal failure (contributing to metformin toxicity), and previous use of diclofenac sodium. CVVHDF has an advantage over conventional intermittent hemodialysis in that it corrects acidosis and removes lactate and metformin without risk of hypernatremia or fluid overload. CONCLUSIONS: MALA should be strongly suspected in diabetic patients presenting with high anion gap metabolic acidosis and increased serum lactate level. In the case described, prompt recognition of lactic acidosis and early application of bicarbonate-buffered CVVHDF produced successful results.