Giuseppe Rombolà

Correction of Hypokalemia with Antialdosterone Therapy in Gitelman’s Syndrome

Six adult patients (4 females and 2 males, age range 26-57 years) with Gitelmans syndrome (GS) were treated with spironolactone 200-300 mg/day (n = 5) and/or amiloride 10-30 mg/day (n = 3) for 1-18 months. The patients had hypokalemia, hyperreninemia, chloride-resistant metabolic alkalosis, renal hypomagnesemia (n = 5), and hypocalciuria (n = 5). Free water clearance studies during maximal water diuresis and furosemide administration were suggestive of a solute reabsorptive defect beyond the loop of Henle. Antialdosterone therapy induced a significant increase of PK (from 2.6 +/- 0.4 to 3.4 +/- 0.4 mM; p < 0.0001) and a decrease of CK (from 21.4 +/- 13.2 to 10.6 +/- 4.8 ml/min, p < 0.02) and FEK (from 21.0 +/- 13.6 to 13.4 +/- 5.7%; p < 0.03); PMg increased from 1.38 +/- 0.38 to 1.64 +/- 0.21 mg/dl (p < 0.03) with a parallel fall of CMg (from 5.5 +/- 2.3 to 2.9 +/- 1.5 ml/min; p < 0.02) and FEMg (from 5.7 +/- 2.6 to 2.9 +/- 0.6%; p < 0.05); arterial blood pH and HCO3- did not change (P = plasma, C = clearance, FE = fractional excretion). The creatinine clearance fell (from 90.5 +/- 16.8 to 65.8 +/- 20.9 ml/min; p < 0.05), and Prenin rose (from 16.6 +/- 8.9 to 35.3 +/- 25.3 ng/ml/h; p < 0.02, as did Paldo (from 26.1 +/- 12.3 to 109 +/- 82.6 ng/dl; p < 0.01), indicating extracellular fluid volume contraction; however no significant clinical symptoms of hypovolemia ensued.(ABSTRACT TRUNCATED AT 250 WORDS)

Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome

BACKGROUND Alport syndrome is a clinically and genetically heterogeneous nephropathy characterized by glomerular basement membrane lesions often associated with hearing loss and ocular anomalies. While the X-linked and the autosomal recessive forms are well known, the autosomal dominant form is not well acknowledged. METHODS We have clinically investigated 38 patients with a diagnosis of autosomal dominant Alport syndrome belonging to eight different families. The analysis of the COL4A4 gene was performed by denaturing high performance liquid chromatography and automated DNA sequencing. RESULTS In our cohort of patients, only 24.3% (9/37) reached end-stage renal disease, at the mean age of 51.2 years. Four patients had hearing loss (13.3%) and none ocular changes. Molecular analysis revealed eight novel private COL4A4 gene mutations: three frameshift, three missense and two splice-site mutations. CONCLUSIONS These data indicate autosomal dominant Alport syndrome as a disease with a low risk of ocular and hearing anomalies but with a significant risk to develop renal failure although at an older age than the X-linked form. We were unable to demonstrate a genotype-phenotype correlation. Altogether, these data make difficult the differential diagnosis with the benign familial haematuria due to heterozygous mutations of COL4A4 and COL4A3, especially in young patients, and with the X-linked form of Alport syndrome in families where only females are affected. A correct diagnosis and prognosis is based on a comprehensive clinical investigation in as many family members as possible associated with a broadly formal genetic analysis of the pedigree.

Divert to ULTRA: differences in infused volumes and clearance in two on-line hemodiafiltration treatments.

Background: Mixed diffusive-convective dialysis therapies offer greater removal capabilities than conventional dialysis. The aim of this study was to compare two different on-line, post-dilution hemodiafiltration (HDF) treatments with regard to achieved convective volume and middle-molecule dialysis efficiency: standard volume control (sOL-HDF) and automated control of the transmembrane pressure (TMP) (UC-HDF). Methods: We enrolled 30 ESRD patients (55.9 ± 14.0 years, 20/10 M/F) in a randomized, prospective, crossover study. The patients received a 3-month period of sOL-HDF followed by UC-HDF for a further 3 months, or vice versa, using the same dialysis machine. In sOL-HDF, fixed exchange volumes were set according to a filtration fraction greater than or equal to 25%. In UC-HDF therapy, the exchanged volume was driven by a biofeedback system controlling the TMP and its set point in a double loop. Patients maintained their treatment time, dialyzer, blood flow rate, and anticoagulant regimen unchanged throughout the study. Results: Greater convective volumes were achieved in UC-HDF than in sOL-HDF (23.8 ± 3.9 vs.19.8 ± 4.8 L; p<0.001) with high pre-dialysis Ht value (sOL-HDF 34.0 ± 4.5% and UC-HDF 34.0 ± 4.4%; p = 0.91). The average clearance values of β2m and P were higher in UC-HDF than in sOL-HDF (respectively 123 ± 24 vs. 111 ± 22 ml/min, p<0.002 and 158 ± 26 vs. 152 ± 25 ml/min, p<0.05). Moreover, the UC-HDF mode led to a significantly increased rate of call-free sessions from 88% to 97% (p<0.0001). Conclusions: This study showed that the biofeedback module, applied to the automatic control of TMP in on-line HDF, results in higher convective volumes and correspondingly higher β2m and P clearances. By making the HDF treatment more automated and less complex to perform, it significantly reduced the staff workload.

Patient-specific modeling of multicompartmental fluid and mass exchange during dialysis

Background Dialysis is associated with a non-negligible rate of morbidity, requiring treatment customization. Many mathematical models have been developed describing solute kinetics during hemodialysis (HD) for an average uremic patient. The clinical need can be more adequately addressed by developing a patient-specific, multicompartmental model. Materials and Methods The data from 148 sessions (20 patients), recorded at the Regional Hospital of Lugano, Switzerland, were used to develop and validate the mathematical model. Diffusive and convective interactions among patient, dialysate and substitution fluid were considered. Three parameters, related to mass transfer efficiency at the cell membrane, at the dialyzer and at the capillary wall, were used to tune the model. The ability of the model to describe the clinical evolution of a specific HD session was evaluated by comparing model outputs with clinically acquired data on solutes and catabolite concentrations. Results The model developed in this study allows electrolyte and catabolite concentration trends during each HD session to be described. The errors obtained before the estimation of the patient-specific parameters drastically decrease after their identification. With the optimized model, plasmatic concentration trends can be described with an average percent error lower than 2.1% for Na+, CI-, Ca2+ and HCO3-, lower than 5% for K+ and lower than 8% for urea. Conclusions The peculiarity of the proposed model is the possibility it offers to perform a real-time simulation enabling quantitative appraisal of hematochemical quantities whose direct measurement is prohibitive. These will be beneficial to dialysis therapy planning, reducing intradialysis complications and improving patients’ quality of life.

Distal Nephron Function in Familial Hypokalemia - Hypomagnesemia (Gitelman's Syndrome)

Dr. Giacomo Colussi, Divisione di Nefrologia e Dialisi, Ospedale Niguarda-Ca’ Granda, Piazza Ospedale Maggiore, 3, I20162 Milan (Italy) Dear Sir, In the November 1992 issue of Nephron , Zarraga Larrondo et al. [1] described a patient with the so-called familial hypokalemia-hy-pomagnesemia, or Gitelman’s syndrome [2], also known as ‘hypocalciuric variant’ of Bartter’s syndrome [3, 4]. They contend that fractional distal solute reabsorption (evaluated as the Ch2o/[CH2o + CCJ ratio during maximally diluted diuresis) was reduced, as expected (indicating abnormal distal nephron function) in the patient when urine dilution was achieved by hypotonic saline infusion, but was instead normal when urine was diluted by an oral water load. These apparently divergent results on distal nephron function are rather difficult to explain, and indeed efforts made by the authors to conciliate them appear rather unconvincing. However, if one looks at their data, it appears that all their efforts might have been unnecessary. In tables 1 and 2 of their paper, C1⁄8o and Cα values are given as 8.09 and 4.15 ml/min, respectively (this latter value was obtained by correcting the reported CCι value of 3.46 ml/dl GF by the corresponding GFR of 120 ml/ min). It is easy to calculate that the Ch2o/(Ch2o + Cα) ratio corresponds to 66.1% (a much lower value than the 80-92 reference range), and not to 88.3%, as reported in table 1 [1]. Accordingly, since CNa is also reported (2.25 ml/dl GF, i.e. 2.7 ml/min), one can calculate a C1⁄8o + CNa value of 10.79 ml/min (and not of 10.31 ml/min as reported in table 1), with a C7⁄8o/(C7⁄8o + CNa) ratio of 75%, again an abnormally low value. Thus, it appears that some computation mistake might have occurred, leading to an erroneous evaluation of the fractional distal solute reabsorption. Indeed, no ‘avid reabsorption of chloride’ can be said to exist in this patient, whereas abnormal distal nephron function could instead be detected not only during hypotonic saline infusion, but also during oral water load. In the same paper [1], the authors compared a series of parameters in their patient with reference values from a paper of ours [5]; unfortunately, some of these reference values were taken incorrectly. Among others, the reference value for Cα after furosemide is not 15.2 ± 1.6 (table 2) but 20.9 ± 6.5 ml/dl GF, CNa after furosemide (table 2) was not given in our paper, and the reference value for C1⁄8o after furosemide is not 15 ± 3 ml/min (table 1). This latter value in our paper [5] represents ‘total’ C7⁄8o generated by the distal nephron, i.e. the sum of C1⁄8o before furosemide and free water back-diffusion (which is the difference between urine flow rate after and before furosemide). Values for free water generation after furosemide administration were not given in our paper [5], and would correspond to 6.2 ± 2.5 ml/min [4]. Thus, it would appear

Diagnostic specificity of autoantibodies to M-type phospholipase A2 receptor (PLA2R) in differentiating idiopathic membranous nephropathy (IMN) from secondary forms and other glomerular diseases

Autoantibody against phospholipase A2 receptor (anti-PLA2R) is a sensitive and specific biomarker of idiopathic membranous nephropathy (iMN), being found in approximately 70% of iMN patients and only occasionally in other glomerular diseases. However, whereas its diagnostic specificity vs. normal controls and other glomerulonephritides (GN) has been firmly established, its specificity vs. membranous nephropathy associated with various diseases (sMN) has given inconsistent results. The aim of our study was to evaluate the prevalence of anti-PLA2R antibodies in iMN in comparison with various control groups, including sMN. A total of 252 consecutive iMN patients, 184 pathological and 43 healthy controls were tested for anti-PLA2R antibody using indirect immunofluorescence (PLA2R IIFT, Euroimmun). Anti-PLA2R autoantibodies were detectable in 178/252 iMN patients, 1/80 primary GN, 0/72 secondary GN, 9/32 sMN and 0/43 healthy controls, with a diagnostic sensitivity of 70.6%. The diagnostic specificity of anti-PLA2R antibody vs. normal and pathological controls was 100 and 94.6% respectively. However, when the diagnostic specificity was calculated only vs. secondary forms of MN, it decreased considerably to 71.9%. Interestingly enough, 9 out of 10 anti-PLA2R positive patients in the disease control groups had membranous nephropathy associated with various diseases (7 cancer, 1 Crohn’s disease, 1 scleroderma). In conclusion, anti-PLA2R positivity in a patient with MN, should not be considered sufficient to abstain from seeking a secondary cause, especially in patients with risk factors for neoplasia. The causal relationship between tumors and anti-PLA2R-induced MN remains to be established, as well as the possible mechanisms through which malignancies provoke autoimmunity.

Rosuvastatin-Induced Acute Interstitial Nephritis

We report a case of acute interstitial nephritis (AIN), most likely induced by rosuvastatin, in an 83-year-old male patient. The patient underwent angioplasty of the left internal carotid artery, after which he began a regimen of rosuvastatin (20 mg/day). After 3 weeks the patient was admitted to our unit for acute renal failure with mild proteinuria with negligible urinary sediment. A left kidney biopsy showed dense interstitial infiltrates, mainly composed of lymphocytes with evident tubulitis. Rosuvastatin withdrawal plus prednisolone (1 mg/kg/day) treatment, which was slowly tapered over a period of 4 weeks, allowed for a complete recovery of renal function. To our knowledge, this is the first case report of rosuvastatin-induced AIN. Acute renal failure is associated with a clear increase in morbidity, length of hospital stay and mortality. Moreover, since statins are among the most widely prescribed drugs in Western countries, we think that the risk of AIN should be taken into account as a possible side effect of rosuvastatin.

Post-procedural hemodiafiltration in acute coronary syndrome patients with associated renal and cardiac dysfunction undergoing urgent and emergency coronary angiography

We investigated the use of a 3‐hr treatment with hemodiafiltration, initiated soon after emergency or urgent coronary angiography in acute coronary syndrome (ACS) patients with associated severe renal and cardiac dysfunction.

Calcium Oxalate (CaOx) Urine Supersaturation in Calcium Stone Formers (CSF): Hypercalciuria versus Hyperoxaluria

Calcium oxalate is the most frequent constituent of urinary calculi in idiopathic stone disease. Urinary excretion of both calcium (Ca) and oxalate (Ox) are recognised as risk factors1; however, there is still disagreement on the relative role played by each of the two in the genesis of urine supersaturation for CaOx. On the one hand, it has been shown that stone recurrence is related to oxalate excretion but not to calcium excretion2. On the other hand, it is widely recognized that reduction in Ca excretion (either by diet or with drugs) is highly effective in reducing the stone recurrence rate3,4, even though Ox excretion may increase. This is because intestinal calcium absorption and Ca excretion are frequently increased in CSF and the decline in urinary calcium is typically more prominent than the modest increase in urinary oxalate3. The aim of our study was to evaluate CaOx urine supersaturation in relation to either Ca or Ox excretion in a large group of idiopathic CSF in an attempt to determine if either of the two has a more relevant clinical importance.

Assessment of intradialysis calcium mass balance by single pool variable‐volume calcium kinetic model

Introduction: A reliable method of intradialysis calcium mass balance quantification is far from been established. We herein investigated the use of a single‐pool variable‐volume Calcium kinetic model to assess calcium mass balance in chronic and stable dialysis patients.