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Paolo Menè,1 Antonella Stoppacciaro,2 Silvia Lai,3 Francescaromana Festuccia4 1Division of Nephrology, Department of Clinical and Molecular Medicine, “Sapienza” University, Rome, Italy; 2Division of Pathology, Department of Clinical and Molecular Medicine, “Sapienza” University, Rome, Italy; 3Division of Nephrology, Department of Translational and Precision Medicine, “Sapienza” University, Rome, Italy; 4Division of Nephrology, Department of Internal Medicine, Sant’Andrea University Hospital, Rome, ItalyCorrespondence: Paolo Menè, Division of Nephrology, Department of Clinical and Molecular Medicine, “Sapienza” University, Via di Grottarossa 1035-1039, Rome, 00189, Italy, Tel +39 06 3377-5949, Email paolo.mene@uniroma1.itAbstract: “Cast nephropathy” (CN) is a pathological feature of myeloma kidney, also seen to a lesser extent in the context of severe nephrotic syndrome from non-haematological diseases. The name relates to obstruction of distal tubules by “casts” of luminal proteins concentrated by intensive water reabsorption resulting from dehydration or high-dose diuretics. Filtered proteins form complexes with endogenous tubular Tamm-Horsfall glycoprotein. The resulting gel further slows or stops luminal flow upon complete obstruction of distal convoluted tubules and collecting ducts. Thus, a tubular obstructive form of acute kidney injury (AKI) is a common consequence of CN. The pathogenesis of CN will be reviewed in light of recent advances in the understanding of monoclonal disorders of B lymphocytes, leading to the release of immunoglobulin components (free light chains, FLC) into the bloodstream and their filtration across the glomerular basement membrane. Treatment aiming at reduction of the circulating burden of FLC may help recovery of renal function in a fraction of these patients, besides filling the void between the onset of AKI, histopathological diagnosis, and full response to pharmacologic treatment.Keywords: light chain cast nephropathy, monoclonal gammopathies, multiple myeloma, immunoglobulins, hemodialysis, HFR-SUPRA

An Italian multidisciplinary working group discussed the current Italian scenario of osteoporosis management during a meeting and highlighted the essential role of calcium and vitamin D supplementation in the prevention of fragility fractures., Purpose: This paper aims to review and discuss data on calcium and vitamin D requirements and the role of combined calcium and vitamin D supplementation in the treatment of patients with osteoporosis., Methods: The discussion of the experts covered literature data on calcium and vitamin D supplementation, gaps in the diagnosis and treatment of osteoporosis, and the role of the primary care physician in identifying and treating patients with osteoporosis. Articles for consideration were identified through PubMed searches using different combinations of pertinent keywords., Results: The discussion highlighted that insufficient calcium or vitamin D intake increases the risk of fragility fractures. The experts also drew attention to the essential role of calcium and vitamin D supplementation in achieving an anti-fracture effect and supporting the efficacy of anti-osteoporotic agents without increasing nephrolithiasis and cardiovascular risks. In addition, the discussion underlined the role of the primary care physician in the initial clinical approach to patients with osteoporosis., Conclusions: The experts believe that efficient treatment for patients with osteoporosis should include calcium and vitamin D supplementation to achieve adequate levels that are able to inhibit the parathyroid hormone and bone resorption., (© 2024. The Author(s).)

Monoclonal gammopathies (MG) encompass a variety of disorders related to clonal expansion and/or malignant transformation of B lymphocytes. Deposition of free immunoglobulin (Ig) components (light or heavy chains, LC/HC) within the kidney during MG may result over time in multiple types and degrees of injury, including acute kidney injury (AKI). AKI is generally a consequence of tubular obstruction by luminal aggregates of LC, a pattern known as "cast nephropathy". Monoclonal Ig LC can also be found as intracellular crystals in glomerular podocytes or proximal tubular cells. Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent form of kidney injury with a sizable impact on renal function. Hypercalcemia (in turn related to bone reabsorption triggered by proliferating plasmacytoid B cells) may lead to AKI via functional mechanisms. Pharmacologic treatment of MG may also result in additional renal injury due to local toxicity or the tumor lysis syndrome. The present review focuses on AKI complicating MG, evaluating predictors, risk factors, mechanisms of damage, prognosis, and options for treatment.

Clinical Background: Cancer therapeutics (for both solid and hematological malignancies) have evolved over the last two decades, from traditional chemotherapies to novel treatments. A better supportive care, older patients with comorbidities who receive multiple chemotherapeutic and pharmacological regimens, multiple CT scans with contrast agents, and new therapeutic options are also increasing the number of cancer patients who can develop acute kidney injury (AKI) or chronic kidney disease (CKD). Challenges: Targeted therapies and immunotherapies, which harness the body's own immune system to fight cancer cells have led to improved survival in cancer patients, yet all are associated with many organ toxicities. Renal toxicity is mainly represented by acute tubular-interstitial damage, glomerular lesions, thrombotic microangiopathy, tumor lysis, proteinuria, arterial hypertension, AKI, CKD, and secondary fluid/electrolyte disturbances. On the other hand, it is important to consider how the presence of CKD, AKI, and other renal disorders may affect treatment options for the oncologists and patient's outcome. All these features require a specialized approach. Prevention and Treatment: A new evolving field, namely Onconephrology, has emerged during the last few years, including the broad spectrum of renal disorders that can arise in patients with cancer. Nephrologists have become an indispensable part of the multidisciplinary cancer care teams, but a clear and updated knowledge of solid and hematological malignancies, always new anticancer therapies, and their relationships with kidney function is essential to ensure the highest quality of care. In this chapter, we summarize the principal aspects of this new field of Nephrology., (© 2021 S. Karger AG, Basel.)

Addison disease is due to the destruction or dysfunction of the entire adrenal cortex. Nowadays, the causes of adrenal insufficiency are autoimmune disease for 70-90% and tuberculosis for 7-20%. Many typical signs and symptoms, such as hyponatremia, hyperkalaemia, or renal insufficiency can represent the reasons for a nephrology consultation, especially in conditions of urgency, and they can easily be confused with other causes. Moreover, the fact that in a short time range we have diagnosed the three cases described as a guide in this review, has aroused our attention as nephrologists on a disease in which we have probably already encountered but without recognizing it. The blood tests showed in all three patients severe electrolyte disorders and acute renal failure which will be discussed in their physiopathogenetic mechanisms. In a peculiar way, these alterations were not controlled with repolarizing solutions, fluid replacement and increased volemia, but only after steroid administration. In conclusion, in this review all the known pathogenic mechanisms causing disorders of nephrological interest in adrenal insufficiency are discussed.

Background/aims: Multiple myeloma (MM) represents 10% of all haematologic malignancies. Renal involvement occurs in 50% of MM patients; of them, 12-20% have acute kidney injury (AKI), with 10% needing dialysis at presentation. While hemodialysis (HD) has no effect upon circulating and tissue levels of monoclonal proteins, novel apheretic techniques aim at removing the paraproteins responsible for glomerular/tubular deposition disease. High cut-off HD (HCO-HD) combined with chemotherapy affords a sustained reduction of serum free light chains (FLC) levels. One alternative technology is haemodiafiltration with ultrafiltrate regeneration by adsorption on resin (HFR-SUPRA), employing a "super high-flux" membrane (polyphenylene S-HF, with a nominal cut-off of 42 kD). Aim of our pilot study was to analyze the effectiveness of HFR-SUPRA in reducing the burden of FLC, while minimizing albumin loss and hastening recovery of renal function in 6 subjects with MM complicated by AKI., Methods: Six HD-dependent patients with MM were treated with 5 consecutive sessions of HFR-SUPRA on a Bellco® monitor, while simultaneously initiating chemotherapy. Levels of albumin and FLC were assessed, calculating the rates of reduction. Renal outcome, HD withdrawal and clinical follow-up or death were recorded., Results: All patients showed a significant reduction of FLC, whereas serum albumin concentration remained unchanged. In three, HD was withdrawn, switching to a chemotherapy alone regimen. The other patients remained HD-dependent and died shortly thereafter for cardiovascular complications., Conclusion: Our study suggests that HFR-SUPRA provides a rapid and effective reduction in serum FLC in patients with MM and AKI, while minimizing the loss of albumin. When started early in combination with chemotherapy, blood purification by HFR-SUPRA was followed by the recovery of renal function in half of the patients treated., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background and Aims: In elderly subjects, renal insufficiency and osteoporosis often coexist with high risk of fracture and elevated socio-economic burden. Today a large number of effective anti-osteoporotic drugs are available but generally they are contraindicated in patients with chronic kidney disease (CKD) because of their progressive accumulation. Denosumab, instead, does not require dose adjustments for different degrees of renal impairment so it can be a valid treatment in osteoporotic patients with CKD. Limited data are available in the literature concerning the use of denosumab in hemodialysis (HD). The aim of our study was, therefore, to study the efficacy and tolerability of this drug in this particular subset of patients., Methods: We retrospectively reviewed the charts of 12 osteoporotic HD patients who received a single 60-mg subcutaneous dose of denosumab every 6 months for an observation period of 24 months. Serum electrolyte, markers of bone turnover and quantitative ultrasound (QUS) were evaluated., Results: Over 24 months, we observed a gradual improvement of bone metabolism: β-CrossLaps from 2567.08 ± 1264 to 1492.5 ± 1182.5 pg/ml; bone alkaline phosphatase (BALP) from 33.5 ± 28.8 to 11.8 ± 3.7 mcg/l, and of QUS index (T-score from -5.33 ± 1.58 to -4.84 ± 1.2; risk of fracture from 13.9 ± 4.7 to 11.07 ± 5.3 %). Few cases of hypocalcemia were detected, more significant after the first and second injection, but with careful monitoring of serum calcium and rapid therapy adjustment we could easily manage serum Ca levels., Conclusions: Our pilot experience highlights the safety and efficacy of denosumab in the treatment of osteoporosis in HD patients, potentially supporting its use to reduce the burden of fractures in this patient population.

Objectives: Despite universal infection control precautions, the risk of hepatitis B virus (HBV) infection in patients on chronic haemodialysis (HD) remains high. For this reason anti-HBV vaccination is recommended in these subjects. In hemodialyzed patients vaccinal response is often suboptimal and it's not clear what factors may influence it., Study Design: The aim of our study is to assess the influence of some clinical and laboratory factors on seroconversion rate after anti HBV vaccination in a cohort of patients on maintenance HD., Methods: We analysed 60 patients on regular HD, 40 men and 20 women (age 64±12 years, range 40-88 years), immunized with Engerix B ® vaccine, followed for an average time of 62 month (12-120 months). For each patient the following data were collected: age, serum albumin (sAlb), Blood urea nitrogen before HD session (BUN), age at vaccination, dialysis vintage, presence of systemic disease, type of vascular access, dialysis modality. Correlation between these factors and anti Hbs titer was estimated with multiple regression analysis., Results: Anti-Hbs seroconversion rate ( Anti Hbs > 10 IU/l) was 77%. Better rate of seroconversion (86%) was observed in patients with arteriovenous fistula (AVF) and serum albumin > 3,5 g/dL (93%), while higher rate of not responders (50%) in patients with systemic diseases. The only parameter correlated to anti Hbs titer was sAlb (p =0,0012). sAlb was correlated to age in all patients (p=0,01) and age was correlated to higher anti Hbs titer in the responder group (p=0,018)., Discussion: In our experience an early vaccination, when patients on chronic HD are younger and in better nutritional conditions, improves anti-HBV response.

Idiopathic retroperitoneal fibrosis (IRF) is a rare disease characterized by fibro-inflammatory reaction surrounding ureters and other inner organs with possible secondary renal involvement. Symptoms are aspecific and recurrent phases of activity are generally associated with elevation of inflammatory indices. 18F-FDG-PET is nowadays an important tool for the detection of this disease, allowing differentiation between metabolically active tissue and fibrotic one. The purpose of this study was to investigate the role of 18F-FDG-PET in the management of IRF and to evaluate possible correlations between biochemical parameters and PET/CT findings of disease activity. We enrolled seven consecutive patients with IRF (in five histology proved the disease) observed from 2003 to 2012 (5 M:2 F, mean age 53.8 years, range 44-86 years). All patients presented with fever as first symptom; two had obstructive renal failure requiring hemodialysis; one underwent monolateral nephrectomy for parenchyma infiltration; six presented ureteral involvement; three underwent ureteral stent placement. For each patient, during a mean total follow-up of 26.5 months we evaluated serum creatinine, BUN, Hb, RBCs, WBCs, PLT, CRP, ESR. Periodic 18F-FDG-PET/CT scans (every 5.9 months-mean) were performed in all patients. Statistical evaluation was performed using "stepwise regression" analysis. Steroids and immunosuppressive agents induced a progressive normalization of PET/CT scans in all patients at the end of follow-up. Stepwise regression analysis showed that BUN, serum creatinine and CRP only if considered together, significantly correlated with SUV max (p value = 0.000003057). 18F-FDG-PET is a useful tool for clinical decision making in patient with IRF, allowing to evaluate the efficacy of the pharmacological treatment and to detect early recurrences, to modify the therapeutic approach. Acute phase reactants are not reliable alone for the management and the follow-up as they are often not concordant with metabolic assessment of the disease. In patients with ureteral involvement, CRP together with BUN and serum creatinine has a significant correlation with PET/CT results, and can help physicians in therapeutic approach, better than a single parameter.

Purpose: Thyroid malignancies can be treated by surgery followed by ablation of the remnant tissue with 131I. As iodide removal from the body occurs by renal extraction, in patients suffering from end-stage renal disease it is necessary to properly evaluate both timing and method of the extracorporeal treatment.
, Methods: We present two patients on regular hemodialysis, admitted in isolation to the Nuclear Medicine Department and treated with 131I for thyroid carcinoma diagnosed during the check-up for transplantation. Both patients underwent two hemodialysis sessions with a portable machine for CRRT (continuous renal replacement therapy), 24 and 48 hours after the administration of 50 mCi of 131I. The nursing staff were monitored with a dosimeter. Radioactivity of the patients, dialysate and urines were measured during hemodialysis. 
, Results: The greater reduction was obtained with the first dialysis, but in both patients a further, though shorter, hemodialysis at 48 hours was necessary for reaching a patient's radioactivity compatible with discharge. Radioactivity measured in the dialysate demonstrated the almost total removal of radioiodine by dialysis alone. In both patients, follow-up exams revealed a complete ablation of thyroid tissue, without signs of local recurrence. The dose of radioactivity of the dialysis staff was below allowable limits. 
, Conclusions: We conclude that a successful reduction of radioactivity, without dispersing its therapeutic efficacy, can be obtained with daily hemodialysis with a CRRT machine in patients in isolation treated with 131I. A therapeutic model is proposed.

The syndrome of inappropriate ADH secretion (SIADH), also termed ''syndrome of inappropriate antidiuresis (SIAD)'', is an often unrecognized cause of hypotonic hyponatremia, arising from ectopic release of ADH in lung cancer or as a side effect of various drugs. In SIADH, hyponatremia results from selectively impaired water excretion by the kidney, whereas the external Na+ balance is normally regulated. Despite the increase in total body water, only a slight reduction of urine output and modest edema are usually seen. Renal function and acid-base balance are generally preserved, while subclinical neurological impairment may occasionally become life-threatening, when hyponatremia has an abrupt onset. The major clinical variants of SIADH are reviewed here, with particular emphasis on causes, iatrogenic complications and hospital-acquired hyponatremia. Effective treatment of SIADH is based on water restriction, hypertonic saline plus loop diuretics, or aquaretics. Worsening of hyponatremia may result from parenteral isotonic fluid administration, emphasizing the importance of an early diagnosis and careful follow-up of these patients.

Background and Aim: Despite a similar Helicobacter pylori prevalence, peptic ulcer is more frequent in cirrhotic patients than in controls. We evaluated whether cirrhotic patients had an increased bacterial density and/or a higher prevalence of H. pylori cagA-positive strains than controls., Methods: A total of 36 dyspeptic cirrhotic patients with H. pylori infection and 72 matched controls were enrolled. H. pylori infection was detected at histology on Giemsa staining, bacterial density was assessed using difference over baseline (DOB) values at 13C urea breath test, and cagA status was established at serology., Results: Overall, both DOB values and prevalence of cagA did not significantly differ between cirrhotic patients and controls. However, peptic ulcer controls showed significantly higher DOB value (27.9 +/- 17.4 vs 19.4 +/- 9.3, respectively; P = 0.009) and cagA positive rate (85%vs 48%; P = 0.01) than non-ulcer dyspepsia patients. Although not statistically significant, a similar trend was observed in cirrhotic patients with peptic ulcer for DOB values (26.5 +/- 16.3 vs 18.3/1000 +/- 9.2, respectively; P = 0.07), whereas the cagA-positive rate was similar between peptic ulcer and non-ulcer dyspepsia patients (60%vs 50%; P = 0.30)., Conclusions: The present data showed that both bacterial density and cagA prevalence did not differ between cirrhotic patients and controls.

Objectives: Few data exist regarding the degree of portal hypertension in hepatitis C virus (HCV)-related cirrhosis, as the majority of studies have included mainly patients with alcoholic cirrhosis. This study was aimed at comparing the severity of portal hypertension in patients with HCV-related or alcoholic cirrhosis., Methods: In total, 59 cirrhotic patients with portal hypertension (HCV-related in 34 cases and alcoholic in 25) underwent main right hepatic vein catheterization, with determination of the wedged and free hepatic venous pressures, and of hepatic venous pressure gradient (HVPG)., Results: HVPG values did not differ between the two groups of patients (19.4 +/- 6.0 mmHg vs 18.5 +/- 3.5 mmHg; P = 0.51). The prevalence and degree of oesophageal and gastric varices and portal hypertensive gastropathy did not correlate with the aetiology. Patients with viral cirrhosis had a lower prevalence of previous bleeding than those with alcoholic cirrhosis, despite a similar proportion of large varices in the two groups and similar HVPG levels. In both groups of patients, HVPG did not differ between patients with previous bleeds and those without., Conclusions: The degree of portal hypertension in cirrhotic patients does not correlate with the cause of the disease. Thus, current statements on the management of portal hypertension, although based upon studies including mainly patients with alcoholic cirrhosis, can be applied also to patients with viral-related cirrhosis.

Recovery from kidney injury through repair mechanisms often linked to inflammation is conditioned by nature and severity of the insult. In the assessment of kidney repair, functional recovery should be kept distinct from structural repair: compensatory hypertrophy/function of intact nephrons often masks the inability of the kidney to heal or replace damaged structures. The mechanisms of repair reflect three degrees of injury, differently handled by the kidney. First, repair of DNA damage is accomplished through proofreading DNA polymerases, along with other controls for sequence misalignment / nucleotide replacement. If DNA cannot be repaired, cells carrying mutation(s) are disposed of through apoptosis, which is also critical to clearing damaged kidney cells and infiltrating leukocytes in acute and chronic ischemic, immunological, or chemical damage. A second mechanism of repair is linked to proliferation of surviving cells. At least 5 types of reparative proliferation are known to occur, some of which implicate stem cell immigration from distant reservoirs, followed by in situ differentiation. A third mode of repair could be referred to as structural repair, indeed limited in the human kidney by the absence of postnatal nephrogenesis. Recovery from acute tubular necrosis involves remodelling of the proximal tubule, with a strict requirement for integrity of the basement membrane. Contrary to the current dogma that only acute injury can be repaired, whereas chronic damage leads to irreversible loss of nephrons, evidence is emerging that some degree of renal remodelling occurs even in chronic renal disease, despite the occurrence of stabilized structural changes.

Kidney injury is repaired by inflammatory and non-inflammatory mechanisms, with the extent of recovery based on severity of the insult. Critical to the assessment of kidney repair is the ability to differentiate functional recovery from structural repair: compensatory increases in the function of intact residual nephrons often mask the inability of the kidney to heal or replace damaged structures. The mechanisms of repair reflect three levels of injury, which are handled differently by the kidney. First, DNA damage is countered by proof-reading DNA polymerases, backed by other controls for sequence misalignment/nucleotide replacement. If DNA cannot be repaired, cells harboring mutation(s) are lost through apoptosis, which is also critical to the disposal of kidney cells and infiltrating leukocytes in both acute and chronic ischemic, immunological, or chemical damage. This leaves room for a second mechanism of repair, i.e., cellular proliferation. At least 5 types of reparative proliferation are known to occur, some of which involve stem cell differentiation and perhaps immigration from distant reservoirs. The final type of repair is referred to as structural repair, actually quite limited by lack of postnatal nephrogenesis in the human kidney. Certain forms of recovery after acute tubular necrosis involve extensive remodeling of the proximal tubule, where integrity of the basement membrane is required for successful repair. Contrary to the long-held belief that only acute injury can be repaired, while ongoing chronic damage leads to progressive nephron loss, evidence is emerging that some degree of renal remodeling occurs even in the presence of persistent structural changes.

Non-enzymatic accumulation of advanced glycation end-products (AGE) is to some extent a physiologic consequence of tissue aging. On the other hand, circulating AGE and tissue deposits mark the course of diabetes mellitus as well as a variety of other vascular or degenerative diseases. AGE generation is paralleled by oxidative damage and lipid peroxidation within target tissue, with features of inflammation through the involvement of monocytes/macrophages expressing receptors for glycated macromolecules. Over the past 15 years, a wealth of data concerning the pharmacology of AGE have been gathered through animal and human investigations, targeting their likely contribution to the progression of diabetic and non-diabetic vascular damage. Several agents have been shown to interfere with the formation of AGE or AGE precursors, bind to tissue receptors, or promote breakdown of deposits. The first and most studied inhibitor, aminoguanidine, has shown extensive beneficial effects in experimental models of diabetic vascular damage, recently entering phase I-III clinical investigation. Newer anti-AGE agents include pyridoxamine and the so-called 'amadorins', cross-link breakers, AGE binders and receptor antagonists.

An 11-year old boy with acute lymphoid leukemia underwent umbilical cord stem cell infusion. This was followed at day 15 by the onset of asymptomatic hypotonic isovolemic hyponatremia. The disorder could be attributed to a syndrome of inappropriate ADH secretion (SIADH), most probably related to the massive i.v. induction treatment with cyclophosphamide. The major causes and clinical variants of SIADH are reviewed, with particular emphasis on the complications of chemotherapy in hematological diseases. Worsening of hyponatremia during routine parenteral feeding, as opposed to normalization of plasma Na+ by infusion of hypertonic saline, emphasize the importance of early accurate diagnosis and careful follow-up of these iatrogenic sequelae of stem cell allograft.