Autosomic Dominant Tubulo Interstitial Kidney Disease: Case Report of a New Variant of the UMOD Gene


Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a low-prevalence pathology mainly associated with pathogenic variants of the UMOD gene. It is characterized by the progressive deterioration of renal function, associated with hyperuricemia and accompanied by a family history of gout or hyperuricemia. Often, clinical variability and a lack of molecular testing results in diagnostic failure to determine the ADTKD-UMOD association.

Case presentation: We describe the case of a 14-year-old male who presented to the nephrology service with hyperuricemia, renal ultrasonographic changes, and progression to chronic kidney disease in 4 years. He had a family history of hyperuricemia. A probable genetic disease with an autosomal dominant inheritance pattern was considered, confirmed by the presence of a probably pathogenic variant of the UMOD gene, not previously reported in the literature.

Conclusion: The investigation of this case led to the identification of a new variant in the UMOD gene, broadening the spectrum of known variants for ADTKD-UMOD. In addition, in this case, a comprehensive anamnesis, that takes into account family history, was the key point to carry out genetic tests that confirmed the diagnosis suspicion. Directed Genetic tests are currently an essential diagnostic tool and should be performed as long as they are available and there is an indication to perform them.

Keywords: UMOD, Uromodulin, hyperuricemia, Uric acid, Familial Juvenile Hyperuricemic Nephropathy, case report


Interstitial nephropathies (IN) compromise not only the interstitial tissue of the kidney, but also the renal parenchyma, affecting the glomerulus, tubules and blood vessels at the renal level [1, 2]. Autosomal dominant tubulointerstitial kidney disease (ADTKD) was recently introduced in the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines [3], and includes genetic disorders with high penetrance (~100%); however, few cases have been reported in unaffected heterozygous individuals [4]. To date (April 2023), five genes associated with the disease have been described: UMOD (ADTKD-UMOD), REN (ADTKD-REN), MUC1 (ADTKD-MUC1), HNF1B (ADTKD-HNF1B) and SEC61A1, the last one still without clear clinical relevance and defined outcome [13, 5].

Regarding frequency, the main cause of ADTKD is secondary to pathogenic variants in the MUC-1 gene (Spain 42.5% and Ireland 64%), followed by the UMOD gene (35%), and in third place HNF1B gene variants (13.9%). So far, only 14 affected families have been reported in the literature with REN gene-related ADTKD [6, 7].

The clinical profile can be heterogeneous according to the variant and age group, even within the same families. Different levels of proteinuria, urinary sediment, and microscopic hematuria could be present [2]; despite this, the progressive decrease in renal function that leads to end-stage chronic kidney disease (ESKD) seems to be a characteristic sign [1, 7], which could be; depending on the genetic variant [3, 7, 8], also accompanied by bilateral renal hypoplasia [1].

Corticomedullary differentiation is compromised, and in severe cases, the presence of cystic lesions can be observed. Some specific pathogenic variants in the UMOD gene (ADTKD-UMOD) are associated with hyperuricemia, which may initially be mild but can progress to severe forms [9]. As renal involvement evolves, it can be associated with high blood pressure (HBP). For patients with the REN gene variant (ADTKD-REN), tubulointerstitial involvement may be more severe, even associated with early anemia [1, 5, 7].

The highly nonspecific symptoms, slow progression, and wide variability in the age of presentation of ADTKD have made this a challenging diagnosis [1]. Chronic kidney disease (CKD) caused by pathogenic variants in the UMOD gene has a low prevalence, although it may be underdiagnosed. The variants in UMOD are closely related to ADTKD and medullary cystic kidney disease type 2 (MCKD2) [1, 7]. Therefore, we suspect that understanding the pathology is crucial to carry out a better follow-up and try to reduce the impact of the disease: diminishing the rapid progression towards CKD and the early identification of relatives at risk [1].


Case presentation

This is a 14-year-old male patient, asymptomatic, who was referred to the pediatric nephrology clinic due to an incidental finding of renal abnormalities evidenced by renal and urinary tract ultrasonography. With no relevant personal pathological history, but with a history of his father diagnosed with gouty nephropathy, end-stage chronic kidney disease at 22 years of age, and a kidney transplant at 28 years of age. Given the paternal history, the parents of the case performed annual laboratory and imaging surveillance, without findings of renal involvement until the patient was 14 years old. In the annual study, bilateral hyperechogenicity of the renal medulla was reported and confirmed with a second ultrasound.

The physical examination revealed a good general condition with vital signs within normal parameters for their age, height, and gender, including blood pressure (below the 95th percentile). The patient had an adequate nutritional status for his height, and body mass index in the normal range and without relevant clinical findings.

Based on the imaging findings, we proceeded to rule out associated pathologies that could be related, such as hyperparathyroidism, hypophosphatasia, hypercalcemia, and hypomagnesemia. There was no evidence of any disorder in the metabolism of calcium, phosphorus, or minerals, nor consumption of vitamin D analogues, hypercalciuria or hyperoxaluria, proximal tubulopathy or loop of Henle involvement. Thyroid function was also normal.

The study showed a serum creatinine of 1.3 mg/dl, which resulted in a calculated glomerular filtration rate by modified Schwartz equation of 58 cc/1.73/min and a serum uric acid of 10.8 mg/dl. Therefore, paraclinical confirmation was established, which reaffirmed the presence of KDIGO 3A1 classification CKD plus hyperuricemia without albuminuria or hyperuricosuria.

Given the clinical context of the patient, the family tree was elaborated (Figure 1). There, other cases of paternal line hyperuricemia were identified. And, due to the inheritance pattern, an autosomal dominant disease was considered as a differential diagnosis.

Figure 1. Family tree of the patient described in the clinical case.
Figure 1. Family tree of the patient described in the clinical case.

A Next Generation Sequencing (NGS) genetic panel was requested for the REN, SEC61A1, and UMOD genes, which reported the presence of a probably pathogenic variant in the UMOD gene: c.287G>C; p.Cys96Ser, which has not been previously described in the literature. A study of the variant was carried out on the patient’s father, confirming its presence and the diagnosis in the father. Genetic counseling was carried out on the patient and his parents, and the family variant study was recommended for his sister and all relatives at risk.

Simultaneously, while the genetic study was carried out, the medical approach involved initiating treatment with a hypouricemic agent (allopurinol) at 50 mg/m2 every 24 hours. During the patient’s follow-up (4 years), the dose was gradually increased, reaching 200 mg/day. At this point, a reduction in hyperuricemia was observed. Despite the progression of the KDIGO stage of chronic kidney disease from 3A1 to 3B1, the treatment dose was stable.

Transition to adult nephrology was made as the patient reached 18 years of age. Currently, the patient is clinically and paraclinically stable, without progression of the CKD stage.



ADTKD due to alteration of the UMOD gene (ADTKD-UMOD), was formerly known as familial juvenile hyperuricemic nephropathy type 1 (FJHN1), medullary cystic kidney disease type 2 (MCKD2), or UMOD-associated kidney disease [2, 10]. This is a disease caused by pathogenic or probably pathogenic variants in uromodulin, which is considered rare, but is the second cause of ADTKD-gen-associated disease [8].

Importantly, although ADTKD-UMOD is related to a high percentage of family history of hyperuricemia and kidney disease, in some cases there may be an apparent lack of family history due to incomplete penetrance and variable expressivity of the disease [8]. Therefore, in patients with hyperuricemia or renal disease with no known family history, the possibility of pathogenic variants in the UMOD gene should be considered and genetic studies should be tracked into account for accurate diagnosis and appropriate management [5, 11].

The clinical characteristics of ADTKD-UMOD are determined by the presence of hyperuricemia with progressive deterioration of renal function at an early age [8]. Hyperuricemia is generally associated with hyperuricosuria, which promotes uric acid adherence at the level of tubular epithelial cells [3]. The formation of uric acid crystals in the renal tubules causes a local inflammatory response and histological changes, not only related to these deposits, but also due to hemodynamic disturbances and changes in the vascular structure, leading to glomerular arterial disease [1, 1214].

Hyperuricemia stimulates the renin-angiotensin system and affects endothelial nitric oxide release and action, leading to magnification of vasoconstriction of the renal vasculature and increased glomerular pressure, followed by glomerulosclerosis and tubulointerstitial fibrosis [3, 1215].

It’s important to remember that ADTKD is one of the causes of ESRD and is associated with the UMOD, MUC, HNF1B, REN, and SEC61A1 genes [1, 7, 15], with UMOD being the most frequent [1, 5].

The UMOD gene encodes uromodulin, also known as the Tamm-Horsfall glycoprotein. This protein is highly glycosylated and contains four epidermal growth factor (EGF) like domains, a cysteine-rich (D8C) domain, and a zona pellucida bipartite domain, allowing for protein polymerization [4]. Uromodulin binds to glycosylphosphatidylinositol and promotes the integrity and impermeability of the thick ascending limb of the loop of Henle [1517]; it is also expressed in the initial part of the distal convoluted tubule [2].

Patients with disease-causing variants have low urinary uromodulin excretion due to impaired uromodulin retention in the endoplasmic reticulum of the tubular cells of the ascending limb of the loop of Henle [1821]. Consequently, the abnormal expression of the protein in the thick ascending branch of the loop of Henle generates a decrease in the reabsorption of Na+K+-2Cl, generating alterations in the urinary concentration capacity, promoting the reabsorption of sodium and urate at the proximal contouring tubule level [16]. All these actions cause local inflammatory processes that generate atrophy and cell death, which leads to an impact on the urinary excretion of uric acid, determining hyperuricemia and progressive CKD [18, 20, 22].

In our patient and his father, the presence of the variant c.287G>C, p.Cys96Ser in heterozygosity, classified as probably pathogenic, located in the exon 4 of the UMOD gene was evidenced. To date, this variant has not been reported in the literature; variants in the same codon have been classified as probably pathogenic, which suggests that this change can generate a deleterious effect on uromodulin. Furthermore, we analyzed fifteen in silico predictors, all of which classified the variant as pathogenetic. It has been described that approximately 95% of the UMOD gene variants are located in exons 3 and 4, which correspond to the N-terminal portion of the protein and encode the four domains similar to EGF and D8C [23].

We would like to highlight that the mutations associated with the ADTKD generate early-onset progressive CKD [3, 10], even in adolescence [2]. Our patient presented hyperuricemia at the age of 14. He also had changes in the renal parenchyma and in the end, the result of a genetic study revealed a probably pathogenic variant in the UMOD gene, which was inherited from his father, who also had renal pathology. The initial findings were incidental and were discovered as part of the active search for renal pathology due to his family history.

In a retrospective study that included 109 patients belonging to 45 families with variants in the UMOD gene and variable degrees of CKD, the presence of 37 different variants was determined; of these, 19 were de novo. Hyperuricemia was found in 80% of the cases [24].

In our case, the early presentation of hyperuricemia in both the patient and his father, and the progressive evolution to CKD are noteworthy. These findings are consistent with what was described in an international cohort study of 726 patients belonging to 585 families, in which a prevalence of hyperuricemia of 66% was reported and a family history of CKD or hyperuricemia was reported in 92% of all cases. In this study, 84% of patients had kidney disease and 43% progressed to CKD [25]. It is important to consider that the diagnosis of ADTKD is purely genetic, which represents a great limitation for an early diagnosis in countries with limited resources (like Colombia), due to regulatory and resource barriers [2]. In Colombia, currently, it is feasible to carry out genetic studies, but there are still difficulties in access and in family screening processes.

To date, there is no specific treatment standardization for ADTKD. Basically, the management of this disease focuses on the control of symptoms, such as hyperuricemia, and on slowing the progression of renal insufficiency [3, 26]. In a retrospective follow-up study, the cases of 27 patients with ADTKD belonging to 8 families were analyzed. All of them were treated with allopurinol when the disease was suspected. In 83.3% of the patients who started treatment with allopurinol and had a serum creatinine greater than 1.35 mg/dl, progression to end-stage CKD occurred between 2 and 10 years later. In contrast, patients with a serum creatinine lower than 1.35 mg/dl who started treatment early showed slower progression, reaching end-stage CKD in a period of 10 to 34 years of follow-up. On the other hand, patients who did not present CKD when starting treatment with allopurinol maintained disease stability for up to 20 years of follow-up [27].

In our patient, the use of xanthine oxidase inhibitors (allopurinol) was considered the initial treatment; however, there was a fast progression of CKD, and treatment follow-up was short, which did not allow evaluation of long-term effects and outcomes.



We report the case of an adolescent with signs of CKD and the presence of a probably pathogenic variant in the UMOD gene, inherited from his father; this variant was not previously reported in the literature.

Our findings highlight the importance of the family history during the anamnesis in order to guide the diagnosis. Genetic confirmation makes it possible to provide a clear aetiology that will further allow specific guidelines for prompt treatment and follow-up, as well as genetic counseling and identification of relatives at risk.



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PGNMID and anti-CD38 monoclonal antibody: a therapeutic challenge


Monoclonal gammopathy of renal significance (MGRS) designates disorders induced by a monoclonal protein secreted by plasma cells or B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma or other B-cell malignancies. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form MGRS.

Until now, no guidelines to decide the best therapeutic approach to manage PGNMID exist, and most patients progress to End Stage Renal Disease (ESRD) without therapy. Recently, daratumumab has showed an acceptable improvement in proteinuria and renal function in patients with PGNMID.

We report the clinical outcome and the histological renal evolution and treatment complication of our patient, who was initially treated with a combination regimen including bortezomib, dexamethasone, and cyclophosphamide and then with anti-CD38 monoclonal antibody-based regimen.

Keywords: monoclonal gammopathy of renal significance, proliferative glomerulonephritis with monoclonal immunoglobulin deposits, histological evaluation, pharmacological therapies, case report


Monoclonal gammopathy of renal significance (MGRS) designates disorders induced by a monoclonal protein secreted by plasma cells or B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma or other B-cell malignancies. MGRS was defined by the Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012 [1] and is classified by the site of the dominant immunoglobulin deposition or even by the ultrastructural findings on renal biopsy. It is important to mention that while light chains and truncated heavy chains can affect all renal compartments, intact immunoglobulin molecules are limited to the glomerulus [12].

Renal damage due to nephrotoxic monoclonal immunoglobulin (MIg) or its light- or heavy-chain fragments include some disorders, such as cast nephropathy, amyloidosis, MIg deposition diseases, immunotactoid glomerulopathy, proliferative GN with monoclonal Ig deposits, light-chain proximal tubulopathy, and the rare entities of crystal-storing histiocytosis and crystalglobulinemia. C3 glomerulonephritis and Thrombotic Microangiopathy (TMA) due to dysregulation of the alternative complement pathway can be seen as a result of indirect mechanisms induced by immunoglobulins [2].

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form of monoclonal gammopathy of renal significance (MGRS) often leading to end-stage kidney disease [3]. In 70% of cases no blood or bone marrow monoclonal immunoglobulins are detected [3].

In PGNMID, deposits are detected in the glomeruli, especially in mesangial and subendothelial space and occasionally in the subepithelial space [4]. In most patients, PGNMID is IgG3-driven, but it can also be IgA-driven or IgM-driven [5].

Plasma cell-derived PGNMID (usually IgG) is treated with bortezomib-based chemotherapy; B-cell-derived PGNMID is usually treated with a rituximab-based regimen [6]. The patients with PGNMID may have plasma cell clones that produce monoclonal proteins, which elicit inflammation. Recently daratumumab showed an acceptable improvement in proteinuria and renal function in patients with PGNMID [7].

Herein we report the clinical outcome and the histological renal evolution and treatment complication of our patient, who was initially treated with a combination regimen including bortezomib, dexamethasone, and cyclophosphamide and then with anti-CD38 monoclonal antibody.


Case report

We report the case of a 66-year-old white man with a history of JAK2 mutation-negative essential thrombocythemia, on cytoreductive therapy with anagrelide, who presented with proteinuria in the nephrotic range. At presentation urinalysis showed 40 RBCs/μL, albuminuria 100 mg/dl and proteinuria 4.3 gr/day. Serum creatinine was 1.8 mg/dL, calcium 8.7 mg/dl, hematuria with 40 RBC, serum immunofixation did not detect any abnormalities and protein electrophoresis showed hypogammaglobulinemia, IgG 508 mg/dl, negative Bence Jones and negative urine immunofixation revealed monoclonal IgA k (87 mg/24 h) and a mild increase in serum kappa free light chain with normal kappa/lambda ratio.

A kidney biopsy was performed (Figure 1) and showed a 30% of fibroepithelial crescent cell, 4% epithelia crescent cell and single fibrinoid necrosis. Immunofluorescence showed positive diffuse staining for IgA (3+), C3 (2+) and k-light chain (3+) involving the basal membrane in intramembranous and subepithelial region and the mesangium, with negative staining for λ-light chain and for heavy chain. The ultrastructural evaluation highlighted subendothelial and mesangial electron dense deposits. Therefore, we reached a diagnosis of proliferative glomerulonephritis with monoclonal IgA-kappa deposits without interstitial fibrosis, with mild tubular atrophy [7].

Figure 1: Renal Biopsy
Figure 1: Renal Biopsy. Photo A: electron microscopy, electron-dense deposits with focally variegated texture (without evidence of well-developed microtubules or fibrils) located in subendothelial area (original magnification ×14,000); photo B: electron microscopy: endocapillary hypercellularity filled by swollen endothelial cell, monocyte and neutrophil granulocyte (original magnification ×1900)

Bone marrow aspiration and biopsy with fluorescence in situ hybridization detected essential thrombocythemia with mild fibrosis MF-1 and presence of 8% κ-restricted plasma cells, considered as monoclonal gammopathy of undetermined significance (MGUS). Whole-body, CT bone scan showed erosive lesions of the temporal bone extended for 3 cm, non-ossifying fibromas (NOF) of the distal epiphysis of the right femur. Consequently, the diagnosis of MRGS was made and chemotherapy with CyBorD regimen (Bortezomib, Dexamethasone and cyclophosphamide) was started. The treatment schedule included 8 cycles of Bortezomib, Dexamethasone and cyclophosphamide with the following doses: cyclophosphamide 350 mg per os on days 1, 8, 15 + bortezomib 1.3 mg/m2 subcutaneously on days 1, 8, 15, 22 + dexamethasone 20 mg per os on days 1, 8, 15,22, each of these for 35 days.

Acyclovir, fluconazole and trimethoprim-sulfamethoxazole was added to the therapy as prophylaxis and after 4 weeks trimethoprim-sulfamethoxazole was withheld due to an allergic reaction.

After the first 4 cycles of therapy, a mild renal improvement was achieved. The serum creatinine decreased to 1.4 mg/dl with a partial reduction of proteinuria up to 3100 mg/24h and a reduction of monoclonal IgA k from 87 to 50 mg/24h. After 6 months of chemotherapy, osteolytic lesions on the sphenoid greater wing were detected on CT bone scan. After 8 cycles of CyBorD chemotherapy, at the 12th month of follow up: monoclonal IgA remained constant and under 50 mg/24h in urine immunofixation; serum free kappa light chain concentration was 32.9 mg/l and serum free light chain lambda was 14.7 mg/l (k/λ ratio = 2.2); a non-monoclonal component was detected in protein electrophoresis, while mild deterioration of renal function (cr: 2.3 mg/dl) without reduction of proteinuria was observed.

During the first 12 month of follow up no adverse effects related to the cytotoxic therapy were observed. At this time another evaluation with BMA and CT bone scan was programmed. The bone marrow aspirate and the biopsy were examined with light microscopy, immunohistochemistry, and flow cytometry, showing the presence of 10% κ-restricted plasma cells, considered as MGUS, with mild fibrosis MF-1. No new bone lesions were detected in the CT scan.

Based on radiological and histological findings, associated with progressive renal impairment (an increase of serum creatinine up to 4.1mg/dl with constant proteinuria nearly 4 gr/day), the second line treatment with Daratumumab-Lenalidomide plus Dexamethasone (D-Rd) was scheduled.

D-Rd regimen chemotherapy was started, despite the stable hematologic disease. The Daratumumab regimen consisted in an intravenous (IV) dose of 16 mg/kg once a week for 8 weeks, followed by the same dose once every 2 weeks plus lenalidomide and dexamethasone (for eight additional doses).

After one month of therapy with D-Rd regimen (4° administration) the patient was admitted to our hospital because of a rapidly progressive loss of renal function and nephrotic syndrome. Lower extremities petechiae were found on physical examination, with pitting edema in the lower limbs.

At admission, ultrasound examination evidenced the normal size of the inferior vena cava with a 40% collapsibility index, and mild bilateral pleural effusion; both kidneys had normal size and normal parenchymal thickness, with normal arterial and vein vascularization without hydronephrosis. Blood and urinary exams showed a progressive renal impairment with increase of creatinine up to 8.7 mg/dl and urea around 270-290 mg/dl, proteinuria increased to 5.5 gr/24h, Hb 8 gr/dl, albumin 1.9 gr/dl, calcium 6.9 mg/dl, magnesium1.3 mg/dl, sodiuria 47 mmol/l, creatinuria 114 mg/dl, procalcitonina 0.4 (normal range <0.5). They also evidenced normal complement C3 and C4 levels, negative cryoglobulins, and Ig levels 130 mg/dl. Protein electrophoresis detected monoclonal gammopathy IgAK 1.7%, 0.06 g/dl, negative rheumatoid factor; serum k free light chain concentration was 21.8 and lambda was 10.8 mg/l (k/λ ratio 2.01). Urinary immunofixation showed IgAk less than 50 mg/24h with microscopic hematuria and 300 mg/dl albuminuria. Skin punch biopsy was performed, revealing acute cutaneous vasculitis.

At this time, based on the deterioration of the renal function and despite the mild hematologic improvement during the first cycle of chemotherapy, ultrasound-guided percutaneous renal biopsy was performed again. The renal biopsy was examined with light microscopy and immunofluorescence. Light microscopy showed an increase of sclerosis up to 70%, 30% of fibroepithelial crescent cell and mild leucocyte interstitial infiltration. Immunofluorescence showed positive staining for IgA (2+) and C3 (1+) and k-light chain (2+) involving mesangial, subendothelial and intramembranous regions.

Given the rapidly progressive renal failure and the presence of fibroepithelial crescent cells in the renal biopsy, accompanied by acute cutaneous vasculitis, in a patient with IgA monoclonal gammopathy, the following renal rescue therapy was programmed: IV cyclophosphamide 500 mg once every 2 weeks for 4 doses adjusted for renal insufficiency and IV metilprednisolone 125/day for 3 days, followed by oral prednisone 50 mg with rapid tapering

On the other hand, the chemotherapy was continued with daratumumab IV at a dose of 16 mg/kg once weekly for 8 weeks, followed by 16mg/kg every two weeks for 8 weeks, plus oral dexamethasone 20 mg (only in the day of chemotherapy, withholding prednisone).

After nearly three weeks of therapy (after the 2nd administration of Daratumumab-dexamethasone and the 2 nd administration of cyclophosphamide) the patient was admitted because of fever, cough and hemoptysis. A CT scan at admission revealed extended consolidation diffused in the entire right lung lobe, characterized by ground glass opacities mixed with parenchymal consolidation and air bronchogram (Figure 2).

Figure 2: Pneumonitis before (A) and after (B) treatment

Serological assessment, sputum and blood cultures were done to identify the type of organism causing the infection and upon admission a broad-spectrum antibiotic therapy with meropenem and teicoplanin associated with a new triazole antifungal, voriconazole, was started. After one week of therapy, there was an improvement in the clinical symptoms. Therapy with voriconazole was continued because of positive serum aspergillus-specific antibody. On the other hand, CMV PCR exam resulted positive (58000 cp/ml) and antiviral therapy with IV ganciclovir (1.25 mg/kg/dose 3 times weekly) was started.

After roughly 7 days of antibiotic therapy, in consideration of the adequate reduction of systemic inflammatory markers with sustained renal failure (creatinine 8.4 mg/dl and urea 320 mg/dl), a central venous catheter (CVC) was inserted in the internal jugular vein and the patient underwent 6 hemodialysis sessions with the HFR Supra Bellco filter system to achieve an acceptable and persistent reduction of free light chains, as the effect of chemotherapy was still persisting.

After 22 days of hospitalization, as a result of febrile neutropenia, antibiotic therapy was continued and filgrastim (granulocyte colony-stimulating factor) was applicated subcutaneously. Suspecting that the neutropenia was induced by ganciclovir and in consideration of the negative PCR CMV test, the induction therapy was withheld. After a mild improvement of the renal function, the CVC was removed, and the creation of surgical arteriovenous fistulas (AVFs) was planned.

Following 4 days of granulocyte colony-stimulating factor therapy, the neutrophils count increased up to the normal range and the fever disappeared; therefore, maintenance therapy with oral valcyte was started and maintained for the following two weeks.

After nearly 35 days of hospitalization, Acinetobacter baumanii was found in sputum culture and was successfully treated with inhaled colistin at a dose of 1000000 UI three times a day for 5 days.

The patient was discharged with serum creatinine reduced from 8.4 mg/dl to 6 mg/dl and urea from 298 mg/dl to 150 mg/dl; CRP and procalcitonin were in the normal range, with negative cultural tests. One month after discharge, laboratory exams showed a further reduction of creatinine, down to 5.2 mg/dl, while urea remained steady around 150 mg/dl; CRP, procalcitonin and complete blood count were all in the normal range. The patient did not need hemodialysis and we decided to continue chemotherapy with Daratumumab-dexamethasone (Table I).

  Time Creatinine mg/dl ProteinuriaGr/ 24h SIF UIF SE KLC k/λ ratio IgG mg/dl
T0 Before treatment 1.8 3 neg IgAK 87mg/24h hypogammaglobulinemia 0.94
CyBorD T1 End of 1th cycle 1.89 3.2 neg IgAK:50.3 mg 24h hypogammaglobulinemia normal, without MC 0.9 508
T4 End of 4th cycle 1.4 2.5 neg IgAK<50 mg 24h hypogammaglobulinemia normal, without MC 1.02
T6 End of 6th cycle 2.1 4.2 neg IgAK<50 mg 24h hypogammaglobulinemia normal, without MC
T7 End of 7th cycle 2.05 4 neg IgAK<50 mg 24h hypogammaglobulinemia normal, without MC 28.16 mg/l 1.8 336
T8 End of 8th cycle 2.3 mg/dl 3.5 neg IgAK<50 mg 24h hypogammaglobulinemia normal, without MC 32.9 mg/l 2.2
2 month follow up 1th month 2.9 3.4 neg IgAK<50 mg 24h 35.05 1.6 362
2th month 4.4 5.9 MC IgAK IgAK<50 mg 24h MC 0.17 g/dl, 3.3 % 43 2.08 319
Anti CD38 monoclonal based chemotherapy T1 After 1th  cycle of D.Rd 6.8 4.4 MC IgAK IgAK<50 mg 24h MC 0.06 g/dl, 1.7 % 21 2.01 130
Second renal biopsy
T2 After 2 cycles of D-d and first administration of CYC 6.1 4.2 MC IgAK IgAK<50 mg 24h 17.3 1.2 91
1 month follow up without therapy 5.4 3.2 MC IgAK IgAK<50 mg 24h 11.3 0.9 540
Resumption of D-d after infection resolution
Table I: The disease progression (CyBorD: Bortezomib, Dexamethasone and cyclophosphamide; D-Rd: daratumumab-lenalidomide plus dexamethasone; SIF: serum immunofixation; UIF: urine immunofixation; SE: serum electrophoresis; KLC: kappa light chain)



The clinical presentation of kidney involvement in MGRS is ambiguous and, according to the IKMG recommendations, a kidney biopsy is mandatory for the correct diagnosis and management [1].

A peculiar aspect of MGRS is that kidney lesions are associated with low-grade plasma cell dyscrasias or lymphoproliferative disorders in the absence of multiple myeloma (MM) or other hematologic malignancies. PGNMID occurs specially is the sixth decade of life and is rarely seen in younger patients. Unlike other MGRS, abnormal monoclonal immunoglobulin in serum or urine or even in bone marrow is detected only in 30 % of the PGNMID [8].

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody anti-CD38 cells [9]. Given the good results of daratumumab in the treatment of patients with refractory MM, it has recently been used in renal disease secondary to PGNMID. The hypothesis is that there is a correlation between kidney injury and monoclonal proteins produced by plasma cells. Therefore, removing the pathologic clone can result in a renal response [10].

Recently, Zand et al. have evaluated, in an open-label, phase 2 trial, daratumumab’s safety and efficacy in 11 adults with PGNMID. Daratumumab was administrated intravenously (16 mg/kg) once a week for 8 weeks, then every other week for eight additional doses. One patient did not complete the first infusion. During the 12-month follow up, six patients had a partial response, and four had a complete response. The trial concluded there was a significant improvement in proteinuria and a stabilization of kidney function in patients with PGNMID on daratumumab [7].

Until now, no guidelines to decide the best therapeutic approach to manage PGNMID exist, and most patients progress to End Stage Renal Disease (ESRD) without therapy [3, 11].

We have described a case of MGRS secondary to PGNMID treated at first with 8 cycles of CyBorD chemotherapy. After one year, monoclonal IgA remained constant, with a deterioration of renal function without reduction of proteinuria. At this time, considering both the findings in BMA and CT bone scan and the progressive renal impairment, we chose a second-line treatment with anti-CD38 monoclonal antibody, which showed good results according to a Mayo Clinic study

Unfortunately, during the first month of this second-line therapy (with daratumumab-lenalidomide-dexamethasone) the patient was hospitalized because of a rapidly progressive renal failure, despite stable hematologic disease. A second renal biopsy showed sclerosis in up to 70% of the glomeruli and 30% of fibroepithelial crescent cells. This was associated to acute cutaneous vasculitis, and the rescue therapy of choice included intravenous cyclophosphamide and oral prednisone; the treatment with daratumumab, without lenalidomide, was continued. Unfortunately, after three weeks, all therapies were withheld because of infective complications and sever febrile neutropenia.

The most common side effects associated with daratumumab are neutropenia (37%), thrombocytopenia (23%), anemia (16%), pneumonia (10%), infusion-related reactions (6%), upper respiratory tract infection (5%), and fatigue (5%) [12].

Some studies find daratumumab to be adequately safe, with an acceptable improvement in proteinuria during the first month of infusion. However, in the case we have described, severe pulmonary infection and life-threatening febrile neutropenia was observed within three months of therapy, with progressive renal impairment. It is possible that the severe pulmonary infection was detected because of the withholding of prophylaxis treatment with trimethoprim-sulfamethoxazole (due in turn to an allergic reaction), but it is also possible that the risk was increased by the association of anti-CD38 monoclonal antibody with alkylating agents. In our case, despite using the therapeutic regimen targeting plasma cell clones responsible for kidney injury, no improvement was achieved, even with the reduction of M-spike protein.



The management of PGNMID remains unclear, and treatment is based on expert consensus, depending on the underlying clone and the risk of renal impairment progression. While low-risk patients without detectable monoclonal disease are treated only with supportive care, chemotherapy is indicated for patients with monoclonal immunoglobulins and a high risk of renal impairment.

Histological evaluation guides all therapeutic decisions, according to the pattern and degree of kidney injury. Once MGRS is diagnosed, the collaboration between nephrology and hematology specialist is recommended to find the most adequate therapy.

The case we have described, of PGNMID with the presence of mild monoclonal IgA k in urine immunofixation, did not respond to first-line therapy with CyBorD regimen, nor to second-line regimen with Daratumumab (anti CD38). According to our experience, further research is needed to assess the management and outcome of PGNMID.



  1. Leung N, Bridaux F, et al. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol 2019; 15(1):45-59.
  2. Jain A, Haynes R, Kothari J, Khera A, Soares M, Ramasamy K. Pathophysiology and management of monoclonal gammopathy of renal significance. Blood Adv 2019; 3(15):2409-23.
  3. Nasr SH, Satoskar A, Markowitz GS, et al. Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol 2009; 20(9):2055-64.
  4. Vignon M, Cohen C, Faguer S, Noel LH, et al. The clinicopathologic characteristics of kidney diseases related to monotypic IgA deposits. Kidney Int 2017; 91(3):720-28.
  5. Nasr SH, Markowitz GS, Stokes MB, et al. Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis. Kidney Int 2004; 65(1):85-96.
  6. Xiao-juan Yu, Mang-ju Wang, et al. Proliferative Glomerulonephritis with Monoclonal IgG3λ Deposits: a Case Report of a Rare Cause of Monoclonal Gammopathy of Renal Significance. Kidney Med 2019; 1(4):221-25.
  7. Zand L, Rajkumar SV, Leung N, et al. Safety and Efficacy of Daratumumab in Patients with Proliferative GN with Monoclonal Immunoglobulin Deposits. J Am Soc Nephrol 2021; 32(5):1163-73.
  8. Bridoux F, Javaugue V, Nasr SH, Leung N. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a nephrologist perspective. Nephrol Dial Transplant 2021; 36(2):208-15.
  9. Krejcik J, Casneuf T, Nijhof IS, Verbist B, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 2016; 128(3):384-94.
  10. Bhutani G, Nasr SH, Said SM, Sethi S, Fervenza FC, Morice WG, et al. Hematologic characteristics of proliferative glomerulonephritides with nonorganized monoclonal immunoglobulin deposits. Mayo Clin Proc 2015; 90:587-96.
  11. Gumber R, Cohen JB, Palmer MB, Kobrin SM, Vogl DT, et al. A clone-directed approach may improve diagnosis and treatment of proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Kidney Int 2018; 94:199-205.
  12. Tzogani K, Penninga E, Schougaard Christiansen ML, Hovgaard D, et al. EMA Review of Daratumumab for the Treatment of Adult Patients with Multiple Myeloma. TheOncologist 2018; 23(5):594-602.

Leptospirosis and kidneys: a clinical case


We describe here the case of a young patient, employed in agriculture, who entered the emergency room with fever, headache, hematuria and a worsening of renal function; we diagnosed leptospirosis with renal involvement. As the patient lamented very generic symptoms, the anamnesis was fundamental in leading us to suspect an infection, execute the right laboratory analysis, and correctly diagnose a pathology which is currently very rare in Italy.

Keywords: case report, leptospirosis, AKI

Sorry, this entry is only available in Italian.


La leptospirosi umana è considerata una delle più diffuse e potenzialmente fatali zoonosi, è determinata da un batterio Gram negativo appartenente alla famiglia delle Spirochetales ordine Leptospiracee e si associa ad elevata morbilità e mortalità, in particolare nei pazienti di età superiore ai 60 anni [1]. 

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Hemodialysis treatment as a trigger cause of cryoglobulinemic purpura: a case report


We describe the clinical case of a patient who developed mixed cryoglobulinemia syndrome after hemodialysis treatment with dialysate temperature lower than 36 °C despite the negativization of the viral genome for HCV after eradication therapy.

Keywords: case report, cryoglobulinemia, mixed cryoglobulinemic syndrome, dialysate temperature

Sorry, this entry is only available in Italian.


Con il termine di Crioglobulinemia ci si riferisce alla presenza di immuglobuline sieriche la cui caratteristica peculiare è quella di precipitare a temperature inferiori a 37°C e dissolversi a temperature più elevate.


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