Medullary Sponge Kidney Disease Research Articles

The impact of kidney stone disease on quality of life in high-risk stone formers.

To assess the impact of kidney stone disease (KSD) and its treatment on the health-related quality of life (HRQOL) of high-risk stone formers with hyperparathyroidism, renal tubular acidosis, malabsorptive disease, and medullary sponge kidney. The Wisconsin Stone Quality of Life questionnaire was used to evaluate HRQOL in 3301 patients with a history of KSD from 16 institutions in North America between 2014 and 2020. Baseline characteristics and medical history were collected from patients, while active KSD was confirmed through radiological imaging. The high-risk group was compared to the remaining patients (control group) using the Wilcoxon rank-sum test. Of 1499 patients with active KSD included in the study, the high-risk group included 120 patients. The high-risk group had significantly lower HRQOL scores compared to the control group (P < 0.01). In the multivariable analyses, medullary sponge kidney disease and renal tubular acidosis were independent predictors of poorer HRQOL, while alkali therapy was an independent predictor of better HRQOL (all P < 0.01). Among patients with active KSD, high-risk stone formers had impaired HRQOL with medullary sponge kidney disease and renal tubular acidosis being independent predictors of poorer HRQOL. Clinicians should seek to identify these patients earlier as they would benefit from prompt treatment and prevention.

Spinal cord stimulation for visceral pain associated with medullary sponge kidney.

Chronic pain is a common reason for which people in the USA seek medical care. It is linked to opioid consumption, anxiety and a reduction in quality of life. Over the past 50years, spinal cord stimulation (SCS) has evolved as a safe and efficacious treatment for chronic pain etiologies. The authors present the first known case of SCS for pain due to medullary sponge kidney disease. This report adds to the growing body of literature supporting the use of SCS for treating visceral organ pain, while also highlighting the utility of ventral lead placement for treating visceral pain. As SCS utilization increases, it is expected that there will be a decrease in opioid consumption, and this will help us contain the opioid epidemic.

Adult presentations of variable kidney and liver phenotypes secondary to biallelic PKHD1 pathogenic variants

The polycystic kidney and hepatic disease 1 (PKHD1) gene located on chromosome 6p12 encodes for a large transmembrane protein called fibrocystin. Biallelic pathogenic variants in this gene cause autosomal recessive polycystic kidney disease (ARPKD). ARPKD often leads to both early-onset polycystic kidney disease as well as congenital hepatic fibrosis. In addition to the early onset phenotypes, some patients present much later with adult-onset liver involvement which is often labeled as Caroli’s syndrome. The kidney phenotype can resemble medullary sponge kidney disease with nephrolithiasis as well as atypical cystic kidney disease. Here, we present two families, each with 2 affected siblings, where the presenting liver and kidney features were variable among the siblings, with presentations including late-onset liver phenotypes, kidney features which had been labeled as medullary sponge kidney, and cystic kidney disease. Molecular genetic investigations identified biallelic pathogenic variants in PKHD1 in the affected siblings, including a novel nonsense allele. These cases emphasize the adult-onset and variable and sometimes discordant phenotypes that may be observed with PKHD1 biallelic pathogenic variants.

A Comprehensive Proteomics Analysis of Urinary Extracellular Vesicles Identifies a Specific Kinase Protein Profile as a Novel Hallmark of Medullary Sponge Kidney Disease

Recent advances in the high-throughput technologies and data analysis have led to better understanding of the biological processes involved in several kidney disorders,1,S1,S2 including the medullary sponge kidney (MSK) disease, a rare congenital malformation characterized by dilation of the collecting ducts in the renal papillae, urinary acidification and concentration defects, cystic anomalies of precalyceal ducts associated with a high risk of nephrocalcinosis, and recurrent kidney stones.2

Nephrectomy in a Patient with Medullary Sponge Kidney Associated with Severe Nephrocalcinosis and Nephrolithiasis: A Rare Condition

Background: Medullary sponge kidney (MSK) is a disturbance of renal development characterized by cystic dilation and diffuse precalyceal duct ectasia. The disease affects both genders in equal proportions and is generally diagnosed in adulthood, as a result of recurrent calcium nephrolithiasis and nephrocalcinosis. The most frequently encountered manifestations being renal colic, microscopic or macroscopic hematuria, and fever. The intravenous pyelogram is standard for diagnosis and metabolic workup is required to identify the underlying cause. The main goal of treatment is to prevent recurrence and disease progression. Though considered a benign condition, a nephrectomy may often be required in patients presenting late with irreversible complications and end-stage renal disease. Aim: To highlight and discuss the presentation and management of a rare case of nephrocalcinosis and nephrolithiasis secondary to the medullary sponge kidney. Case presentation: We report herein the case of a 56-year-old male with long-standing hematuria in whom a diagnosis of medullary sponge kidney disease was made and he underwent a left total nephrectomy. The postoperative course was uneventful. Conclusion: Nephrocalcinosis and nephrolithiasis are complications of MSK and can result in irreversible renal damage. A high index of suspicion is necessary for patients presenting with renal colic, recurrent urinary tract infections, or hematuria for prompt diagnosis and management.

Sphingomyelin and Medullary Sponge Kidney Disease: A Biological Link Identified by Omics Approach.

Background: Molecular biology has recently added new insights into the comprehension of the physiopathology of the medullary sponge kidney disease (MSK), a rare kidney malformation featuring nephrocalcinosis and recurrent renal stones. Pathogenesis and metabolic alterations associated to this disorder have been only partially elucidated.Methods: Plasma and urine samples were collected from 15 MSK patients and 15 controls affected by idiopathic calcium nephrolithiasis (ICN). Plasma metabolomic profile of 7 MSK and 8 ICN patients was performed by liquid chromatography combined with electrospray ionization tandem mass spectrometry (UHPLC–ESI-MS/MS). Subsequently, we reinterrogated proteomic raw data previously obtained from urinary microvesicles of MSK and ICN focusing on proteins associated with sphingomyelin metabolism. Omics results were validated by ELISA in the entire patients' cohort.Results: Thirteen metabolites were able to discriminate MSK from ICN (7 increased and 6 decreased in MSK vs. ICN). Sphingomyelin reached the top level of discrimination between the two study groups (FC: −1.8, p < 0.001). Ectonucleotide pyrophophatase phosphodiesterase 6 (ENPP6) and osteopontin (SPP1) resulted the most significant deregulated urinary proteins in MSK vs. ICN (p < 0.001). ENPP6 resulted up-regulated also in plasma of MSK by ELISA.Conclusion: Our data revealed a specific high-throughput metabolomics signature of MSK and indicated a pivotal biological role of sphingomyelin in this disease.

P0059CLINICAL AND IMAGING FEATURES OF A NOVEL DNAJB11 MUTATION COMPARED TO PKD1-PKD2 ADULT POLYCYSTIC KIDNEY DISEASE (ADPKD). TWO DIFFERENT DISEASES?

Abstract Background and Aims ADPKD is characterized by the progressive development of bulky renal cysts, often resulting in end-stage renal disease (ESRD). Among this group 85% of cases recognize a genetic mutation concerning PKD1/PKD2 genes (ADPKD). Among the remaining 15% of ADPKD patients, DNAJB11 mutations (DNAJB11-PKD) has been recently recognized. [Cornec-Le Gall E, Olson RJ, Beesse W t al. Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease. Am Journ Hum Gen 2018, 102:832-844.] DNAJB11 encodes a co-chaperone of the endoplasmic reticulum (ER) also called ERdj3. It is part of the HSP40 protein family and plays a central role in both intracellular and extracellular proteomic homeostasis (proteostasis). In the intracellular compartment it acts as a co-chaperone in the pathway of the unfolded protein response (UPR) in which it binds misfolded proteins which have to be secreted and activates BiP an HSP70 of ER whose function is to correct the misfolding. In our Nephrology Unit we collected the largest cohort of patients with a new stop codon mutation (p.Arg34*) of DNAJB11. All patients are relatives of different ranks and were born in a small village in the mountains of the Parma province.In this study we compare clinical features of DNAJB11-PKD with ADPKD to define differences between the two groups. Method We identified retrospectively from outpatient and dialysis databases of the Nephrology Unit of Parma patients carrying pArg34* DNAJB11 or PKD1-PKD2 mutations. We collected the clinical features and the available diagnostic imaging of all identified patients. Results We collected 19 patients with DNAJB11-PKD and 37 with ADPKD. The clinical characteristics are reported in Figure 1 . Our DNAJB11-PKD cohort vs ADPKD presented significantly a normal renal size (median value 10.5cm vs 16cm respectively) and smaller cysts size (median value 2cm vs 5cm respectively). Interestingly 5/19 DNAJB11 patients had type 2 diabetes vs no cases in the ADPKD group (p&amp;lt;0.05). ADPKD patients presented ESRD about 10 years before DNAJB11-PKD and renal survival resulted significantly worse (Figure 2).We revised also the previous diagnosis of our DNAJB11-PKD patients; 3/19 DNAJB11-PKD cases were diagnosed as having ADPKD. The remaining were classified as medullary sponge kidney disease (7/19), diabetic nephropathy (3/19) or nephroangiosclerosis (6/19). Conclusion DNAJB11 mutations were reported as a cause of ADPKD for the first time in May 2018 by Cornec-Le-Gall and colleagues. In their study were reported 7 different mutations in 23 patients and they identified 2/23 patients with type II diabetes. We here report the larger single DNAJB11 mutation cohort in the literature and compared it with genetic proven ADPKD. We documented differences in pathognomonic clinical features of ADPKD like renal survival, enlarged kidneys and bulky cysts. Moreover about 30% of DNAJB11-PKD patients present Type II diabetes that would be related to altered proteostasis in the ER. Since DNAJB11-PKD appears to differ in relevant aspects from well known ADPKD, it would be less confusing to classify DNAJB11-PKD indipendently from ADPKD.

Proteomic Analysis of Urinary Extracellular Vesicles Reveals a Role for the Complement System in Medullary Sponge Kidney Disease.

Medullary sponge kidney (MSK) disease is a rare and neglected kidney condition often associated with nephrocalcinosis/nephrolithiasis and cystic anomalies in the precalyceal ducts. Little is known about the pathogenesis of this disease, so we addressed the knowledge gap using a proteomics approach. The protein content of microvesicles/exosomes isolated from urine of 15 MSK and 15 idiopathic calcium nephrolithiasis (ICN) patients was investigated by mass spectrometry, followed by weighted gene co-expression network analysis, support vector machine (SVM) learning, and partial least squares discriminant analysis (PLS-DA) to select the most discriminative proteins. Proteomic data were verified by ELISA. We identified 2998 proteins in total, 1764 (58.9%) of which were present in both vesicle types in both diseases. Among the MSK samples, only 65 (2.2%) and 137 (4.6%) proteins were exclusively found in the microvesicles and exosomes, respectively. Similarly, among the ICN samples, only 75 (2.5%) and 94 (3.1%) proteins were exclusively found in the microvesicles and exosomes, respectively. SVM learning and PLS-DA revealed a core panel of 20 proteins that distinguished extracellular vesicles representing each clinical condition with an accuracy of 100%. Among them, three exosome proteins involved in the lectin complement pathway maximized the discrimination between MSK and ICN: Ficolin 1, Mannan-binding lectin serine protease 2, and Complement component 4-binding protein β. ELISA confirmed the proteomic results. Our data show that the complement pathway is involved in the MSK, revealing a new range of potential therapeutic targets and early diagnostic biomarkers.

Urinary proteome in inherited nephrolithiasis.

In the last decades, proteomics has been largely applied to the Nephrology field, with the double aim to (1) elucidate the biological processes underlying renal diseases; (2) identify disease-specific biomarkers, predictor factors of therapeutic efficacy and prognostic factors of disease progression. Kidney stone disease, and in particular, inherited nephrolithiasis (INL) are not an exception. Given the multifactorial origin of these disorders, the combination of genomics and proteomics studies may complement each other, with the final objective to give a global and comprehensive mechanistic view. In this review, we summarize the results of recent proteomic studies which have expanded our knowledge about INL, focusing the attention on monogenic forms of nephrolithiasis (cystinuria, Dent's disease, Bartter syndrome, distal renal tubular acidosis and primary hyperoxaluria), on polygenic hypercalciuria and on medullary sponge kidney disease.

Breaking the ice: urine proteomics of medullary sponge kidney disease

Urinary proteomics is a promising tool for biomarker investigation, particularly in complex kidney diseases. Fabris and colleagues report that urinary laminin subunit alpha-2 is a potential diagnostic marker of medullary sponge kidney (MSK) disease by using a label-free quantitative proteomics platform and a clinically compatible enzyme-linked immunosorbent assay. The neglected issue of stone pathogenesis was also evidenced. This commentary discusses several considerations in biomarker validation, and how urinary proteomics breaks new ground in MSK research.

Proteomic-based research strategy identified laminin subunit alpha 2 as a potential urinary-specific biomarker for the medullary sponge kidney disease

Medullary sponge kidney (MSK) disease, a rare kidney malformation featuring recurrent renal stones and nephrocalcinosis, continues to be diagnosed using expensive and time-consuming clinical/instrumental tests (mainly urography). Currently, no molecular diagnostic biomarkers are available. To identify such we employed a proteomic-based research strategy utilizing urine from 22patients with MSK and 22 patients affected by idiopathic calcium nephrolithiasis (ICN) as controls. Notably, two patients with ICN presented cysts. In the discovery phase, the urine of 11 MSK and 10 controls, were randomly selected, processed, and analyzed by mass spectrometry. Subsequently, several statistical algorithms were undertaken to select the most discriminative proteins between the two study groups. ELISA, performed on the entire patients' cohort, was used to validate the proteomic results. After aninitial statistical analysis, 249 and 396 proteins were identified exclusive for ICN and MSK, respectively. A Volcano plot and ROC analysis, performed to restrict the number of MSK-associated proteins, indicated that 328 and 44 proteins, respectively, were specific for MSK. Interestingly, 119 proteins were found to differentiate patients with cysts (allpatients with MSK and the two ICN with renal cysts) from ICN without cysts. Eventually, 16 proteins were found to be common to three statistical methods with laminin subunit alpha 2 (LAMA-2) reaching the higher rank by a Support Vector Machine, a binary classification/prediction scheme. ELISA for LAMA-2 validated proteomic results. Thus, usinghigh-throughput technology, our study identified a candidate MSK biomarker possibly employable in future forthe early diagnosis of this disease.

[PS 08-37] RARE RENAL DISEASE CAUSE OF SEVERE HYPERTENSION - CASE REPORT

Objective: To present a case of medullary sponge kidney (Cacchi-Ricci disease) in a 33-years-old woman with severe hypertension with special reference to the ultrasound findings that permitted early diagnosis of this rare condition. Design and Method: The most relevant clinical features and ultrasound findings in a patient with Cacchi-Ricci disease are described. Results: We describe here a 33-years-old Moldavian woman with negative family history for hypertension who presented to the physician with severe hypertension, established in a couple of months after childbirth, and resistant to usual treatment with angiotensine conversion enzyme inhibitors. She also had concomitant features of distal renal tubular acidosis (alkaline urine, hypercalciuria). Extensive diagnostic workup was undertaken to find secondary causes for it. The most informative proved to be renal ultrasound which revealed bilateral increased medullary echogenicity, highly suggestive for MSK. Conclusions: Medullary sponge kidney disease might be responsible for secondary hypertension, and simple kidney ultrasound increase the probability of early diagnosis of this rare condition.

Nephrocalcinosis in Calcium Stone Formers Who Do Not have Systemic Disease

Nephrocalcinosis is commonly present in primary hyperparathyroidism, distal renal tubular acidosis and medullary sponge kidney disease. To our knowledge it has not been studied in patients with calcium phosphate stones who do not have systemic disease. We studied patients undergoing percutaneous nephrolithotomy who had calcium phosphate or calcium oxalate stones and did not have hyperparathyroidism, distal renal tubular acidosis or medullary sponge kidney disease. On postoperative day 1 all patients underwent noncontrast computerized tomography. If there were no residual calcifications, the patient was categorized as not having nephrocalcinosis. If there were residual calcifications, the patient underwent secondary percutaneous nephrolithotomy. If the calcifications were found to be stones, the patient was categorized as not having nephrocalcinosis. If the calcifications were not stones, the patient was categorized as having nephrocalcinosis. Patients were grouped based on the type of stones that formed, including hydroxyapatite, brushite and idiopathic calcium oxalate. The extent of nephrocalcinosis was quantified as 0--absent nephrocalcinosis to 3--extensive nephrocalcinosis. Patients with residual calcifications on postoperative day 1 noncontrast computerized tomography who did not undergo secondary percutaneous nephrolithotomy were excluded from analysis. The presence or absence of nephrocalcinosis was correlated with metabolic studies. A total of 67 patients were studied, including 14 with hydroxyapatite, 19 with brushite and 34 with idiopathic calcium oxalate calculi. Nephrocalcinosis was present in 10 of 14 (71.4%), 11 of 19 (57.9%) and 6 of 34 patients (17.6%) in the hydroxyapatite, brushite and idiopathic calcium oxalate groups, respectively (chi-square p = 0.01). The mean extent of nephrocalcinosis per group was 1.98, 1.32 and 0.18 for hydroxyapatite, brushite and idiopathic calcium oxalate, respectively (p ≤0.001). The presence of nephrocalcinosis positively correlated with urine calcium excretion (mean ± SD 287.39 ± 112.49 vs 223.68 ± 100.67 mg per day, p = 0.03). Patients without systemic disease who form hydroxyapatite and brushite stones commonly have coexistent nephrocalcinosis. Nephrocalcinosis can occur in calcium oxalate stone formers but the quantity and frequency of nephrocalcinosis in this group are dramatically less.

Identification of GDNF Gene Sequence Variations in Patients with Medullary Sponge Kidney Disease

Medullary sponge kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the "ureteric bud/metanephric blastema" interface caused by critical developmental genes functioning abnormally. Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development. Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}:c.-45G>C and c.-27+18G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[-45G>C; -27+18G>A] complex allele, and the others had the c.-27+18G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant pattern of inheritance. Patients revealed no mutations in the RET gene. This is the first report identifying GDNF gene sequence variations in patients with MSK and suggesting a role for this gene in the pathogenesis of some cases of the disease.

Medullary sponge kidney presenting in a neonate with distal renal tubular acidosis and failure to thrive: a case report

IntroductionMedullary sponge kidney is a congenital anomaly characterized by diffuse ectasy of the collecting tubules of one or both kidneys. It is usually diagnosed in the second or third decade of life.Case presentationDistal renal tubular acidosis is commonly observed in patients with medullary sponge kidney. We describe here a 50-day-old Egyptian Caucasian girl with medullary sponge kidney who had features of distal renal tubular acidosis, (persistent alkaline urine, hypercalciuria, hypocitraturia) and failure to thrive. Renal ultrasound revealed left renal increased medullary echogenicity and bilateral nephrocalcinosis.ConclusionEarly gene(s) expression of medullary sponge kidney disease might be responsible for persistent metabolic acidosis during the neonatal period.

Medullary Sponge Kidney

Medullary sponge kidney (MSK) is a developmental anomaly that occurs in the medullary pyramids of the kidney. MSK is characterized by cystic dilation of the distal collecting tubules and ducts in one or more renal pyramids. Many patients remain asymptomatic, but patients with symptoms of nephrolithiasis, hematuria, and infection should be carefully evaluated for medullary sponge kidney disease. A case is presented in which sonography is used to diagnose MSK.

The Use of Monoclonal Antibodies in Microscopic Urinalysis in Analgesic Nephropathy, Polycystic Kidney Disease and Medullary Sponge Kidney Disease

The Use of Monoclonal Antibodies in Microscopic Urinalysis in Analgesic Nephropathy, Polycystic Kidney Disease and Medullary Sponge Kidney Disease

Juvenile Nephronophthisis, Congenital Hepatic Fibrosis and Retinal Hypoplasia in Twins

Juvenile nephronophthisis has been recognized recently as an important cause of chronic renal failure in childhood and adolescence. This report describes clinical and morphological findings in monozygotic twins in whom the triad of juvenile nephronophthisis, congenital hepatic fibrosis and retinal hypoplasia coexisted. The findings are discussed in relation to previous reports of nephronophthisis associated with either retinal abnormalities or congenital hepatic fibrosis. The occurrence of similar ocular and hepatic anomalies with the other cystic kidney diseases, polycystic disease and medullary sponge kidney disease is reviewed. A spectrum of oculo-hepato-renal syndromes is identified with many interrelated features which suggest a shared basic aetiology.

Medullary sponge kidney disease.

Although medullary sponge kidney disease has been described in the Italian and Swedish literature it is infrequently reported in the English and North American journals. It is not accepted by all as a disease entity, and its importance is somewhat minimized because of the frequent statements that it is benign. It is, perhaps, looked upon as a disease of interest only to radiologists and a curiosity of little importance. The material in the University of Michigan Medical Center has been surveyed, and forty patients with this entity compose the basis for this report. The historical aspects are now widely known, and the earliest descriptions by Lenarduzzi (1) and Cacci and Ricci (2) are established. The monograph of Ekström et al. (3) and the several papers by Lindvall (4) have created in our institution the idea that this is a “Swedish” disease. It consists of a cystic dilatation of the collecting tubules in the renal pyramids. These vary in size and distribution affecting all or only one or a few pyramids. These cavities mayor may not contain calculi, and the disease is diagnosed in the absence of calculi. The etiology is assumed to be congenital, and there are those who would associate it with polycystic disease (5). Vermooten has indicated that the etiology may be the result of uric acid crystal obstruction during the fetal period (6). It is less frequently described in children and seems to be primarily an adult affliction. In 1960 Reilly and Neuhauser reported 11 cases which appeared to be associated with cystic disease of the liver, and they believed that this disease represented an uncommon form of polycystic disease (7). Edith Potter has indicated that cystic dilatation of the collecting tubules does not exist except with accompanying cystic liver involvement and is invariably fatal (5). These fetal and pediatric forms of the disease are not identified in the adult (8). In fact, if adult medullary sponge kidney disease were not complicated by pyelonephritis, calculus formation, and hemorrhage, it would surely attract little attention. Differential Diagnosis The differentiation of this entity from renal tuberculosis is sometimes difficult and may require urine culture if the tuberculosis is confined to the renal pyramids. However, the cavities formed by this infectious disease are irregular in form and size and usually fill secondarily from the pelvis. Timed films after the injection of the urographic contrast medium may elucidate this problem (3). Hyperparathyroidism is more likely to result in calcifications of large or varying size not strictly confined to the renal pyramids. Renal tubular acidosis may present genuine problems of differentiation but is distinguished by the uniformity of involvement of every pyramid of both kidneys, with all the calcifications of about the same size and shape. There also is an absence of demonstrable dilatation or cystic deformity of the collecting tubules. Small localized areas of papillary necrosis and calicine diverticula can prove troublesome to the inexperienced observer.