A case of diffuse kidney hyperechogenicity in early childhood associated with biallelic PKHD1 variants.

BACKGROUND: Nephrocalcinosis (NC) is characterized by an excessive accumulation of calcium deposits in the kidneys. In children, it is often incidentally discovered with an uncertain prognosis. CASE-DIAGNOSIS/TREATMENT: A 3-month-old girl suspected to have a milk protein allergy underwent an ultrasound that revealed increased echogenicity in the kidney pyramids suggestive of medullary NC. At the age of 18 months, imaging findings revealed not only hyperechogenicity in the medulla but also in the cortex. Over the course of a long follow-up, her kidneys maintained size within the upper limits but showed an increase by age 7. Genetic analysis identified PKHD1 variants, which required structural predictive tools to guide clinical diagnosis. Until the age of 7, her kidney function has remained intact; however, her prognosis is uncertain. CONCLUSIONS: NC in newborns is a rare condition, but its incidence is rising. Recurrent urinary infections or kidney stones may lead to kidney failure. A proactive approach in sporadic NC enables an early diagnosis to orientate clinical supervision and facilitates counseling to support family planning decisions.

Exploring the relationship of supernumerary recurrent renal calculi formation and tick-borne infections: a case report.

A 51-year-old male with a history of Cacchi-Ricci disease and long-standing infection with various species of Borrelia, Babesia, and Bartonella presented with recurrent symptoms of right-sided flank pain. Numerous renal calculi were identified on imaging. The etiology of the calculi had not been previously elucidated. Symptoms intermittently date back to 2002 when uric acid stones were identified. Subsequent calculi analysis revealed calcium oxalate stones. Despite the commonality of nephrolithiasis in patients with Cacchi-Ricci disease, the extreme number of calculi and recurrent presentation of symptoms persisted despite a plethora of medical evaluations, dietary changes, and hereditary testing. This case raises questions of etiology including possible immune deficiency and whether his uncommon microbial history contributes to recurrent stone formation.

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

OBJECTIVE: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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 50 years, 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.

Chronic pain is one of the most common reasons that people in the USA seek medical care. It is associated with an increased reliance on opioids, anxiety, depression and a lower quality of life. Over the past 50 years, a treatment modality known as spinal cord stimulation (SCS) has emerged and evolved. Based on evidence, SCS has shown promising results in treating chronic pain related to different causes and has also led to an improvement in the quality of life in those suffering from pain. In this case report, the authors present a case of a patient with chronic pain due to recurrent kidney stones secondary to their hereditary kidney disease, and who responded well to treatment with SCS. The patient self-reported almost 80% pain relief after undergoing treatment with SCS as well as an improved quality of life, based on their ability to engage in their daily professional and leisurely activities without being so restricted by pain from their recurrent kidney stones. This case report adds to the growing body of literature that underscores the utility of SCS in treating a variety of pain mediated pathologies. As SCS continues to show promising results, we hope that SCS usage to target pain will increase, and this will lead to a decrease in opioid prescriptions and help curb the opioid epidemic.

Ultrasound Patterns and Disease Progression in Medullary Sponge Kidney in Adults.

Our paper presents the ultrasound (US) patterns of a rare kidney disease-medullary sponge kidney (MSK)-that have not been described before in comparison with other causes of medullary hyperechogenicity and correlates them with the severity of the disease and prognosis. This is a clinical observational study of all US examinations in the Nephrology Department over a period of 6 years. The abdominal US focused on the kidneys was recorded. US characteristics of the medulla and cortex were analyzed. We found 10 patients with characteristic daisy flower (DF) kidneys. Positive diagnosis in association with other renal risk factors, prognosis, and evolution were evaluated. Two patterns of medullary hyperechogenicity were found and were correlated with disease severity and kidney function. The first pattern is a homogenous echogenicity of the medulla described as a "daisy-like" appearance. The second pattern: calcifications associated with medullar echogenicity, stone production, nephrocalcinosis, and impaired kidney function: "atypical daisy-like." Medullary hyperechogenicity can have more US patterns. In MSK, if the medullary echogenicity is homogenous the evolution is benign, whereas the second, inhomogeneous pattern, has a variable clinical presentation with nephrocalcinosis and the outcome is more severe, leading to chronic kidney disease and impairing the quality of life.

Amyloid A amyloidosis on medullary sponge kidney in a 28-year-old male with gout: A case report and literature review.

Amyloidosis is a large group of diseases that occur through misfolding of extracellular proteins that accumulate in tissues and organs. Gout is the most common inflammatory arthritis worldwide and starts with the crystallization of uric acid within the joints and soft tissues. Although gouty arthritis is accompanied by inflammation, AA amyloidosis is rarely seen in patients with gout. Here we present a case of AA amyloidosis on the medullary sponge kidney in a 28-year-old man with gout. Our case had been diagnosed with gout 3 years previously, and his older brother was also diagnosed with early-onset gout. As a result of the hyperuricemic nephropathy clinic and familial history, a whole gene sequence analysis was performed on the HPRT1 gene and UMOD gene, but no pathogenic changes were detected. Renal ultrasound revealed a bilateral medullary sponge kidney and amyloidosis was detected in the renal needle biopsy performed for the etiology of proteinuria. In our literature review, we found 16 cases in which gout was accompanied by AA amyloidosis. We present a 17th case and compare it with the other 16 cases.

Hypokalemic Periodic Paralysis Secondary to Medullary Sponge Kidney Complicated With Renal Tubular Acidosis.

Hypokalemic periodic paralysis has a high risk of life-threatening dysrhythmias. Hyperchloremic acidosis with hypokalemia is a dangerous condition. There are several causes of hypokalemia, in addition to common diseases, such as hyperthyroidism, hyperaldosteronism, and Cushing's syndrome; the other rare diseases include renal tubular acidosis (RTA), Bartter's syndrome, and Gitelman's syndrome. We present an unusual case of hypokalemic periodic paralysis, which was caused by a medullary sponge kidney with distal RTA. The patient had no significant medical history and was not taking any conventional drugs. Investigations demonstrated a combination of hypokalemia, hyperchloremia, metabolic acidosis with a normal anion gap, relatively raised urinary pH, and decreased phosphate level. Results suggested a diagnosis of RTA with secondary hyperparathyroidism. After potassium citrate replacement and correction of acidosis, the patient's condition was in remission. This case highlights the rare etiology of hypokalemia and the need to actively search for the pathogenesis of unexplained hypokalemia to avoid delaying the condition.

Proteomics Insights into Medullary Sponge Kidney Disease: Review of the Recent Results of an Italian Research Collaborative Network.

BACKGROUND: Medullary sponge kidney (MSK) disease is a rare and neglected congenital condition typically associated with nephrocalcinosis/nephrolithiasis, urinary concentration defects, and cystic anomalies in the precalyceal ducts that, although sporadic in the general population, is relatively frequent in renal stone formers. The physiopathologic mechanism associated with this disease is not fully understood, and omics technologies may help address this gap. SUMMARY: The aim of this review was to provide an overview of the current state of the application of proteomics in the study of this rare disease. In particular, we focused on the results of our recent Italian collaborative studies that, analyzing the MSK whole and extracellular vesicle urinary content by mass spectrometry, have displayed the existence of a large and multifactorial MSK-associated biological machinery and identified some main regulatory biological elements able to discriminate patients affected by this rare disorder from those with idiopathic calcium nephrolithiasis and autosomal dominant polycystic kidney disease (including laminin subunit alpha 2, ficolin 1, mannan-binding lectin serine protease 2, complement component 4-binding protein ß, sphingomyelin, ephrins). KEY MESSAGES: The application of omics technologies has provided new insights into the comprehension of the physiopathology of the MSK disease and identified novel potential diagnostic biomarkers that may replace in future expensive and invasive radiological tests (including CT) and select novel therapeutic targets potentially employable, whether validated in a large cohort of patients, in the daily clinical practice.

Medullary sponge kidney: unusual finding in kidney transplant recipient.

BACKGROUND: Medullary sponge kidney is generally considered a benign condition, gold standard for the diagnosis is urography but it has almost been replaced by UroCT that did not present the same sensibility. Although it is really rare, our sonography's findings were consistent with medullary sponge kidney in the transplanted kidneys. CASE PRESENTATION: A 45-year-old woman with a long history of double-kidney transplantation complained of frequent urinary tract infections, a history of vague loin pain and came to our attention for sonography follow-up. Her kidney function was normal, we did not find signs of infections in the transplanted kidneys and urinary findings were normal. Curiously, the transplanted kidneys came from a newborn and the patient received a double-kidney transplantation in order to guarantee a satisfactory renal function. CONCLUSIONS: Despite a long history of kidney transplantation, genetic disease should not be forgotten when symptoms and images recall to specific inherited alterations. Sonography has to be considered in diagnostic path of kidney cystic disease.

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.

Marginal parent donors-Process and ethics.

BACKGROUND: Pre-emptive kidney transplantation for end-stage kidney disease in children has many advantages and may lead to the consideration of marginal parent donors. METHODS: Using the example of the transplant of a kidney with medullary sponge disease from a parent to the child, we review the ethical framework for working up such donors. RESULTS: The four principles of health ethics include autonomy (the right of the patient to retain control over his/her own body); beneficence (healthcare providers must do all they can do to benefit the patient in each situation); non-maleficence ("first do no harm"-providers must consider whether other people or society could be harmed by a decision made, even if it is made for the benefit of an individual patient) and justice (there should be an element of fairness in all medical decisions). Highly motivated donors may derive significant psychological benefit from their donation and may thus be willing to incur more risk. The transplantation team and, ideally, an independent donor advocate team must make a judgment about the acceptability of the risk-benefit ratio for particular potential donors, who must also make their own assessment. The transplantation team and donor advocate team must be comfortable with the risk-benefit ratio before proceeding. CONCLUSIONS: An independent donor advocacy team that focuses on the donor needs is needed with sufficient multidisciplinary ethical, social, and psychological expertise. The decision to accept or reject the donor should be within the authority of the independent donor advocacy team and not the providers or the donor.

Considerations for utilizing medullary sponge kidney allografts in pediatric patients.

BACKGROUND: Medullary sponge kidney (MSK) disease predisposes patients to recurrent nephrolithiasis, which affects one in every 5000 people in the United States. METHODS: We report a rare case of a pediatric recipient of a living donor MSK transplant and discuss considerations when discussing risks and benefits of accepting MSK allografts for this population. RESULTS: The recipient was admitted due to concerns for nephrolithiasis, hydronephrosis, and urinary tract infection at 1-month post-transplant. The hydronephrosis was resolved by surgical removal of an encrusted ureteral stent; this was followed by supplementation with oral medications to prevent future episodes of nephrolithiasis. The recipient did not have any further episodes after this as seen at a 1-year follow-up. The donor has remained well through this period. CONCLUSIONS: With increasing organ shortages, the use of variety of donors may need to be considered to enlarge the organ pool.

Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease.

INTRODUCTION: In humans, heterozygous mutations of hepatocyte nuclear factor 1beta (HNF1B) are responsible for a dominant inherited disease with both renal and extrarenal phenotypes. HNF1B nephropathy is the umbrella term that includes the various kidney phenotypes of the disease, ranging from congenital anomalies of the kidney and urinary tract (CAKUT), to tubular transport abnormalities, to chronic tubulointerstitial and cystic renal disease. METHODS: We describe 7 families containing 13 patients with ascertained HNF1B nephropathy. All patients underwent genetic testing and clinical, laboratory, and instrumental assessment, including renal imaging and evaluation of extrarenal HNF1B manifestations. RESULTS: Significant inter- and intrafamilial variability of HNF1B nephropathy has been observed. In our cohort, HNF1B pathogenic variants presented with renal cysts and diabetes syndrome (RCAD); renal cystic phenotype mimicking autosomal dominant polycystic kidney disease (ADPKD); autosomal dominant tubulointerstitial kidney disease (ADTKD) with or without hyperuricemia and gout; CAKUT; and nephrogenic diabetes insipidus (NDI). Of note, for the first time, we describe the occurrence of medullary sponge kidney (MSK) in a family harboring the HNF1B whole-gene deletion at chromosome 17q12. Genotype characterization led to the identification of an additional 6 novel HNF1B pathogenic variants, 3 frameshift, 2 missense, and 1 nonsense. CONCLUSION: HNF1B nephropathy may present with a highly variable renal phenotype in adult patients. We expand the HNF1B renal clinical picture to include MSK as a potential new finding. Finally, we expand the allelic repertoire of the disease by adding novel HNF1B pathogenic variants.

Ultrasound to address medullary sponge kidney: a retrospective study.

BACKGROUND: Medullary sponge kidney (MSK) is a rare disease characterized by cystic dilatation of papillary collecting ducts. Intravenous urography is still considered the gold standard for diagnosis. We identified a cohort of patients from our outpatient clinic with established diagnosis of MSK to outline some ultrasonographic characteristics that may help establish a diagnosis. METHODS: We conducted a retrospective study of patients seen between January 1st 2009 and January 1st 2019 in our clinic. Out of 4321 patients, 18 had a diagnosis of MSK. We reviewed their clinical and family history, laboratory data and imaging studies. Specifically, we focused on ultrasound imaging. RESULTS: Patients were referred to our outpatient clinic because of renal impairment (44%), family history of nephropathy (17%), nephrolithiasis or an established diagnosis of MSK (39%). Seventy-two percent of patients presented with chronic kidney disease, 22% required hemodialysis. Urinary tract infections (44%), nephrolithiasis (33%), microscopic hematuria (50%) and proteinuria (44%) were reported. Seven patients underwent computed tomography; all of them received ultrasound. Ultrasound examination showed bilateral renal cysts, usually small and located in the renal medulla, and microcalcifications located in the medulla or within the cysts. CONCLUSION: We identified a peculiar tetrad associated with MSK: 1) hypoechoic medullary areas, 2) hyperechoic spots, 3) microcystic dilatation of papillary zone, 4) multiple calcifications (linear, small stones or calcified intracystic sediment) in each papilla. The presence of this diagnostic tetrad, added to laboratory data and clinical history, could be helpful in the differential diagnosis to identify patients with MSK.

Ambiguous clear cell carcinoma in medullary sponge kidney: A case report.

Medullary sponge kidney (MSK) is a characteristic renal malformation, with a relatively low incidence. Radiologically, identification of MSK is sometimes ambiguous when compared to a renal mass. Here, we report a novel renal clear cell carcinoma in MSK, and discuss our approach to treatment. We recommended that a preoperative biopsy should be performed, followed by a comprehensive discussion regarding the appropriate perioperative preparations and careful surgical techniques that should be performed for this complex disease.

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 coexpression 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 ß. 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.

Medullary Sponge Kidney: Current Perspectives.

Medullary Sponge Kidney (MSK) disease is a rare congenital malformation of the distal nephron where cystic dilatation is appreciable in the collecting ducts and renal papillae. Most cases of the malformation are thought to arise from a malfunction within neurotrophic factor and tyrosine kinase interactions. Presentation and prognosis are usually indolent; however, they include urinary tract infections (UTI), nephrolithiasis and nephrocalcinosis, distal renal tubular acidosis (dRTA) and hypocitraturia. With an insidious and asymptomatic onset, MSK is a difficult renal manifestation to both diagnose and treat. Difficulty diagnosing MSK today arises from clinical settings deviating from the usage of contrast methods when assessing the urogenital tract. Many healthcare standards for kidney disorders center diagnosis around imaging techniques rather than contrast methods. This ultimately leads to a decrease in the total number of confirmed cases of MSK. Though intra-venous urogram (IVU) remains as the current gold standard to diagnose MSK, other methods such as endoscopy and Multi-detector computed tomography (MDCT) are being put into place. Endoscopic examination and renal biopsy may allow definitive diagnosis; however, such invasive methods may be considered excessive. Moving forward, differential diagnoses for MSK can be made more precisely when patients present with other renal manifestations, especially in groups at risk. These groups include patients between the age of 20 and 30, patients with other renal malformations, high sodium diet patients, hyperparathyroid patients, and patients with family history of MSK. Basic treatment is aimed at controlling stone formation by stabilizing urinary pH. Treatment for patients, especially those prone to forming stones, includes the application of potassium citrate compounds, prophylactic water and diet control, surgical intervention or lithotripsy for removal of symptomatic kidney stones.

Proteomic Analysis of Urinary Microvesicles and Exosomes in Medullary Sponge Kidney Disease and Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: Microvesicles and exosomes are involved in the pathogenesis of autosomal dominant polycystic kidney disease. However, it is unclear whether they also contribute to medullary sponge kidney, a sporadic kidney malformation featuring cysts, nephrocalcinosis, and recurrent kidney stones. We addressed this knowledge gap by comparative proteomic analysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The protein content of microvesicles and exosomes isolated from the urine of 15 patients with medullary sponge kidney and 15 patients with autosomal dominant polycystic kidney disease was determined by mass spectrometry followed by weighted gene coexpression network analysis, support vector machine learning, and partial least squares discriminant analysis to compare the profiles and select the most discriminative proteins. The proteomic data were verified by ELISA. RESULTS: A total of 2950 proteins were isolated from microvesicles and exosomes, including 1579 (54%) identified in all samples but only 178 (6%) and 88 (3%) specific for medullary sponge kidney microvesicles and exosomes, and 183 (6%) and 98 (3%) specific for autosomal dominant polycystic kidney disease microvesicles and exosomes, respectively. The weighted gene coexpression network analysis revealed ten modules comprising proteins with similar expression profiles. Support vector machine learning and partial least squares discriminant analysis identified 34 proteins that were highly discriminative between the diseases. Among these, CD133 was upregulated in exosomes from autosomal dominant polycystic kidney disease and validated by ELISA. CONCLUSIONS: Our data indicate a different proteomic profile of urinary microvesicles and exosomes in patients with medullary sponge kidney compared with patients with autosomal dominant polycystic kidney disease. The urine proteomic profile of patients with autosomal dominant polycystic kidney disease was enriched of proteins involved in cell proliferation and matrix remodeling. Instead, proteins identified in patients with medullary sponge kidney were associated with parenchymal calcium deposition/nephrolithiasis and systemic metabolic derangements associated with stones formation and bone mineralization defects. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_04_24_CJASNPodcast_19_06_.mp3.